tbuckley/cabot-search huggingface dataset:
Topical diltiazem and bethanechol decrease anal sphincter pressure without side effects
Authors: E A Carapeti, M A Kamm, B K Evans, R K S Phillips
Journal: Gut (1999)

<h3>BACKGROUND</h3> Topical nitrates lower anal sphincter pressure and heal anal fissures, but a majority of patients experience headache. The internal anal sphincter has a calcium dependent mechanism to maintain tone, and also receives an inhibitory extrinsic cholinergic innervation. It may therefore be possible to lower anal sphincter pressure using calcium channel blockers and cholinergic agonists without side effects. <h3>AIMS</h3> To investigate the effect of oral and topical calcium channel blockade and a topical cholinomimetic on anal sphincter pressure. <h3>METHODS</h3> Three studies were conducted, each involving 10 healthy volunteers. In the first study subjects were given oral 60 mg diltiazem or placebo on separate occasions. They were then given diltiazem once or twice daily for four days. In the second and third studies diltiazem and bethanechol gels of increasing concentration were applied topically to lower anal pressure. <h3>RESULTS</h3> A single dose of 60 mg diltiazem lowered the maximum resting anal sphincter pressure (MRP) by a mean of 21%. Once daily diltiazem produced a clinically insignificant effect but a twice daily regimen reduced anal pressure by a mean of 17%. Diltiazem and bethanechol gel produced a dose dependent reduction of the anal pressure; 2% diltiazem produced a maximal 28% reduction, and 0.1% bethanechol a maximal 24% reduction, the effect lasting three to five hours. <h3>CONCLUSIONS</h3> Topical diltiazem and bethanechol substantially reduce anal sphincter pressure for a prolonged period, and represent potential low side effect alternatives to topical nitrates for the treatment of anal fissures.
Neutrophil impairment associated with iron therapy in hemodialysis patients with functional iron deficiency.
Authors: S I Patruta, R Edlinger, G Sunder-Plassmann, W H Hörl
Journal: Journal of the American Society of Nephrology (1998)

Hemodialysis patients treated with recombinant human erythropoietin (rhEPO) need adequate iron supplementation to avoid rhEPO hyporesponsiveness due to iron deficiency. Low serum ferritin reflects absolute iron deficiency, whereas normal or high ferritin values in combination with low transferrin saturation (< 20%) indicate functional iron deficiency. In this study, healthy subjects (group I) were compared with intravenous (i.v.) rhEPO-treated and i.v. iron-saccharate-treated regular hemodialysis patients that were subdivided into three groups as follows: patients with serum ferritin > 100 and < 350 micrograms/L (group II), patients with ferritin < 60 micrograms/L (group III), and patients with ferritin > 650 micrograms/L but transferrin saturation < 20% (group IV). Polymorphonuclear leukocyte (PMNL) parameters (phagocytosis, intracellular killing of bacteria, oxidative metabolism, glucose uptake, intracellular calcium) for each group were compared with those of multitransfused, iron-overloaded primary hematologic patients (group V) and those of patients suffering from hereditary hemochromatosis (group VI). Compared with PMNL obtained from healthy subjects (group I), group II hemodialysis patients showed mild inhibition of phagocytosis but significant inhibition of intracellular killing of bacteria. Oxidative burst of PMNL from group II patients was also significantly reduced after stimulation in vitro. These dysfunctions were not affected by absolute iron deficiency (comparable data in group III patients). However, impairment of PMNL was markedly aggravated in group IV patients. Intracellular calcium concentration under basal conditions and after stimulation was not different. These data suggest that iron is responsible for the PMNL dysfunctions observed in group IV patients. The PMNL defect of group IV patients was comparable to group V and group VI patients with normal renal function, suggesting again a direct inhibitory effect of iron. It is concluded that hemodialysis patients with high ferritin but low serum iron and low transferrin saturation ("functional iron deficiency") display a significant impairment of fundamental PMNL functions during i.v. iron and rhEPO therapy. This may result in increased risk of infectious complications. Therefore, overtreatment of hemodialysis patients with i.v. iron should be avoided.
Identification of the first nonsense<i>CDSN</i>mutation with expression of a truncated protein causing peeling skin syndrome type B
Authors: A. Mallet, M. Kypriotou, K. George, E. Leclerc, D. Rivero, J. Mazereeuw-Hautier, G. Serre, M. Huber, N. Jonca, D. Hohl
Journal: British Journal of Dermatology (2013)

