tbuckley/cabot-search huggingface dataset:
Effects of 13-nle-motilin on the electrical and mechanical activity of the isolated perfused canine stomach and duodenum.
Authors: W E Green, H Ruppin, D L Wingate, W Domschke, D E Wunsch, L Demling, H D Ritchie
Journal: Gut (1976)

Synthetic 13-norleucine-motilin (13-nle-motilin), structural and biological analogue of the naturally-occurring duodenal polypeptide, motilin, is known to stimulate antral and duodenal motor activity in vitro, but delays gastric emptying in man. In this study the direct actions of the synthetic polypeptide on myoelectrical activity and intraluminal pressure have been studied in the isolated vascular-perfused canine stomach and duodenum. 13-nle-motilin increased intraluminal pressure in the pylorus and duodenum, and dose-response analysis showed the duodenum to be twice as sensitive as the pylorus to the polypeptide. Pressure changes in the antrum were small and not dose-related, but, whereas the basic electrical rhythm in the duodenum was not altered, slow wave frequency, rhythm, and propagation in the antrum were disturbed. Electronic analysis of the duodenal spike increase which accompanied pressure rises demonstrated correlations between increases in spikes, intraluminal pressure, and dose. These results show that the direct effect of the polypeptide on adjacent organs may explain the combination of increased motor activity with delayed gastric emptying as a consequence of disturbance in the co-ordination between antrum, pylorus, and duodenum.
THE INTERPRETATION OF GASTRIC SYMPTOMS
Authors: C. Bolton
Journal: BMJ (1928)

AFTER a short survev of the views that had beeni advanced by older writers, Dr. Bolton said that the conception of dyspepsia had returnied to that of two hundred years ago, aind that it was now widely regarded as signifying a gr'oup of symptoms resulting from functional disturbance of the stomach as a primary affection or due to organic disease; and the leading idea to be kept in mind in in- vestigating cases should be the exclu'sion of organic disease.Tlme first object in diagnosis was to ascertain the part of tlie gastric mechanism that was upset and the disturbance in action that it showed, and then to discover the cause of the disturbance.A thorough examination of the symptoms of the patient afforded the earliest and most delicate index of this disturbed action.Neglect of this was the greatest source of.danger of missing serious
Foundation trust leader warns of hospital closures and job loss risk
Authors: A. O'Dowd
Journal: BMJ (2011)

Some hospitals might have to close and thousands of jobs might be lost while patient services suffer as a result of the financial pressure being put on foundation trusts, claims the head of the trusts’ main representative body.

Risk of failures have been raised in a confidential letter sent by Foundation Trust Network director Sue Slipman to NHS deputy chief executive David Flory, but which has been released accidentally by another party.

The network, which represents foundation trusts as part of the NHS Confederation, surveyed its 136 member organisations a month ago and responses showed that some were experiencing financial problems over expected efficiency savings.

Although the government has said that trusts …
Inferences on the Evolutionary History of the S-Element Family of Drosophila melanogaster
Authors: Xulio Maside, Carolina Bartolomé, Brian Charlesworth
Journal: Molecular Biology and Evolution (2003)

The S-element family of transposable elements has been characterized in D. melanogaster. Attempts to find it in other Drosophila-related species have failed, suggesting that this element family may have recently invaded the D. melanogaster genome by horizontal transfer. In order to investigate its evolutionary history, we analyzed the patterns of DNA polymorphism among the S-element copies present in a sample genome (Drosophila Genome Project). The observed levels of nucleotide diversity are significantly lower than theoretical expectations based on the neutral model. This is consistent with evidence for ongoing gene conversion among copies and for purifying selection on the elements' sequences, particularly on the terminal inverted repeats. A phylogenetic analysis revealed that the members of the S-element family can be grouped into at least two genetically differentiated clusters. The level of divergence between these clusters suggests that the S elements invaded the genome of the ancestor of D. melanogaster before the speciation of the D. melanogaster complex. However, other relevant scenarios are also discussed.
Prostate Cancer Cell Cycle Regulators: Response to Androgen Withdrawal and Development of Androgen Independence
Authors: D B Agus, C Cordon-Cardo, W Fox, M Drobnjak, A Koff, D W Golde, H I Scher
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Androgen withdrawal is a standard therapy for prostate cancer that results in a decrease in tumor volume and a decline in serum prostate-specific antigen in the majority of patients. To understand the factors associated with regression of prostate cancers after androgen withdrawal, we studied cell cycle regulator changes in the CWR22 human prostate cancer xenograft model. METHODS: Established tumors in nude athymic BALB/c mice were sampled at various times after androgen withdrawal and after the development of androgen independence. Changes in the expression of cell cycle regulators were categorized into early and mid-to-late events. RESULTS and CONCLUSIONS: Early events included a decrease in androgen receptor expression, followed by a short-term increase in expression of the p53 and p21/WAF1 proteins and a marked decrease in the Ki67 proliferative index. Mid-to-late events included progressive and sustained increases in p27 and p16 protein expression, a decrease in retinoblastoma protein expression, and an increase in the transcription factor E2F1. Changes in apoptosis (programmed cell death) were not observed at any time after androgen withdrawal. These data suggest that androgen withdrawal results in a cell stress response, in which increased p53 protein produces a cell cycle arrest, without activation of p53-mediated apoptosis. The proliferative index is further decreased through the action of the cyclin-dependent kinase inhibitors p27 and p16. Androgen-independent sublines emerged 80-400 days after androgen withdrawal, and these sublines had variable growth phenotypes but were associated with mdm2 protein overexpression and increased expression of cyclin D1. These results indicate that tumor regression in this human prostate cancer model is due to cell cycle arrest rather than to apoptosis and that the emergence of androgen independence is associated with a release from cell cycle arrest.
Soluble fractalkine in the cerebrospinal fluid of patients with neuropsychiatric lupus
Authors: E Sato, N Iikuni, T Yoshio, S Minota, N Kamatani, H Okamoto
Journal: Annals of the Rheumatic Diseases (2006)

