tbuckley/cabot-search huggingface dataset:
Pertussis in the Adult
Authors: C C Linnemann, J Nasenbeny
Journal: Annual Review of Medicine (1977)

I believe . . . that pertussis in adults is often unrecognized, and this is accountable in many cases for the spread of the disease. In one year in three different families, I saw six cases of pertussis contracted from nurses who had coughs, which they thought were due to ordinary colds. The prevalent idea among the laity, and sometimes among physicians and nurses, that adults seldom contract who�ping cough is responsible for lack of quaran­ tine. John Phillips, 1921 (I) +7235
A new perspective on concepts of asthma severity and control
Authors: D. R. Taylor, E. D. Bateman, L-P. Boulet, H. A. Boushey, W. W. Busse, T. B. Casale, P. Chanez, P. L. Enright, P. G. Gibson, J. C. de Jongste, H. A. M. Kerstjens, S. C. Lazarus, M. L. Levy, P. M. O'Byrne, M. R. Partridge, I. D. Pavord, M. R. Sears, P. J. Sterk, S. W. Stoloff, S. J. Szefler, S. D. Sullivan, M. D. Thomas, S. E. Wenzel, H. K. Reddel
Journal: European Respiratory Journal (2008)

Concepts of asthma severity and control are important in the evaluation of patients and their response to treatment but the terminology is not standardised and the terms are often used interchangeably. This review, arising from the work of an American Thoracic Society/European Respiratory Society Task Force, identifies the need for separate concepts of control and severity, describes their evolution in asthma guidelines and provides a framework for understanding the relationship between current concepts of asthma phenotype, severity and control. "Asthma control" refers to the extent to which the manifestations of asthma have been reduced or removed by treatment. Its assessment should incorporate the dual components of current clinical control (e.g. symptoms, reliever use and lung function) and future risk (e.g. exacerbations and lung function decline). The most clinically useful concept of asthma severity is based on the intensity of treatment required to achieve good asthma control, i.e. severity is assessed during treatment. Severe asthma is defined as the requirement for (not necessarily just prescription or use of) high-intensity treatment. Asthma severity may be influenced by the underlying disease activity and by the patient's phenotype, both of which may be further described using pathological and physiological markers. These markers can also act as surrogate measures for future risk.
Global effects of fluvastatin on the prothrombotic status of patients with antiphospholipid syndrome
Authors: Chary López-Pedrera, Patricia Ruiz-Limón, Maria Ángeles Aguirre, Nuria Barbarroja, Carlos Pérez-Sánchez, Paula Buendía, Ines-Carmen Rodriguez-García, Antonio Rodriguez-Ariza, Eduardo Collantes-Estevez, Francisco Velasco, Munther Khasmahta, Maria José Cuadrado
Journal: Annals of the Rheumatic Diseases (2010)

Objective Numerous mechanisms have been proposed to explain the thrombotic/proinflammatory tendency of antiphospholipid syndrome (APS) patients. Prothrombotic monocyte activation by antiphospholipid antibodies involves numerous proteins and intracellular pathways. The anti-inflammatory, anticoagulant and immunoregulatory effects of statins have been aimed as a therapeutic tool in APS patients. This study delineates the global effects of fluvastatin on the prothrombotic tendency of monocytes from APS patients. Methods Forty-two APS patients with thrombosis and 35 healthy donors were included in the study. APS patients received 20 mg/day fluvastatin for 1 month. Blood samples were obtained before the start, at the end and 2 months after the end of treatment. Results After 1 month of treatment, monocytes showed a significant inhibition of tissue factor, protein activator receptors 1 and 2, vascular endothelial growth factor and Flt1 expression that was related to the inhibition of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B/Rel DNA-binding activity. Proteomic analysis showed proteins involved in thrombotic development (annexin II, RhoA and protein disulphide isomerase) with altered expression after fluvastatin administration. In-vitro studies indicated that the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by fluvastatin might inhibit protein prenylation and MAPK activation. Conclusion The data from this study support the belief that fluvastatin has multiple profound effects in monocyte activity, which might contribute to thrombosis prevention in APS patients.
Elevation in cytosolic free calcium concentration early in myocardial ischemia in perfused rat heart.
Authors: C Steenbergen, E Murphy, L Levy, R E London
Journal: Circulation Research (1987)

