tbuckley/cabot-search huggingface dataset:
Theophylline inhibits the cough reflex through a novel mechanism of action
Authors: Eric Dubuis, Michael A. Wortley, Megan S. Grace, Sarah A. Maher, John J. Adcock, Mark A. Birrell, Maria G. Belvisi
Journal: Journal of Allergy and Clinical Immunology (2014)

Theophylline has been used in the treatment of asthma and chronic obstructive pulmonary disease for more than 80 years. In addition to bronchodilator and anti-inflammatory activity, clinical studies have suggested that theophylline acts as an antitussive agent. Cough is the most frequent reason for consultation with a family doctor, and treatment options are limited. Determining how theophylline inhibits cough might lead to the development of optimized compounds.We sought to investigate the inhibitory activity of theophylline on vagal sensory nerve activity and the cough reflex.Using a range of techniques, we investigated the effect of theophylline on human and guinea pig vagal sensory nerve activity in vitro and on the cough reflex in guinea pig challenge models.Theophylline was antitussive in a guinea pig model, inhibited activation of single C-fiber afferents in vivo and depolarization of human and guinea pig vagus in vitro, and inhibited calcium influx in airway-specific neurons in vitro. A sequence of pharmacological studies on the isolated vagus and patch clamp and single-channel inside-out experiments showed that the effect of theophylline was due to an increase in the open probability of calcium-activated potassium channels. Finally, we demonstrated the antitussive activity of theophylline in a cigarette smoke exposure model that exhibited enhanced tussive responses to capsaicin.Theophylline inhibits capsaicin-induced cough under both normal and "disease" conditions by decreasing the excitability of sensory nerves through activation of small- and intermediate-conductance calcium-activated potassium channels. These findings could lead to the development of optimized antitussive compounds with a reduced side effect potential.
Allostery at G Protein-Coupled Receptor Homo- and Heteromers: Uncharted Pharmacological Landscapes
Authors: Nicola J. Smith, Graeme Milligan
Journal: Pharmacological Reviews (2010)

For many years seven transmembrane domain G protein-coupled receptors (GPCRs) were thought to exist and function exclusively as monomeric units. However, evidence both from native cells and heterologous expression systems has demonstrated that GPCRs can both traffic and signal within higher-order complexes. As for other protein-protein interactions, conformational changes in one polypeptide, including those resulting from binding of pharmacological ligands, have the capacity to alter the conformation and therefore the response of the interacting protein(s), a process known as allosterism. For GPCRs, allosterism across homo- or heteromers, whether dimers or higher-order oligomers, represents an additional topographical landscape that must now be considered pharmacologically. Such effects may offer the opportunity for novel therapeutic approaches. Allosterism at GPCR heteromers is particularly exciting in that it offers additional scope to provide receptor subtype selectivity and tissue specificity as well as fine-tuning of receptor signal strength. Herein, we introduce the concept of allosterism at both GPCR homomers and heteromers and discuss the various questions that must be addressed before significant advances can be made in drug discovery at these GPCR complexes.
Neuromuscular adjustments of the knee extensors and plantar flexors following match-play tennis in the heat
Authors: Julien D Périard, Olivier Girard, Sébastien Racinais
Journal: British Journal of Sports Medicine (2014)