Proinflammatory cytokines increase in concentration in the cerebrospinal fluid (CSF) of patients with neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE), and some reports have shown that cytokines are elevated intrathecally.1–3 Recently, levels of Th1 chemokines, monocyte chemotactic protein 1 (MCP-1; CCL2) and interferon inducible protein-10 (IP-10; CXCL10) have been reported to be raised in the CSF of patients with NPSLE, implicating important roles for these chemokines in the pathogenesis of NPSLE.4,5 Here we study the role of soluble fractalkine (CX3CL1) in NPSLE.

A total of 165 patients (161 women and 4 men, aged 16–58 years; mean age 32.4 years) fulfilling the criteria of the American College of Rheumatology for systemic lupus erythematosus (SLE) classification were selected. NPSLE was diagnosed under the American College of Rheumatology criteria for neuropsychiatric lupus syndromes.1 In all, 84 patients were diagnosed with NPSLE and 81 patients did not fulfill our criteria …
The optimal ribavirin dose for patients infected with hepatitis C virus genotype 3: Should we utilize more?
Authors: Alessio Aghemo, Maria Grazia Rumi, Gian Maria Prati, Massimo Colombo
Journal: Hepatology (2009)

The article by Ferenci et al.1 investigating the efficacy of combination therapy with a low dose of ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) genotype 2 or 3, suggests that 400 mg/day of RBV suffices in patients infected with HCV genotype 3 (HCV-3) to achieve as high sustained virological response (SVR) rates as those attained by the standard 800 mg/day dosing (SVR: 63.9% versus 67.5%), whereas the same results could not be replicated in patients with HCV-2. In the latter patients, in fact, the SVR rates following low-dose RBV were significantly lower than those attained with a standard dose of RBV (55.6% versus 77.8%). At variance with the author comments, we believe that the 67% SVR rate obtained in patients with HCV-3 by the standard-of-care RBV regimen is less than satisfactory, too. In fact, it negatively compares with the majority of other reports, especially studies assessing a weight-based dosing of RBV.2-4 In fact, when the efficacy is analyzed of a 24-week treatment with pegylated interferon-α2a given at 180 μg/week plus RBV at 800 mg/day in 34 consecutive patients with HCV-3 treated at our center in the last 2 years, and the response rates are stratified by RBV dosing, a ≥11.5 mg/kg/day RBV dose led to higher SVR rates and lower relapse rates, reaching statistical significance by per-protocol analysis (Table 1). Although we acknowledge that the sample size of our study was too small to draw definite conclusions, it should be noted that the prevalence of moderators of treatment outcome like cirrhosis and baseline viremia >800,000 IU/mL was equally balanced between patients given ≤11.5 mg/kg/day RBV and ≥11.5 mg/kg/day RBV (14% versus 20% and 45% versus 64%, respectively). We wonder whether body weight–based dosing of RBV matters also in the Ferenci study, where in fact relapsers were heavier than sustained responders (mean body weight: 78.8 kg versus 70.4 kg). We think that a controlled study would help understanding whether weight-based RBV can improve the 24-week treatment outcome of patients with HCV-3 who are given pegylated interferon-α2a at 180 μg/week. Alessio Aghemo*, Maria Grazia Rumi*, Gian Maria Prati*, Massimo Colombo*, * A.M. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico, Mangiagalli e Regina Elena, University of Milan, Milan, Italy.
Evolutionary conservation of major histocompatibility complex-DR/peptide/T cell interactions in primates.
Authors: A Geluk, D G Elferink, B L Slierendregt, K E van Meijgaarden, R R de Vries, T H Ottenhoff, R E Bontrop
Journal: The Journal of Experimental Medicine (1993)

