tbuckley/cabot-search huggingface dataset:
Thirty Years of Research on the Dawn Phenomenon: Lessons to Optimize Blood Glucose Control in Diabetes
Authors: Francesca Porcellati, Paola Lucidi, Geremia B. Bolli, Carmine G. Fanelli
Journal: Diabetes Care (2013)

More than 30 years ago in Diabetes Care , Schmidt et al. (1) defined “dawn phenomenon,” the night-to-morning elevation of blood glucose (BG) before and, to a larger extent, after breakfast in subjects with type 1 diabetes (T1D). Shortly after, a similar observation was made in type 2 diabetes (T2D) (2), and the physiology of glucose homeostasis at night was studied in normal, nondiabetic subjects (3–5). Ever since the first description, the dawn phenomenon has been studied extensively with at least 187 articles published as of today (6). In this issue, Monnier et al. (7) report an additional observation on the dawn phenomenon in a large group of T2D subjects and quantify its role on overall BG control. Given this information and the extensive data to date, an assessment of our knowledge in this area should be determined. Specifically, what have we learned from the last 30 years of research on the dawn phenomenon? What is the appropriate definition, the identified mechanism(s), the importance (if any), and the treatment of the dawn phenomenon in T1D and T2D?

Physiology of glucose homeostasis in normal, nondiabetic subjects indicates that BG and plasma insulin concentrations remain remarkably flat and constant overnight, with a modest, transient increase in insulin secretion just before dawn (3,4) to restrain hepatic glucose production (4) and prevent hyperglycemia. Thus, normal subjects do not exhibit the dawn phenomenon sensu strictiori because they secrete insulin to prevent it.

In T1D, the magnitude of BG elevation at dawn first reported was impressive and largely secondary to the decrease of plasma insulin concentration overnight (1), commonly observed with evening administration of NPH or lente insulins (8) (Fig. 1). Even in early studies with intravenous insulin by the “artificial pancreas” (Biostator) (2), plasma insulin decreased overnight because of progressive inactivation …
A double-blind, placebo-controlled trial of topical PUVA in persistent palmoplantar pustulosis
Authors: ALISON M. LAYTON, R. SHEEHAN-DARE, W. J. CUNLIFFE
Journal: British Journal of Dermatology (1991)

The effect of topical PUVA was investigated in the treatment of patients with persistent palmoplantar pustulosis (PPP). In this double‐blind, placebo‐controlled trial of 27 patients with PPP there was an overall improvement of the hands and feet in both the active and placebo‐treated areas and little difference between them.
Remission of renal disease: recounting the challenge, acquiring the goal
Authors: Barry M. Brenner
Journal: Journal of Clinical Investigation (2002)

Renal excretory function begins at the glomerular capillaries with the formation of a nearly ideal ultrafiltrate of plasma.The volume and composition of the ultrafiltrate undergo sequential change along the nephron, ultimately regulated to preserve near-constancy of mineral, electrolyte, and fluid balance.Modest derangement of these processes often escapes clinical or laboratory detection, because the myriad of unimpaired nephrons compensate more or less completely.Beyond a certain level of injury, however, compensatory adaptations no longer keep pace with nephron loss.As a result, glomerular filtration rate declines and organic nitrogenous wastes (e.g., creatinine, urea) accumulate in plasma and other body fluids.In acute renal failure, injury is usually transient, so that deterioration of function is short-lived and reversible.Not so, however, with the many forms of irreversible nephron damage, which typically progress over time, often eventuating in complete loss of renal function, systemic toxicity (uremia), and death unless the lost function is replaced by chronic dialysis and/or successful renal transplantation.Much of the effort in nephrology since the 1970s has been concerned with improving the effectiveness of these renal-replacement therapies.In the late 1960s, we fortuitously gained access to a unique strain of rats with many glomeruli that are situated on the renal cortical surface.For the first time, mammalian glomeruli were therefore accessible to direct study by new microtechniques developed in our laboratory.We therefore addressed the following questions: (a) What are the precise hemodynamic forces and biophysical properties that govern glomerular capillary function in health?(b) How are these elements modified during renal injury?(c) Do these modifications contribute to the relentless progression of renal disease?(d) If so, can they be reversed, so as to retard further deterioration of renal function and prevent end-stage renal disease (ESRD)?
AMINO ACID COMPOSITION OF HIGHLY PURIFIED VIRAL PARTICLES OF INFLUENZA A AND B
Authors: C. A. Knight
Journal: The Journal of Experimental Medicine (1947)

