tbuckley/cabot-search huggingface dataset:
Is topical tacrolimus effective in alopecia areata universalis?
Authors: K.A. Feldmann, C. Kunte, A. Wollenberg, H. Wolff
Journal: British Journal of Dermatology (2002)

SIR, tacrolimus (FK506) is a powerful immunomodulatory macrolide and is used in transplantation medicine to prevent graft rejection. Topical tacrolimus is used successfully in the treatment of atopic dermatitis.1 Similar to cyclosporin, tacrolimus inhibits the activation and maturation of T cells and blocks the transcriptional activation of several lymphokine genes.2,In vitro and in vivo, tacrolimus is about 100 times more effective than cyclosporin.3 Alopecia areata is an autoimmune disease caused by a T‐lymphocytic infiltrate around the bulb of the hair follicle.4 In rats with alopecia areata, tacrolimus is able to induce a drastic reduction in the follicular inflammatory infiltrate on the site of topical application.5 In addition, there was regrowth of hair in C3H7HeJ mice with alopecia areata treated with topical tacrolimus.6 Based on these data, topical tacrolimus might also be effective in humans with alopecia areata. To date, there are few data on this hypothesis.7 Therefore, we offered topical treatment with 0·1% tacrolimus ointment (Protopic®) to patients with long‐standing alopecia areata.
Making an Impact
Authors: V Wright
Journal: Annals of the Rheumatic Diseases (1990)

The man who played a large part in getting Mrs Thatcher elected three times deserves a hearing, whatever else you may wish to do to him.He combines with Liz Gill, a journalist who regularly contributes to The Times, to produce a most readable and informative book.Every person who has the misfortune to be given the responsibility of organising a large conference should read this volume-and those who organise smaller ones would benefit also.Harvey Thomas is an international public relations consultant and director of presentation of the Conservative party, having previously directed many of the Billy Graham international crusades.The 10 chapters are presented in three sections.The first deals with public speaking (whether to a meeting, on the radio, or before television cameras), the second with organising special events, and the third with improving grass roots support.
Neutropenia and agranulocytosis in England and Wales: Incidence and risk factors
Authors: T.P. van Staa, F. Boulton, C. Cooper, A. Hagenbeek, H. Inskip, H.G.M. Leufkens
Journal: American Journal of Hematology (2003)

Abstract The objectives of this study were to estimate the incidence of idiosyncratic neutropenia and agranulocytosis in England and Wales and to evaluate their risk factors and outcomes. The study was conducted using data from the General Practice Research Database. All cases of idiosyncratic neutropenia or agranulocytosis were identified and the incidence was estimated. This was followed by a nested case‐control study, estimating odds ratios with drug exposure from conditional logistic regression. From 1987 to 1999, 3,224 patients with idiosyncratic neutropenia (50 with agranulocytosis) were identified. The incidences of neutropenia and agranulocytosis were estimated to be 120 and 7 cases per million people per year, respectively. The adjusted odds ratios for neutropenia were 34.7 (95% confidence interval 12.0–99.7) for current users of thyroid inhibitors, 9.5 (4.4–20.8) for users of disease‐modifying antirheumatic drugs, and 7.6 (4.9–11.9) for users of aminosalicylates. Other drugs with statistically significantly increased risks of neutropenia included antibacterial drugs, non‐opioid analgesics, NSAIDs, antidepressants, ulcer‐healing drugs, and anti‐epileptics. The increase in risk of neutropenia predominantly occurred during the first months of treatment. For most drugs investigated in this study, there was no relationship to daily dose. The excess 1‐year mortality was low among neutropenia and agranulocytosis cases and mostly explained by the underlying disease state. In conclusion, the highest risks of neutropenia were generally found in patients starting treatment. The excess 1‐year mortality was low among neutropenia and agranulocytosis cases and can be mostly explained by the underlying disease state. Am. J. Hematol. 72:248–254, 2003. © 2003 Wiley‐Liss, Inc.
A budesonide prodrug accelerates treatment of colitis in rats.
Authors: N Cui, D R Friend, R N Fedorak
Journal: Gut (1994)

