tbuckley/cabot-search huggingface dataset:
Aerosolized endothelin-1, but not its C-terminal hexapeptide, causes airway narrowing in the rat
Authors: GU Di Maria, S Bellofiore, LS Malatino, CA Maggi, A Torrisi, A Mistretta
Journal: European Respiratory Journal (1991)

We investigated the effects of aerosolized endothelin-1 (ET-1) and of its C-terminal hexapeptide, ET-(16-21), on the pulmonary mechanics of anaesthetized spontaneously-breathing rats. ET-1 inhalation caused a concentration-dependent increase in pulmonary resistance (RL) and decrease in dynamic lung compliance (Cdyn). In control conditions RL and Cdyn were 0.17 +/- 0.04 cmH2O.ml-1.s (mean +/- SE; n = 6) and 6.25 +/- 0.66 ml.cmH2O.1. respectively. After ET-1 4 x 10(-5) M RL and Cdyn averaged 1.45 +/- 0.28 cmH2O.ml-1.s (p less than 0.05) and 1.12 +/- 0.36 ml.cmH2O-1 (p less than 0.05), respectively. The pulmonary responses to ET-1 lasted up to 60 min. By contrast, ET-(16-21) inhaled up to a concentration of 10(-3) M did not affect pulmonary mechanics. These results indicate that the bronchoconstrictor activity of aerosolized endothelin-1 in the rat is not dependent on its C-terminal sequence, and suggests a role for endothelin-1 in the regulation of airway calibre.
Absorption and Metabolic Effect of Inhaled Insulin
Authors: Ayesh D. Perera, Christoph Kapitza, Leszek Nosek, Robert S. Fishman, David A. Shapiro, Tim Heise, Lutz Heinemann
Journal: Diabetes Care (2002)

OBJECTIVE—To compare the intrapatient variability of the pharmacokinetic and pharmacodynamic responses to inhaled regular insulin (INH) delivered via the Aerodose Insulin Inhaler with that of subcutaneously injected regular insulin (SC) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 15 patients with type 2 diabetes (nonsmokers, 10 men, aged 47–77 years) received two 240-unit doses of INH, delivered via a clinical Aerodose Insulin Inhaler and two 24-unit doses of SC under euglycemic clamp conditions on four separate study days. Glucose infusion rates (GIRs) and serum insulin concentrations were monitored over the following 8 h. Comparisons of intrapatient coefficients of variation (CV) were used to assess the reproducibility of INH versus SC. RESULTS—INH showed a bioavailability (0–8 h postdosing) of 16% and biopotency of 13% relative to SC. Comparison of the CVs (%) for area under the curve for serum insulin and GIR between INH and SC showed no significant differences between the treatments during 0–3 h (19% for INH versus 23% for SC) or 0–8 h (22% for INH versus 16% for SC). INH exhibited a shorter time to peak insulin concentration (Tmax [mean ± SD] 76 ± 51 vs. 193 ± 66 min) and shorter time to peak metabolic effect (TGIRmax 170 ± 53 vs. 244 ± 75 min) compared with SC (P &amp;lt; 0.001). No adverse events were observed. CONCLUSIONS—Comparable dosing reproducibility and shorter time to peak action of INH compared with SC suggest that INH delivered via the Aerodose Insulin Inhaler can provide reliable preprandial dosing of insulin in patients with type 2 diabetes.
Anemia, Diabetes, and Chronic Kidney Disease
Authors: Uzma Mehdi, Robert D. Toto
Journal: Diabetes Care (2009)