Peeling skin disease (PSD), a generalized inflammatory form of peeling skin syndrome, is caused by autosomal recessive nonsense mutations in the corneodesmosin gene (CDSN).To investigate a novel mutation in CDSN.A 50-year-old white woman showed widespread peeling with erythema and elevated serum IgE. DNA sequencing, immunohistochemistry, Western blot and real-time polymerase chain reaction analyses of skin biopsies were performed in order to study the genetics and to characterize the molecular profile of the disease.Histology showed hyperkeratosis and acanthosis of the epidermis, and inflammatory infiltrates in the dermis. DNA sequencing revealed a homozygous mutation leading to a premature termination codon in CDSN: p.Gly142*. Protein analyses showed reduced expression of a 16-kDa corneodesmosin mutant in the upper epidermal layers, whereas the full-length protein was absent.These results are interesting regarding the genotype-phenotype correlations in diseases caused by CDSN mutations. The PSD-causing CDSN mutations identified heretofore result in total corneodesmosin loss, suggesting that PSD is due to full corneodesmosin deficiency. Here, we show for the first time that a mutant corneodesmosin can be stably expressed in some patients with PSD, and that this truncated protein is very probably nonfunctional.
Atrial fibrillation and atrial flutter in athletes
Authors: Naiara Calvo, Josep Brugada, Marta Sitges, Lluís Mont
Journal: British Journal of Sports Medicine (2012)

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, with an estimated prevalence of 0.4% to 1% in the general population, increasing with age to 8% in those above 80 years. The recognised risk factors for developing AF include age, structural heart disease, hypertension, diabetes mellitus or hyperthyroidism. However, the mechanisms underlying the initiation of AF in patients below 60 years of age, in whom no cardiovascular disease or any other known causal factor is present, remain to be clarified. This condition, termed as lone AF, may be responsible for as many as 30% of patients with paroxysmal AF seeking medical attention. Recent studies suggest that long-term endurance exercise may increase the incidence of AF and atrial flutter (AFl) in this population. This review article is intended to analyse the prevalence of AF and AFl, the pathophysiological mechanisms responsible for the association between endurance sport practice and AF or AFl and the recommended therapeutic options in endurance athletes.
MAPK-Activated Protein Kinase-2 in Cardiac Hypertrophy and Cyclooxygenase-2 Regulation in Heart
Authors: John M. Streicher, Shuxun Ren, Harvey Herschman, Yibin Wang
Journal: Circulation Research (2010)

Rationale : Activation of p38 mitogen-activated protein kinase (MAPK) has a significant impact on cardiac gene expression, contractility, extracellular matrix remodeling, and inflammatory response in heart. The p38 kinase pathway also has a controversial role in cardiac hypertrophy. MAPK-activated protein kinase-2 (MK2) is a well-established p38 downstream kinase, yet its contribution to p38-mediated pathological response in heart has not been investigated. Objective : We examined the specific contribution of MK2 to the pathological remodeling induced by p38. Methods and Results : We used a cardiomyocyte specific and inducible transgenic approach to determine the functional and molecular impact of acute activation of the p38 pathway in heart in either a MK2 wild-type or a MK2-null background. p38 activation in wild-type mice led to a rapid onset of lethal cardiomyopathy associated with cardiomyocyte hypertrophy, interstitial fibrosis, and contractile dysfunction. Inactivation of MK2 partially but significantly reduced cardiomyocyte hypertrophy, improved contractile performance, and prevented early lethality. MK2 inactivation had no effect on the mRNA levels of hypertrophic marker genes or the proinflammatory gene cyclooxygenase (COX)-2. However, MK2 had a major role in COX-2 protein synthesis without affecting the mRNA level or protein stability. Conclusions : p38 activity in adult myocytes can contribute to pathological hypertrophy and remodeling in adult heart and that MK2 is an important downstream molecule responsible for specific features of p38-induced cardiac pathology.
Increasing Rates of Contralateral Prophylactic Mastectomy Among Patients With Ductal Carcinoma In Situ
Authors: Todd M. Tuttle, Stephanie Jarosek, Elizabeth B. Habermann, Amanda Arrington, Anasooya Abraham, Todd J. Morris, Beth A. Virnig
Journal: Journal of Clinical Oncology (2009)