Microbiological assays for amino acids were made on hydrolysates of four to five highly purified preparations each of influenza A virus (PR8 strain) and influenza B virus (Lee strain). The results of the assays indicated that these strains of influenza virus contain approximately the same amounts of alanine, aspartic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, and valine. However, significant differences were found in the values for arginine, glutamic acid, lysine, tryptophane, and tyrosine. It is believed that these differences may provide, at least in part, a chemical explanation for some of the differing properties of the PR8 and Lee strains of influenza viruses.
Habit Reversal Versus Supportive Psychotherapy for Tourette’s Disorder: A Randomized Controlled Trial
Authors: Sabine Wilhelm, Thilo Deckersbach, Barbara J Coffey, Antje Bohne, Alan L Peterson, Lee Baer
Journal: American Journal of Psychiatry (2003)

The authors investigated the efficacy of habit reversal for Tourette's disorder, which is characterized by multiple motor and vocal tics.Thirty-two patients with Tourette's disorder were randomly assigned to 14 sessions of either habit reversal or supportive psychotherapy. Habit reversal consisted of awareness training, self-monitoring, relaxation training, competing response training, and contingency management. Changes in severity of Tourette's disorder and psychosocial impairment were investigated over the course of the 14-session treatment for the 29 patients who completed at least eight treatment sessions.In contrast to the 13 patients in the supportive psychotherapy group, the 16 patients in the habit reversal group improved significantly. The habit reversal patients remained significantly improved over pretreatment at 10-month follow-up.Habit reversal may be an effective behavioral treatment for Tourette's disorder.
Computer-Assisted Delivery of Cognitive-Behavioral Therapy: Efficacy and Durability of CBT4CBT Among Cocaine-Dependent Individuals Maintained on Methadone
Authors: Kathleen M. Carroll, Brian D. Kiluk, Charla Nich, Melissa A. Gordon, Galina A. Portnoy, Daniel R. Marino, Samuel A. Ball
Journal: American Journal of Psychiatry (2014)

A previous pilot trial evaluating computer-based training for cognitive-behavioral therapy (CBT4CBT) in 77 heterogeneous substance users (alcohol, marijuana, cocaine, and opioids) demonstrated preliminary support for its efficacy in the context of a community-based outpatient clinic. The authors conducted a more definitive trial in a larger, more homogeneous sample.In this randomized clinical trial, 101 cocaine-dependent individuals maintained on methadone were randomly assigned to standard methadone maintenance or methadone maintenance with weekly access to CBT4CBT, with seven modules delivered within an 8-week trial.Treatment retention and data availability were high and comparable across the treatment conditions. Participants assigned to the CBT4CBT condition were significantly more likely to attain 3 or more consecutive weeks of abstinence from cocaine (36% compared with 17%; p<0.05, odds ratio=0.36). The group assigned to CBT4CBT also had better outcomes on most dimensions, including urine specimens negative for all drugs, but these reached statistical significance only for individuals completing the 8-week trial (N=69). Follow-up data collected 6 months after treatment termination were available for 93% of the randomized sample; these data indicate continued improvement for those assigned to the CBT4CBT group, replicating previous findings regarding its durability.This trial replicates earlier findings indicating that CBT4CBT is an effective adjunct to addiction treatment with durable effects. CBT4CBT is an easily disseminable strategy for broadening the availability of CBT, even in challenging populations such as cocaine-dependent individuals enrolled in methadone maintenance programs.
Clinical Dilemma of Ductal Carcinoma in Situ
Authors: Jay R. Harris, Monica Morrow
Journal: Journal of Clinical Oncology (2009)

and long-term survival in more than 95% of patients with DCIS. 1 A survival benefit for RT after excision in patients with invasive breast cancer has been clearly established by the Early Breast Cancer Trialists’ Collaborative Group meta-analysis, 2 an important finding that changed the conceptual view of the role of local therapy in breast cancermanagement.Eliminationofmicrometastaticdiseasewithsystemic therapy has been considered the path to progress in invasive cancer, and the idea of improved survival with more aggressive local therapy, particularly for patients with node-positive disease, was counterintuitive to some clinicians. In contrast, DCIS is an entity for which micrometastases are not a consideration. Yet, the need for adding RT after excision to maintain local control in patients with DCIShasremaineduncertain.Someofthiscontroversycanbetraced
Uptake of <i>Leishmania major</i> Amastigotes Results in Activation and Interleukin 12 Release from Murine Skin–derived Dendritic Cells: Implications for the Initiation of Anti-<i>Leishmania</i> Immunity
Authors: Esther von Stebut, Yasmine Belkaid, Thilo Jakob, David L. Sacks, Mark C. Udey
Journal: The Journal of Experimental Medicine (1998)