Objectives This study tested the hypothesis that impairments in lower limb maximal strength and voluntary activation (VA) are exacerbated following match-play tennis in hot compared with cool conditions. Methods Torque and VA were evaluated during brief (5 s) and sustained (20 s) maximal voluntary isometric contractions of the knee extensors (KE) and plantar flexors (PF) in 12 male tennis players before (pre) and after (post, 24 h and 48 h) ∼115 min of play in hot (∼37°C) and cool (∼22°C) conditions. Results Rectal temperature was higher following play in hot than in cool (∼39.2 vs ∼38.5°C; p&lt;0.05). Torque production decreased from prematch to postmatch during the brief and sustained contractions in hot (KE: ∼22%; PF: ∼13%) and cool (KE: ∼9%, PF: ∼7%) (p&lt;0.05). KE strength losses in hot were greater than in cool (p&lt;0.05) and persisted for 24 h (p&lt;0.05). Postmatch brief and sustained KE VA was lower in hot than in cool (p&lt;0.05), in which VA was maintained. PF VA was maintained throughout the protocol. Peak twitch torque and maximum rates of torque development and relaxation in the KE and PF were equally reduced postmatch relative to prematch in hot and cool conditions (p&lt;0.05), and were restored near baseline within 24 h. Conclusions Neuromuscular system integrity of the lower limbs is compromised immediately following match-play tennis in hot and cool conditions due to the development of peripheral fatigue. The larger and persistent KE strength losses observed under heat stress are associated with greater levels of central fatigue especially during sustained contractions.
Photodynamic therapy for the treatment of extramammary Paget's disease
Authors: S. Shieh, A.S. Dee, R.T. Cheney, N.P. Frawley, N.C. Zeitouni, A.R. Oseroff
Journal: British Journal of Dermatology (2002)

Summary Background Surgical and ablative treatment modalities for extramammary Paget's disease (EMPD) have high recurrence rates and can be associated with significant morbidity. Objectives To evaluate photodynamic therapy (PDT) for the treatment of EMPD. Methods We conducted a retrospective review of notes and histology of five men with anogenital, groin and axillary EMPD treated with PDT at Roswell Park Cancer Institute between 20 April 1995 and 1 February 2001. Results Sixteen EMPD lesions were treated with topical aminolaevulinic acid (ALA)-PDT. Eleven of these lesions had failed previous Mohs micrographic surgery, excision or laser ablation. When evaluated 6 months after one treatment with ALA-PDT, eight of 16 (50%) sites achieved a complete clinical response (CR); six of eight CRs were in lesions that had failed prior conventional therapies. Three of the eight CRs (37·5%) recurred at 9, 10 and 10 months. One patient who was partially responsive to topical ALA-PDT subsequently received systemic Photofrin®-PDT, with a complete clinical and histological response at 1 year. Functional and cosmetic outcome was excellent in all patients. Conclusions PDT is an effective treatment for EMPD. Recurrence rates are high with topical ALA-PDT, but comparable with standard therapies. Topical ALA-PDT causes little scarring and is preferred for superficial disease and mucosal surfaces. Systemic Photofrin®-PDT may be better suited for bulky disease. While further studies are indicated, PDT is well tolerated and appears to be a useful therapy for EMPD.
Podocytes Contribute to the Formation of Glomerular Crescents
Authors: Paul S. Thorner, Michael Ho, Vera Eremina, Yoshikazu Sado, Susan Quaggin
Journal: Journal of the American Society of Nephrology (2008)

The cellular composition of crescents in glomerular disease is controversial. The role of podocytes in crescent formation has been especially difficult to study because podocytes typically lose their characteristic terminally differentiated phenotype under disease conditions, making them difficult to identify. We reasoned that the intermediate filament protein nestin, a marker of progenitor cells that has recently been identified in podocytes, may allow the investigation of podocyte involvement in glomerular crescents. In a series of 35 biopsies with crescentic glomerular disease, all showed nestin-positive cells in the crescents, ranging in number from occasional to approximately 50% of crescent cells. Other podocyte markers, such as podocin and WT1, failed to identify cells in crescents, and no contribution by endothelial or myogenic cells was noted. CD68-positive cells were observed in 80% of cases but were never as numerous as the nestin-positive cells. Nestin and CD68 were not coexpressed by the same cells, providing no evidence of trans-differentiation of podocytes into a macrophage phenotype. Keratin-positive cells were found in crescents in 51% of cases, but only as occasional cells. Up to one third of crescent cells were cycling in 48% of biopsies, and double immunostaining identified these cells as a mixture of nestin-positive cells and "null" cells (negative for nestin, CD68, and keratin). In addition to our observations in human disease, we also identified nestin-positive proliferating podocytes in the crescents of 2 mouse models of crescentic glomerulonephritis. We conclude that podocytes play a role in the formation of glomerular crescents.
The identification of small nodules in liver adenomatosis
Authors: Sébastien Lepreux, Christophe Laurent, Jean Frédéric Blanc, Hervé Trillaud, Brigitte Le Bail, Hélène Trouette, Jean Saric, Jessica Zucman-Rossi, Charles Balabaud, Paulette Bioulac-Sage
Journal: Journal of Hepatology (2003)
Effect of inhaled H1 and H2 receptor antagonist in normal and asthmatic subjects.
Authors: N C Thomson, J W Kerr
Journal: Thorax (1980)