Diabetes is the leading cause of chronic kidney disease (CKD) and is associated with excessive cardiovascular morbidity and mortality (1,2). Anemia is common among those with diabetes and CKD and greatly contributes to patient outcomes (3,4). Observational studies indicate that low Hb levels in such patients may increase risk for progression of kidney disease and cardiovascular morbidity and mortality (5). Controlled clinical trials of anemia treatment with erythropoietin stimulating agents (ESAs) demonstrated improved quality of life (QOL) but have not demonstrated improved outcomes (6–10). In some trials, ESA treatment for high Hb levels is associated with worse outcomes such as increased thrombosis risk (6,11). Consequently, the U.S. Food and Drug Administration (FDA) and the National Kidney Foundation (NKF) have modified their recommendations regarding anemia treatment for CKD patients (12). The objectives of this review are to 1 ) update clinicians on the prevalence, causes, and clinical consequences of anemia; 2 ) discuss the benefits and risks of treatment; and 3 ) provide insight into anemia management based on clinical trial evidence in patients with diabetes and kidney disease who are not on dialysis.

The NKF defines anemia in CKD as an Hb level <13.5 g/dl in men and 12.0 g/dl in women (13). This definition is based on the fact that these levels are outside the 95% CIs of the mean for normal men and women. Anemia is common in diabetic patients with CKD (5). It is estimated that one in five patients with diabetes and stage 3 CKD have anemia, and its severity worsens with more advanced stages of CKD and in those with proteinuria (7,14,15) For example, in a 5-year prospective observational study conducted in a diabetes clinic in Australia, anemia was found in early kidney disease, and declining …
Is the time taken for sputum cultures to become negative in multidrug-resistant TB related to treatment outcome?
Authors: F Morell-Ducos
Journal: Thorax (2006)

▴ Holtz TH, Sternberg M, Kammerer S, et al . Time to sputum culture conversion in multidrug-resistant tuberculosis: predictors and relationship to treatment outcome. Ann Intern Med2006;144: 650–69[OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] Periodic sputum culture is used to monitor treatment efficacy in multidrug resistant tuberculosis (TB), and conversion of cultures from positive to negative for Mycobacterium tuberculosis is the most important indicator of progress. However, few studies have reported or evaluated sputum culture conversion status as an interim indicator of final treatment … [1]: {openurl}?query=rft.jtitle%253DAnnals%2Bof%2BInternal%2BMedicine%26rft.stitle%253DANN%2BINTERN%2BMED%26rft.aulast%253DHoltz%26rft.auinit1%253DT.%2BH.%26rft.volume%253D144%26rft.issue%253D9%26rft.spage%253D650%26rft.epage%253D659%26rft.atitle%253DTime%2Bto%2BSputum%2BCulture%2BConversion%2Bin%2BMultidrug-Resistant%2BTuberculosis%253A%2BPredictors%2Band%2BRelationship%2Bto%2BTreatment%2BOutcome%26rft_id%253Dinfo%253Adoi%252F10.7326%252F0003-4819-144-9-200605020-00008%26rft_id%253Dinfo%253Apmid%252F16670134%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=10.7326/0003-4819-144-9-200605020-00008&link_type=DOI [3]: /lookup/external-ref?access_num=16670134&link_type=MED&atom=%2Fthoraxjnl%2F61%2F8%2F670.atom [4]: /lookup/external-ref?access_num=000237293700004&link_type=ISI
Successful Treatment With Meloxicam, a Cyclooxygenase-2 Inhibitor, of Patients With Extra-Abdominal Desmoid Tumors: A Pilot Study
Authors: Yoshihiro Nishida, Satoshi Tsukushi, Yoji Shido, Junji Wasa, Naoki Ishiguro, Yoshihisa Yamada
Journal: Journal of Clinical Oncology (2009)
Intrathoracic Impedance Monitoring in Patients With Heart Failure
Authors: Cheuk-Man Yu, Li Wang, Elaine Chau, Raymond Hon-Wah Chan, Shun-Ling Kong, Man-Oi Tang, Jill Christensen, Robert W. Stadler, Chu-Pak Lau
Journal: Circulation (2005)

