tbuckley/cabot-search huggingface dataset:
Inhaled dry powder mannitol in cystic fibrosis: an efficacy and safety study
Authors: D. Bilton, P. Robinson, P. Cooper, C.G. Gallagher, J. Kolbe, H. Fox, A. Jaques, B. Charlton
Journal: European Respiratory Journal (2011)

This international phase III study of inhaled dry powder mannitol was a randomised, double-blind, 26-week study, followed by a further 26-week, open-label (OL) extension. 324 cystic fibrosis (CF) patients were randomised, in a 3:2 ratio, to mannitol (400 mg b.i.d. ) and control groups. The primary efficacy end-point was to determine the change in forced expiratory volume in 1 s (FEV 1 ) over the double-blind phase. Secondary end-points included changes in forced vital capacity and pulmonary exacerbations. A significant improvement in FEV 1 was seen over 26 weeks (p&lt;0.001) and was apparent by 6 weeks, irrespective of concomitant recombinant human deoxyribonuclease (rhDNase) use. At 26 weeks, there was a significant improvement in FEV 1 of 92.9 mL for subjects receiving mannitol compared with controls (change from baseline 118.9 mL (6.5%) versus 26.0 mL (2.4%); p&lt;0.001). Improvements in FEV 1 were maintained up to 52 weeks in the OL part of the study. There was a 35.4% reduction in the incidence of having an exacerbation on mannitol (p=0.045). The incidence of adverse events (AEs) was similar in both groups, although treatment-related AEs were higher in the mannitol compared with the control group. The most common mannitol-related AEs were cough, haemoptysis and pharyngolaryngeal pain. Mannitol showed sustained, clinically meaningful benefit in airway function in CF, irrespective of concomitant rhDNase use. Mannitol appears to have an acceptable safety profile for patients with CF.
Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A2
Authors: David Shoseyov, Haim Bibi, Sarit Offer, Ouri Schwob, Miron Krimsky, Marina Kleiman, Saul Yedgar
Journal: Thorax (2005)

The pathophysiology of asthma involves the action of inflammatory/allergic lipid mediators formed following membrane phospholipid hydrolysis by phospholipase A(2) (PLA(2)). Cysteinyl leukotrienes are considered potent inducers of bronchoconstriction and airway remodelling. Ovalbumin (OVA) induced bronchoconstriction in rats is associated with increased secretory PLA(2) (sPLA(2)) activation and cysteinyl leukotriene production, together with suppression of cytosolic PLA(2) and prostaglandin E(2). These processes are reversed when the animals are pretreated systemically with an extracellular cell impermeable sPLA(2) inhibitor which also suppresses the early allergic reaction to OVA challenge. In this study we examine the capacity of the sPLA(2) inhibitor to ameliorate inflammatory and allergic manifestations (early and late bronchoconstriction) of OVA induced allergic bronchitis in rats when the inhibitor was administered by inhalation to confine it to the airways.Rats sensitised with OVA were treated with the sPLA(2) inhibitor hyaluronic acid-linked phosphatidyl ethanolamine (HyPE). The rats were divided into four groups (n = 10 per group): (1) naïve controls (no sensitisation/no treatment); (2) positive controls (sensitisation + challenge with OVA inhalation and subcutaneous injection of 1 ml saline before each challenge; (3) sensitisation + challenge with OVA and HyPE inhalation before every challenge; and (4) sensitisation + challenge with OVA and treatment with subcutaneous dexamethasone (300 mug) before each challenge as a conventional reference. Another group received no treatment with HyPE during the sensitisation process but only before or after challenge of already sensitised rats. Pulmonary function was assessed and changes in the histology of the airways, levels of cysteinyl leukotrienes in BAL fluid, and the production of nitric oxide (No) and tumour necrosis factor alpha (TNFalpha) by BAL macrophages were determined.Inhalation of HyPE markedly suppressed OVA induced early and late asthmatic reactions as expressed by bronchoconstriction, airway remodelling (histology), cysteinyl leukotriene level in BAL fluid, and production of TNFalpha and NO by BAL macrophages. OVA induced bronchoconstriction in sensitised non-pretreated rats was also inhibited by inhalation of HyPE either before or after the challenge.These findings confirm the pivotal role of sPLA(2) in the pathophysiology of both the immediate allergic response and the inflammatory asthmatic process. Control of airway sPLA(2) may be a new therapeutic approach to the treatment of asthma.
Splenic immunoglobulin-secreting cells and their regulation in autoimmune mice.
Authors: A N Theofilopoulos, D L Shawler, R A Eisenberg, F J Dixon
Journal: The Journal of Experimental Medicine (1980)

