tbuckley/cabot-search huggingface dataset:
Effects of inhalation of N-formyl-methionyl-leucyl-phenylalanine in the well elderly and in patients with chronic bronchitis.
Authors: M J Peters, A B Breslin, N Berend
Journal: Thorax (1992)

BACKGROUND: Inhalation of the bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) produces bronchoconstriction in normal subjects. FMLP thus has a putative role as a mediator of bronchoconstriction associated with bacterial bronchial infection. METHODS: The effects of FMLP inhalation were examined in ten subjects with a history of chronic bronchitis and ten age matched control subjects. Each subject inhaled FMLP doses from 0.025 to 0.8 mumol to determine the provocative dose of FMLP causing a 20% fall in FEV1(PD20FMLP). FEV1 was recorded every five minutes after the final FMLP inhalation until it had returned to 95% of baseline FEV1 or 60 minutes had elapsed. The time to return to 95% baseline FEV1 was recorded or extrapolated from the recovery curve as an index of rapidity of recovery. Total and differential white cell counts were performed on each subject at baseline and five and 15 minutes after the final FMLP inhalation. RESULTS: The geometric mean PD20 FMLP in the patients with chronic bronchitis was 0.06 mumol (95% confidence interval 0.015-0.26), which was significantly lower than that in the control subjects (0.21 mumol (0.02-1.9)). PD20 FMLP in the patients with chronic bronchitis but not age matched controls (p = 0.35) was lower than that found previously in young normal subjects (0.35 mumol (0.07-1.8). The return to 95% baseline FEV1 occurred after 86(10) minutes in subjects with chronic bronchitis and in 81(23) minutes in their age matched controls, in both cases being much slower than that seen in young subjects (29(9) minutes). CONCLUSION: Patients with chronic bronchitis may be especially susceptible to formyl peptides elaborated by bacteria during bacterial bronchial infection.
Power-afterload relation in the failing human ventricle.
Authors: Y C Chiu, P W Arand, J D Carroll
Journal: Circulation Research (1992)

Animal studies have shown that the power output of the left ventricle is related to afterload by a bell-shaped curve. Furthermore, the normal ventricle operates at the maximum power point, whereas the diseased ventricle operates off the maximum power point because of increased afterload. We studied this relation in eight patients with dilated cardiomyopathy. A high-fidelity catheter with micromanometer pressure and electromagnetic velocity transducers was used to measure blood pressure and flow velocity in the ascending aorta. The latter was converted into volumetric flow by calibrating with the simultaneously determined thermodilution cardiac output. Ventricular power was calculated by dividing the integral of the aortic blood pressure-flow product by the duration of the cardiac cycle. Intravenous nitroprusside was used to alter afterload and the power-afterload relation was obtained by plotting power against mean aortic blood pressure. In all patients, as blood pressure was lowered initially, the power output of the left ventricle increased. As the dose of nitroprusside was increased further, the total power either plateaued or actually decreased. The averaged power and the mean blood pressure at control were 1.00 +/- 0.62 W and 92 +/- 9.3 mm Hg, respectively. The averaged maximum increase in power with nitroprusside was 22%, to 1.22 +/- 0.73 W, and this occurred at a mean pressure of 80 +/- 8.8 mm Hg. This study showed that the power-afterload relation in the human ventricle has a maximum power point at some intermediate level of afterload, similar to that found in animal studies.(ABSTRACT TRUNCATED AT 250 WORDS)
Chemotherapy-Phased Imatinib Pulses Improve Long-Term Outcome of Adult Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Northern Italy Leukemia Group Protocol 09/00
Authors: Renato Bassan, Giuseppe Rossi, Enrico M. Pogliani, Eros Di Bona, Emanuele Angelucci, Irene Cavattoni, Giorgio Lambertenghi-Deliliers, Francesco Mannelli, Alessandro Levis, Fabio Ciceri, Daniele Mattei, Erika Borlenghi, Elisabetta Terruzzi, Carlo Borghero, Claudio Romani, Orietta Spinelli, Manuela Tosi, Elena Oldani, Tamara Intermesoli, Alessandro Rambaldi
Journal: Journal of Clinical Oncology (2010)