Patients with heart failure are frequently hospitalized for fluid overload. A reliable method for chronic monitoring of fluid status is therefore desirable. We evaluated an implantable system capable of measuring intrathoracic impedance to identify potential fluid overload before heart failure hospitalization and to determine the correlation between intrathoracic impedance and standard measures of fluid status during hospitalization.Thirty-three patients with NYHA class III and IV heart failure were implanted with a special pacemaker in the left pectoral region and a defibrillation lead in the right ventricle. Intrathoracic impedance was regularly measured and recorded between the lead and the pacemaker case. During hospitalizations, pulmonary capillary wedge pressure and fluid status were monitored. Ten patients were hospitalized for fluid overload 25 times over 20.7+/-8.4 months. Intrathoracic impedance decreased before each admission by an average of 12.3+/-5.3% (P<0.001) over an average of 18.3+/-10.1 days. Impedance reduction began 15.3+/-10.6 days (P<0.001) before the onset of worsening symptoms. There was an inverse correlation between intrathoracic impedance and pulmonary capillary wedge pressure (r=-0.61, P<0.001) and between intrathoracic impedance and net fluid loss (r=-0.70, P<0.001) during hospitalization. Automated detection of impedance decreases was 76.9% sensitive in detecting hospitalization for fluid overload, with 1.5 false-positive (threshold crossing without hospitalization) detections per patient-year of follow-up.Intrathoracic impedance is inversely correlated with pulmonary capillary wedge pressure and fluid balance and decreased before the onset of patient symptoms and before hospital admission for fluid overload. Regular monitoring of impedance may provide early warning of impending decompensation and diagnostic information for titration of medication.
Hereditary deficiency of the sixth component of complement in man. II. Studies of hemostasis.
Authors: R S Heusinkveld, J P Leddy, M R Klemperer, R T Breckenridge
Journal: Journal of Clinical Investigation (1974)

Prompted by previous observations of defective blood clotting in rabbits deficient in the sixth component of complement (C6), an evaluation was made of the hemostatic functions of the homozygous proband of a newly recognized human kindred with hereditary C6 deficiency. This human subject, who had no clinical evidence of a bleeding disorder, exhibited a total lack of C6 by functional and immunoprecipitin assays of serum or plasma. Standard tests of hemostatic function were normal; however, when the whole blood clotting time was measured at 25 degrees C in plastic tubes, it was at the upper range of our normal values. In confirmation of this observation, prothrombin consumption, when performed at 37 degrees C in plastic tubes, was at the lower range of normal. Inulin and endotoxin, in concentrations shown to cause activation of human complement, had little or no effect on clotting times or prothrombin consumption of normal or C6-deficient human blood. These observations indicate that absence of C6 does not have a significant effect on hemostatic function in man. In the light of other investigations, the observed differences in clotting function between C6-deficient human blood and C6-deficient rabbit blood could be due to species differences governing the susceptibility of platelets to complement activation.
ELK4 neutralization sensitizes glioblastoma to apoptosis through downregulation of the anti-apoptotic protein Mcl-1
Authors: Bryan W. Day, Brett W. Stringer, Mark D. Spanevello, Sara Charmsaz, Paul R. Jamieson, Kathleen S. Ensbey, Jacinta C. Carter, Joanne M. Cox, Vicky J. Ellis, Christopher L. Brown, David G. Walker, Po L. Inglis, Suzanne Allan, Brent A. Reynolds, Jason D. Lickliter, Andrew W. Boyd
Journal: Neuro-Oncology (2011)