Some women with unilateral ductal carcinoma in situ (DCIS) undergo contralateral prophylactic mastectomy (CPM) to prevent cancer in the opposite breast. The use and trends of CPM for DCIS in the United States have not previously been reported.We used the Surveillance, Epidemiology, and End Results database to analyze the initial treatment (within 6 months) of patients with unilateral DCIS diagnosed from 1998 through 2005. We determined the CPM rate as a proportion of all surgically treated patients and as a proportion of all patients who underwent mastectomy. We compared demographic and tumor variables in women with unilateral DCIS who underwent surgical treatment.We identified 51,030 patients with DCIS; 2,072 patients chose CPM. The CPM rate was 4.1% for all surgically treated patients and 13.5% for patients undergoing mastectomy. Among all surgically treated patients (including breast-conserving surgery), the CPM rate increased by 148% from 1998 (2.1%) to 2005 (5.2%). Among patients who underwent mastectomy to treat DCIS (excluding patients undergoing breast-conserving surgery), the CPM rate increased by 188% from 1998 (6.4%) to 2005 (18.4%). Young patient age, white race, recent year of diagnosis, and the presence of lobular carcinoma in situ were significantly associated with higher CPM rates among all surgically treated patients and all patients undergoing mastectomy. Large tumor size and higher grade were significantly associated with increased CPM rates among all surgically treated patients but lower CPM rates among patients undergoing mastectomy.The use of CPM for DCIS in the United States markedly increased from 1998 through 2005.
Global Health Governance and the Commercial Sector: A Documentary Analysis of Tobacco Company Strategies to Influence the WHO Framework Convention on Tobacco Control
Authors: Heide Weishaar, Jeff Collin, Katherine Smith, Thilo Grüning, Sema Mandal, Anna Gilmore
Journal: PLoS Medicine (2012)

In successfully negotiating the Framework Convention on Tobacco Control (FCTC), the World Health Organization (WHO) has led a significant innovation in global health governance, helping to transform international tobacco control. This article provides the first comprehensive review of the diverse campaign initiated by transnational tobacco corporations (TTCs) to try to undermine the proposed convention.The article is primarily based on an analysis of internal tobacco industry documents made public through litigation, triangulated with data from official documentation relating to the FCTC process and websites of relevant organisations. It is also informed by a comprehensive review of previous studies concerning tobacco industry efforts to influence the FCTC. The findings demonstrate that the industry's strategic response to the proposed WHO convention was two-fold. First, arguments and frames were developed to challenge the FCTC, including: claiming there would be damaging economic consequences; depicting tobacco control as an agenda promoted by high-income countries; alleging the treaty conflicted with trade agreements, "good governance," and national sovereignty; questioning WHO's mandate; claiming the FCTC would set a precedent for issues beyond tobacco; and presenting corporate social responsibility (CSR) as an alternative. Second, multiple tactics were employed to promote and increase the impact of these arguments, including: directly targeting FCTC delegations and relevant political actors, enlisting diverse allies (e.g., mass media outlets and scientists), and using stakeholder consultation to delay decisions and secure industry participation.TTCs' efforts to undermine the FCTC were comprehensive, demonstrating the global application of tactics that TTCs have previously been found to have employed nationally and further included arguments against the FCTC as a key initiative in global health governance. Awareness of these strategies can help guard against industry efforts to disrupt the implementation of the FCTC and support the development of future, comparable initiatives in global health.
Skp2 Protein Expression in Soft Tissue Sarcomas
Authors: Andre M. Oliveira, Scott H. Okuno, Antonio G. Nascimento, Ricardo V. Lloyd
Journal: Journal of Clinical Oncology (2003)