We have investigated in vitro the magnitude, nature, and regulation of spontaneous and mitogen-induced Ig secretion by splenic lymphocytes from several autoimmune murine strains (NZB, NZB X W, MRL/l BXSB) and appropriate, normal mice. All autoimmune strains had increased numbers of mature splenic B lymphocytes, which secreted and/or contained Ig, compared to age-matched normal strains. In NZB and NZB X W mice, the high frequency of mature B cells was apparent early in life, whereas in MRL/l and BXSB mice it was first noted shortly before the clinical onset of disease. Spleen cells from young autoimmune mice of all four strains secreted predominantly IgM, but with aging and the appearance of disease, the cells switched to IgG secretion predominantly. In contrast, spleen cells from normal mice were predominantly IgM, but with aging and the appearance of disease, the cells switched to IgG secretion predominantly. In contrast, spleen cells from normal mice were predominantly IgM secretors throughout the animals' lives. Approximately 15% of the total Ig-secreting cells in older NZB, NZB X W, and MRL mice were committed to secretion of anti-ssDNA antibodies. In both autoimmune and normal spleen cells, the B-cell population alone contained fewer secreting cells than the total lymphocyte population, indicating that T cells were required to achieve maximal levels of plaque-forming cells. Spleen cells of NZB and NZB X W mice had a greater response to lipopolysaccharide (LPS) than other autoimmune and normal strains. Responsiveness to LPS, as measured by the frequency of induced Ig-secreting cells, was considerably diminished with age and onset of disease in all autoimmune but not in normal strains. LPS-induced Ig secretion by B cells of autoimmune and normal mice was subject to regulation by splenic T cells. No significant differences were observed between concanavalin-A (Con A) stimulated spleen cells from young and older autoimmune mice and normal control strains in effectively suppressing spontaneous and LPS-induced Ig secretion. Moreover, B cells from autoimmune mice and from normal strains were equally receptive to Con A-induced suppressor signals. T cells from young and older NZB and BXSB mice added to a standard number of B cells from syngeneic young mice provided equal help in enhancing LPS-induced Ig secretion, and this help in turn was equivalent to that provided by T cells from normal mice of the same H-2 haplotype. The exception was the MRL/l strain; T cells from older animals provided considerably more help than T cells from young MRL/l or T cells from young and older H-2-compatible normal mice.
Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway
Authors: Hyunkyung Jeong, Dena E Cohen, Libin Cui, Andrea Supinski, Jeffrey N Savas, Joseph R Mazzulli, John R Yates, Laura Bordone, Leonard Guarente, Dimitri Krainc
Journal: Nature Medicine (2011)
Dialysis, Kidney Transplantation, or Pancreas Transplantation for Patients with Diabetes Mellitus and Renal Failure
Authors: Greg A. Knoll, Graham Nichol
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Patients with type 1 diabetes mellitus and end-stage renal disease may remain on dialysis or undergo cadaveric kidney transplantation, living kidney transplantation, sequential pancreas after living kidney transplantation, or simultaneous pancreas-kidney transplantation. It is unclear which of these options is most effective. The objective of this study was to determine the optimal treatment strategy for type 1 diabetic patients with renal failure using a decision analytic Markov model. Input data were obtained from the published medical literature, the United Network for Organ Sharing registry, and patient interviews. The outcome measures were life expectancy (in life-years [LY]) and quality-adjusted life expectancy (in quality-adjusted life-years [QALY]). Living kidney transplantation was associated with 18.30 LY and 10.29 QALY; pancreas after kidney transplantation, 17.21 LY and 10.00 QALY; simultaneous pancreas-kidney transplantation, 15.74 LY and 9.09 QALY; cadaveric kidney transplantation, 11.44 LY and 6.53 QALY; dialysis, 7.82 LY and 4.52 QALY. The results were sensitive to the value of several key variables. Simultaneous pancreas-kidney transplantation had the greatest life expectancy and quality-adjusted life expectancy when living kidney transplantation was excluded from the analysis. These data indicate that living kidney transplantation is associated with the greatest life expectancy and quality-adjusted life expectancy for type 1 diabetic patients with renal failure. Treatment strategies involving pancreas transplantation should be considered for patients with frequent metabolic complications of diabetes and for those patients who favor kidney-pancreas transplantation over kidney transplantation alone. For patients without a living donor, simultaneous pancreas-kidney transplantation is associated with the greatest life expectancy. E-mail: gknoll@ottawahospital.on.ca
The Global Problem of Multidrug-Resistant Tuberculosis
Authors: C. Robert Horsburgh, Jr
Journal: JAMA (2000)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Synergistic Augmentation of Rapamycin-Induced Autophagy in Malignant Glioma Cells by Phosphatidylinositol 3-Kinase/Protein Kinase B Inhibitors
Authors: Hayato Takeuchi, Yasuko Kondo, Keishi Fujiwara, Takao Kanzawa, Hiroshi Aoki, Gordon B. Mills, Seiji Kondo
Journal: Cancer Research (2005)