Glioma is the most common adult primary brain tumor. Its most malignant form, glioblastoma multiforme (GBM), is almost invariably fatal, due in part to the intrinsic resistance of GBM to radiation- and chemotherapy-induced apoptosis. We analyzed B-cell leukemia–2 (Bcl-2) anti-apoptotic proteins in GBM and found myeloid cell leukemia–1 (Mcl-1) to be the highest expressed in the majority of malignant gliomas. Mcl-1 was functionally important, as neutralization of Mcl-1 induced apoptosis and increased chemotherapy-induced apoptosis. To determine how Mcl-1 was regulated in glioma, we analyzed the promoter and identified a novel functional single nucleotide polymorphism in an uncharacterized E26 transformation-specific (ETS) binding site. We identified the ETS transcription factor ELK4 as a critical regulator of Mcl-1 in glioma, since ELK4 downregulation was shown to reduce Mcl-1 and increase sensitivity to apoptosis. Importantly the presence of the single nucleotide polymorphism, which ablated ELK4 binding in gliomas, was associated with lower Mcl-1 levels and a greater dependence on Bcl-xL. Furthermore, in vivo, ELK4 downregulation reduced tumor formation in glioblastoma xenograft models. The critical role of ELK4 in Mcl-1 expression and protection from apoptosis in glioma defines ELK4 as a novel potential therapeutic target for GBM.
Major Histocompatibility Complex HLA Region Largely Explains the Genetic Variance Exercised on Neutrophil Membrane Proteinase 3 Expression
Authors: Sibylle von Vietinghoff, Andreas Busjahn, Constanze Schönemann, Gero Massenkeil, Björn Otto, Friedrich C. Luft, Ralph Kettritz
Journal: Journal of the American Society of Nephrology (2006)

ANCA-associated vasculitides, a common cause of rapidly progressive glomerulonephritis, are influenced by genetic variance. Neutrophil membrane expression of the ANCA antigen proteinase 3 (PR3) is pathogenically important. A subset of membrane PR3-positive neutrophils can be distinguished from a membrane-negative subset in any given subject. The percentage of membrane PR3-positive neutrophils is genetically determined. In this study, 17 pairs of HLA-matched siblings were typed for their percentage of membrane PR3-positive neutrophils. The HLA-matched siblings showed a high concordance (r = 0.67, P < 0.05), similar to that seen in monozygotic twins. For testing of whether the HLA system influences membrane PR3 percentage, membrane PR3 typing and HLA typing of 51 unrelated patients with Wegener's granulomatosis and 49 normal control subjects was performed. Using two independent statistical methods, a group of 34 HLA antigens was found to predict a large fraction of the membrane PR3 phenotype in patients and control subjects. Certain major histocompatibility HLA antigens have been implicated to conflicting degrees in ANCA-associated vasculitides. However, in earlier studies, the contribution of the HLA system to the genetic variance of the disease was unclear. In this cohort, found was an association of Wegener's granulomatosis with the same group of HLA antigens that predicted for membrane PR3 percentage and a similar correlation with clinical parameters at initial presentation. The disease status in 80% of the patients and 82% of the control subjects could be predicted correctly on the basis of HLA typing by discriminate function analysis (P < 0.001). After removal of the predicted individual from the sample, this association remained significant (64 and 63% correct prediction; P < 0.001). The data suggest that a complex interaction of the entire HLA system is responsible for the genetic influence on membrane PR3 percentage and Wegener's granulomatosis.
Evolution of Clinical Trial Design in Early Drug Development: Systematic Review of Expansion Cohort Use in Single-Agent Phase I Cancer Trials
Authors: Arif Manji, Irene Brana, Eitan Amir, George Tomlinson, Ian F. Tannock, Philippe L. Bedard, Amit Oza, Lillian L. Siu, Albiruni R. Abdul Razak
Journal: Journal of Clinical Oncology (2013)