Short imatinib pulses were added to chemotherapy to improve the long-term survival of adult patients with Philadelphia chromosome (Ph) -positive acute lymphoblastic leukemia (ALL), to optimize complete remission (CR) and stem-cell transplantation (SCT) rates.Of 94 total patients (age range, 19 to 66 years), 35 represented the control cohort (ie, imatinib-negative [IM-negative] group), and 59 received imatinib 600 mg/d orally for 7 consecutive days (ie, imatinib-positive [IM-positive] group), starting from day 15 of chemotherapy course 1 and from 3 days before chemotherapy during courses 2 to 8. Patients in CR were eligible for allogeneic SCT or, alternatively, for high-dose therapy with autologous SCT followed by long-term maintenance with intermittent imatinib.CR and SCT rates were greater in the IM-positive group (CR: 92% v 80.5%; P = .08; allogeneic SCT: 63% v 39%; P = .041). At a median observation time of 5 years (range, 0.6 to 9.2 years), 22 patients in the IM-positive group versus five patients in the IM-negative group were alive in first CR (P = .037). Patients in the IM-positive group had significantly greater overall and disease-free survival probabilities (overall: 0.38 v 0.23; P = .009; disease free: 0.39 v 0.25; P = .044) and a lower incidence of relapse (P = .005). SCT-related mortality was 28% (ie, 15 of 54 patients), and postgraft survival probability was 0.46 overall.This imatinib-based protocol improved long-term outcome of adult patients with Ph-positive ALL. With SCT, post-transplantation mortality and relapse remain the major hindrance to additional therapeutic improvement. Additional intensification of imatinib therapy should warrant a better molecular response and clinical outcome, both in patients selected for SCT and in those unable to undergo this procedure.
The regulation of leucocyte transendothelial migration by endothelial signalling events
Authors: M. Fernandez-Borja, J. D. van Buul, P. L. Hordijk
Journal: Cardiovascular Research (2010)

Leucocytes use sophisticated mechanisms to cross the endothelium lining the vasculature. This is initiated by chemokine- and adhesion molecule-induced intracellular signalling that controls adhesion, spreading, and motility. At the same time, adherent leucocytes trigger the endothelium, manipulating the barrier to promote their transmigration into the underlying tissues. Over the past years, our insights in the associated signalling events within the endothelium have increased considerably, albeit the order of events, their crosstalk, and the consequences for endothelial cells and leucocytes are only partially resolved. Here, we briefly review endothelial signalling that is initiated at the apical endothelial membrane, where the first contact with the leucocytes takes place and signal transduction is induced. In addition, we discuss subsequent events at endothelial cell–cell junctions insofar as they have been linked to transendothelial migration. Finally, we briefly touch upon the modulation of endothelial signalling by infectious pathogens, since these have developed additional, elegant ways to manipulate the endothelium and transendothelial migration that may provide new, relevant insights into this process.
Anchoring Proteins as Regulators of Signaling Pathways
Authors: Alessia Perino, Alessandra Ghigo, John D. Scott, Emilio Hirsch
Journal: Circulation Research (2012)

Spatial and temporal organization of signal transduction is coordinated through the segregation of signaling enzymes in selected cellular compartments. This highly evolved regulatory mechanism ensures the activation of selected enzymes only in the vicinity of their target proteins. In this context, cAMP-responsive triggering of protein kinase A is modulated by a family of scaffold proteins referred to as A-kinase anchoring proteins. A-kinase anchoring proteins form the core of multiprotein complexes and enable simultaneous but segregated cAMP signaling events to occur in defined cellular compartments. In this review we will focus on the description of A-kinase anchoring protein function in the regulation of cardiac physiopathology.
Natural Variation in Abiotic Stress Responsive Gene Expression and Local Adaptation to Climate in Arabidopsis thaliana
Authors: Jesse R. Lasky, David L. Des Marais, David B. Lowry, Inna Povolotskaya, John K. McKay, James H. Richards, Timothy H. Keitt, Thomas E. Juenger
Journal: Molecular Biology and Evolution (2014)