Epidermal Langerhans cells (LC) are immature dendritic cells (DC) located in close proximity to the site of inoculation of infectious Leishmania major metacyclic promastigotes by sand flies. Using LC-like DC expanded from C57BL/6 fetal skin, we characterized interactions involving several developmental stages of Leishmania and DC. We confirmed that L. major amastigotes, but not promastigotes, efficiently entered LC-like DC. Parasite internalization was associated with activation manifested by upregulation of major histocompatibility complex (MHC) class I and II surface antigens, increased expression of costimulatory molecules (CD40, CD54, CD80, and CD86), and interleukin (IL)-12 p40 release within 18 h. L. major–induced IL-12 p70 release by DC required interferon γ and prolonged (72 h) incubation. In contrast, infection of inflammatory macrophages (Mφ) with amastigotes or promastigotes did not lead to significant changes in surface antigen expression or cytokine production. These results suggest that skin Mφ and DC are infected sequentially in cutaneous leishmaniasis and that they play distinct roles in the inflammatory and immune response initiated by L. major. Mφ capture organisms near the site of inoculation early in the course of infection after establishment of cellular immunity, and kill amastigotes but probably do not actively participate in T cell priming. In contrast, skin DC are induced to express increased amounts of MHC antigens and costimulatory molecules and to release cytokines (including IL-12 p70) by exposure to L. major amastigotes that ultimately accumulate in lesional tissue, and thus very likely initiate protective T helper cell type 1 immunity.
Acalculous disease of the gall bladder.
Authors: R C Williamson
Journal: Gut (1988)