Purpose To evaluate the use and objectives of expansion cohorts in phase I cancer trials and to explore trial characteristics associated with their use. Methods We performed a systematic review of MEDLINE and EMBASE, limiting studies to single-agent phase I trials recruiting adults and published after 2006. Eligibility assessment and data extraction were performed by two reviewers. Data were assessed descriptively, and associations were tested by univariable and multivariable logistic regression. Results We identified 611 unique phase I cancer trials, of which 149 (24%) included an expansion cohort. The trials were significantly more likely to use an expansion cohort if they were published more recently, were multicenter, or evaluated a noncytotoxic agent. Objectives of the expansion cohort were reported in 74% of trials. In these trials, safety (80%), efficacy (45%), pharmacokinetics (28%), pharmacodynamics (23%), and patient enrichment (14%) were cited as objectives. Among expansion cohorts with safety objectives, the recommended phase II dose was modified in 13% and new toxicities were described in 54% of trials. Among trials aimed at assessing efficacy, only 11% demonstrated antitumor activity assessed by response criteria that was not previously observed during dose escalation. Conclusion The utilization of expansion cohorts has increased with time. Safety and efficacy are common objectives, but 26% fail to report explicit aims. Expansion cohorts may provide useful supplementary data for phase I trials, particularly with regard to toxicity and definition of recommended dose for phase II studies.
Recombinant Human Lactoferrin as a Biomaterial for Bone Tissue Engineering: Mechanism of Antiapoptotic and Osteogenic Activity
Authors: Ashley A. Amini, Lakshmi S. Nair
Journal: Advanced Healthcare Materials (2013)

Lactoferrin is a bioactive globular protein with unique properties towards musculo‐skeletal cells and anabolic to bone in vivo. Even though the potent anti‐apoptotic and osteogenic activity of lactoferrin has been reported, the mechanism of action has not been fully elucidated. The study demonstrates that the anti‐apoptotic effect of rhLF towards MC3T3 pre‐osteoblast cells is mediated by Wnt5a/PKA pathway and the stabilization of β‐catenin by rhLF is dependent on PKA/LRP6 signaling pathway. The study also investigates the feasibility of developing rhLF as a biomaterial for cell delivery. The injectable rhLF cell delivery vehicles are prepared by enzymatic crosslinking of tyramine‐modified rhLF in the presence of hydrogen peroxide and horseradish peroxidase. The modified rhLF shows bioactivity similar to unmodified rhLF. The rhLF gels support encapsulated MC3T3 cell viability, proliferation, and differentiation, as well as phosphorylation of signaling proteins. In conclusion, the study demonstrates the involvement of Wnt5a, LRP6, and PKA signaling in rhLF‐mediated bioactivity towards MC3T3 cells and the feasibility of developing an injectable cell delivery vehicle from rhLF.
Respiratory disease associated with solid biomass fuel exposure in rural women and children: systematic review and meta-analysis
Authors: J. Y. T. Po, J. M. FitzGerald, C. Carlsten
Journal: Thorax (2011)

<h3>Background</h3> Numerous studies with varying associations between domestic use of solid biomass fuels (wood, dung, crop residue, charcoal) and respiratory diseases have been reported. <h3>Objective</h3> To present the current data systematically associating use of biomass fuels with respiratory outcomes in rural women and children. <h3>Methods</h3> Systematic searches were conducted in 13 electronic databases. Data were abstracted from original articles that satisfied selection criteria for meta-analyses. Publication bias and heterogeneity of samples were tested. Studies with common diagnoses were analysed using random-effect models. <h3>Results</h3> A total of 2717 studies were identified. Fifty-one studies were selected for data extraction and 25 studies were suitable for meta-analysis. The overall pooled ORs indicate significant associations with acute respiratory infection in children (OR 3.53, 95% CI 1.94 to 6.43), chronic bronchitis in women (OR 2.52, 95% CI 1.88 to 3.38) and chronic obstructive pulmonary disease in women (OR 2.40, 95% CI 1.47 to 3.93). In contrast, no significant association with asthma in children or women was noted. <h3>Conclusion</h3> Biomass fuel exposure is associated with diverse respiratory diseases in rural populations. Concerted efforts in improving stove design and lowering exposure to smoke emission may reduce respiratory disease associated with biomass fuel exposure.
Aortic sinus of Valsalva aneurysms simulating primary right-sided valvular heart disease.
Authors: B H Bulkley, G M Hutchins, R S Ross
Journal: Circulation (1975)

