tbuckley/cabot-search huggingface dataset:
Increased levels of protein kinase C in lymphocytes in asthma: possible mechanism of regulation
Authors: SK Bansal, A Jha, AS Jaiswal, SK Chhabra
Journal: European Respiratory Journal (1997)

Asthma is an inflammatory disease of the airways. Activation of lymphocytes leads to elaboration of inflammatory mediators which are likely to initiate and perpetuate the asthmatic response. During activation of lymphocytes, the role of protein kinase C (PKC) has been emphasized. Therefore, changes in PKC activity in peripheral blood lymphocytes in bronchial asthma can be expected, which may be due to alterations in the regulatory mechanisms of the enzyme molecule. To understand the mechanism of regulation of PKC activity the effects of drugs, such as carbachol, histamine, sphingosine and disodium cromoglycate (DSCG), on the lymphocytes of healthy subjects were studied. The study included 27 asthmatic patients and 14 healthy volunteers. Disease was classified as mild, moderate-to-severe, and cases in remission. PKC activity was determined in peripheral blood lymphocytes by [3H] phorbol 12,13-dibutyrate ([3H]PDBu)-binding assay. A highly significant (p < 0.001) increase was observed in total, cytosolic and membrane PKC activity in all of the asthmatic patients as compared to the healthy group. There was an increased translocation of PKC from cytosol to membrane in all of the groups, and the extent of translocation of the enzyme indicates physiological activation of the cells. A highly significant (p < 0.001) reciprocal relationship (r = -0.47) existed between forced expiratory volume in one second (FEV1) as percentage predicted and total PKC activity in bronchial asthma. Carbachol and histamine significantly (p < 0.001) increased PKC activity in lymphocytes, the increase being dose-dependent for histamine. Sphingosine or disodium cromoglycate (DSCG) brought about complete inhibition of PKC activity at 100 nM. We conclude that protein kinase C activity is increased in lymphocytes in bronchial asthma. Our findings suggest that the mediators (carbachol and histamine), and drugs (sphingosine and disodium cromoglycate) possibly exert their action on protein kinase C by influencing the regulatory domain of the enzyme.
Pulmonary rehabilitation in chronic obstructive pulmonary disease
Authors: H Folgering, J Rooyackers
Journal: European Respiratory Journal (1998)

<h3>Background</h3> Leadership is a core competency of medical professionals, including junior doctors. In junior doctor representative committees at Oxford University Hospitals (OUH): Motivation for engagement has historically dropped throughout the year There is a perceived lack of formal leadership development opportunities available There is an appetite for leadership training To address these concerns the Oxford Emerging Leaders’ Programme (ELP) was developed. <h3>Development</h3> The programme was developed from existing resources at OUH through interviews with potential participants. The 4 month programme included 6 half-day workshops alongside team quality improvement projects (QIPs). 13 participants completed the course. Guest presentations were given by NHS healthcare leaders and QIPs were mentored by hospital consultants with experience in leadership and quality improvement. <h3>Evaluation</h3> Evaluation was conducted with a mixed-methods approach based on Kirkpatrick’s framework for evaluation of educational outcomes (Harden, Grant and Buck, 1999; Hammick, Dornan and Steinert, 2010). Levels 1 and 2 (Reaction/Learning) Self-assessment questionnaires based on Pendleton and Furnham’s Primary Colours model (2016) Level 3 (Behavioural Change) Post-course questionnaire; interviews Level 4 (System) Quality Improvement Project outcomes. <h3>Results</h3> Course participants found the combination of workshops and practical work engaging. Many participants struggled to arrange their clinical duties to attend all workshops. Self-assessment results showed an increase in leadership capacity, with statistically significant increases in 50% of domains. There were large increases related to strategy, alignment and relationships with managers. Confidence, motivation and job satisfaction rose amongst participants. Objective improvements were demonstrated in 2/4 QIP’s. <h3>Conclusions</h3> By aligning the programme with organisational goals (Quality Improvement) course faculty were able to access support and development opportunities to the benefit of the organisation, the individuals and their patients. A solution to workshop timing problems continues to elude faculty. A longer timeframe could support course outcomes. <h3>References</h3> Hammick M, Dornan T, Steinert Y. Conducting a best evidence systematic review. Part 1: From idea to data coding. BEME Guide No. 13’. Medical Teacher2010;32(1):3–15. doi:10.3109/01421590903414245 Harden R, Grant J, Buck G. BEME Guide No. 1: Best evidence medical education. Medical Teacher1999;21(6):553–562. doi:10.1080/01421599978960 Pendleton D, Furnham A. <i>Leadership: All You Need To Know</i>2016.
Effects of short term high frequency negative pressure ventilation on gas exchange using the Hayek oscillator in normal subjects.
Authors: F M Hardinge, R J Davies, J R Stradling
Journal: Thorax (1995)