Gene expression varies widely in natural populations, yet the proximate and ultimate causes of this variation are poorly known. Understanding how variation in gene expression affects abiotic stress tolerance, fitness, and adaptation is central to the field of evolutionary genetics. We tested the hypothesis that genes with natural genetic variation in their expression responses to abiotic stress are likely to be involved in local adaptation to climate in Arabidopsis thaliana. Specifically, we compared genes with consistent expression responses to environmental stress (expression stress responsive, "eSR") to genes with genetically variable responses to abiotic stress (expression genotype-by-environment interaction, "eGEI"). We found that on average genes that exhibited eGEI in response to drought or cold had greater polymorphism in promoter regions and stronger associations with climate than those of eSR genes or genomic controls. We also found that transcription factor binding sites known to respond to environmental stressors, especially abscisic acid responsive elements, showed significantly higher polymorphism in drought eGEI genes in comparison to eSR genes. By contrast, eSR genes tended to exhibit relatively greater pairwise haplotype sharing, lower promoter diversity, and fewer nonsynonymous polymorphisms, suggesting purifying selection or selective sweeps. Our results indicate that cis-regulatory evolution and genetic variation in stress responsive gene expression may be important mechanisms of local adaptation to climatic selective gradients.
Activated memory T helper cells in bronchoalveolar lavage fluid from patients with atopic asthma: relation to asthma symptoms, lung function, and bronchial responsiveness.
Authors: D S Robinson, A M Bentley, A Hartnell, A B Kay, S R Durham
Journal: Thorax (1993)

BACKGROUND: Bronchial mucosal inflammation and epithelial damage are characteristic features of asthma. Activation of T helper lymphocytes may contribute to this process by mechanisms including the release of cytokines promoting eosinophil infiltration and activation. METHODS: Bronchial washings and bronchoalveolar lavage fluid were obtained from 29 atopic asthmatic patients (19 with current symptoms and 10 symptom free) and 13 normal volunteers. Flow cytometry was used to assess T cell phenotype and activation status in bronchoalveolar lavage fluid and peripheral blood, and differential cell counts were made on bronchial washings and bronchoalveolar lavage fluid. Findings were related to severity of disease as reflected by symptom scores, baseline lung function, and airway responsiveness. RESULTS: CD4 T lymphocytes in bronchoalveolar lavage fluid and blood from asthmatic patients were activated by comparison with controls (CD4 CD25, median 16.8% v 8.7% for bronchoalveolar lavage fluid, and 15.3% v 8.7% in blood). Bronchoalveolar lavage fluid CD4 T cells from both asthmatic patients and controls were of memory phenotype (95.8% and 96.8% CD45RO and 1.7% and 0.4% CD45RA respectively), whereas both CD45RO and CD45RA T cells were present in blood. Patients with asthma and current symptoms showed increased bronchoalveolar T cell activation compared with patients without symptoms (CD4 CD25 18.7% v 12.3%). Within the asthmatic group there was a significant association between CD4 CD25 lymphocytes and asthma symptom scores (rs = 0.75), airway methacholine responsiveness (log PC20, rs = -0.43) and baseline FEV1 (rs = -0.39). A correlation was also found between CD4 CD25 lymphocytes and eosinophils in bronchoalveolar lavage fluid (rs = 0.48). Eosinophils in bronchoalveolar lavage fluid were increased in asthmatic patients compared with controls and the percentage of eosinophils in bronchoalveolar lavage fluid correlated with asthma symptom score. A relation was found between percentage of epithelial cells in bronchoalveolar lavage fluid and FEV1 and methacholine PC20. CONCLUSION: These results support the hypothesis that selective activation of memory CD4 T cells contributes to eosinophil accumulation, bronchial hyperresponsiveness, and symptoms in asthma.
Inhibition of FcεRI-dependent mediator release and calcium flux from human mast cells by sialic acid–binding immunoglobulin-like lectin 8 engagement
Authors: Hidenori Yokoi, Oksoon H. Choi, Walter Hubbard, Hyun-Sil Lee, Brendan J. Canning, Hyun H. Lee, Seung-Duk Ryu, Stephan von Gunten, Carol A. Bickel, Sherry A. Hudson, Donald W. MacGlashan, Bruce S. Bochner
Journal: Journal of Allergy and Clinical Immunology (2007)
Exempting mental health units from smoke-free laws: Nicotine can have beneficial effects
Authors: T Everett Julyan
Journal: BMJ (2006)