The effects on airflow resistance of an inhaled H1 receptor antagonist, clemastine, and an H2 receptor antagonist, cimetidine, have been investigated in normal and asthmatic subjects. No significant changes in specific conductance (sGaw) were seen in six normal subjects. In eight asthmatic subjects a significant increase in forced expiratory volume in one second (FEV1) occurred at 60 min (< 0.02), and 120 (< 0.05) after the inhalation of clemastine, whereas inhaled cimetidine had no effect on airflow resistance. Clemastine and cimetidine were tested on histamine-induced bronchoconstriction in eight normal and eight asthmatic subjects. Clemastine significantly reduced the fall in sGaw in normal subjects and the fall in FEV1 in asthmatic subjects, whereas cimetidine had no protective effect. Clemastine and ipratropium bromide were tested on methacholine-induced bronchoconstriction in eight normal subjects. Ipratropium bromide, but not clemastine, significantly reduced the fall in sGaw after methacholine. These results suggest that in normal and asthmatic subjects histamine-induced bronchoconstriction is mediated predominantly via H1 rather than H2 receptors in the airways.
Targeted delivery of CD40L promotes restricted activation of antigen-presenting cells and induction of cancer cell death
Authors: Kim L Brunekreeft, Corinna Strohm, Marloes J Gooden, Anna A Rybczynska, Hans W Nijman, Götz U Grigoleit, Wijnand Helfrich, Edwin Bremer, Daniela Siegmund, Harald Wajant, Marco de Bruyn
Journal: Molecular Cancer (2014)

Stimulation of CD40 can augment anti-cancer T cell immune responses by triggering effective activation and maturation of antigen-presenting cells (APCs). Although CD40 agonists have clinical activity in humans, the associated systemic activation of the immune system triggers dose-limiting side-effects. To increase the tumor selectivity of CD40 agonist-based therapies, we developed an approach in which soluble trimeric CD40L (sCD40L) is genetically fused to tumor targeting antibody fragments, yielding scFv:CD40L fusion proteins. We hypothesized that scFv:CD40L fusion proteins would have reduced CD40 agonist activity similar to sCD40L but will be converted to a highly agonistic membrane CD40L-like form of CD40L upon anchoring to cell surface exposed antigen via the scFv domain. Targeted delivery of CD40L to the carcinoma marker EpCAM on carcinoma cells induced dose-dependent paracrine maturation of DCs ~20-fold more effective than a non-targeted control scFv:CD40L fusion protein. Similarly, targeted delivery of CD40L to the B cell leukemia marker CD20 induced effective paracrine maturation of DCs. Of note, the CD20-selective delivery of CD40L also triggered loss of cell viability in certain B cell leukemic cell lines as a result of CD20-induced apoptosis. Targeted delivery of CD40L to cancer cells is a promising strategy that may help to trigger cancer-localized activation of CD40 and can be modified to exert additional anti-cancer activity via the targeting domain.
Small cell carcinoma: combined approach to treatment.
Authors: A Gregor, P G Morgan, R L Morgan, F H Scadding, M Turner-Warwick
Journal: Thorax (1979)

Fifty-six patients with untreated small cell carcinoma of the bronchus were treated with three courses of chemotherapy (cyclophosphamide, vincristine, and procarbazine and methotrexate) and assessed for response. Thirty-one patients (55.4%) were classified as responders; they were given a course of radiotherapy and were then randomly allocated to continued cyclical chemotherapy or not further chemotherapy until relapse. Non-responders to chemotherapy were treated with radiotherapy or palliatively. The median survival was 10.5 months in responders and 6 months in non-responders (P less than 0.01). The one-year survival in responders was 42%. There was no statistical difference in survival between patients treated with continued chemotherapy and those treated at relapse. Sixty-nine per cent of patients experienced no side effects from chemotherapy. Three indicators of non-response to chemotherapy were identified--exercise tolerance at diagnosis, macroscopic liver metastases, and inappropriate ADH secretion.
The Role of Mutational Dynamics in Genome Shrinkage
Authors: M. J. A. van Hoek, P. Hogeweg
Journal: Molecular Biology and Evolution (2007)

