tbuckley/cabot-search huggingface dataset:
Tiotropium for stable chronic obstructive pulmonary disease: a meta-analysis
Authors: R G Barr
Journal: Thorax (2006)

<b>Background:</b> A systematic review was undertaken to evaluate the efficacy of tiotropium, a long acting anticholinergic drug, on clinical events, symptom scales, pulmonary function, and adverse events in stable chronic obstructive pulmonary disease (COPD). <b>Methods:</b> A systematic search was made of the Cochrane trials database, MEDLINE, EMBASE, CINAHL, and a hand search of 20 respiratory journals. Missing data were obtained from authors and the manufacturer. Randomised controlled trials of ⩾12 weeks' duration comparing tiotropium with placebo, ipratropium bromide, or long acting β<sub>2</sub> agonists (LABA) were reviewed. Studies were pooled to yield odds ratios (OR) or weighted mean differences with 95% confidence intervals (CI). <b>Results:</b> Nine trials (8002 patients) met the inclusion criteria. Tiotropium reduced the odds of a COPD exacerbation (OR 0.73; 95% CI 0.66 to 0.81) and related hospitalisation (OR 0.68; 95% CI 0.54 to 0.84) but not pulmonary (OR 0.50; 95% CI 0.19 to 1.29) or all-cause (OR 0.96; 95% CI 0.63 to 1.47) mortality compared with placebo and ipratropium. Reductions in exacerbations and hospitalisations compared with LABA were not statistically significant. Similar patterns were evident for quality of life and symptom scales. Tiotropium yielded greater increases in forced expiratory volume in 1 second (FEV<sub>1</sub>) and forced vital capacity (FVC) from baseline to 6–12 months than did placebo, ipratropium, and LABA. Decline in FEV<sub>1</sub> over 1 year was 30 ml (95% CI 7 to 53) slower with tiotropium than with placebo and ipratropium (data were not available for LABA). Reports of dry mouth and urinary tract infections were increased with tiotropium. <b>Conclusions:</b> Tiotropium reduced COPD exacerbations and related hospitalisations, improved quality of life and symptoms, and may have slowed the decline in FEV<sub>1</sub>. Long term trials are warranted to evaluate the effects of tiotropium on decline in FEV<sub>1</sub> and to clarify its role compared with LABA.
Liposome/water lipophilicity: Methods, information content, and pharmaceutical applications
Authors: Georgette Plemper van Balen, Catherine a Marca Martinet, Giulia Caron, Géraldine Bouchard, Marianne Reist, Pierre‐Alain Carrupt, Roberta Fruttero, Alberto Gasco, Bernard Testa
Journal: Medicinal Research Reviews (2004)

Abstract This review discusses liposome/water lipophilicity in terms of the structure of liposomes, experimental methods, and information content. In a first part, the structural properties of the hydrophobic core and polar surface of liposomes are examined in the light of potential interactions with solute molecules. Particular emphasis is placed on the physicochemical properties of polar headgroups of lipids in liposomes. A second part is dedicated to three useful methods to study liposome/water partitioning, namely potentiometry, equilibrium dialysis, and 1 H‐NMR relaxation rates. In each case, the principle and limitations of the method are discussed. The next part presents the structural information encoded in liposome/water lipophilicity, in other words the solutes' structural and physicochemical properties that determine their behavior and hence their partitioning in such systems. This presentation is based on a comparison between isotropic (i.e., solvent/water) and anisotropic (e.g., liposome/water) systems. An important factor to be considered is whether the anisotropic lipid phase is ionized or not. Three examples taken from the authors' laboratories are discussed to illustrate the factors or combinations thereof that govern liposome/water lipophilicity, namely (a) hydrophobic interactions alone, (b) hydrophobic and polar interactions, and (c) conformational effects plus hydrophobic and ionic interactions. The next part presents two studies taken from the field of QSAR to exemplify the use of liposome/water lipophilicity in structure–disposition and structure–activity relationships. In the conclusion, we summarize the interests and limitations of this technology and point to promising developments. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 3, 299–324, 2004
Increased renal catabolism of 1,25-dihydroxyvitamin D3 in murine X-linked hypophosphatemic rickets.
Authors: H S Tenenhouse, A Yip, G Jones
Journal: Journal of Clinical Investigation (1988)

