tbuckley/cabot-search huggingface dataset:
Controlled therapeutic trial of levamisole and sulphasalazine in acute ulcerative colitis.
Authors: A Hermanowicz, A Nowak, L Gajos
Journal: Gut (1984)

Forty five patients with acute ulcerative colitis were randomly allocated to receive (a) sulphasalazine, (b) levamisole, or (c) a combination of sulphasalazine and levamisole. Each group contained 15 patients. The ulcerative colitis activity index (UCAI), the remission and relapse rates were compared at three monthly intervals for one year. The UCAI fell in each group. Detailed analysis of all clinical and biochemical parameters used for estimation of UCAI showed that the only difference was in patients receiving combined therapy who continued to have a raised ESR and platelet count. Fewer patients, however, went into remission on levamisole therapy (46.6%) compared with the other two groups (66.6%). The cumulative relapse rate was 20% for those receiving levamisole compared with 6.6% in the other groups. Side effects were observed in 20% of patients receiving levamisole, 26% receiving sulphasalazine, and 40% in those having combined therapy. The results indicate that levamisole is unlikely to have a major role in the management of patients with ulcerative colitis.
Interleukin-10 Is a Natural Suppressor of Cytokine Production and Inflammation in a Murine Model of Allergic Bronchopulmonary Aspergillosis
Authors: Gabriele Grünig, David B. Corry, Michael W. Leach, Brian W.P. Seymour, Viswanath P. Kurup, Donna M. Rennick
Journal: The Journal of Experimental Medicine (1997)

We have used interleukin-10 (IL-10) gene knockout mice (IL-10−/−) to examine the role of endogenous IL-10 in allergic lung responses to Aspergillus fumigatus Ag. In vitro restimulated lung cells from sensitized IL-10−/− mice produced exaggerated amounts of IL-4, IL-5, and interferon-γ (IFN-γ) compared with wild-type (WT) lung cells. In vivo, the significance of IL-10 in regulating responses to repeated A. fumigatus inhalation was strikingly revealed in IL-10−/− outbred mice that had a 50–60% mortality rate, while mortality was rare in similarly treated WT mice. Furthermore, IL-10−/− outbred mice exhibited exaggerated airway inflammation and heightened levels of IL-5 and IFN-γ in bronchoalveolar lavage (BAL) fluids. In contrast, the magnitude of the allergic lung response was similar in intranasally (i.n.) sensitized IL-10−/− and wild-type mice from a different strain (C57BL/6). Using a different route of priming (intraperitoneal) followed by one i.n. challenge we found that IL-10−/− C57BL/6 mice had heightened eosinophilic airway inflammation, BAL–IL-5 levels, and numbers of αβT cells in the lung tissues compared with WT mice. We conclude that IL-10 can suppress inflammatory Th2-like lung responses as well as Th1-like responses given the constraints of genetic background and route of priming.
Optimal Timing of Intervention in Non–ST-Segment Elevation Acute Coronary Syndromes
Authors: Jason W. Ryan, Eric D. Peterson, Anita Y. Chen, Matthew T. Roe, E. Magnus Ohman, Christopher P. Cannon, Peter B. Berger, Jorge F. Saucedo, Elizabeth R. DeLong, Sharon-Lise Normand, Charles V. Pollack, David J. Cohen
Journal: Circulation (2005)