Progress reportAcalculous disease of the gall bladder Cholecystectomy is a common operation in many countries of the world and gall stones are the overwhelming indication.Autopsy studies and sono- graphic screening in developed countries indicate that at least a quarter of the elderly female population possess gall stones, although the epidemic may have reached its peak.'The extreme prevalence of cholelithiasis diverts attention from the fact that the gall bladder can be host to a number of other conditions (Table ), some of which are lethal. Congenital anomalies-adenomyosis (diverticulosis) Neoplastic -(pseudotumours) -adenoma -other benign tumours (rare) -carcinoma (adeno, squamous) -melanoma (primary, secondary) -metastatic carcinoma *acalculous cholecystitis can be acute or chronic.
Orthostatic increase of respiratory gas exchange in hyperventilation syndrome
Authors: L P. Malmberg
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Hyperventilation syndrome (HVS) is a common disorder which is difficult to diagnose because of somatic symptoms and its episodic nature. In previous studies respiratory alkalosis in arterial blood was often found during orthostatic tests in patients with HVS. The purpose of this study was to assess these orthostatic changes by non-invasive pulmonary gas exchange measurements and to evaluate whether these responses discriminate patients with HVS from healthy subjects. <h3>METHODS</h3> Respiratory gases were collected with a face mask and pulmonary gas exchange was measured after 10 minutes at rest and after eight minutes standing upright in 16 patients with HVS and 13 healthy control subjects. In patients with HVS arterial blood samples were also drawn at rest and in the standing position. <h3>RESULTS</h3> At rest the variables of respiratory gas exchange did not differ significantly between the groups. As a response to standing, minute ventilation increased in both study groups but significantly more in the patients with HVS (mean difference 5.4 l/min (95% CI 1.1 to 9.6)). The changes in end tidal CO<sub>2</sub> fraction (Fetco<sub>2</sub>) and in ventilatory equivalents for oxygen (V˙e/V˙o<sub>2</sub>) and for CO<sub>2</sub>(V˙e/V˙co<sub>2</sub>) during the orthostatic test were also significantly larger in patients with HVS than in healthy controls. During standing Fetco<sub>2</sub> was significantly lower (mean difference –1.1 kPa; 95% CI –1.5 to –0.6) andV˙e/V˙o<sub>2</sub> (mean difference 18.4; 95% CI 7.7 to 29.0) andV˙e/V˙co<sub>2</sub> (mean difference 11.7; 95% CI 4.8 to 18.6) were significantly higher in HVS patients than in healthy controls. By using the cut off level of 4% for Fetco<sub>2</sub> the sensitivity and specificity of the test to discriminate HVS were 87% and 77%, respectively, and by using the cut off level of 37 forV˙e/V˙o<sub>2</sub> they were 93% and 100%, respectively. In the HVS patients arterial Pco<sub>2</sub> and Fetco<sub>2</sub> were closely correlated during the orthostatic test (<i>r</i> = 0.93, p&lt;0.0001). <h3>CONCLUSIONS</h3> As a response to change in body position from supine to standing, patients with HVS have an accentuated increase in ventilation which distinguishes them from healthy subjects. These findings suggest that non-invasive measurements of pulmonary gas exchange during orthostatic tests are useful in the clinical evaluation of patients with hyperventilation disorders.
Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial
Authors: Werner Poewe, Klaus Seppi, Cheryl J Fitzer-Attas, Gregor K Wenning, Sid Gilman, Phillip A Low, Nir Giladi, Paolo Barone, Cristina Sampaio, Eli Eyal, Olivier Rascol
Journal: The Lancet Neurology (2014)
Peroxisome Proliferator-Activated Receptor γ Is Highly Expressed in Pancreatic Cancer and Is Associated With Shorter Overall Survival Times
Authors: Glen Kristiansen, Juliane Jacob, Ann-Christin Buckendahl, Robert Grützmann, Ingo Alldinger, Bence Sipos, Günter Klöppel, Marcus Bahra, Jan M. Langrehr, Peter Neuhaus, Manfred Dietel, Christian Pilarsky
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that has been implicated in carcinogenesis and progression of various solid tumors, including pancreatic carcinoma. We aimed to clarify the expression patterns of PPARγ in pancreatic ductal carcinomas and to correlate these to clinicopathologic variables, including patient survival. Experimental Design: Array-based expression profiling of 19 microdissected carcinomas and 14 normal ductal epithelia was conducted. Additionally, Western blots of pancreatic cancer cell lines and paraffinized tissue of 129 pancreatic carcinomas were immunostained for PPARγ. For statistical analysis, Fisher's exact test, χ2 test for trends, correlation analysis, Kaplan-Meier analysis, and Cox's regression were applied. Results: Expression profiles showed a strong overexpression of PPARγ mRNA (change fold, 6.9; P = 0.04). Immunohistochemically, PPARγ expression was seen in 71.3% of pancreatic cancer cases. PPARγ expression correlated positively to higher pT stages and higher tumor grade. Survival analysis showed a significant prognostic value for PPARγ, which was found to be independent in the clinically important subgroup of node-negative tumors. Conclusions: PPARγ is commonly up-regulated in pancreatic ductal adenocarcinoma and might be a prognostic marker in this disease. Both findings corroborate the importance of PPARγ in tumor progression of pancreatic cancer.
Topical aminolaevulinic acid-photodynamic therapy produces an inflammatory infiltrate but reduces Langerhans cells in healthy human skin in vivo
Authors: G. Evangelou, M.D. Farrar, R.D. White, N.B. Sorefan, K.P. Wright, K. McLean, S. Andrew, R.E.B. Watson, L.E. Rhodes
Journal: British Journal of Dermatology (2011)

Topical photodynamic therapy (PDT) elicits a therapeutic response in both skin cancer and immune-mediated skin disorders. While PDT induces direct cell death, host inflammatory and immune responses to PDT may contribute to the therapeutic effects.To examine the impact of topical PDT on leucocyte trafficking and mediators of chemotaxis in healthy human skin.Aminolaevulinic acid (ALA)-PDT was performed on the buttock skin of seven healthy volunteers. Biopsies for immunohistochemical assessment were taken 1, 4 and 24 h post-PDT and from untreated contralateral buttock skin (baseline).A significant dermal neutrophilic infiltrate appeared early, peaking at 4 h (P < 0·01) and returning to near baseline by 24 h. Expression of E-selectin was significantly higher at 4 h (P < 0·05) and correlated strongly with neutrophil numbers (r = 0·93). Expression of intercellular adhesion molecule 1 was significantly elevated after 24 h (P < 0·05) with an apparent gradual increase in CD4+ T cells up to this time point. Notably, epidermal Langerhans cells were significantly reduced 24 h post-PDT compared with baseline (P < 0·01) and comprised a significantly larger proportion of cells with migratory rather than dendritic morphology (P < 0·05). The number of epidermal cells expressing tumour necrosis factor-α significantly increased at 4 h (P < 0·05) and remained elevated 24 h post-PDT, whereas no significant change in expression of interleukin (IL)-1β or IL-8 was seen.Reduction of Langerhans cells by topical PDT of human skin may play a significant role in PDT-induced local immunosuppression, potentially benefiting the treatment of immune-mediated skin disorders but negatively impacting on antitumour responses. Further exploration according to disease indication/treatment protocol is warranted.
A gain-of-function SNP in TRPC4 cation channel protects against myocardial infarction
Authors: Carole Jung, Gemma G. Gené, Marta Tomás, Cristina Plata, Jana Selent, Manuel Pastor, César Fandos, Mariano Senti, Gavin Lucas, Roberto Elosua, Miguel A. Valverde
Journal: Cardiovascular Research (2011)