Abstract The mammalian target of rapamycin (mTOR) is a downstream effector of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and a central modulator of cell proliferation in malignant gliomas. Therefore, the targeting of mTOR signaling is considered a promising therapy for malignant gliomas. However, the mechanisms underlying the cytotoxic effects of a selective mTOR inhibitor, rapamycin, on malignant glioma cells are poorly understood. The purpose of this study was thus to elucidate how rapamycin exerts its cytotoxic effects on malignant glioma cells. We showed that rapamycin induced autophagy but not apoptosis in rapamycin-sensitive malignant glioma U87-MG and T98G cells by inhibiting the function of mTOR. In contrast, in rapamycin-resistant U373-MG cells, the inhibitory effect of rapamycin was minor, although the phosphorylation of p70S6 kinase, a molecule downstream of mTOR, was remarkably inhibited. Interestingly, a PI3K inhibitor, LY294002, and an Akt inhibitor, UCN-01 (7-hydroxystaurosporine), both synergistically sensitized U87-MG and T98G cells as well as U373-MG cells to rapamycin by stimulating the induction of autophagy. Enforced expression of active Akt in tumor cells suppressed the combined effects of LY294002 or UCN-01, whereas dominant-negative Akt expression was sufficient to increase the sensitivity of tumor cells to rapamycin. These results indicate that rapamycin exerts its antitumor effect on malignant glioma cells by inducing autophagy and suggest that in malignant glioma cells a disruption of the PI3K/Akt signaling pathway could greatly enhance the effectiveness of mTOR inhibitors.
Response of Granular Juxtaglomerular Cells and Tissue Mast Cells in Various Experimental States
Authors: HARRY DEMOPOULOS, GABOR KALEY, BENJAMIK W. ZWEIFACH
Journal: Circulation Research (1961)

Mast cells, granular juxtaglomerular (j.g.) cells, and renal renin levels were studied in five different experimental conditions involving renal hypertension, DOCA hypertension, prolonged administration of NaCl in the drinking water, and treatment with compound 48/80, and dextran. The j.g. cells and mast cells behaved differently in each of these cir cumstances. A correlation between refill con tent and j.g. cells was observed. Metachro inasia could not be detected in j.g. cells and their location appeared to he unique.
The Effect of Two Different Dosages of Intravenous Immunoglobulin on the Incidence of Recurrent Infections in Patients with Primary Hypogammaglobulinemia
Authors: Heleen W. Eijkhout, Jos W.M. van der Meer, Cees G.M. Kallenberg, Ron S. Weening, Jaap T. van Dissel, Lieke A.M. Sanders, Paul F.W. Strengers, Henriët Nienhuis, Peter Th.A. Schellekens
Journal: Annals of Internal Medicine (2001)