Although oral glucocorticoids are the treatment of choice for moderate to severe ulcerative pancolitis, their systemic side effects and adrenal suppression account for considerable morbidity. An oral glucocorticoid-conjugate (prodrug), budesonide-beta-D-glucuronide, which is not absorbed in the small intestine but is hydrolysed by colonic bacterial and mucosal beta-glucuronidase to release free budesonide into the colon was synthesised. The objective of this study was to compare treatment with budesonide-beta-D-glucuronide with treatment with free budesonide by examining: (1) the healing of experimental colitis and (2) the extent of adrenal suppression. Pancolitis was induced with 4% acetic acid. Animals were then randomised to receive oral therapy for 72 hours with (1) budesonide-beta-D-glucuronide, (2) free budesonide, or (3) vehicle. Drug efficacy and colitic healing was determined by measuring gross colonic ulceration, myeloperoxidase activity, and in vivo colonic fluid absorption. Adrenal suppression was determined by measuring plasma adrenocorticotrophic hormone and serum corticosterone. Vehicle-treated colitis animals had gross ulceration, increased myeloperoxidase activity, and net colonic fluid secretion. Treatment with oral budesonide-beta-D-glucuronide accelerated all measures of colitis healing at a fourfold lower dose than did free budesonide. Furthermore, treatment with budesonide-beta-D-glucuronide did not result in adrenal suppression whereas free budesonide treatment did. A newly synthesised orally administered glucocorticoid-conjugate accelerates colitis healing with limited adrenal suppression. Development of an orally administered colon-specific steroid delivery system represents a novel approach to inflammatory bowel disease treatment.
Modulation of the Major Histocompatibility Complex Class II–Associated Peptide Repertoire by Human Histocompatibility Leukocyte Antigen (Hla)-Do
Authors: Marieke van Ham, Marcel van Lith, Björn Lillemeier, Esther Tjin, Ulrike Grüneberg, Dinah Rahman, Liesbeth Pastoors, Krista van Meijgaarden, Corinne Roucard, John Trowsdale, Tom Ottenhoff, Darryl Pappin, Jacques Neefjes
Journal: The Journal of Experimental Medicine (2000)

Antigen presentation by major histocompatibility complex class II molecules is essential for antibody production and T cell activation. For most class II alleles, peptide binding depends on the catalytic action of human histocompatibility leukocyte antigens (HLA)-DM. HLA-DO is selectively expressed in B cells and impedes the activity of DM, yet its physiological role remains unclear. Cell surface iodination assays and mass spectrometry of major histocompatibility complex class II–eluted peptides show that DO affects the antigenic peptide repertoire of class II. DO generates both quantitative and qualitative differences, and inhibits presentation of large-sized peptides. DO function was investigated under various pH conditions in in vitro peptide exchange assays and in antigen presentation assays using DO− and DO+ transfectant cell lines as antigen-presenting cells, in which effective acidification of the endocytic pathway was prevented with bafilomycin A1, an inhibitor of vacuolar ATPases. DO effectively inhibits antigen presentation of peptides that are loaded onto class II in endosomal compartments that are not very acidic. Thus, DO appears to be a unique, cell type–specific modulator mastering the class II–mediated immune response induced by B cells. DO may serve to increase the threshold for nonspecific B cell activation, restricting class II–peptide binding to late endosomal compartments, thereby affecting the peptide repertoire.
Prevalence of long term steroid treatment and the frequency of decision making to prevent steroid induced osteoporosis in daily clinical practice
Authors: B Gudbjornsson
Journal: Annals of the Rheumatic Diseases (2002)

Background: The use of oral corticosteroids (CS) is one of the most common causes of iatrogenic osteoporosis. Recently, therapeutic guidelines dealing with the skeletal complication of CS have been published. Objective: To evaluate how CS are used in the community and the frequency of active intervention against corticosteroid induced osteoporosis in daily clinical practice. Material and methods: After approval by the Committee on Medical Ethics and the Data Protection Commission all prescriptions for CS which were filled by pharmacies in the northeast area of Iceland (population 26 664) during a two year period were collected. Thereafter, clinical information was obtained from medical records at the healthcare centres and from the local hospital. Patients who were taking CS for at least three months a year or for repeated periods (for a total of three months annually) were included in the study. These patients also received a questionnaire about hormone replacement therapy, bisphosphonates, and dietary consumption of calcium and vitamin D. Results: A total of 191 patients were included in the study or 0.7% of the population. Their mean age was 66 years (17–93) and 106/191 (55%) were women. Only 63 (33%) patients had no registered complication due to the treatment, according their medical records. Thirty nine (20%) patients had had an osteoporosis related fracture and 50 (26%) of the patients had presumed CS induced osteoporosis. A total of 52% patients were receiving supplementary vitamin D (fish liver oil) and 37% were taking calcium tablets regularly, while 91% of the patient group were consuming milk products regularly. Only 17 (9%) patients were taking bisphosphonates and 18/81 (22%) of the postmenopausal women were receiving hormone replacement therapy. Conclusions: Relatively few patients receiving long term treatment with CS are also receiving primary prevention against CS induced osteoporosis, although several patients are taking vitamin D and calcium tablets. Specific treatment against osteoporosis was in most cases instituted secondary to osteoporotic complications. Thus although there are available treatment alternatives against CS induced osteoporosis, the doctors who prescribed CS did not make use of this form of treatment for their patients.
JAK1/2 and Pan-Deacetylase Inhibitor Combination Therapy Yields Improved Efficacy in Preclinical Mouse Models of JAK2V617F-Driven Disease
Authors: Emeline Evrot, Nicolas Ebel, Vincent Romanet, Claudia Roelli, Rita Andraos, Zhiyan Qian, Arno Dölemeyer, Ernesta Dammassa, Dario Sterker, Robert Cozens, Francesco Hofmann, Masato Murakami, Fabienne Baffert, Thomas Radimerski
Journal: Clinical Cancer Research (2013)

