tbuckley/cabot-search huggingface dataset:
Effect of Combination Glipizide GITS/Metformin on Fibrinolytic and Metabolic Parameters in Poorly Controlled Type 2 Diabetic Subjects
Authors: William T. Cefalu, David J. Schneider, Harold E. Carlson, Phyllis Migdal, Leonil Gan Lim, Meriam P. Izon, Anoop Kapoor, Audrey Bell-Farrow, James G. Terry, Burton E. Sobel
Journal: Diabetes Care (2002)

Epidemiological studies have implicated increased plasminogen-activated inhibitor 1 (PAI-1) as a marker or predictor of accelerated coronary atherosclerotic disease in type 2 diabetes. We sought to determine whether metabolic control, independent of its oral mode of implementation, affects PAI-1 in patients with marked hyperglycemia.A total of 91 subjects were screened, subjected to a 4-week drug washout, and randomized to daily treatment with glipizide GITS (maximum 20 mg, n = 46) or metformin (maximum 2,550 mg, n = 45) as monotherapy. After monotherapy, combination therapy was initiated by adding the second agent to the regimen. Plasma glucose (fasting and postprandial), HbA(1c), fructosamine, and PAI-1 were assayed before and after randomization and sequentially thereafter in all subjects; hepatic glucose output (HGO) and abdominal fat distribution were each measured in a subset of subjects.Glycemic control was markedly impaired at baseline (mean HbA(1c) 10.4 +/- 0.2% glipizide GITS; 10.0 +/- 0.2% metformin) but improved comparably with each agent as monotherapy and in combination (P < 0.0001 vs. baseline), as assessed with meal tolerance studies, fructosamine values, and HGO. Body weight and abdominal fat distribution did not change significantly in either group. PAI-1 concentrations were extraordinarily high (5- to 10-fold more than normal) at baseline (202 +/- 12 ng/ml glipizide GITS; 201 +/- 13 ng/ml metformin) but declined comparably, and significantly, after treatment with either agent as monotherapy and decreased further with combination therapy.When hyperglycemia is profound, increases in PAI-1 are also profound. Control of hyperglycemia with either glipizide GITS, an insulin secretagogue, or metformin as monotherapy comparably ameliorates elevated PAI-1.
The Peroxisome Proliferator WY-14,643 Promotes Hepatocarcinogenesis Caused by Endogenously Generated Oxidative DNA Base Modifications in Repair-Deficient <i>Csbm/m/Ogg1</i>−/− Mice
Authors: Christian Trapp, Michael Schwarz, Bernd Epe
Journal: Cancer Research (2007)

Basal levels of endogenously generated oxidative DNA modifications such as 7,8-dihydro-8-oxoguanine (8-oxoG) are present in apparently all mammalian cells, but their relevance for the generation of spontaneous cancers remains to be established. Both the 8-oxoG levels and the resulting spontaneous mutations are increased in the livers of Csb(m/m)/Ogg1(-/-) mice, which are deficient in the repair of 8-oxoG. In order to determine the consequences of these additional oxidative DNA modifications and mutations and thus assess the tumor initiating potency of this type of endogenous DNA damage, we treated Csb(m/m)/Ogg1(-/-) mice and repair-proficient controls with the peroxisome proliferator WY-14,643 (0.025% ad libitum), a potent inducer of liver cell proliferation. The treatment did not generate any additional oxidative DNA damage; the elevated levels of 8-oxoG in the Csb(m/m)/Ogg1(-/-) mice even decreased. Also, the spontaneous mutation frequencies observed in the lacI gene of BigBlue Csb(m/m)/Ogg1(-/-) mice, which were approximately 3-fold higher than in the repair-proficient mice, declined by 39% under the treatment, whereas the frequencies in the livers of the repair-proficient animals remained unchanged. Preneoplastic lesions (staining positive or negative for glucose-6-phoshatase) developed in the livers of both wild-type and Csb(m/m)/Ogg1(-/-) mice after 30 weeks. Both the numbers and the total volumes of the lesions were approximately 6-fold higher in the repair-deficient mice than in the wild-type mice. The results indicate that spontaneous mutations generated from endogenous oxidative DNA base damage efficiently translate into increased tumorigenesis when cell proliferation is stimulated.
Obesity Is Associated with Worse Peritoneal Dialysis Outcomes in the Australia and New Zealand Patient Populations
Authors: Stephen P McDonald, John F Collins, David W Johnson
Journal: Journal of the American Society of Nephrology (2003)