Genome shrinkage occurs after whole genome duplications (WGDs) and in the evolution of parasitic or symbiotic species. The dynamics of this process, whether it occurs by single gene deletions or also by larger deletions are however unknown. In yeast, genome shrinkage has occurred after a WGD. Using a computational model of genome evolution, we show that in a random genome single gene deletions cannot explain the observed pattern of gene loss in yeast. The distribution of genes deleted per event can be very well described by a geometric distribution, with a mean of 1.1 genes per event. In terms of deletions of a stretch of base pairs, we find that a geometric distribution with an average of 500-600 base pairs per event describes the data very well. Moreover, in the model, as in the data, gene pairs that have a small intergenic distance are more likely to be both deleted. This proves that simultaneous deletion of multiple genes causes the observed pattern of gene deletions, rather than deletion of functionally clustered genes by selection. Furthermore, we found that in the bacterium Buchnera aphidicola larger deletions than in yeast are necessary to explain the clustering of deleted genes. We show that the excess clustering of deleted genes in B. aphidicola can be explained by the clustering of genes in operons. Therefore, we show that selection has little effect on the clustering of deleted genes after the WGD in yeast, while it has during genome shrinkage in B. aphidicola.
The future of cardiology and psychogeriatrics
Authors: K Bergmann
Journal: BMJ (1981)

AIM--To investigate the quality of perinatal and infant necropsies and assess the relation between the quality and value of this investigation in different outcome groups. METHODS--Cohort analysis of 540 deaths during 1993 of babies between 20 weeks9 gestation and one year of age born to women usually resident in Wales. Cases were identified from the All Wales Perinatal Survey. Each case was assessed to establish whether the necropsy yielded clinically relevant information. The quality of necropsy was assessed by scoring aspects identified as being part of the necropsy. RESULTS--Necropsy was performed in 335 (62%) cases, and the report was available for assessment in 314 cases. The quality of necropsy was below the minimum standard in 46% (143/314) of cases. The highest quality necropsies were carried out on fetal deaths at 20 to 23 weeks9 gestation (12% (10/85) below standard), compared with 65% (87/133) below standard on stillbirths and 68% (21/31) on sudden unexpected infant death. Overall, 42% (131/314) of necropsies were performed in a regional paediatric pathology centre including 88% (76/88) of fetal deaths, 23% (31/133) of stillbirths and 30% (29/96) of infant deaths. The quality score for the necropsy performed in a regional centre failed to achieve the minimum acceptable score in 8% (11/131) of cases compared with 72% (132/182) for those done elsewhere. The cause of death was detected by necropsy in 17% (52/314) of cases. The quality of necropsy was significantly higher when the cause of death was revealed than when nothing new was found. CONCLUSIONS--The overall quality of the perinatal and infant necropsy is poor. This is regrettable as valuable information can be revealed frequently by a good quality necropsy. Adherence to Guidelines for Postmortem Reports recently published by the Royal College of Pathologists should improve the situation.
Recent advances: Management of patients in fast track surgery
Authors: D. W Wilmore
Journal: BMJ (2001)

Surgery is slowly undergoing revolutionary changes due to newer approaches to pain control, the introduction of techniques that reduce the perioperative stress response, and the use of minimally invasive operations. Subsequently, many surgical procedures (such as arthroscopic surgery, laparoscopic cholecystectomy, eye surgery, sterilisation procedures, herniorrhaphy, and cosmetic operations) are routinely performed on an outpatient basis. Recently published pilot studies suggest that when these newer approaches are used in patients undergoing more complex elective surgical procedures, postoperative complications can be reduced, length of hospital stay decreased, and time to recovery shortened. This review of recent advances made in this newly developing specialty of fast track surgery will emphasise techniques that facilitate early recovery after major surgical procedures.