The myeloproliferative neoplasm myelofibrosis is characterized by frequent deregulation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, and JAK inhibitors were shown to reduce splenomegaly and ameliorate disease-related symptoms. However, the mutant clone and bone marrow fibrosis persist in the majority of patients. Using preclinical models, we explored whether JAK and pan-deacetylase inhibitor combination yielded additional benefits.The combination of the JAK1/2 inhibitor ruxolitinib and panobinostat was investigated using two different mouse models of JAK2(V617F)-driven disease. A Ba/F3 JAK2(V617F) cell-driven leukemic disease model was used to identify tolerated and efficacious doses. The drugs were then evaluated alone and in combination in a mouse model of myeloproliferative neoplasm-like disease based on transplantation of bone marrow transduced with a retrovirus expressing JAK2(V617F). Exposures were determined in blood and tissues, and phosphorylated STAT5 and acetylated histone H3 pharmacodynamic readouts were assessed in spleen and bone marrow. Histologic analysis was conducted on spleen and bone marrow, including staining of reticulin fibers in the latter organ.The combination of ruxolitinib and panobinostat was found to have a more profound effect on splenomegaly, as well as on bone marrow and spleen histology, compared with either agent alone, and the analysis of pharmacodynamic readouts showed that ruxolitinib and panobinostat have nonoverlapping and complementary effects.Combining JAK1/2 and pan-deacetylase inhibitors was fairly well tolerated and resulted in improved efficacy in mouse models of JAK2(V617F)-driven disease compared with the single agents. Thus, the combination of ruxolitinib and panobinostat may represent a promising novel therapeutic modality for myeloproliferative neoplasms.
Prevalence of Type 1 and Type 2 Diabetes Among Children and Adolescents From 2001 to 2009
Authors: Dana Dabelea, Elizabeth J. Mayer-Davis, Sharon Saydah, Giuseppina Imperatore, Barbara Linder, Jasmin Divers, Ronny Bell, Angela Badaru, Jennifer W. Talton, Tessa Crume, Angela D. Liese, Anwar T. Merchant, Jean M. Lawrence, Kristi Reynolds, Lawrence Dolan, Lenna L. Liu, Richard F. Hamman
Journal: JAMA (2014)