Evidence based diagnosis We may need to be open to new ideasEditor-If evidence based diagnosis is still in the dark ages, as Delamothe writes, 1 then so is evidence based treatment.The doctor's job is to choose the right treatment.If the diagnosis is wrong then the treatment will be wrong.Inaccurate diagnoses will also affect clinical trials.A treatment may be "evidence based" because it has worked in a published study, but some patients who would have responded might have been left out because of diagnostic inaccuracy while some patients with no prospect of responding might have been included incorrectly. 2vidence based diagnosis is about convincing others using shared rules of evidence that a diagnosis (and its implications in terms of treatment) should be accepted by others.Evidence is gathered from the individual and from groups of patients. 3Evidence based diagnosis means specifying the individual's facts in addition to pointing to facts relating to that diagnosis in the literature. 4ayes's theorem uses unconditional initial prior probabilities.Diagnostic leads are based on conditional probabilities and are used to initiate diagnostic thought processes. 4owever, closely related theorems can be used to interpret diagnostic leads, which allow doctors to reason with diagnostic evidence in a more familiar way, 3 thus reducing misunderstandings. 5So to improve evidence based diagnosis we also need to collect better data on diagnostic leads.The published evidence given for a diagnosis and any related actions cannot realistically be assembled when actually seeing a patient.A draft evidence based rationale might be prepared in advance.It would have to be capable of being accessed in seconds to provide evidence in support of a suspected diagnosis and decision arrived at by using kindness, imagination, and common sense.It could be put into context by inserting the patient's details into the draft evidence summoned up from a computer.If we are to make progress and allow evidence based diagnosis to emerge from the dark ages then in addition to doing more of the same, we may also have to be receptive to new ideas.
Shorter Telomeres Associate with a Reduced Risk of Melanoma Development
Authors: Hongmei Nan, Mengmeng Du, Immaculata De Vivo, JoAnn E. Manson, Simin Liu, Anne McTiernan, J. David Curb, Lawrence S. Lessin, Matthew R. Bonner, Qun Guo, Abrar A. Qureshi, David J. Hunter, Jiali Han
Journal: Cancer Research (2011)

Epidemiologic studies have linked shortened telomeres with the development of many cancers. However, recent studies have suggested that longer telomeres may lead to prolonged senescence in melanocytes, providing increased opportunity for malignant transformation. We therefore examined whether shorter prediagnostically measured relative telomere length in peripheral blood leukocytes (PBL) was associated with a decreased risk of cutaneous melanoma. Telomere length in prospectively collected PBLs was measured in incident melanoma cases and age-matched controls selected from participants in three large prospective cohorts: the Women's Health Initiative Observational Study (WHI-OS), the Health Professionals Follow-up Study (HPFS), and the Nurses' Health Study (NHS). Shorter telomere lengths were associated with decreased risk of melanoma in each cohort. The P(trend) across quartiles was 0.03 in the WHI-OS and 0.008 in the HPFS. When combining these two datasets with published data in the NHS (P(trend), 0.09), compared with individuals in the fourth quartile (the longest telomere lengths), those in the first quartile had an OR of 0.43 (95% CI: 0.28-0.68; P(trend), 0.0003). Unlike findings for other tumors, shorter telomeres were significantly associated with a decreased risk of melanoma in this study, suggesting a unique role of telomeres in melanoma development.
Should abnormal oesophageal motility in gastro-oesophageal reflux disease (GORD) influence decisions about fundoplication?
Authors: R C Heading
Journal: Gut (2002)