Recent studies indicate that a routine invasive approach for patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI) yields improved outcomes compared with a conservative approach, but the optimal timing of this approach remains open to debate.We used day of hospital presentation as an instrumental variable to study the impact of timing of cardiac catheterization and revascularization therapy on acute outcomes (death, reinfarction, stroke, cardiogenic shock, or congestive heart failure) among patients with UA and NSTEMI. Between January 2001 and September 2003, 56,352 patients with UA or NSTEMI were treated at 310 US hospitals participating in the CRUSADE national quality improvement initiative. Weekend patients were defined as those who presented to the hospital between 5 PM on Friday and 7 AM on Sunday. All other patients were classified as weekday. Weekday patients were similar to weekend patients in terms of demographics, clinical characteristics, and the use of medical therapies in the first 24 hours. Although overall rates of cardiac catheterization and revascularization were similar for the 2 groups, median time to catheterization was significantly longer for weekend than for weekday patients (46.3 versus 23.4 hours, P<0.0001). This delay was not associated with increased in-hospital adverse events, including death (weekend 4.4% versus weekday 4.1%, P=0.23), recurrent MI (2.9% versus 3.0%, P=0.36), or their combination (6.6% versus 6.6%, P=0.86). These findings were not affected by risk adjustment or use of alternative definitions of weekend versus weekday presentation. When weekend presentation was used as the basis for an instrumental variable analysis, we found that catheterization within the first 12 hours of presentation was associated with a nonsignificant trend toward reduced in-hospital mortality (absolute risk reduction 1.9%; 95% CI 6.7% lower to 2.9% higher; P=0.43) that decreased with longer treatment delays.Although weekend presentation is associated with a delay in invasive management among patients with UA and NSTEMI, in the context of contemporary medical therapy, this does not increase adverse events. Weekend presentation appears to fulfill accepted criteria as an instrumental variable for studying the optimal timing of invasive management for acute coronary syndrome patients. Using weekend status as an instrumental variable, we found no significant benefit to early catheterization, although we could not exclude an important risk reduction, particularly for catheterization within 12 hours of presentation.
Three year follow up of patients with gastrooesophageal reflux disease.
Authors: N E Schindlbeck, A G Klauser, G Berghammer, W Londong, S A Muller-Lissner
Journal: Gut (1992)

Data on the natural course of gastrooesophageal reflux disease are sparse. One hundred and sixty six patients with typical reflux symptoms (heartburn and/or acid regurgitation) and pathologic pH monitoring (reflux time &gt; 8.2% upright and/or &gt; 3.0% supine) were studied. The patients were followed up by questionnaire and interview for a mean of 41 (seven to 86) months after diagnosis of reflux disease. Ten patients had died of diseases not reflux related. In 117 (75%) of the remaining 156 patients data on the course of gastrooesophageal reflux disease could be obtained. In 12 patients anti reflux surgery had been performed. Forty one (39%) of the remaining 105 patients have stopped taking medical therapy, in 13 of these patients symptoms had completely disappeared. Sixty four patients continued on medication (40 on demand, 24 regularly). When asked how their symptoms would be if they completely stopped medication, 71 patients considered their symptoms to be equal or worse and 21 patients to be improved as compared with the initial investigation. Patients with persisting symptoms at follow up had significantly more supine reflux (p &lt; 0.05) at the initial pH monitoring as compared with patients with improved symptoms. The presence and grade of oesophageal erosions at initial endoscopy, duration of symptoms, age, sex, and smoking habits had no influence on the course of gastrooesophageal reflux disease. In conclusion, reflux symptoms disappear only in a minority of patients with proven gastrooesophageal reflux disease. More than half of all patients continue medication, either on demand or regularly. Severe supine reflux is an unfavourable prognostic factor.
Polyclonal Evolution of Multiple Secondary <i>KIT</i> Mutations in Gastrointestinal Stromal Tumors under Treatment with Imatinib Mesylate
Authors: Eva Wardelmann, Sabine Merkelbach-Bruse, Katharina Pauls, Nadja Thomas, Hans-Ulrich Schildhaus, Thomas Heinicke, Nicola Speidel, Torsten Pietsch, Reinhard Buettner, Daniel Pink, Peter Reichardt, Peter Hohenberger
Journal: Clinical Cancer Research (2006)

Abstract Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor α (PDGFRα) gene. Both PDGFRα and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.
Setting standards for the prevention and management of travellers' diarrhoea in elite athletes: an audit of one team during the Youth Commonwealth Games in India
Authors: E Tillett, M Loosemore
Journal: British Journal of Sports Medicine (2009)