The hypophosphatemic (Hyp) mouse, a murine homologue of human X-linked hypophosphatemic rickets, is characterized by renal defects in brush border membrane phosphate transport and vitamin D3 metabolism. The present study was undertaken to examine whether elevated renal 25-hydroxyvitamin D3-24-hydroxylase activity in Hyp mice is associated with increased degradation of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] by side chain oxidation. Metabolites of 1,25(OH)2D3 were separated by HPLC on Zorbax SIL and identified by comparison with standards authenticated by mass spectrometry. Production of 1,24,25-trihydroxyvitamin D3, 24-oxo-1,25-dihydroxyvitamin D3, and 24-oxo-1,23,25-trihydroxyvitamin D3 was twofold greater in mitochondria from mutant Hyp/Y mice than from normal +/Y littermates. Enzyme activities, estimated by the sum of the three products synthesized per milligram mitochondrial protein under initial rate conditions, were used to estimate kinetic parameters. The apparent Vmax was significantly greater for mitochondria from Hyp/Y mice than from +/Y mice (0.607 +/- 0.064 vs. 0.290 +/- 0.011 pmol/mg per protein per min, mean +/- SEM, P less than 0.001), whereas the apparent Michaelis-Menten constant (Km) was similar in both genotypes (23 +/- 2 vs. 17 +/- 5 nM). The Km for 1,25(OH)2D3 was approximately 10-fold lower than that for 25-hydroxyvitamin D3 [25(OH)D3], indicating that 1,25(OH)2D3 is perhaps the preferred substrate under physiological conditions. In both genotypes, apparent Vmax for 25(OH)D3 was fourfold greater than that for 1,25(OH)2D3, suggesting that side chain oxidation of 25(OH)D3 may operate at pharmacological concentrations of substrate. The present results demonstrate that Hyp mice exhibit increased renal catabolism of 1,25(OH)2D3 and suggest that elevated degradation of vitamin D3 hormone may contribute significantly to the clinical phenotype in this disorder.
Resident Skin-specific γδ T Cells Provide Local, Nonredundant Regulation of Cutaneous Inflammation
Authors: Michael Girardi, Julia Lewis, Earl Glusac, Renata B. Filler, Liping Geng, Adrian C. Hayday, Robert E. Tigelaar
Journal: The Journal of Experimental Medicine (2002)

The function of the intraepithelial lymphocyte (IEL) network of T cell receptor (TCR) γδ+ (Vγ5+) dendritic epidermal T cells (DETC) was evaluated by examining several mouse strains genetically deficient in γδ T cells (δ−/− mice), and in δ−/− mice reconstituted with DETC or with different γδ cell subpopulations. NOD.δ−/− and FVB.δ−/− mice spontaneously developed localized, chronic dermatitis, whereas interestingly, the commonly used C57BL/6.δ−/− strain did not. Genetic analyses indicated a single autosomal recessive gene controlled the dermatitis susceptibility of NOD.δ−/− mice. Furthermore, allergic and irritant contact dermatitis reactions were exaggerated in FVB.δ−/−, but not in C57BL/6.δ−/− mice. Neither spontaneous nor augmented irritant dermatitis was observed in FVB.β−/− δ−/− mice lacking all T cells, indicating that αβ T cell–mediated inflammation is the target for γδ-mediated down-regulation. Reconstitution studies demonstrated that both spontaneous and augmented irritant dermatitis in FVB.δ−/− mice were down-regulated by Vγ5+ DETC, but not by epidermal T cells expressing other γδ TCRs. This study demonstrates that functional impairment at an epithelial interface can be specifically attributed to absence of the local TCR-γδ+ IEL subset and suggests that systemic inflammatory reactions may more generally be subject to substantial regulation by local IELs.
Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer
Authors: M. Akiyama
Journal: Journal of Clinical Investigation (2005)