Background: In patients with hypogammaglobulinemia, substitution with immunoglobulin is the treatment of choice to reduce both frequency and severity of bacterial infections. Even with treatment, however, infections still occur in these patients. Objective: To determine whether doubling the standard dose of intravenous immunoglobulin would affect the incidence and duration of infections. Design: Multicenter, double-blind, randomized, crossover study. Setting: 15 outpatient clinics in the Netherlands. Patients: 43 patients with primary hypogammaglobulinemia, 41 of whom completed the protocol. Intervention: Patients received standard-dose immunoglobulin therapy for 9 months, followed by a 3-month washout period, and high-dose intravenous immunoglobulin therapy for 9 months, or vice versa. Measurements: The primary outcome measures were total number and duration of infections. Other measures were periods of fever, hospital admissions, use of antibiotics, absence from school or work, and trough levels of serum immunoglobulin. Side effects from the study medication were also recorded. Results: Compared with the standard dose of intravenous immunoglobulin (adults, 300 mg/kg of body weight every 4 weeks; children, 400 mg/kg every 4 weeks), high-dose therapy (adults, 600 mg/kg every 4 weeks; children, 800 mg/kg every 4 weeks) significantly reduced the number (3.5 vs. 2.5 per patient; P = 0.004) and duration (median, 33 days vs. 21 days; P = 0.015) of infections. Trough levels of IgG increased significantly during high-dose therapy. The incidence and type of side effects did not differ significantly for the two dosages. Conclusion: In patients with hypogammaglobulinemia, doubling the standard dose of intravenous immunoglobulin significantly reduced the number and duration of infections.
Macrophage Metalloelastase Accelerates the Progression of Atherosclerosis in Transgenic Rabbits
Authors: Jingyan Liang, Enqi Liu, Ying Yu, Shuji Kitajima, Tomonari Koike, Yingji Jin, Masatoshi Morimoto, Kinta Hatakeyama, Yujiro Asada, Teruo Watanabe, Yasuyuki Sasaguri, Shigeyuki Watanabe, Jianglin Fan
Journal: Circulation (2006)

Macrophage metalloelastase (matrix metalloproteinase [MMP]-12) is upregulated in atherosclerotic lesions and aneurysm; thus, increased MMP-12 activity may play an important role in the pathogenesis of atherosclerosis. However, the pathological roles of MMP-12 in the initiation and progression of atherosclerosis have not been defined.We compared the susceptibility of MMP-12 transgenic (Tg) rabbits to cholesterol-rich diet-induced atherosclerosis with that of non-Tg littermate rabbits. The rabbits were maintained at either relatively lower levels of hypercholesterolemia for shorter periods or higher levels of hypercholesterolemia for longer periods through a diet containing different amounts of cholesterol. We found no significant difference in the aortic atherosclerotic lesion size or quality between Tg and non-Tg rabbits at lower hypercholesterolemia. At higher hypercholesterolemia for longer periods, however, Tg rabbits developed more extensive atherosclerosis in the aortas and coronary arteries than did non-Tg rabbits. Histological examinations revealed that atherosclerotic lesions of Tg rabbits contained prominent macrophage infiltration associated with marked disruption of the elastic lamina in the tunica media with occasional formation of aneurysm-like lesions. Furthermore, increased expression of MMP-12 derived from macrophages was associated with elevated expression of MMP-3, suggesting that MMP-12 may play a pivotal role in the cascade activation of other MMPs, thereby exacerbating extracellular matrix degradation during the progression of atherosclerosis.Overexpression of MMP-12 causes accelerated atherosclerosis in Tg rabbits. These results suggest that macrophage-derived MMP-12 participates in the progression of atherosclerosis.
Indirect influences of gonadal hormones on sexual differentiation
Authors: Lesley J. Rogers
Journal: Behavioral and Brain Sciences (1998)

Indirect routes by which gonadal hormones influence sexual differentiation are considered. In rats, differentiation may depend on the way in which the mother responds to the hormonal condition of her pups, and this has implications for the interpretation of the data for humans. Interaction between gonadal hormones and light experience in chicks is compared with the mammalian systems covered in Fitch &amp; Denenberg's review.
Electrocardiographic Measures and Prediction of Cardiovascular and Noncardiovascular Death in CKD
Authors: Rajat Deo, Haochang Shou, Elsayed Z. Soliman, Wei Yang, Joshua M. Arkin, Xiaoming Zhang, Raymond R. Townsend, Alan S. Go, Michael G. Shlipak, Harold I. Feldman
Journal: Journal of the American Society of Nephrology (2015)