AimsThe TRPC4 non-selective cation channel is widely expressed in the endothelium, where it generates Ca2+ signals that participate in the endothelium-mediated vasodilatory response. This study sought to identify single-nucleotide polymorphisms (SNPs) in the TRPC4 gene that are associated with myocardial infarction (MI).
B-Raf and the inhibitors: from bench to bedside
Authors: Tiangui Huang, Michael Karsy, Jian Zhuge, Minghao Zhong, Delong Liu
Journal: Journal of Hematology & Oncology (2013)

Abstract The B-Raf protein is a key signaling molecule in the mitogen activated protein kinase (MAPK) signaling pathway and has been implicated in the pathogenesis of a variety of cancers. An important V600E mutation has been identified and can cause constitutive B-Raf activation. Recent studies have evaluated a variety of small molecule inhibitors targeting B-Raf, including PLX4032/vemurafenib, dabrafenib, LGX818, GDC0879, XL281, ARQ736, PLX3603 (RO5212054), and RAF265. Therapeutic resistance has been identified and various mechanisms described. This review also discussed the current understanding of B-Raf signaling mechanism, methods of mutation detection, treatment strategies as well as potential methods of overcoming therapeutic resistance.
RNAi-mediated gene silencing in inflammatory monocytes for efficient immuno-intervention in experimental arthritis
Authors: Jessy Présumey, Gabriel Courties, Louis-Marie Charbonnier, Virginie Escriou, Daniel Scherman, Yves-Marie Pers, Pascale Louis-PLence, Diego Kyburz, Steffen Gay, Christian Jorgensen, Florence Apparailly
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background and objectives</h3> The inflammatory monocyte subset is essential in innate immunity but it also contributes to the pathogenesis of many inflammatory and autoimmune disorders including rheumatoid arthritis (RA). Strategies to manipulate this cell subset are thus of importance both scientifically and therapeutically. The pre-B cell colony enhancing factor (PBEF/visfatin/Nampt) is an essential enzyme in the NAD biosynthetic pathway that exerts a key role in the persistence of inflammation through the induction of the expression of the tumour necrosis factor α (TNFα) and IL-6 pro-inflammatory cytokines and is highly expressed in patients with a variety of autoimmune disorders. Here the authors aimed at evaluating whether the precise targeting of PBEF within the inflammatory monocytes could be therapeutically beneficial in RA. <h3>Materials and methods</h3> Using an optimised lipid nanoparticle formulated with a PBEF-silencing short interfering (si) RNA or a non-targeting fluorescent siRNA (0,5mg/kg), and systemic administration to collagen-induced arthritic mice (CIA), fluorescence and PBEF expression were monitored in various leucocyte populations including Ly6C<sup>high</sup> monocytes within blood, spleen, and inflamed joints by cytometry. Clinical and biological features of CIA were monitored as previously described. <h3>Results</h3> Upon intravenous injection, siRNA-containing liposomes are engulfed by circulating Ly6C<sup>high</sup> inflammatory monocytes and provide efficient down-regulation of PBEF expression as well as of PBEF-induced pro-inflammatory cytokines (TNF and IL-6) in this subset but not in the non-inflammatory subset, leading to decreased number of infiltrating leucocytes in arthritic joints and reduced count of effector T cells. Importantly, when the liposome formulation is optimised for translation to the clinic, siRNA lipoplexes efficiently silence PBEF in human CD14<sup>+</sup>CD16<sup>-</sup> inflammatory monocytes ex vivo. <h3>Conclusions</h3> Delivery into the inflammatory mouse Ly-6C<sup>high</sup> monocyte population of a siRNA against PBEF is able to reduce molecular and cellular markers of inflammation in a preclinical model of RA, both systemically and locally, inhibiting disease progression.