Objective: Devise and implement evidence-based guidelines for the prevention and management of travellers’ diarrhoea (TD), and establish the incidence of TD during an elite sporting trip to India. Design: Literature review and audit. Setting: Youth Commonwealth Games in India 2008. Participants: All members of the Team England Squad. Main outcome measures: Hygiene guidelines included only drinking bottled water, eating hot food and regular hand washing with alcohol gel. Ciprofloxacin was offered to non-athlete team members as prophylaxis but not to athletes due to its possible association with tendon disease. Following implementation of these guidelines, the incidence of travellers’ diarrhoea (TD) in the whole squad was 24/122 (20%), compared with 7/14 (50%) on the reconnaissance trip (preguidelines). In those taking prophylactic ciprofloxacin, the incidence was 4/33 (12%), compared with 20/89 (23%) in those not taking ciprofloxacin. No athlete missed their event due to TD. Conclusions: The incidence of TD was less during the event than on the reconnaissance trip. The relative contribution to this reduction in strict hygiene guidelines as compared with potentially improved catering hygiene arrangements is unknown. Prophylactic ciprofloxacin also reduced the incidence of TD but it is probably not appropriate for use in elite athletes. Rifaximin may be an alternative for this group.
Site-specific deletions involving the tal-1 and sil genes are restricted to cells of the T cell receptor alpha/beta lineage: T cell receptor delta gene deletion mechanism affects multiple genes.
Authors: T M Breit, E J Mol, I L Wolvers-Tettero, W D Ludwig, E R van Wering, J J van Dongen
Journal: The Journal of Experimental Medicine (1993)

Site-specific deletions in the tal-1 gene are reported to occur in 12-26% of T cell acute lymphoblastic leukemias (T-ALL). So far two main types of tal-1 deletions have been described. Upon analysis of 134 T-ALL we have found two new types of tal-1 deletions. These four types of deletions juxtapose the 5' part of the tal-1 gene to the sil gene promoter, thereby deleting all coding sil exons but leaving the coding tal-1 exons undamaged. The recombination signal sequences (RSS) and fusion regions of the tal-1 deletion breakpoints strongly resemble the RSS and junctional regions of immunoglobulin/T cell receptor (TCR) gene rearrangements, which implies that they are probably caused by the same V(D)J recombinase complex. Analysis of the 134 T-ALL suggested that the occurrence of tal-1 deletions is associated with the CD3 phenotype, because no tal-1 deletions were found in 25 TCR-gamma/delta + T-ALL, whereas 8 of the 69 CD3- T-ALL and 11 of the 40 TCR-alpha/beta + T-ALL contained such a deletion. Careful examination of all TCR genes revealed that tal-1 deletions exclusively occurred in CD3- or CD3+ T-ALL of the alpha/beta lineage with a frequency of 18% in T-ALL with one deleted TCR-delta allele, and a frequency of 34% in T-ALL with TCR-delta gene deletions on both alleles. Therefore, we conclude that alpha/beta lineage commitment of the T-ALL and especially the extent of TCR-delta gene deletions determines the chance of a tal-1 deletion. This suggests that tal-1 deletions are mediated via the same deletion mechanism as TCR-delta gene deletions.
Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience
Authors: Syed Johar Raza, Ali Al-Daghmin, Sharon Zhuo, Zayn Mehboob, Katy Wang, Gregory Wilding, Eric Kauffman, Khurshid A. Guru
Journal: European Urology (2014)
Pattern of asthma control and inhaled corticosteroid (ICS) use in an Australian asthma population
Authors: Matthew Peters, Susan Sawyer, Paul Flood, Peter Everett, Helen Reddel
Journal: European Respiratory Journal (2013)