Changes in cytosolic free calcium concentration during myocardial ischemia were measured by 19F NMR in 5FBAPTA-loaded perfused rat hearts. The hearts were perfused with Krebs-Henseleit buffer containing 5 microM of the acetoxymethyl ester of 5FBAPTA, which was hydrolyzed by cytosolic esterases to achieve cytosolic concentrations of 5FBAPTA of 0.12 to 0.65 mM. Cytosolic free calcium concentrations were calculated as the product of the ratio of peak areas for bound and free 5FBAPTA in the NMR spectra and the dissociation constant (708 nM). The basal cytosolic calcium concentration, measured in potassium or magnesium arrested hearts, was 252 nM, and the time-average calcium concentration in beating hearts was 630 nM. Following the onset of total ischemia, there was no immediate substantial change in cytosolic calcium despite a rapid decline in creatine phosphate and ATP and a marked increase in inorganic phosphate as monitored by 31P NMR, but by 10 minutes, there was a substantial increase in free calcium concentration. The ratio of peak areas of bound and free 5FBAPTA returned to the preischemic value during reperfusion, and there was no detectable loss of 5FBAPTA from the heart. Creatine phosphate was also restored to its preischemic level during reperfusion. These results indicate that cytosolic free calcium increases during ischemia and is not immediately associated with lethal injury. This increase in cytosolic calcium may activate degradative enzymes that eventually could compromise myocyte viability.
Immune role of hepatic TLR-4 revealed by orthotopic mouse liver transplantation
Authors: Beena John, Ingo Klein, Nicholas I. Crispe
Journal: Hepatology (2006)

Activated CD8+ T cells migrate to the liver at the end of an immune response and go through apoptosis there, but this mechanism is impaired in mice lacking Toll-like receptor-4. This allowed us to test the importance of liver trapping in an ongoing immune response. In the absence of Toll-like receptor-4, reduced liver accumulation was associated with an increase in the circulating CD8+ T cell pool, more long-lived memory T cells and increased CD8+ T cell memory responses. Using experimental orthotopic liver transplantation, we showed that the effect of Toll-like receptor-4 on the formation of the CD8+ T cell memory resides in the liver.These studies reveal a new function for the liver, which is to regulate the magnitude of T cell memory responses through a Toll-like receptor-4-dependent mechanism.
Angiographically Undetected Small Hepatocellular Carcinoma: Clinicopathological Characteristics, Follow–Up and Treatment
Authors: Takashi Sonoda, Ken Shirabe, Kenji Takenaka, Takashi Kanematsu, Kotaro Yasumori, Keizo Sugimachi
Journal: Hepatology (1989)

We studied 36 cases (38 nodules) of small hepatocellular carcinoma with special attention directed to detectability using angiography and histology. Among the 38 nodules, 31 nodules (81.6%) were evident. The remaining seven (18.4%) were not evident angiographically but were detected using ultrasonography and/or computed tomography, prior to angiography. An elevated level of serum alpha-fetoprotein also suggested a diagnosis of hepatocellular carcinoma. When comparisons were made between angiographically detected and undetected nodules, there was no statistically significant difference in parameters, including sex of the patient, tumor size, location of the tumor, positive rate for hepatitis B surface antigen, history of liver disease and values of alpha-fetoprotein. The small hepatocellular carcinomas not detected angiographically and evidenced only histologically had the following characteristics: (i) no fibrous capsule surrounding the nodules; (ii) well-differentiated tumors; (iii) replacing growth pattern of cancer cells, and (iv) remains of portal tracts within the tumor. The replacing growth pattern and the presence of portal tracts may correlate with the low detectability in angiography. When a definite diagnosis of angiographically undetectable tumors cannot be made using close surveillance with ultrasonography or alpha-fetoprotein and/or needle biopsy under ultrasonic guide, surgical intervention should be considered, particularly for patients at high risk for hepatocellular carcinoma.
High-dose cladribine therapy for chronic myelogenous leukemia in the accelerated or blast phase.
Authors: E J Dann, J Anastasi, R A Larson
Journal: Journal of Clinical Oncology (1998)