BACKGROUND--The Hayek oscillator is a negative pressure cuirass that can operate at a range of frequencies to provide ventilation, and is a technique which could potentially be used on a general ward. This study examined the effect of different frequencies and different ranges of inspiratory and expiratory pressures on gas exchange, respiratory rate, and blood pressure in normal subjects. METHODS--Eight normal subjects received five minute periods of ventilation using the Hayek oscillator at five different frequencies, and a combination of two spans of inspiratory and expiratory pressures and two mean chamber pressures. A "sham" or control period was also performed at each frequency. Measurements were made of changes in gas exchange, spontaneous respiratory rate, and blood pressure before and after ventilation. RESULTS--There was significant intersubject variation in all results, independent of their height and weight. "Sham" settings acted as true controls in terms of gas exchange, but produced a fall in respiratory rate at 30 oscillations/min. The lower oscillatory frequencies of 30 and 60 oscillations/min produced the greatest increase in oxygenation, decrease in end tidal carbon dioxide pressure, and decrease in spontaneous respiratory rate. These effects were most significant at higher spans of pressure and were different from "sham" settings. No adverse effects were observed on blood pressure. CONCLUSIONS--The Hayek oscillator can provide assisted ventilation for short periods in normal conscious subjects with no adverse side effects on blood pressure. Maximal changes in gas exchange and a significant reduction in the spontaneous respiratory rate are seen when a combination of lower frequencies (30 and 60 oscillations/min) and higher spans of pressure are used.
Health effects of passive smoking bullet 9: Parental smoking and spirometric indices in children
Authors: D. G Cook, D. P Strachan, I. M Carey
Journal: Thorax (1998)

Optimal CD4<sup>+</sup> T cell activation requires the cooperation of multiple signaling pathways coupled to the TCR-CD3 complex and to the CD28 costimulatory molecule. In this study, we have investigated the expression of surface CXC chemokine receptor 4 (CXCR4) in enriched populations of CD4<sup>+</sup> T PBL, stimulated with anti-CD3 and anti-CD28 mAbs, immobilized on plastic. Anti-CD3 alone induced a progressive down-regulation of surface CXCR4, accompanied by a significant decline in the entry of the HXB2 T cell line-tropic (X4-tropic) HIV-1 clone in CD4<sup>+</sup> T cells. Of note, this effect was strictly dependent on the presence in culture of CD14<sup>+</sup> monocytes. On the other hand, anti-CD28 alone induced a small but reproducible increase in the expression of surface CXCR4 as well as in the entry of HXB2 HIV-1 clone in resting CD4<sup>+</sup> T cells. When the two mAbs were used in combination, anti-CD28 potently synergized with anti-CD3 in inducing the expression of CD69 activation marker and stimulating the proliferation of CD4<sup>+</sup> T cells. On the other hand, anti-CD28 counteracted the CXCR4 down-modulation induced by anti-CD3. The latter effect was particularly evident when anti-CD28 was associated to suboptimal concentrations of anti-CD3. Because CXCR4 is the major coreceptor for the highly cytopathic X4-tropic HIV-1 strains, which preferentially replicate in proliferating CD4<sup>+</sup> T cells, the ability of anti-CD28 to up-regulate the surface expression of CXCR4 in both resting and activated CD4<sup>+</sup> T cells provides one relevant mechanism for the progression of HIV-1 disease.
METHYLATION PHARMACOGENETICS: Catechol O-Methyltransferase, Thiopurine Methyltransferase, and Histamine N-Methyltransferase
Authors: Richard M. Weinshilboum, Diane M. Otterness, Carol L. Szumlanski
Journal: The Annual Review of Pharmacology and Toxicology (1999)