Harlequin ichthyosis (HI) is a devastating skin disorder with an unknown underlying cause. Abnormal keratinocyte lamellar granules (LGs) are a hallmark of HI skin. ABCA12 is a member of the ATP-binding cassette transporter family, and members of the ABCA subfamily are known to have closely related functions as lipid transporters. ABCA3 is involved in lipid secretion via LGs from alveolar type II cells, and missense mutations in ABCA12 have been reported to cause lamellar ichthyosis type 2, a milder form of ichthyosis. Therefore, we hypothesized that HI might be caused by mutations that lead to serious ABCA12 defects. We identify 5 distinct ABCA12 mutations, either in a compound heterozygous or homozygous state, in patients from 4 HI families. All the mutations resulted in truncation or deletion of highly conserved regions of ABCA12. Immunoelectron microscopy revealed that ABCA12 localized to LGs in normal epidermal keratinocytes. We confirmed that ABCA12 defects cause congested lipid secretion in cultured HI keratinocytes and succeeded in obtaining the recovery of LG lipid secretion after corrective gene transfer of ABCA12. We concluded that ABCA12 works as an epidermal keratinocyte lipid transporter and that defective ABCA12 results in a loss of the skin lipid barrier, leading to HI. Our findings not only allow DNA-based early prenatal diagnosis but also suggest the possibility of gene therapy for HI.
The BCL11 gene family: involvement of BCL11A in lymphoid malignancies
Authors: Ed Satterwhite, Takashi Sonoki, Tony G. Willis, Lana Harder, Rachael Nowak, Emma L. Arriola, Hui Liu, Helen P. Price, Stefan Gesk, Doris Steinemann, Brigitte Schlegelberger, David G. Oscier, Reiner Siebert, Philip W. Tucker, Martin J. S. Dyer
Journal: Blood (2001)
Three periods of one and a half decade of ischemic stroke susceptibility gene research: lessons we have learned
Authors: Anita Maasz, Bela Melegh
Journal: Genome Medicine (2010)

Candidate gene association studies, linkage studies and genome-wide association studies have highlighted the role of genetic factors in the development of ischemic stroke. This research started over a decade ago, and can be separated into three major periods of research. In the first wave classic susceptibility markers associated with other diseases (such as the Leiden mutation in Factor V and mutations in the prothrombin and 5,10-methylenetetrahydrofolate reductase (MTHFR) genes) were tested for their role in stroke. These first studies used just a couple of hundred samples or even less. The second and still ongoing period bridges the two other periods of research and has led to a rapid increase in the spectrum of functional variants of genes or genomic regions, discovered primarily in relation to other diseases, tested on larger stroke samples of clinically better stratified patients. Large numbers of these alleles were originally discovered by array-based genome-wide association studies. The third period of research involves the direct array screening of large samples; this approach represents significant progress for research in the field. Research into susceptibility genes for stroke has taught us that careful stratification of patients is critical, that susceptibility alleles are often shared between diseases, and that not all susceptibility factors that associate with clinical traits that are themselves risk factors for stroke (such as increase of triglycerides) necessarily represent susceptibility for stroke. Research so far has been mainly focused on large- and small-vessel associated stroke, and knowledge on other types of stroke, which represent much smaller population samples, is still very scarce. Although some susceptibility allele tests are on the palette of some direct-to-consumer companies, the clinical utility and clinical validity of these test results still do not support their use in clinical practice.
Phase II study of "dose-dense" high-dose chemotherapy treatment with peripheral-blood progenitor-cell support as primary treatment for patients with advanced ovarian cancer.
Authors: C Aghajanian, D Fennelly, F Shapiro, R Waltzman, L Almadrones, C O'Flaherty, K O'Conner, E Venkatraman, R Barakat, J Curtin, C Brown, L Reich, D Wuest, L Norton, W Hoskins, D R Spriggs
Journal: Journal of Clinical Oncology (1998)

PURPOSE We performed a pilot phase II study to evaluate the potential for delivery of rapidly sequenced high-dose chemotherapy treatments rescued with autologous peripheral-blood progenitor cells (PBP) in patients with previously untreated, advanced ovarian cancer. PATIENTS AND METHODS A single cycle of mobilization was used, primed with cyclophosphamide (CPA)/paclitaxel (Txl) and filgrastim (granulocyte colony-stimulating factor [G-CSF]), followed by three cycles of high-dose carboplatin (CBDCA)/Txl and one cycle of high-dose melphalan (MEL), each rescued by PBP. We then analyzed the outcome for a total of 56 consecutive patients treated with high-dose chemotherapy as part of this program. RESULTS In the phase II pilot, 21 patients were enrolled. There were no treatment-related deaths through 98 high-dose treatments, although 34 treatments were complicated by hospitalization, primarily for neutropenic fever. Seventy-six percent of patients experienced grade 3 to 4 gastrointestinal toxicity and 62% experienced grade 2 to 3 neuropathy. Five of 15 (33%) patients who underwent second-look surgery attained a pathologic complete response. In the overall analysis, 56 patients were reviewed. Forty-four patients were assessable for response by second-look surgery or clinical progression. Fifteen of 44 patients achieved a pathologic complete response (34%). The pathologic complete response rate in optimal-disease patients was 12 of 22 (55%), while only three of 22 (13%) suboptimal stage III and IV patients achieved a pathologic complete response. CONCLUSION The Gynecologic Oncology Group has initiated a pilot phase II trial of this approach in patients with optimally debulked stage III ovarian cancer. There is no evidence to support the use of this or other aggressive regimens outside of a clinical trial.
Transmural temporospatial left ventricular activation during pacing from different sites: potential implications for optimal pacing
Authors: K. M. Kavanagh, I. Belenkie, H. J. Duff
Journal: Cardiovascular Research (2007)