PURPOSE A phase II clinical trial was performed to evaluate the effectiveness of high-dose cladribine (2CDA) for treatment of chronic myelogenous leukemia (CML) in the accelerated or blast phase. PATIENTS AND METHODS Nineteen patients were treated. The median age was 55 years (range, 30 to 73). Six were older than 60 years. Eight had progressed after intensive combination chemotherapy and three after allogeneic or autologous transplantation. For the first course, 16 patients received 2CDA at 15 mg/m2/d intravenously (i.v.) over 1 hour for 5 days. Two received 18 mg/m2 and one received 21.5 mg/m2 daily. The second course was escalated to 20 mg/m2/d in five patients. RESULTS Rapid cytoreduction of leukemia occurred in the blood, with the nadir at 10 to 12 days. The median WBC count decreased from 36,900/microL before treatment to 500/microL at the nadir and recovered to 5,200/microL at day 30. The median platelet count changed from 113,000/microL to 24,000/microL at the nadir and 71,000/microL at day 30. The complete remission (CR) plus partial remission (PR) rate was 47% (95% confidence interval [CI], 23% to 72%). One 64-year-old man with lymphoid blast phase of CML had a morphologic and cytogenetic CR that lasted 9 months. The median survival for all patients was 34 weeks, and the median survival for the eight responders was 56 weeks (range, 11 to 167). The median number of days spent in hospital over the entire treatment period was 19 (range, 4 to 60). CONCLUSION High-dose 2CDA therapy provides effective palliation for CML in accelerated or blast phases, even for heavily pretreated patients.
Occupational exposures and chronic obstructive pulmonary disease: a hospital based case-control study
Authors: N. Govender, U. G. Lalloo, R. N. Naidoo
Journal: Thorax (2011)

<h3>Background</h3> Occupational exposures are associated with chronic obstructive pulmonary disease (COPD). This study investigated this association among a population with a high prevalence of tuberculosis and smoking. <h3>Methods</h3> Cases (n=110) diagnosed by pulmonologists were selected from specialist respiratory clinics. Frequency sex- and age-matched controls (n=102) were selected from other clinics at the same institutions. Lifetime occupational exposure histories were obtained through interviews. Exposure variables derived from the ALOHA Job Exposure Matrix (JEM) were used to complement the self-reporting variables. ORs were calculated from logistic regression models, adjusting for smoking and past history of tuberculosis. Percentage population attributable risk (PAR%) was also calculated. <h3>Results</h3> The adjusted ORs for COPD from the JEM-derived high cumulative biological dust exposure, high cumulative mineral dust exposure and high cumulative gas and fumes exposure were 2.1 (95% CI 1.1 to 4.2), 1.1 (95% CI 0.6 to 2.4) and 1.8 (95% CI 0.8 to 3.9), respectively. Self-reported occupational exposures were associated with higher risks, with adjusted ORs for high dust exposure-years and high chemical, gas and fumes exposure-years of 5.9 (95% CI 2.6 to 13.2) and 3.6 (95% CI 1.6 to 7.9), respectively. Among ever smokers, there was an increased risk for COPD, with ORs ranging from 5.0 to 5.5. Tuberculosis was a strong risk factor, with an OR ranging from 7.7 to 8.1. The PAR% was 25% for self-reported high exposures, but lower when the JEM variables were used. <h3>Conclusions</h3> Lifetime occupational exposures contribute to the risk of COPD, adjusted for smoking. These risks are present in populations with a high burden of tuberculosis, which is considered an important causative factor.
The 12/15-lipoxygenase pathway counteracts fibroblast activation and experimental fibrosis
Authors: Gerhard Krönke, Nicole Reich, Carina Scholtysek, Alfiya Akhmetshina, Stefan Uderhardt, Pawel Zerr, Katrin Palumbo, Veronika Lang, Clara Dees, Oliver Distler, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Idiopathic and inflammation-dependent fibrotic diseases such systemic sclerosis (SSc) impose a major burden on modern societies. Understanding endogenous mechanisms, which counteract fibrosis, may yield new therapeutic approaches. Lipoxins are highly potent lipid mediators, which have recently been found to be decreased in SSc. <h3>Objectives</h3> To determine the potential role of 12/15-lipoxygenase (12/15-LO), the key enzyme for the synthesis of lipoxins, in fibrosis. <h3>Methods</h3> Two mouse models for experimental dermal fibrosis (bleomycin-induced dermal fibrosis and tight-skin 1 mouse model) together with bone marrow transfers were used in wildtype and 12/15-LO<sup>−/−</sup> mice to elucidate the role of this enzyme during dermal fibrosis. Primary dermal fibroblasts of wildtype and 12/15-LO<sup>−/−</sup> mice, and 12/15-LO-derived eicosanoids, were used to identify underlying molecular mechanisms <h3>Results</h3> In both models, 12/15-LO<sup>−/−</sup> mice exhibited a significant exacerbation of the fibrotic tissue response. Bone marrow transfer experiments disclosed a predominant role of mesenchymal cell-derived 12/15-LO in these antifibrotic effects. Indeed, 12/15-LO<sup>−/−</sup> fibroblasts showed an enhanced activation of the mitogen-activated protein-kinase pathway and an increased col 1a2 mRNA expression in response to stimulation with transforming growth factor β (TGFβ), whereas 12/15-LO-derived eicosanoids blocked these TGFβ-induced effects. <h3>Conclusions</h3> These data indicate that 12/15-LO and its metabolites have a prominent antifibrotic role during dermal fibrosis. This opens new opportunities for therapeutic approaches in the treatment of fibrotic diseases.
Phenylphosphonate: a 31P-NMR indicator of extracellular pH and volume in the isolated perfused rabbit bladder.
Authors: M J Fisher, P F Dillon
Journal: Circulation Research (1987)