Methyl conjugation is an important pathway in the biotransformation of many exogenous and endogenous compounds. Pharmacogenetic studies of methyltransferase enzymes have resulted in the identification and characterization of functionally important common genetic polymorphisms for catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. In recent years, characterization of these genetic polymorphisms has been extended to include the cloning of cDNAs and genes, as well as a determination of the molecular basis for the effects of inheritance on these methyltransferase enzymes. The thiopurine methyltransferase genetic polymorphism is responsible for clinically significant individual variations in the toxicity and therapeutic efficacy of thiopurine drugs such as 6-mercaptopurine. Phenotyping for the thiopurine methyltransferase genetic polymorphism represents one of the first examples in which testing for a pharmacogenetic variant has entered standard clinical practice. The full functional implications of pharmacogenetic variation in the activities of catechol O-methyltransferase and histamine N-methyltransferase remain to be determined. Finally, experimental strategies used to study methylation pharmacogenetics illustrate the rapid evolution of biochemical, pharmacologic, molecular, and genomic approaches that have been used to determine the role of inheritance in variation in drug metabolism, effect, and toxicity.
HLA typing in families with multiple cases of rheumatoid arthritis.
Authors: M Strotzer, H Menninger, S Scholz, E.D Albert
Journal: Annals of the Rheumatic Diseases (1991)

Thirty one white patients from 14 families with multiple cases of rheumatoid arthritis (RA) and 42 of their healthy relatives were completely HLA typed. In contrast with class I antigens, the class II antigens DR1 and DR4 were significantly more common in the patients than in a group of 200 healthy local white controls (DR1: 32% v 12%; DR4: 48% v 28%, in patients and controls respectively). Owing to the small number of cases the data from this study were combined with those of published reports. Examination of patients for DR1 and DR4 homozygosity and DR1/4 heterozygosity showed an increase of DR1 homozygous patients, which was not statistically significant. There was no striking deviation from random expectation in haplotype sharing of affected sib pairs. These results are compatible with a dominant influence of DR1 and DR4 in the mode of inheritance. The nearly random haplotype sharing and the molecular relation between DR1 and DR4 support the hypothesis of a direct influence of these antigens in the pathogenesis of RA. Only 68% of the patients in this study possessed either DR1 or DR4, possibly indicating a subtype of RA which is independent of HLA. Clinical and serological variables were measured and indicated no significant difference between DR1 (or DR4) positive and DR1 (or DR4) negative disease. In this small group of patients the clinical course of RA seemed to be determined mainly by other genetic or environmental factors.
A case-control study of the pathology of oesophageal disease in systemic sclerosis (scleroderma)
Authors: C G P Roberts, L K Hummers, W J Ravich, F M Wigley, G M Hutchins
Journal: Gut (2006)

<b>Background:</b> Atrophy of the smooth muscle layers of the muscularis propria characterises oesophageal involvement in systemic sclerosis (scleroderma). The aetiology of this atrophy and of the resultant oesophageal dysfunction is unknown. <b>Objectives:</b> To examine oesophageal tissue for evidence of fibrosis, vascular disease, inflammatory reactions and neural abnormalities to determine the possible causes of this disease process. <b>Methods:</b> A case–control survey was conducted using oesophageal tissue from 74 scleroderma cases and 74 age, race and sex-matched controls from our autopsy files. Histological evidence of oesophageal muscle atrophy was correlated with the degree of vascular changes, inflammatory infiltration, fibrosis, abnormalities of the myenteric plexus and reduction of interstitial cells of Cajal (ICC) using a predesigned semiquantitative descriptive method. <b>Results:</b> Smooth-muscle atrophy was found in 94% of scleroderma cases, and in 5% of controls (p&lt;0.001). Atrophy was evident in the circular smooth muscle in 93% of cases, and in the longitudinal smooth muscle in 66% of cases. Intimal proliferation of arterioles was found in 38% of cases and in 5% of controls (p&lt;0.001), but was not associated with smooth-muscle atrophy (p = 0.29). Despite these vascular changes, there was no evidence of compromised perfusion, such as findings suggestive of acute ischaemic necroses. Minimal cellular infiltrates were seen in the myenteric plexus in 82% of cases and in 92% of controls (p = 0.091). ICC were found in fewer numbers in areas of atrophic smooth muscle compared with adjacent normal smooth muscle in selected scleroderma cases. <b>Conclusion:</b> The pathological findings of oesophageal lesions in scleroderma seem inconsistent with either an ischaemic or an inflammatory process. The loss of circular and longitudinal smooth muscle in the distal scleroderma oesophagus may represent loss of normal neural function followed by secondary tissue atrophy, or may be a primary smooth muscle lesion.
Merkel Cell Carcinoma: Prognosis and Treatment of Patients From a Single Institution
Authors: Peter J. Allen, Wilbur B. Bowne, David P. Jaques, Murray F. Brennan, Klaus Busam, Daniel G. Coit
Journal: Journal of Clinical Oncology (2005)