Fast track surgery combines various techniques used in the care of patients undergoing elective operations. The methods used include epidural or regional anaesthesia, minimally invasive techniques, optimal pain control, and aggressive postoperative rehabilitation, including early enteral (oral) nutrition and ambulation. The combination of these approaches reduces the stress response and organ dysfunction and therefore greatly shorten the time required for full recovery.

Recent advances in understanding perioperative pathophysiology have indicated that multiple factors contribute to postoperative morbidity, length of stay in hospital, and convalescence (fig 1). Major improvements in surgical outcome may therefore require multifaceted interventions (fig 2). Ambulatory surgery has become routine for many procedures with a well documented record for safety and low morbidity, even in patients at high risk. 1 2 Studies of fast track surgery have evaluated somewhat similar approaches toward larger operations which carry more risk (box). Preliminary results from predominantly non-randomised trials have been positive (table). These studies have included high risk elderly patients undergoing operations such as segmental colonic resection, prostatectomy, and aortic aneurysmectomy. These preliminary data indicate topics for further randomised trials; the data need to …
Noneosinophilic asthma in children: relation with airway remodelling
Authors: S. Baraldo, G. Turato, E. Bazzan, A. Ballarin, M. Damin, E. Balestro, K. Lokar Oliani, F. Calabrese, P. Maestrelli, D. Snijders, A. Barbato, M. Saetta
Journal: European Respiratory Journal (2011)

Noneosinophilic asthma is increasingly recognised as an important clinical-pathological phenotype in adults. However, this entity has scarcely been investigated in children. In particular, it is unknown whether airway remodelling would develop in children with non-eosinophilic asthma to the same degree as in children with eosinophilic disease. We analysed bronchial biopsies from 80 children undergoing bronchoscopy for appropriate clinical indications: 21 with noneosinophilic asthma, 34 with eosinophilic asthma and 25 control children. Features of airway remodelling - basement membrane thickening, epithelial loss and angiogenesis - and immune activation - inflammatory infiltrate, interleukin (IL)-4, IL-5, transforming growth factor (TGF)-β, TGF-β receptor type II - were quantified by histology and immunohistochemistry. The main components of airway remodelling were present in children with noneosinophilic asthma just as in those with eosinophilic disease. Indeed, compared with control children, both noneosinophilic and eosinophilic asthmatic children had thickened basement membrane, increased epithelial loss and higher number of vessels. Moreover, in both groups of asthmatics, expression of IL-4 and IL-5 was increased, while that of TGF-β receptor type II was reduced, compared with controls. This study demonstrates that structural changes typical of asthma develop in asthmatic children even in the absence of a prominent eosinophilic infiltrate, indicating that other mechanisms, besides eosinophilic inflammation, may promote airway remodelling early in life.
Cervical Cancer Screening
Authors: Edward E. Partridge, Nadeem R. Abu-Rustum, Susan M. Campos, Patrick J. Fahey, Michael Farmer, Rochelle L. Garcia, Anna Giuliano, Howard W. Jones, Subodh M. Lele, Richard W. Lieberman, Stewart L. Massad, Mark A. Morgan, R. Kevin Reynolds, Helen E. Rhodes, Diljeet K. Singh, Karen Smith-McCune, Nelson Teng, Cornelia Liu Trimble, Fidel Valea, Sharon Wilczynski
Journal: Journal of the National Comprehensive Cancer Network (2010)

Despite a significant decrease in the incidence and mortality of cervical carcinoma in the United States, an estimated 12,200 women will be diagnosed with the disease in 2010, with 4210 expected deaths. 1 High-risk groups include women without access to health care and those who have immigrated to the United States from countries where cervical cancer screening is not routinely performed. 2Because cervical cytology screening is the current method for early detection of this neoplasm, the purpose of these guidelines is to provide direction for the evaluation and management of cervical cytology.These guidelines include recommendations on screening techniques, initiation, and frequency of screening, and management of abnormal screen