AimsPrevious studies showed that right ventricular (RV) endocardial pacing can be deleterious even in individuals with initially normal left ventricular (LV) function. The mechanism(s) by which RV endocardial pacing may cause LV dysfunction is unknown. This study compares the temporospatial LV transmyocardial activation profiles during sinus rhythm with normal His/Purkinje conduction vs. currently utilized and proposed cardiac pacing sites.
Akt Promotes Increased Cardiomyocyte Cycling and Expansion of the Cardiac Progenitor Cell Population
Authors: Natalie Gude, John Muraski, Marta Rubio, Jan Kajstura, Erik Schaefer, Piero Anversa, Mark A. Sussman
Journal: Circulation Research (2006)

Activation of Akt is associated with enhanced cell cycling and cellular proliferation in nonmyocytes, but this effect of nuclear Akt accumulation has not been explored in the context of the myocardium. Cardiac-specific expression of nuclear-targeted Akt (Akt/nuc) in transgenics prolongs postnatal cell cycling as evidenced by increased numbers of Ki67 + cardiomyocytes at 2 to 3 weeks after birth. Similarly, nuclear-targeting of Akt promotes expansion of the presumptive cardiac progenitor cell population as assessed by immunolabeling for c-kit in combination with myocyte-specific markers Nkx 2.5 or MEF 2C. Increases in pro-proliferative cytokines, including tumor-necrosis superfamily 8, interleukin-17e, and hepatocyte growth factor, were found in nuclear-targeted Akt myocardial samples. Concurrent signaling mediated by paracrine factors downstream of Akt/nuc expression may be responsible for phenotypic effects of nuclear-targeted Akt in the myocardium, including enhanced cell proliferation and expansion of the stem cell population.
Self-Administered Stress Management Training in Patients Undergoing Radiotherapy
Authors: Mindy M. Krischer, Ping Xu, Cathy D. Meade, Paul B. Jacobsen
Journal: Journal of Clinical Oncology (2007)

This study sought to continue research on psychosocial interventions for patients being treated with radiation therapy across multiple centers and to replicate positive findings of a single-center study of patients being treated with chemotherapy. The primary objective of this study was to determine if a stress management intervention was effective in improving quality of life and decreasing psychological distress in patients undergoing radiotherapy for cancer.A total of 310 patients about to begin radiotherapy treatment were randomly assigned to receive usual care only or self-administered stress management training. Quality-of-life assessments occurred at baseline and for 3 weeks after the beginning of radiotherapy treatment.Overall, patients assigned to receive stress management training did not report significantly less psychological distress on the Medical Outcomes Study 36-Item Short Form (SF-36) Mental Component Summary Scale than did those assigned to usual care. When divided into subgroups based on the SF-36 Mental Component Summary Scale scores immediately after their first radiotherapy treatment, patients with above-average levels of psychological distress (scores < or = 50) who were randomly assigned to the intervention condition reported significant improvement in their distress compared with those assigned to usual care only on the SF-36 Mental Health Subscale and the Center for Epidemiologic Studies Depression Scale.This study found that self-administered stress management training is effective only in those radiotherapy patients with initially higher levels of psychological distress. Additional research should examine the benefits of stress management training targeted specifically to patients experiencing heightened distress.
Long-term Benefits of an Early Online Problem-Solving Intervention for Executive Dysfunction After Traumatic Brain Injury in Children
Authors: Brad G. Kurowski, Shari L. Wade, Michael W. Kirkwood, Tanya M. Brown, Terry Stancin, H. Gerry Taylor
Journal: JAMA Pediatrics (2014)