Limited studies have assessed the resting 12-lead electrocardiogram (ECG) as a screening test in intermediate risk populations. We evaluated whether a panel of common ECG parameters are independent predictors of mortality risk in a prospective cohort of participants with CKD. The Chronic Renal Insufficiency Cohort (CRIC) study enrolled 3939 participants with eGFR<70 ml/min per 1.73 m2 from June 2003 to September 2008. Over a median follow-up of 7.5 years, 750 participants died. After adjudicating the initial 497 deaths, we identified 256 cardiovascular and 241 noncardiovascular deaths. ECG metrics were independent risk markers for cardiovascular death (hazard ratio, 95% confidence interval): PR interval ≥200 ms (1.62, 1.19–2.19); QRS interval 100–119 ms (1.64, 1.20–2.25) and ≥120 ms (1.75, 1.17–2.62); corrected QT (QTc) interval ≥450 ms in men or ≥460 ms in women (1.72, 1.19–2.49); and heart rate 60–90 beats per minute (1.21, 0.89–1.63) and ≥90 beats per minute (2.35, 1.03–5.33). Most ECG measures were stronger markers of risk for cardiovascular death than for all-cause mortality or noncardiovascular death. Adding these intervals to a comprehensive model of cardiorenal risk factors increased the C-statistic for cardiovascular death from 0.77 to 0.81 (P<0.001). Furthermore, adding ECG metrics to the model adjusted for standard risk factors resulted in a net reclassification of 12.1% (95% confidence interval 8.1%–16.0%). These data suggest common ECG metrics are independent risk factors for cardiovascular death and enhance the ability to predict death events in a population with CKD.
B cell function in mice transgenic for mCTLA4-H gamma 1: lack of germinal centers correlated with poor affinity maturation and class switching despite normal priming of CD4+ T cells.
Authors: P Lane, C Burdet, S Hubele, D Scheidegger, U Müller, F McConnell, M Kosco-Vilbois
Journal: The Journal of Experimental Medicine (1994)

This report outlines the B cell phenotype of transgenic mice that overexpresses the mouse CTLA-4-human gamma 1 (mCTLA4-H gamma 1) protein. Despite the fact that these mice prime CD4+ T cells (Ronchese, F., B. Housemann, S. Hubele, and P. Lane. 1994. J. Exp. Med. 179:809), antibody responses to T-dependent antigens are severely impaired. In contrast, T-independent responses are normal which suggests mCTLA4-H gamma 1 does not act directly on B cells, but acts indirectly by impairing T cell help. The impaired antibody defect is associated with impaired class switching, with low total immunoglobulin (Ig)G and antigen-specific IgG responses, and an absence of germinal center formation in spleen and lymph nodes but not gut-associated tissues. The defective germinal center formation is associated with a reduction in the degree of somatic mutation in hybridomas made from transgenic mice in comparison with those made from normal mice. It seems likely that mCTLA4-H gamma 1 exerts its effect by blocking an interaction between T and B cells that induce T cell help for B cells.
Reduction of regulatory T cells in skin lesions but not in peripheral blood of patients with systemic scleroderma
Authors: S. Klein, C. C. Kretz, V. Ruland, C. Stumpf, M. Haust, W. Hartschuh, M. Hartmann, A. Enk, E. Suri-Payer, N. Oberle, P. H. Krammer, A. Kuhn
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objective</h3> To determine the frequency and suppressive capacity of regulatory T cells (T<sub>reg</sub>) and their association with clinical parameters in patients with systemic scleroderma (SSc). <h3>Methods</h3> Peripheral blood from 25 patients with SSc, 15 patients with localised scleroderma (LS) and 29 healthy controls (HC) was studied. Analysis of CD4<sup>+</sup> forkhead box P3 (Foxp3)<sup>+</sup> and CD4<sup>+</sup>CD25<sup>++</sup>Foxp3<sup>+</sup> Treg subpopulations was carried out by flow cytometry and cell proliferation was quantified by <sup>3</sup>H-thymidine incorporation. Quantitative analysis of T<sub>reg</sub> was further performed in skin biopsies from 17 patients with SSc and 21 patients with LS using anti-CD4 and anti-Foxp3 monoclonal antibodies for immunohistochemistry. <h3>Results</h3> The frequency of CD4<sup>+</sup>Foxp3<sup>+</sup> and CD4<sup>+</sup>CD25<sup>++</sup>Foxp3<sup>+</sup> Treg in peripheral blood from patients with SSc was not significantly different from that of patients with LS or HC. The suppressive capacity of CD4<sup>+</sup>CD25<sup>++</sup> Treg in SSc was also found to be similar to that of HC. Phenotypic and functional data revealed no significant difference between the limited or diffuse form of SSc. Moreover, therapy with bosentan showed no significant effect on the frequency of T<sub>reg</sub> during the course of the disease. However, the frequency of T<sub>reg</sub> in skin lesions from patients with SSc or LS, determined as the percentage of CD4<sup>+</sup> cells expressing Foxp3 in the inflammatory infiltrate, was significantly reduced compared with other inflammatory skin diseases. <h3>Conclusion</h3> These results indicate that although the authors found no defect in the frequency or function of peripheral T<sub>reg</sub> subpopulations, the reduction of CD4<sup>+</sup>Foxp3<sup>+</sup> T<sub>reg</sub> in the skin of patients with SSc may be important in the pathogenesis of the disease.