Many major histocompatibility complex (MHC) polymorphisms originate from ancient structures that predate speciation. As a consequence, members of the Mhc-DRB1*03 allelic lineage are not only present in humans but in chimpanzees and rhesus macaques as well. This emphasizes that Mhc-DRB1*03 members must have been present in a common ancestor of these primate species that lived about 30 million years ago. Due to the accumulation of genetic variation, however, alleles of the Mhc-DRB1*03 lineage exhibit species-unique sequences. To investigate the biological importance of such conservation and variation, we have studied both the binding and antigen presentation capacity of various trans-species Mhc-DRB1*03 lineage members. Here we show that p3-13 of the 65-kD heat-shock protein (hsp65) of Mycobacterium leprae and M. tuberculosis binds not only to HLA-DR17(3) but also to some chimpanzee and rhesus macaque class II-positive cells. Comparison of the corresponding human, chimpanzee, and rhesus macaque Mhc-DRB1*03 lineage members revealed the presence of uniquely shared amino acid residues, at positions 9-13 and 26-31, of the antigen-binding site that are critical for p3-13 binding. In addition it is shown that several nonhuman primate antigen-presenting cells that bind p3-13 can activate HLA-DR17-restricted T cells. Certain amino acid replacements, however, in Mhc-DRB1*03 lineage members did not influence peptide binding or T cell recognition. Therefore, these studies demonstrate that some polymorphic amino acid residues (motifs) within the antigen-binding site of MHC class II molecules that are crucial for peptide binding and recognition by the T cell receptor have been conserved for over 30 million years.
Recurrent lung shadowing in adult juvenile idiopathic arthritis
Authors: T. Lian, J. Brittenden, S. Pearson, P. Emery
Journal: Annals of the Rheumatic Diseases (1999)

A 25 year old Asian woman with a 11 year history of juvenile idiopathic arthritis (polyarthritis, rheumatoid factor positive) was referred from a peripheral hospital with poor disease control despite multiple disease modifying anti-rheumatic drugs (DMARDS). She was not a cigarette smoker and had been taking azathioprine 125 mg daily and prednisolone 5 mg daily for the past 10 months. Her past medical history included pulmonary tuberculosis diagnosed 14 months ago for which she had completed six months of antituberculous treatment. Details of her previous respiratory management including radiographs were not available. Physical examination revealed generalised synovitis with normal respiratory findings. She was treated with intra-articular corticosteroid injections into multiple joints and sulfasalazine was added to her above medications. Sulfasalazine was increased to a dose of 2 g daily over a four week period.

One month later, she re-presented with about two weeks history of dry cough and dyspnoea. Physical examination revealed that she was apyrexial with normal respiratory findings and persistent synovitis. Based on her chest radiograph (fig 1A) showing patchy consolidation in the right lung, more prominently in the right mid and upper zones, and left lower zone, the presumed diagnosis was pneumonia, possibly with an atypical microorganism and she was treated with a course of ampicillin and erythromycin while investigations were performed. The main differential diagnosis was the recurrence of pulmonary tuberculosis. Laboratory investigations were largely unchanged from the previous month, with a normochromic …
Short‐ and long‐term functional results after lung volume reduction surgery for severe emphysema
Authors: H Teschler, A.b Thompson, G Stamatis
Journal: European Respiratory Journal (1999)

Lung volume reduction surgery (LVRS) has emerged as a surgical therapeutic intervention for advanced emphysema. Designed for the relief of dyspnoea, LVRS has been demonstrated to be efficacious in a subset of carefully selected patients. Short-term improvements in dyspnoea are accompanied by improvements in forced expiratory volume in one second ranging 13-96%. Lung volumes likewise improve, with lessening of trapped gas, residual volume, and total lung capacity. Improvements in functional status and quality-of-life measures parallel the improvements in dyspnoea and lung function. One preliminary study suggests that life expectancy after 3 yrs may be improved following LVRS. Many questions regarding lung volume reduction surgery in terms of operative technique, selection of patients, and outcome remain to be answered. Data are available which begin to address some of these issues. Bilateral procedures have greater short-term improvements than unilateral procedures, but the rate of loss of function following the surgery may also be greater. Stapled resection of lung tissue has been demonstrated to be superior to laser ablation. In a majority of reports, outcome is superior in patients with heterogeneous distribution of their emphysema, and patients with alpha1-proteinase inhibitor deficiency emphysema do less well than patients with smoker9s emphysema.
Phase Ib Study of Buparlisib plus Trastuzumab in Patients with HER2-Positive Advanced or Metastatic Breast Cancer That Has Progressed on Trastuzumab-Based Therapy
Authors: Cristina Saura, Johanna Bendell, Guy Jerusalem, Shaun Su, Qinhua Ru, Stefan De Buck, David Mills, Sophie Ruquet, Ana Bosch, Ander Urruticoechea, Joseph T. Beck, Emmanuelle Di Tomaso, David W. Sternberg, Cristian Massacesi, Samit Hirawat, Luc Dirix, Jose Baselga
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2+) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2+ advanced/metastatic breast cancer resistant to trastuzumab-based therapy. Experimental Design: In the dose-escalation portion of this phase I/II study, patients with trastuzumab-resistant locally advanced or metastatic HER2+ breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (&amp;gt;25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, 7 (58%) patients had stable disease (≥6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways. Conclusions: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. Clin Cancer Res; 20(7); 1935–45. ©2014 AACR.
A randomized, double-blind, placebo-controlled study of the efficacy of tetracaine gel (AmetopR) for pain relief during topical photodynamic therapy
Authors: M.V. Holmes, R.S. Dawe, J. Ferguson, S.H. Ibbotson
Journal: British Journal of Dermatology (2004)