Executive dysfunction after traumatic brain injury (TBI) in children is common and leads to significant short- and long-term problems in functioning across multiple settings. We hypothesized that improvements in short-term executive function would be maintained to 24 months after injury and that improvements would increase over time in a counselor-assisted problem-solving (CAPS) intervention.To evaluate the efficacy of a CAPS intervention administered within 7 months of complicated mild to severe TBI compared with an Internet resource condition in improving long-term executive dysfunction.Multisite, assessor-blinded, randomized clinical trial at 3 tertiary pediatric hospitals and 2 tertiary general medical centers. Participants included 132 adolescents aged 12 to 17 years who sustained a moderate to severe TBI 1 to 7 months before study enrollment.Web-based CAPS intervention.The primary outcome was the parent-reported Global Executive Composite (GEC) of the Behavior Rating Inventory of Executive Function. Secondary outcomes included the Behavioral Regulation Index (BRI) and Metacognition Index (MI) of the GEC.In older (>14 to 17 years) adolescents, the CAPS intervention was associated with lower GEC ratings at 12 (β = -0.46; P = .03) and 18 (β = -0.52; P = .02) months after enrollment. Trends were also observed for older adolescents toward lower GEC ratings at 6 months (β = -0.40; P = .05), lower BRI ratings at 12 (β = -0.40; P = .06) and 18 (β = -0.47; P = .04) months, and lower MI ratings at 6 (β = -0.41; P = .05), 12 (β = -0.46; P = .03), and 18 (β = -0.50; P = .03) months. In younger (12-14 years) adolescents, no group differences were found on the GEC, BRI, or MI ratings.Delivery of the CAPS intervention early after TBI in older adolescents improves long-term executive function. This trial is, to our knowledge, one of the few large, randomized clinical treatment trials performed in pediatric TBI to demonstrate the efficacy of an intervention for management of executive dysfunction and long-term benefits of an intervention delivered soon after injury. Use of the CAPS intervention clinically should be considered; however, further research should explore ways to optimize delivery.clinicaltrials.gov Identifier: NCT00409448.
Peptidomimetic Regulation of Growth Hormone Secretion
Authors: Roy G. Smith, Lex H. T. Van der Ploeg, Andrew D. Howard, Scott D. Feighner, Kang Cheng, Gerard J. Hickey, Matthew J. Wyvratt, Mike H. Fisher, Ravi P. Nargund, Arthur A. Patchett
Journal: Endocrine Reviews (1997)

I. Introduction II. Identification of Peptidomimetic GH Secretagogues A. Mechanism of action of GHRH, GHRP-6, and somatostatin B. In vitro assays III. Molecular Design by Medicinal Chemistry A. Benzolactams and L-692,429 B. Spiroindanes and MK-0677 C. Isonipecotic acid peptidomimetics IV. Characterization of the MK-0677 Receptor A. Pituitary gland B. Hypothalamus V. Signal Transduction Pathway VI. Cloning the GH Secretagogue Receptor A. Chromosomal localization VII. Action of the Peptidomimetic GH Secretagogues in the Central Nervous System VIII. Peptidomimetic GH Secretagogues in Vivo A. Animal models B. Clinical studies in humans IX. Regulation of Pulsatile GH Release A. GHRH and somatostatin B. The role of GHS-R X. Concluding Comments
Constitutive Repression of Interleukin-1α in Endothelial Cells
Authors: Gregory J. Brunn, Soheyla Saadi, Jeffrey L. Platt
Journal: Circulation Research (2008)

Activation of complement stimulates inflammation and provides an initial vigorous defense against infection. Insertion of the membrane attack complex in cell membranes of vascular endothelial cells induces changes in cell differentiation that promote coagulation, thrombosis, inflammation, and immunity. These changes are mediated by production of interleukin (IL)-1alpha by endothelial cells, which acts locally on endothelial cells to contain infection and promote healing of the affected site. In healthy tissues, however, promoting coagulation and inflammation would be dysphysiologic. Accordingly, endothelial cell activation by the membrane attack complex depends on both transcriptional regulation of IL-1alpha and availability of that cytokine to broadly modify endothelial cell physiology. Here, we report that the IL-1alpha gene contains a suppressor sequence that cooperates with histone modification to regulate production of IL-1alpha by endothelial cells. The suppressor sequence binds C/EBP (CCAAT enhancer-binding protein) family DNA-binding proteins isolated from the nucleus of quiescent endothelial cells. These results suggest constitutive suppression of IL-1alpha maintains quiescence of endothelium and that terminal complement complexes remove that suppression, allowing IL-1alpha transcription and, ultimately, activation of endothelium to proceed.