IMPORTANCE Despite concern about an "epidemic," there are limited data on trends in prevalence of either type 1 or type 2 diabetes across US race and ethnic groups.OBJECTIVE To estimate changes in the prevalence of type 1 and type 2 diabetes in US youth, by sex, age, and race/ethnicity between 2001 and 2009.DESIGN, SETTING, AND PARTICIPANTS Case patients were ascertained in 4 geographic areas and 1 managed health care plan.The study population was determined by the 2001 and 2009 bridged-race intercensal population estimates for geographic sites and membership counts for the health plan.MAIN OUTCOMES AND MEASURES Prevalence (per 1000) of physician-diagnosed type 1 diabetes in youth aged 0 through 19 years and type 2 diabetes in youth aged 10 through 19 years. RESULTSIn 2001, 4958 of 3.3 million youth were diagnosed with type 1 diabetes for a prevalence of 1.48 per 1000 (95% CI, 1.44-1.52).In 2009, 6666 of 3.4 million youth were diagnosed with type 1 diabetes for a prevalence of 1.93 per 1000 (95% CI, 1.88-1.97).In 2009, the highest prevalence of type 1 diabetes was 2.55 per 1000 among white youth (95% CI, 2.48-2.62)and the lowest was 0.35 per 1000 in American Indian youth (95% CI, 0.26-0.47)and type 1 diabetes increased between 2001 and 2009 in all sex, age, and race/ethnic subgroups except for those with the lowest prevalence (age 0-4 years and American Indians).Adjusted for completeness of ascertainment, there was a 21.1% (95% CI, 15.6%-27.0%)increase in type 1 diabetes over 8 years.In 2001, 588 of 1.7 million youth were diagnosed with type 2 diabetes for a prevalence of 0.34 per 1000 (95% CI, 0.31-0.37).In 2009, 819 of 1.8 million were diagnosed with type 2 diabetes for a prevalence of 0.46 per 1000 (95% CI, 0.43-0.49).In 2009, the prevalence of type 2 diabetes was 1.20 per 1000 among American Indian youth (95% CI, 0.96-1.51);1.06 per 1000 among black youth (95% CI, 0.93-1.22);0.79 per 1000 among Hispanic youth (95% CI, 0.70-0.88);and 0.17 per 1000 among white youth (95% CI, 0.15-0.20).Significant increases occurred between 2001 and 2009 in both sexes, all age-groups, and in white, Hispanic, and black youth, with no significant changes for Asian Pacific Islanders and American Indians.Adjusted for completeness of ascertainment, there was a 30.5% (95% CI, 17.3%-45.1%)overall increase in type 2 diabetes.Between 2001 and 2009 in 5 areas of the United States, the prevalence of both type 1 and type 2 diabetes among children and adolescents increased.Further studies are required to determine the causes of these increases. CONCLUSIONS AND RELEVANCE
The Topoisomerase I Poison CPT-11 Enhances the Effect of the Aurora B Kinase Inhibitor AZD1152 both <i>In vitro</i> and <i>In vivo</i>
Authors: Jayasree S. Nair, Elisa de Stanchina, Gary K. Schwartz
Journal: Clinical Cancer Research (2009)

Abstract Purpose: AZD1152 is an Aurora B kinase inhibitor currently in clinical trials. As the topoisomerase I poison CPT-11 induces a G2 arrest, a mechanistic understanding of the cell cycle interactions between these agents may prove critical for combination therapy. Methods: AZD1152 was tested in vitro and in vivo with SN-38 and CPT-11 against HCT-116 cells. Inhibition of clonogenicity, induction of apoptosis, effects on polyploidy, and tumor growth were examined. Results: AZD1152 alone induced polyploidy of HCT-116 cells at low nanomolar concentrations. The induction of apoptosis required prolonged exposure (48 hours) and higher concentrations of drug. When SN-38 was given before or concomitantly with AZD1152, SN-38 blocked the AZD1152 effect by arresting cells in G2 and inhibiting cells from undergoing polyploidy. With the reverse combination (AZD1152 followed by SN-38), there was a significant induction of polyploidy and apoptosis, even with shorter exposure (24 hours) of AZD1152. In vivo, AZD1152 alone suppressed HCT-116 xenograft tumor growth in a dose-dependent manner with target inhibition of phosphoH3, induction of multinucleated giant cells, but without induction of apoptosis. In combination, both sequences in vivo (CPT-&amp;gt;AZD, AZD-&amp;gt;CPT, P = 0.008, AUC/d) proved superior to either single agent therapy. However, AZD-&amp;gt;CPT still showed a greater increase in apoptosis and greater suppression of tumor regrowth than CPT-&amp;gt;AZD (P = 0.02, AUC/d). Conclusions: The results from these studies indicate a promising therapeutic strategy for combining AZD1152 with CPT-11, and suggest that the sequence of drug administration is pivotal when an Aurora B kinase inhibitor is administered with a topoisomerase I poison.
The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry
Authors: Hemant Kulkarni, Vincent C. Marconi, Weijing He, Michael L. Landrum, Jason F. Okulicz, Judith Delmar, Dickran Kazandjian, John Castiblanco, Seema S. Ahuja, Edwina J. Wright, Robin A. Weiss, Robert A. Clark, Matthew J. Dolan, Sunil K. Ahuja
Journal: Blood (2009)
Inhaled disodium cromoglycate as maintenance therapy for childhood asthma: time to consign to history?
Authors: P. J HELMS
Journal: Thorax (2000)

Disodium cromoglycate was introduced in the late 1960s as maintenance therapy for persistent asthma and as a modifier of exercise induced bronchoconstriction. It was the first treatment designed to manage the chronic nature of the disease and modify the inflammatory component without untoward systemic side effects. After its anti-inflammatory effects had been established,1 clinical trial data began to appear in the late 1960s and, although it remains as an option in the 1995 British guidelines on asthma management,2 its use was already in steep decline3-4 and it has now become a minority therapeutic option. In the current issue of Thorax a systematic review is presented which argues against its continuation as an option for the management of persistent symptoms in childhood.5 Why has it taken so long for the evidence of few, if any, beneficial effects in the management of persistent childhood asthma to appear in the face of its virtual disappearance from the prescribing armamentarium? What lessons can be drawn from the now passing cromoglycate era?