31P-NMR has been used extensively to estimate intracellular pH. It also can be used to measure extracellular pH and volume when an NMR-detectable extracellular phosphorous probe is used. Phosphonic acids have been suggested as useful 31P-NMR extracellular markers. The present study was designed to assess the utility of phenylphosphonic acid (PPA) as a 31P-NMR extracellular marker in perfused smooth muscle. Rabbit bladder strips were exposed to PPA concentrations of 1-20 mM. Tension development in response to maximal carbachol challenges (10 microM) was independent of PPA concentration. Addition of PPA (6 mM) to the perfusate supplying the isolated resting rabbit bladder had no effect on 31P-NMR-detectable phosphatic compounds. PPA's resonance frequency was distinctly downfield from endogenous phosphates and demonstrated a pH-dependent chemical shift of +/- 1.12 ppm/pH unit over the range of 6.4 to 7.6 with a pK' of 7.09 at 23 degrees C. The time courses for washing PPA in and out of the resting bladder were best described by monotonic exponential growth (r = 0.972; n = 3) and decay (r = 0.972; n = 3) equations, respectively. Rate and time constants for PPA wash-in (0.039 +/- 0.004 min-1 and 25.7 +/- 2.3 minutes) and washout (0.038 +/- 0.000 min-1 and 26.3 +/- 0.0 minutes) were not significantly different. Using steady state PPA and ATP peak intensities and concentrations, an extracellular-to-intracellular ratio was calculated to be 0.31 +/- 0.03 (n = 3). These data indicate that PPA remains distributed exclusively in the extracellular spaces.(ABSTRACT TRUNCATED AT 250 WORDS)
Transverse Spread and Longitudinal Dissociation in the Distal A-V Conducting System
Authors: Robert J. Myerburg, Kristina Nilsson, Benjamin Befeler, Agustin Castellanos, Henry Gelband
Journal: Journal of Clinical Investigation (1973)

Isolated preparations of portions of the canine intraventricular conducting system were studied by microelectrode techniques in order to determine the nature of transverse spread and longitudinal dissociation of impulses in bundle branches and false tendons. Driving stimuli were delivered to an eccentric location on normal conducting tissue, and the arrival times of the propagating impulses were mapped along the length and width of the bundle branch, or along the false tendon ipsilateral and contralateral to the site of stimulation. The difference between the arrival times on the two sides was found to decrease progressively as a function of distance from the site of stimulation, the data suggesting that transverse spread of impulses involves propagation through transverse crossover points between the longitudinally oriented conducting elements. Impulses originating eccentrically became uniformly conducted across the transverse axis of bundle branches 8-15 mm from the level of the stimulating electrode, and of false tendons 2-4 mm from the stimulus site. True longitudinal dissociation, producing conduction maps different from those representing normal transverse propagation, was seen occasionally in tissue having longitudinally oriented strips of abnormal tissue. However, early premature stimulation commonly resulted in longitudinal temporal dissociation of the premature responses, possibly due to functional block in the transverse crossover fibers.
Inhibition of phagosome-lysosome fusion in macrophages by certain mycobacteria can be explained by inhibition of lysosomal movements observed after phagocytosis.
Authors: P D Hart, M R Young, A H Gordon, K H Sullivan
Journal: The Journal of Experimental Medicine (1987)