p45 S phase kinase-associated protein-2 (p45(skp2)), a member of the F-box family of proteins, is an important component of the Skp1-Cullin-F-box protein (SCF) ubiquitin-ligase complex (SCF(skp2)). The latter has been implicated in the ubiquitination and degradation of p27(kip1) (p27) and G(1)-S cell cycle progression. The expression and prognostic role of Skp2 in a large series of soft tissue sarcomas has not been previously investigated.Clinicopathologic features and immunohistochemical expression of Skp2, p27, and Ki-67 proteins were studied in 182 cases of soft tissue sarcomas (American Joint Committee on Cancer stages II and III). Survival analyses were performed using the Kaplan-Meier method and the Cox regression model.The male to female ratio was 1.2:1, and the median age at the diagnosis was 53 years. The tumors were predominantly located in the lower extremities (n = 163; 90%) and had a median size of 9 cm. High Skp2 expression (> or = 10% of the cells) was identified in 68 tumors (37%), and was correlated with high grade histology (P =.002) and Ki-67 proliferative index (r = 0.44; P <.0001), but not with p27 expression (r = -0.02; P =.80). By univariate analysis, high Skp2 expression was associated with decreased metastasis-free, disease-free, and overall survival. In a multivariate model, high Skp2 expression was an independent predictor for decreased local recurrence-free, disease-free, and overall survival.These results indicate that Skp2 expression is associated with cell proliferation and a worse prognosis in soft tissue sarcomas. The lack of an inverse correlation between Skp2 and p27 suggests that additional molecular events associated with either Skp2 expression or p27 proteolysis may be operating in these tumors.
Randomised controlled comparison of single-dose ciprofloxacin and doxycycline for cholera caused by Vibrio cholerae O1 or O139
Authors: WasifAli Khan, Michael L Bennish, Carlos Seas, Eradul Haq Khan, Anne Ronan, Ujjwal Dhar, Wilhelm Busch, Mohammed Abdus Salam
Journal: The Lancet (1996)
Management of paracetamol poisoning
Authors: R. E. Ferner, J. W. Dear, D. N. Bateman
Journal: BMJ (2011)

#### Summary points

Paracetamol (acetaminophen) is an effective oral analgesic, with few adverse effects when used at the recommended dose. Nevertheless, paracetamol poisoning is common and potentially fatal.1 It is a leading cause of acute liver failure in the United Kingdom2 and the United States.3 Potential liver damage, predicted from blood paracetamol concentration and time from ingestion, can be prevented by prompt treatment with antidote. However, young and otherwise healthy patients still risk serious liver injury, especially if they present more than a few hours after overdose or take staggered overdoses over hours or days.4

#### Sources and selection criteria

We based our review on a PubMed search for articles on paracetamol (or acetaminophen) and acetylcysteine or ( N- acetylcysteine) published between 1 January 1990 and 31 December 2010, without language limits. The search was limited to human clinical trials, meta-analyses, randomised controlled trials, reviews, and case reports. We also searched a newspaper database for reports published after 1988 of coroners’ inquests and procurators’ fiscal inquiries into fatal cases of paracetamol poisoning. In addition, we used a bibliography and our own collections of relevant references.5

The …
A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma
Authors: D.P.S. Sohal, K. Mykulowycz, T. Uehara, U.R. Teitelbaum, N. Damjanov, B.J. Giantonio, M. Carberry, P. Wissel, M. Jacobs-Small, P.J. O'Dwyer, A. Sepulveda, W. Sun
Journal: Annals of Oncology (2013)
Reply to P.K.L. Chin et al, P. Chambers et al, and J.H. Beumer et al
Authors: Gary H. Lyman, Jennifer J. Griggs
Journal: Journal of Clinical Oncology (2012)