In the years …
Obstructive respiratory events and premature atrial contractions after cardioversion
Authors: Dominik Linz, Mathias Hohl, Christian Ukena, Felix Mahfoud, Klaus Wirth, Hans-Ruprecht Neuberger, Michael Böhm
Journal: European Respiratory Journal (2015)

Recurrence of atrial fibrillation (AF) after electrical cardioversion (ECV) is increased in patients with obstructive sleep apnoea (OSA). In patients with persistent AF, with (n=40) and without (n=32) obstructive respiratory events (OREs) during sedation for ECV, we determined the occurrence of premature atrial contractions (PACs) before and after insertion of a nasopharyngeal tube. The influence of acute obstructive respiratory events on atrial electrophysiology after termination of AF was studied in pigs. Incidence of PACs directly after ECV was higher in patients with OREs compared to those without OREs (7±2 versus 1±1 per 10 s, respectively; p&lt;0.01). Occurrence of PACs could be reduced by 79% by insertion of a nasopharyngeal tube. In a subsequent sleeping study, patients with OREs had higher apnoea–hypopnoea indices and more PACs during night. 16 patient with and four patients without OREs had a relapse of AF during 1 week after ECV (p&lt;0.01). In pigs, acute OREs after 30 min of AF increased occurrence of PACs and vulnerability for reinduction of AF, which could be attenuated by atropine, beta-blockers and renal denervation. OREs are associated with increased occurrence of PACs and more early relapse of AF. OREs increase occurrence of PACs and vulnerability for reinduction of AF by sympathovagal imbalance.
Evaluation of the user-friendliness of 11 home mechanical ventilators
Authors: J. Gonzalez-Bermejo, V. Laplanche, F. E. Husseini, A. Duguet, J-P. Derenne, T. Similowski
Journal: European Respiratory Journal (2006)

The home ventilator market has grown in size and complexity. The aim of this study was to determine if common home ventilators are user-friendly for trained intensive care unit (ICU) physicians. Eleven ventilator models were tested by 13 ICU physicians without practical experience in home mechanical ventilation. Six tests were defined (start-up, unlocking, mode and setting recognition, mode change, pressure setting and alarm). For each test, the physicians were timed and their performance compared with a reference time established by a technician. The physicians also had to rate their global assessment of each machine on a visual analogue scale. The start-up test was the only test for which there was no significant difference between the physicians and the technician, except for two ventilators. The physicians were slower than the technician to unlock the ventilator and change the ventilatory mode, with some complete failures during these tests and heterogeneous results between physicians and between ventilators. Mistakes occurred in close to 50% of cases during the ventilatory mode and settings recognition test. The mean time for the most rapid of the physicians for all the tests was 58±53 s, compared with 15±9 s for the technician. In conclusion, trained intensive care unit physicians perform poorly when confronted with home mechanical ventilators without specific prior training. Therefore, it is hypothesised that the user-friendliness of home ventilators for other categories of users might be questionable.
Vibromyographic recording from human muscles with known fibre composition differences.
Authors: D Mealing, G Long, P W McCarthy
Journal: British Journal of Sports Medicine (1996)

To determine the relation between the vibromyographic (VMG) frequency characteristics and fibre composition in postural and non-postural human muscle undergoing a standardised voluntary contraction.Two human muscles with different fibre compositions [soleus: postural, mainly type I (slow) fibres; biceps brachii: non-postural, mixed type I and II (fast) fibres] were recorded from 18 healthy males isometrically contracting at 50% of their maximum voluntary contraction (MVC). Muscle vibrations were recorded using a contact microphone and the frequency content of the signals calculated using fast fourier transform algorithms.The non-postural biceps brachii showed predominantly bimodal power spectra with significantly increased power in the 10-30 Hz bands (P < 0.01), as compared with soleus recordings which tended to be unimodal, with the majority of power below 10 Hz.Muscles with a large proportion of type I fibres generate VMG signals which contain an increased percentage of low frequencies as compared to muscles with a mixed population of type I and type II fibres. The VMG appears to be generated, in part at least, by the mechanical twitching of motor units within the muscle; frequency domain analysis of this signal may provide a non-invasive measure of muscle fibre composition.