We have investigated the mechanism of the inhibition of phagosome-lysosome (P-L) fusion in macrophages known to occur after infection by Mycobacterium tuberculosis and by the mouse pathogen Mycobacterium microti. We have used an M. microti infection and have studied, first, the saltatory movements of periphagosomal secondary lysosomes by means of visual phase-contrast microscopy (a similar use of the method having been previously supported by computer analyses). The movements became slow or static after ingestion of live but not of heat-killed M. microti. They were unaffected by a fusiogenic mycobacterium M. lepraemurium. Second, we studied the behavior of a normally fusiogenic unrelated organism, Saccharomyces cerevisiae, after its phagocytosis by cells already containing live M. microti ingested 18 h previously. We observed, using a fluorescent assay of fusion, that many of these yeast phagosomes now also failed to fuse with the lysosomes; in contrast, when the host M. microti had been heat killed the yeast phagosomes fused normally. These observations were extended by ultrastructural quantitative analyses of P-L fusion, which confirmed the nonfusion of phagosomes of live M. microti and, more particularly, the change to nonfusion from the normal fusion behavior of the separate phagosomes of accompanying yeasts. Third, we have assembled evidence against the likelihood that these M. microti-induced phenomena are nonspecific, i.e., secondary to a general depression of activity of heavily infected host cells. The evidence includes the feasibility of adjusting the degree of infection so as to facilitate visual assessment of organelle movements without the presence of detectable damage to the cells studied; the absence of lysosomal stasis after comparable infection with another mycobacterium of comparable virulence (M. lepraemurium); and the reversibility of the stasis. We conclude that inhibition of lysosome saltatory movements (and consequently its secondary effect on the associated yeasts) is a significant, specifically induced phenomenon. From these observations and considerations, therefore, in conjunction with the analogous inhibition of lysosomal movements in normal macrophages by some chemical inhibitors of P-L fusion, and our suggestion that this association is causally related, we now suggest that M. microti-induced focal lysosomal stasis is also the main means by which the inhibition of P-L fusion is brought about by this organism. This concept is strengthened by the observations on S. cerevisiae, which provide strong evidence that stasis can cause suppression of fusion.
Airway antioxidant and inflammatory responses to diesel exhaust exposure in healthy humans
Authors: A. F. Behndig, I. S. Mudway, J. L. Brown, N. Stenfors, R. Helleday, S. T. Duggan, S. J. Wilson, C. Boman, F. R. Cassee, A. J. Frew, F. J. Kelly, T. Sandström, A. Blomberg
Journal: European Respiratory Journal (2006)

Pulmonary cells exposed to diesel exhaust (DE) particles in vitro respond in a hierarchical fashion with protective antioxidant responses predominating at low doses and inflammation and injury only occurring at higher concentrations. In the present study, the authors examined whether similar responses occurred in vivo , specifically whether antioxidants were upregulated following a low-dose DE challenge and investigated how these responses related to the development of airway inflammation at different levels of the respiratory tract where particle dose varies markedly. A total of 15 volunteers were exposed to DE (100 µg·m −3 airborne particulate matter with a diameter of &lt;10 µm for 2 h) and air in a double-blinded, randomised fashion. At 18 h post-exposure, bronchoscopy was performed with lavage and mucosal biopsies taken to assess airway redox and inflammatory status. Following DE exposure, the current authors observed an increase in bronchial mucosa neutrophil and mast cell numbers, as well as increased neutrophil numbers, interleukin-8 and myeloperoxidase concentrations in bronchial lavage. No inflammatory responses were seen in the alveolar compartment, but both reduced glutathione and urate concentrations were increased following diesel exposure. In conclusion, the lung inflammatory response to diesel exhaust is compartmentalised, related to differing antioxidant responses in the conducting airway and alveolar regions.