Does abnormal oesophageal motility in gastro-oesophageal reflux disease affect the outcome of laparoscopic fundoplication? Is it important to perform oesophageal function tests before surgery for gastro-oesophageal reflux disease (GORD)? For some years now, oesophageal manometry and a pH study have formed part of the “work up” of GORD patients being considered for fundoplication, supposedly (i) to ensure that the diagnosis of GORD is correct, (ii) to allow surgery to be “tailored”—a partial wrap fundoplication being performed in patients with especially poor oesophageal motility to minimise the risk of postoperative dysphagia,1–3 and (iii) to obtain preoperative data so that the success of treatment can be appraised from postoperative measurements in the same patient. As technology has advanced, the increasing complexity of manometry reports and 24 hour pH data have allowed impressively detailed documents from the oesophageal laboratory to be inserted into each patient's case notes but also raise some questions about whether all of these numbers really contribute to clinical decisions about antireflux surgery. Fibbe C, Layer P, Keller J, et al . Esophageal motility in reflux disease before and after fundoplication: a prospective randomized, clinical and manometric study. Gastroenterology2001;121:5–14. [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Background : The role of impaired oesophageal motility, which is found in up to 50% … [1]: {openurl}?query=rft.jtitle%253DGastroenterology%26rft.stitle%253DGastroenterology%26rft.aulast%253DFIBBE%26rft.auinit1%253DC.%26rft.volume%253D121%26rft.issue%253D1%26rft.spage%253D5%26rft.epage%253D14%26rft.atitle%253DEsophageal%2BMotility%2Bin%2BReflux%2BDisease%2BBefore%2Band%2BAfter%2BFundoplication%253A%2BA%2BProspective%252C%2BRandomized%252C%2BClinical%252C%2Band%2BManometric%2BStudy%26rft_id%253Dinfo%253Adoi%252F10.1053%252Fgast.2001.25486%26rft_id%253Dinfo%253Apmid%252F11438489%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1053/gast.2001.25486&link_type=DOI [3]: /lookup/external-ref?access_num=11438489&link_type=MED&atom=%2Fgutjnl%2F50%2F5%2F592.atom [4]: /lookup/external-ref?access_num=000169485600004&link_type=ISI
Reversal of Idiopathic Hypogonadotropic Hypogonadism
Authors: Taneli Raivio, John Falardeau, Andrew Dwyer, Richard Quinton, Frances J. Hayes, Virginia A. Hughes, Lindsay W. Cole, Simon H. Pearce, Hang Lee, Paul Boepple, William F. Crowley, Nelly Pitteloud
Journal: New England Journal of Medicine (2007)

Idiopathic hypogonadotropic hypogonadism, which may be associated with anosmia (the Kallmann syndrome) or with a normal sense of smell, is a treatable form of male infertility caused by a congenital defect in the secretion or action of gonadotropin-releasing hormone (GnRH). Patients have absent or incomplete sexual maturation by the age of 18. Idiopathic hypogonadotropic hypogonadism was previously thought to require lifelong therapy. We describe 15 men in whom reversal of idiopathic hypogonadotropic hypogonadism was sustained after discontinuation of hormonal therapy.We defined the sustained reversal of idiopathic hypogonadotropic hypogonadism as the presence of normal adult testosterone levels after hormonal therapy was discontinued.Ten sustained reversals were identified retrospectively. Five sustained reversals were identified prospectively among 50 men with idiopathic hypogonadotropic hypogonadism after a mean (+/-SD) duration of treatment interruption of 6+/-3 weeks. Of the 15 men who had a sustained reversal, 4 had anosmia. At initial evaluation, 6 men had absent puberty, 9 had partial puberty, and all had abnormal secretion of GnRH-induced luteinizing hormone. All 15 men had received previous hormonal therapy to induce virilization, fertility, or both. Among those whose hypogonadism was reversed, the mean serum level of endogenous testosterone increased from 55+/-29 ng per deciliter (1.9+/-1.0 nmol per liter) to 386+/-91 ng per deciliter (13.4+/-3.2 nmol per liter, P<0.001), the luteinizing hormone level increased from 2.7+/-2.0 to 8.5+/-4.6 IU per liter (P<0.001), the level of follicle-stimulating hormone increased from 2.5+/-1.7 to 9.5+/-12.2 IU per liter (P<0.01), and testicular volume increased from 8+/-5 to 16+/-7 ml (P<0.001). Pulsatile luteinizing hormone secretion and spermatogenesis were documented.Sustained reversal of normosmic idiopathic hypogonadotropic hypogonadism and the Kallmann syndrome was noted after discontinuation of treatment in about 10% of patients with either absent or partial puberty. Therefore, brief discontinuation of hormonal therapy to assess reversibility of hypogonadotropic hypogonadism is reasonable. (ClinicalTrials.gov number, NCT00392756 [ClinicalTrials.gov].).