Merkel cell carcinoma (MCC) is an uncommon cutaneous malignancy. Most reports consist of single-institution experiences of fewer than 30 patients. The natural history of MCC is poorly defined.A review was performed of Memorial Sloan-Kettering Cancer Center's MCC database, identifying 251 patients who had been treated between 1970 and 2002. Patient, tumor, and treatment-related factors were analyzed for their association with recurrence and survival.The average follow-up for all patients was 40 months and 46 months for patients alive at last follow-up. The 5-year disease-specific survival rate was 64%. Disease stage was the only independent predictor of survival (stage I, 81%; stage II, 67%; stage III, 52%; stage IV, 11%; P = .001). Pathologic staging of the draining nodal basin was performed in 71 (40%) of 177 patients who presented with clinically negative nodes, and 16 of these patients (23%) were found to have node-positive disease. Pathologic nodal staging was associated with improved stage-specific survival probabilities (clinical node-negative, 75% v pathologic node-negative disease, 97%; P = .009) and decreased nodal recurrence (44% v 11%, P < .001). The median time to recurrence was 9 months, and 102 patients (43%) recurred. Local recurrence developed in 8% of patients after margin-negative excision.These data demonstrate that the natural history of MCC is variable and dependent on the stage of disease at presentation. Pathologic nodal staging identifies a group of patients with excellent long-term survival. After margin-negative excision and pathologic nodal staging, local and nodal recurrence rates are low.
Latent coeliac disease or coeliac disease beyond villous atrophy?
Authors: K. Kaukinen, P. Collin, M. Maki
Journal: Gut (2007)

<h3>Abstract</h3> RNA polymerase III (RNAPIII) synthesizes essential and abundant non-coding RNAs such as tRNAs. Controlling RNAPIII span of activity by accurate and efficient termination is a challenging necessity to ensure robust gene expression and to prevent conflicts with other DNA-associated machineries. The mechanism of RNAPIII termination is believed to be simpler than that of other eukaryotic RNA polymerases, solely relying on the recognition of a T-tract in the non-template strand. Here we combine high-resolution genome-wide analyses and <i>in vitro</i> transcription termination assays to revisit the mechanism of RNAPIII transcription termination in budding yeast. We show that T-tracts are necessary but not always sufficient for termination and that secondary structures of the nascent RNAs are important auxiliary cis-acting elements. Moreover, we show that the helicase Sen1 plays a key role in a fail-safe termination pathway. Our results provide a comprehensive model illustrating how multiple mechanisms cooperate to ensure efficient RNAPIII transcription termination.
Tylosis following post-corrosive stricture of the oesophagus
Authors: A.S. THAMBIAH, P. YESUDIAN, S.M. AUGUSTINE, A. KAMALAM, S. PREMALATHA
Journal: British Journal of Dermatology (1975)