Background Many patients find topical 5-aminolaevulinic acid (ALA) photodynamic therapy (PDT) painful. Local anaesthetics are not routinely used and their effect on PDT pain has not been examined. Objectives To evaluate the efficacy of tetracaine gel (Ametop®) for pain relief during and after PDT. Methods A prospective, double-blind, placebo-controlled study of 42 patients with lesions (≤ 2 cm diameter) of superficial nonmelanoma skin cancer or dysplasia. Patients were randomized to either tetracaine (4% w/w) (n = 22) or vehicle (n = 20) gel under occlusion for 1 h pre-irradiation. Pain was assessed during and after irradiation using a visual analogue scale (VAS) and faces pain scale. Results Patients who received tetracaine gel experienced only slightly less pain during PDT (median VAS 4) compared with those who received placebo (median VAS 4·5) (95% confidence interval for difference 0–3, P = 0·08). No significant difference in pain was experienced between the treatment groups immediately after irradiation or later. Conclusions When compared with placebo, tetracaine gel did not significantly reduce pain during or after PDT for small lesions of superficial basal cell carcinoma, Bowen's disease or actinic keratosis.
Multiple Verrucous Asymptomatic Lesions in an Elderly Patient
Authors: Rita Cabral, José Pedro Reis, Oscar Tellechea
Journal: JAMA Dermatology (2013)

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Surgery for adult Crohn's disease: what is the actual risk?
Authors: G. Bouguen, L. Peyrin-Biroulet
Journal: Gut (2011)

When Crohn and his colleagues first described regional ileitis in 1932,1 intestinal resection was the only effective treatment available for these patients. Until the introduction of steroids during the 1950s, medical treatments for Crohn's disease (CD) were limited to digestive rest or ‘High vitamin, high protein, high carbohydrate, low residue diet with liver, iron and calcium supplements and the judicious use of sedatives and antispasmodics’.2 3

In the mid-1990s, the advent of antitumour necrosis factor α (TNFα) agents changed the treatment of CD refractory to standard medications.4 5 In 2011, the ultimate therapeutic goal in CD should be to reduce the long-term risk for intestinal resection. Despite an increasing use of immunosuppressants and anti-TNFα treatments, surgery is still required for many patients with CD. Whether these drugs impact on reducing the long-term requirement for surgery remains debated.

The aim of this article is to review the risk of surgery before and in the era of biologics (based on infliximab approval in 1998) and to discuss the impact of medications on this risk, with a focus on adult luminal CD. Data were analysed using three types of studies—randomised controlled trials, referral centre studies and population-based studies (table 1).

View this table:

Table 1 
Summary of data available from population-based studies, randomised controlled trials and referral centre studies reporting the overall rate of major abdominal surgery according to the period of enrolment



### Before the era of anti-TNFα

To our knowledge, only one randomised controlled trial has reported the rate of surgery in adult CD before the advent of anti-TNFα therapy. In this randomised crossover study of 11 patients who were treated with azathioprine at a maintenance dose of 50 mg, one patient in each group flared and required surgery (figure 1A and table 1).6



Figure 1 
(A) Overall rate of surgery with its range before and in the era …
Viral latent membrane protein 1 (LMP-1)–induced CD99 down-regulation in B cells leads to the generation of cells with Hodgkin's and Reed-Sternberg phenotype
Authors: Soon Ha Kim, Young Kee Shin, Im-soon Lee, Young Mee Bae, Hae Won Sohn, Young Ho Suh, Howe J. Ree, Martin Rowe, Seong Hoe Park
Journal: Blood (2000)