While acute regurgitation is the most common valvular lesion associated with aortic sinus of Valsalva aneurysms, this report describes the pathological findings in five patients in whom primary right-sided valve dysfunction was simulated by sinus of Valsalva aneurysms. In two patients aneurysms of the noncoronary sinus projected into the right atrium at the level of the tricuspid valve and caused tricuspid incomptence. In three patients aneurysms of the right sinus of Valsalva projected into the right ventricle immediately below the pulmonic valve and caused pulmonary outflow tract obstruction. In only one of these patients was the aneurysm perforated at necropsy. Although valvular dysfunction was evident clinically, in none was there a clinical suspicion of a sinus of Valsalva aneurysm. In addition to valvular dysfunction, two patients had conduction disturbances and two, right coronary arterial occlusions found to be the result of aneurysms. The risks of valve dysfunction, arrythmias, aneurysm rupture, and sudden death and the ability to correct this lesion surgically make it especially important to consider aortic sinus of Valsalva aneurysm as a cause of obscure right-sided valvular disease.
The Infants’ Dermatitis Quality of Life Index
Authors: M.S. Lewis-Jones, A.Y. Finlay, P.J. Dykes
Journal: British Journal of Dermatology (2001)

Journal Article The Infants’ Dermatitis Quality of Life Index Get access M.S. Lewis‐Jones, M.S. Lewis‐Jones Department of Dermatology, Ninewells Hospital and Medical School, Dundee DD1 9SY, U.K. Search for other works by this author on: Oxford Academic Google Scholar A.Y. Finlay, A.Y. Finlay Department of Dermatology, University of Wales College of Medicine, Cardiff CF14 4XN, U.K. Search for other works by this author on: Oxford Academic Google Scholar P.J. Dykes P.J. Dykes Department of Dermatology, University of Wales College of Medicine, Cardiff CF14 4XN, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 144, Issue 1, 1 January 2001, Pages 104–110, https://doi.org/10.1046/j.1365-2133.2001.03960.x Published: 01 January 2001
Electrophysiological Actions of Lidocaine on Canine Ventricular Muscle and Purkinje Fibers
Authors: L. D. DAVIS, J. V. TEMTE
Journal: Circulation Research (1969)

Isolated canine papillary muscles with attached false tendons were perfused with Tyrode's solution containing lidocaine. Transmembrane action potentials of ventricular muscle fibers and Purkinje fibers were recorded with glass microelectrodes. Repolarization of Purkinje fibers was accelerated by lidocaine but that of ventricular muscle fibers was unaffected. The maximum rate of rise of the action potential of Purkinje fibers decreased only at 50.0 mg/liter lidocaine; that of ventricular muscle fibers was unchanged by any concentration. The curve relating rate of rise of premature responses to level of membrane potential for Purkinje fibers was unchanged with 5.0 mg/liter but shifted down and to the right with 10.0 and 50.0 mg/liter. The effective refractory period of Purkinje fibers shortened at 5.0 and lengthened at 50.0 mg/liter. The level of membrane potential needed to elicit premature propagated responses in Purkinje fibers with a standardized test stimulus increased and the earliest responses obtained in the presence of lidocaine were relatively large. Duration of the effective refractory period of ventricular muscle fibers was unchanged with 5.0 mg/liter but lengthened progressively with 10.0 and 50.0 mg/liter. Lidocaine impaired the ability of both fibers to respond to rapid frequencies of stimulation, slowed the rate of inherent diastolic depolarization of driven Purkinje fibers, decreased the rate of discharge of spontaneously beating preparations, and minimized the increase in rate and magnitude of diastolic depolarization caused normally by epinephrine. The possible role of these effects of lidocaine in regard to its antiarrhythmic actions was discussed.