A case of tylosis following corrosive stricture of the oesophagus in a male of 26 years is recorded. It is suggested that there is probably a connection between the state of the oesophagus and the state of palms and soles and that an oesophageal abnormality may precede tylosis of the late onset type.
Cardiac mast cells cause atrial fibrillation through PDGF-A–mediated fibrosis in pressure-overloaded mouse hearts
Authors: Chien-hui Liao, Hiroshi Akazawa, Masaji Tamagawa, Kaoru Ito, Noritaka Yasuda, Yoko Kudo, Rie Yamamoto, Yukako Ozasa, Masanori Fujimoto, Ping Wang, Hiromitsu Nakauchi, Haruaki Nakaya, Issei Komuro
Journal: Journal of Clinical Investigation (2009)

Atrial fibrillation (AF) is a common arrhythmia that increases the risk of stroke and heart failure. Here, we have shown that mast cells, key mediators of allergic and immune responses, are critically involved in AF pathogenesis in stressed mouse hearts. Pressure overload induced mast cell infiltration and fibrosis in the atrium and enhanced AF susceptibility following atrial burst stimulation. Both atrial fibrosis and AF inducibility were attenuated by stabilization of mast cells with cromolyn and by BM reconstitution from mast cell-deficient WBB6F1-KitW/W-v mice. When cocultured with cardiac myocytes or fibroblasts, BM-derived mouse mast cells increased platelet-derived growth factor A (PDGF-A) synthesis and promoted cell proliferation and collagen expression in cardiac fibroblasts. These changes were abolished by treatment with a neutralizing antibody specific for PDGF alpha-receptor (PDGFR-alpha). Consistent with these data, upregulation of atrial Pdgfa expression in pressure-overloaded hearts was suppressed by BM reconstitution from WBB6F1-KitW/W-v mice. Furthermore, injection of the neutralizing PDGFR-alpha-specific antibody attenuated atrial fibrosis and AF inducibility in pressure-overloaded hearts, whereas administration of homodimer of PDGF-A (PDGF-AA) promoted atrial fibrosis and enhanced AF susceptibility in normal hearts. Our results suggest a crucial role for mast cells in AF and highlight a potential application of controlling the mast cell/PDGF-A axis to achieve upstream prevention of AF in stressed hearts.
Omega-3s and childhood asthma
Authors: C Mermer
Journal: Thorax (2002)

In their study, Haby and colleagues1 found a high intake of dietary polyunsaturated fats to be a risk factor for asthma in preschool children. They suggest that reducing the consumption of these fats represents an intervention that has great potential for lowering asthma rates. However, this may be much too broad a conclusion as it is not the total content of polyunsaturated fats in the diet but their composition that is likely to be causing adverse health effects. The problem most probably stems from the imbalance of n-6 to n-3 …
Papilloma protein E6 abrogates shear stress-dependent survival in human endothelial cells: Evidence for specialized functions of paxillin
Authors: S MATTIUSSI, K MATSUMOTO, B ILLI, F MARTELLI, M CAPOGROSSI, C GAETANO
Journal: Cardiovascular Research (2006)

To investigate how endothelial cells transduce intracellular signals in response to laminar shear stress (SS), we made use of the papilloma virus oncoprotein E6 which interacts with and induces degradation of numerous cellular proteins including p53 and members of the PDZ-domain family. E6 also recognizes paxillin (PXN), a fundamental component of focal adhesions, interfering with its association to focal adhesion kinase (FAK).Human umbilical vein endothelial cells, expressing E6 or its mutated variant DeltaE6(105-110) (DeltaE6) which does not inactivate p53, were cultured under static conditions or exposed to a laminar SS of 12 dyn/cm(2) for 16h. In response to SS, cells expressing E6 or DeltaE6 failed to synthesise nitric oxide and directionally remodel their cytoskeleton, as indicated by morphology and phalloidin staining of actin microfilaments. Under these conditions, PXN association with FAK, its localization to the plasma membrane, and its phosphorylation on tyrosine-31, which partially encompasses the PXN/FAK docking site, were severely compromised. These alterations were paralleled by the impairment of important SS-dependent endothelial functions, including nitric oxide production and survival upon serum deprivation. The direct targeting of PXN expression by RNA interference partially reproduced the E6 phenotype, impairing flow-dependent cell orientation and survival but not nitric oxide production.These results provide evidence that papilloma virus E6 protein interferes with the function of the SS-mechanosensor and suggests a potential a role for PXN in this process.