Introduction : Australia implemented a concerted national approach to asthma two decades ago with consensus guidelines supported by universal health care and subsidised treatment. Deaths and hospitalisations have fallen but we lack data for broader measures of asthma control.  Methods : Survey responses were sought from an online survey panel. Inclusion criteria: age >15; health professional-diagnosed asthma; symptoms or asthma medication use in past year. The sample was weighted to the Australian asthma population by age, gender and State. Using the Asthma Control Test, asthma control was categorised as well-controlled (WC;20-25), not well controlled (NWC;16-19) or very poorly controlled (VPC; Results : 9388 potential respondents with diagnosed asthma were identified: 6370 had no symptoms or recent treatment and were excluded. 2686 completed the survey; response rate 89%. 43% were male, median age range was 40-49. 64% had a post-school qualification. 45% were told they had asthma before age 14. 54% had WC, 23 % NWC and 23% VPC asthma.   Discussion:  Interpretation of reported control vs pattern of ICS use is confounded by severity. Almost half of study subjects do not have ACT - Well Controlled asthma. ICS use at less than recommended frequency is common. 40% of non-users of ICS had poor control (NWC or VPC). Clinical guidelines suggest this group should use ICS.
Effects of Tadalafil on Erectile Dysfunction in Men With Diabetes
Authors: Iñigo Sáenz de Tejada, Greg Anglin, James R. Knight, Jeffrey T. Emmick
Journal: Diabetes Care (2002)

OBJECTIVE—To evaluate the efficacy and safety of tadalafil taken as needed before sexual activity by men with diabetes and erectile dysfunction (ED). RESEARCH DESIGN AND METHODS—Men with type 1 or type 2 diabetes and a minimum 3-month history of ED were randomly allocated to one of three groups: placebo (n = 71), tadalafil 10 mg (n = 73), or tadalafil 20 mg (n = 72) taken up to once daily for 12 weeks. Changes from baseline in mean scores on the erectile function domain of the International Index of Erectile Function (IIEF) and changes from baseline in the proportion of “yes” responses to question 2, “Were you able to penetrate?,” and 3, “Were you able to complete intercourse?,” of the Sexual Encounter Profile were coprimary outcome measures. RESULTS—A total of 191 (88%) of 216 patients completed the study. Treatment with tadalafil significantly improved all primary efficacy variables, regardless of baseline HbA1c level. Therapy with tadalafil also significantly improved a number of secondary outcome measures, including changes in other IIEF domains, individual IIEF questions, and percentage of positive responses to a global assessment question measuring erection improvement. Treatment with tadalafil did not alter mean HbA1c levels. Tadalafil was well tolerated, with headache and dyspepsia being the most frequent adverse events with active treatment. CONCLUSIONS—Tadalafil therapy significantly enhanced erectile function and was well tolerated by men with diabetes and ED.
Altered brain microstructure assessed by diffusion tensor imaging in patients with chronic pancreatitis
Authors: J. B. Frokjaer, S. S. Olesen, M. Gram, Y. Yavarian, S. A. W. Bouwense, O. H. G. Wilder-Smith, A. M. Drewes
Journal: Gut (2011)

<h3>Objective</h3> In patients with painful chronic pancreatitis (CP) there is increasing evidence of abnormal pain processing in the central nervous system. Using magnetic resonance (MR) diffusion tensor imaging, brain microstructure in areas involved in processing of visceral pain was characterised and these findings were correlated to clinical pain scores. <h3>Methods</h3> 23 patients with CP pain and 14 controls were studied in a 3T MR scanner. Apparent diffusion coefficient (ADC) (ie, diffusivity of water) and fractional anisotropy (FA) (ie, organisation of fibres) values were assessed in the amygdala, cingulate cortex, insula, prefrontal cortex and secondary sensory cortex. Daily pain scores and the Brief Pain Inventory Short Form were collected 1 week before the investigation. <h3>Results</h3> In grey matter, patients had increased ADC values in amygdala, cingulate cortex, insula and prefrontal cortex, as well as decreased FA values in cingulate cortex and secondary sensory cortex. In white matter, patients had increased ADC values in insula and prefrontal cortex, and decreased FA values in insula and prefrontal cortex (all p values &lt;0.05). An effect modification from the pain pattern (attacks vs continuous pain) was seen in the insula and secondary sensory cortex (p values &lt;0.05), but no effect modifications from diabetes, alcoholic aetiology and opioid treatment were seen (all p values &gt;0.05). Microstructural changes in cingulate and prefrontal cortices were correlated to patients9 clinical pain scores. <h3>Conclusion</h3> The findings suggest that microstructural changes of the brain accompany pain in CP. The changes are likely to be a consequence of ongoing pain and structural reorganisation of the neuromatrix as also seen in other diseases characterised by chronic pain.
Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention
Authors: W. Grisold, G. Cavaletti, A. J. Windebank
Journal: Neuro-Oncology (2012)