study collating data from these trials to compare the outcomes of those patients with dose capping and those fully dosed.Of the 4,856 patients, 2,202 (45%) were classified as normal weight (body mass index [BMI] Ͻ 25), 1,774 (37%) as overweight (BMI 25-29), and 880 (18%) as obese (BMI Ն 30).There was a significant association between increasing weight subgroup and the proportion with a reduced dose (normal weight, 6%; overweight, 17%; obese, 55%; P Ͻ .001).There was no evidence that obese patients experienced more toxicity in those fully dosed (normal weight, 21%; overweight, 20%; obese, 17%) or that reducing the doses of obese patients resulted in less toxicity (full dose, 17%; reduced dose, 16%).An important additional piece of information from our analysis was a suggestion that those obese patients who were given reduced doses had a slightly worse survival than those who were fully dosed (hazard ratio, 1.16; 95% CI, 1.00 to 1.35; P ϭ .055).Although not randomized, this adds considerable weight to the argument against dose capping.Thus our results complement and add to the evidence for the new ASCO guidelines.We would encourage clinical practice and future trial designs to adopt the new guidelines to ensure that obese and overweight patients are dosed appropriately.
Fluorodeoxyglucose Positron Emission Tomography as an Outcome Measure for Castrate Metastatic Prostate Cancer Treated with Antimicrotubule Chemotherapy
Authors: Michael J. Morris, Timothy Akhurst, Steven M. Larson, Marisa Ditullio, Elaina Chu, Karen Siedlecki, David Verbel, Glenn Heller, W. Kevin Kelly, Susan Slovin, Lawrence Schwartz, Howard I. Scher
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Standard imaging studies are limited as outcome measures for patients with metastatic prostate cancer. We tested the hypothesis that serial fluorodeoxyglucose positron emission tomography (FDG-PET) scans can serve as an outcome measure for patients with castrate metastatic prostate cancer treated with antimicrotubule chemotherapy. Experimental Design: FDG-PET scans were done at baseline, 4, and 12 weeks of treatment. The average maximum standardized uptake value (SUVmaxavg) was measured in up to five lesions and was tested as the quantitative outcome measure. Prostate-specific antigen (PSA) at 4 weeks and PSA, bone scan, and soft tissue imaging at 12 weeks were considered standard outcome measures. The change in SUVmaxavg that distinguished clinically assessed progression from nonprogression was sought. Results: Twenty-two PET scans were reviewed and compared with PSA at 4 weeks; 18 PETs were compared at 12 weeks with standard outcome measures. Applying the PSA Working Group Consensus Criteria guideline that a 25% PSA increase constitutes progression to the SUVmaxavg, PET correctly identified the clinical status of 20 of 22 patients (91%) at 4 weeks and 17 of 18 patients at 12 weeks (94%). The accuracy of PET could be further optimized if a &amp;gt;33% increase in PSA and SUVmaxavg were used to define progression. Conclusion: FDG-PET is promising as an outcome measure in prostate cancer. As a single modality, it can show treatment effects that are usually described by a combination of PSA, bone scintigraphy, and soft tissue imaging. Preliminarily, a &amp;gt;33% increase in SUVmaxavg or the appearance of a new lesion optimally dichotomizes patients as progressors or nonprogressors.
RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance
Authors: Yanping Xiao, Sanhong Yu, Baogong Zhu, Denis Bedoret, Xia Bu, Loise M. Francisco, Ping Hua, Jonathan S. Duke-Cohan, Dale T. Umetsu, Arlene H. Sharpe, Rosemarie H. DeKruyff, Gordon J. Freeman
Journal: The Journal of Experimental Medicine (2014)

We report that programmed death ligand 2 (PD-L2), a known ligand of PD-1, also binds to repulsive guidance molecule b (RGMb), which was originally identified in the nervous system as a co-receptor for bone morphogenetic proteins (BMPs). PD-L2 and BMP-2/4 bind to distinct sites on RGMb. Normal resting lung interstitial macrophages and alveolar epithelial cells express high levels of RGMb mRNA, whereas lung dendritic cells express PD-L2. Blockade of the RGMb-PD-L2 interaction markedly impaired the development of respiratory tolerance by interfering with the initial T cell expansion required for respiratory tolerance. Experiments with PD-L2-deficient mice showed that PD-L2 expression on non-T cells was critical for respiratory tolerance, but expression on T cells was not required. Because PD-L2 binds to both PD-1, which inhibits antitumor immunity, and to RGMb, which regulates respiratory immunity, targeting the PD-L2 pathway has therapeutic potential for asthma, cancer, and other immune-mediated disorders. Understanding this pathway may provide insights into how to optimally modulate the PD-1 pathway in cancer immunotherapy while minimizing adverse events.
Effect of portal-systemic anastomosis on renal haemodynamics in cirrhosis.
Authors: H Ring-Larsen, B Hesse, B Stigsby
Journal: Gut (1976)

In 12 patients with portal hypertension and repeated bleedings from oesophageal varices the central haemodynamics, portal pressure, and mean renal blood flow (RBF) were investigated immediately before and two to seven months after portal-systemic shunt. Cardiac output increased significantly, whereas arterial pressure was unchanged after operation. RBF, which was initially less than in controls, did not change. As portal pressure decreased significantly, a direct portal-renal, neural, or humoral reflex mechanism does not explain the subnormal RBF in cirrhosis. As plasma volume was large and unchanged after operation a "diminished circulating plasma volume" is an unlikely explanation. Therefore, on the basis of the present observations, previously postulated causes of renal hypoperfusion in cirrhosis need revision.
Report calls for co-location of primary care with A&amp;E
Authors: J. Wise
Journal: BMJ (2015)

Primary care services should be located alongside hospital emergency departments, a new report from the Royal College of Emergency Medicine and the Patients Association concludes.1

The report said that patients continued to go to emergency departments even when they were aware of the alternatives, such as out-of-hours GP services, walk-in centres, and the NHS 111 telephone service. In many cases this was because the alternative services may not have had enough capacity or were not available when needed. However, the report added that a substantial and increasing number of patients attended emergency departments …