Peripheral neuropathies induced by chemotherapy (CIPN) are an increasingly frequent problem. Contrary to hema­tologic adverse effects, which can be treated with hematopoetic growth factors, neither prophylaxis nor spe­cific treatment is available, and only symptomatic treatment can be offered. Neurotoxic drugs are becoming a major dose-limiting factor. The epidemiology is still unclear. Several drug-dependent pathogenetic mechanisms exist. CIPN are predominately sensory, length-dependent neuropathies that develop after a typical cumulative dose. Usually, the appearance of CIPN is dose dependent, although in at least 2 drugs (oxaliplatin and taxanes), immediate toxic effects occur. The most frequent substances causing CIPN are platin compounds, vinka alkaloids, taxanes, and bortezomib and thalidomide. The role of synergistic neurotoxicity caused by previously given chemo­therapies and concomitant chemotherapies and the role pre-existent neuropathy on the development of a CIPN is not clear. As the number of long-term cancer survivors increases and a new focus on long-term effects of chemotherapy-induced neuropathies emerge, concepts of rehabili­tation need to be implemented to improve the patients' functions and quality of life.
A Novel Kinase Inhibitor, INCB28060, Blocks c-MET–Dependent Signaling, Neoplastic Activities, and Cross-Talk with EGFR and HER-3
Authors: Xiangdong Liu, Qian Wang, Gengjie Yang, Cindy Marando, Holly K. Koblish, Leslie M. Hall, Jordan S. Fridman, Elham Behshad, Richard Wynn, Yu Li, Jason Boer, Sharon Diamond, Chunhong He, Meizhong Xu, Jincong Zhuo, Wenqing Yao, Robert C. Newton, Peggy A. Scherle
Journal: Clinical Cancer Research (2011)

Abstract Purpose: The c-MET receptor tyrosine kinase plays important roles in the formation, progression, and dissemination of human cancer and presents an attractive therapeutic target. This study describes the preclinical characterization of INCB28060, a novel inhibitor of c-MET kinase. Experimental Design: Studies were conducted using a series of in vitro and in vivo biochemical and biological experiments. Results: INCB28060 exhibits picomolar enzymatic potency and is highly specific for c-MET with more than 10,000-fold selectivity over a large panel of human kinases. This inhibitor potently blocks c-MET phosphorylation and activation of its key downstream effectors in c-MET–dependent tumor cell lines. As a result, INCB28060 potently inhibits c-MET–dependent tumor cell proliferation and migration and effectively induces apoptosis in vitro. Oral dosing of INCB28060 results in time- and dose-dependent inhibition of c-MET phosphorylation and tumor growth in c-MET–driven mouse tumor models, and the inhibitor is well tolerated at doses that achieve complete tumor inhibition. In a further exploration of potential interactions between c-MET and other signaling pathways, we found that activated c-MET positively regulates the activity of epidermal growth factor receptors (EGFR) and HER-3, as well as expression of their ligands. These effects are reversed with INCB28060 treatment. Finally, we confirmed that circulating hepatocyte growth factor levels are significantly elevated in patients with various cancers. Conclusions: Activated c-MET has pleiotropic effects on multiple cancer-promoting signaling pathways and may play a critical role in driving tumor cell growth and survival. INCB28060 is a potent and selective c-MET kinase inhibitor that may have therapeutic potential in cancer treatment. Clin Cancer Res; 17(22); 7127–38. ©2011 AACR.