Although obesity is associated with increased risks of morbidity and death in the general population, a number of studies of patients undergoing hemodialysis have demonstrated that increasing body mass index (BMI) is correlated with decreased mortality risk. Whether this association holds true among patients treated with peritoneal dialysis (PD) has been less well studied. The aim of this investigation was to examine the association between BMI and outcomes among new PD patients in a large cohort, with long-term follow-up monitoring. Using data from the Australia and New Zealand Dialysis and Transplant Registry, an analysis of all new adult patients (n = 9679) who underwent an episode of PD treatment in Australia or New Zealand between April 1, 1991, and March 31, 2002, was performed. Patients were classified as obese (BMI of >/=30 kg/m(2)), overweight (BMI of 25.0 to 29.9 kg/m(2)), normal weight (BMI of 20 to 24.9 kg/m(2)), or underweight (BMI of <20 kg/m(2)). In multivariate analyses, obesity was independently associated with death during PD treatment (hazard ratio, 1.36; 95% confidence interval, 1.14 to 1.54; P < 0.05) and technique failure (hazard ratio, 1.17; 95% confidence interval, 1.07 to 1.26; P < 0.01), except among patients of New Zealand Maori/Pacific Islander origin, for whom there was no significant relationship between BMI and death during PD treatment. A supplementary fractional polynomial analysis modeled BMI as a continuous predictor and indicated a J-shaped relationship between BMI and patient mortality rates and a steady increase in death-censored technique failure rates up to a BMI of 40 kg/m(2); the mortality risk was lowest for BMI values of approximately 20 kg/m(2). In conclusion, obesity at the commencement of renal replacement therapy is a significant risk factor for death and technique failure. Such patients should be closely monitored during PD and should be considered for early transfer to an alternative renal replacement therapy if difficulties are experienced.
Long-term clearance from small airways in patients with cystic fibrosis
Authors: M. Lindström, P. Camner, R. Falk, L. Hjelte, K. Philipson, M. Svartengren
Journal: European Respiratory Journal (2005)

Impaired mucociliary clearance is a hallmark of cystic fibrosis (CF). Early morphological changes first appear in the small airways. Lung clearance was investigated in 11 young CF adults with mild-to-moderate lung disease using a method depositing particles mainly in the small airways. Radiolabelled Teflon particles (6 µm) were inhaled with an extremely slow inhalation flow, 0.05 L·s −1 . Lung retention was measured immediately following inhalations and, on four occasions up to 21 days. The results were compared with data from healthy subjects. The lung retention at 24 h in % of deposition was 67% (95% confidence interval 58–76) in the CF patients, compared to 48% (42–53) in the healthy subjects. Clearance on days 1–7 was larger in the CF patients, 22% (15–29) compared to the healthy subjects, 14% (12–16). No difference was observed between the CF patients and the healthy subjects in the slow clearance phase at day 7 to day 21, representing small airway clearance. Impaired mucociliary clearance in CF patients results in increased 24-h retention and a prolonged rapid clearance phase. The results of the study do not support the current authors' hypothesis that clearance from small airways is slower in cystic fibrosis patients compared to healthy subjects. Furthermore, the data suggest that mucociliary transport is not the dominant clearance mechanism in small airways.
A Critical Analysis of the Current Knowledge of Surgical Anatomy of the Prostate Related to Optimisation of Cancer Control and Preservation of Continence and Erection in Candidates for Radical Prostatectomy: An Update
Authors: Jochen Walz, Jonathan I. Epstein, Roman Ganzer, Markus Graefen, Giorgio Guazzoni, Jihad Kaouk, Mani Menon, Alexandre Mottrie, Robert P. Myers, Vipul Patel, Ashutosh Tewari, Arnauld Villers, Walter Artibani
Journal: European Urology (2016)
US healthcare industry sees NHS as “unopened oyster,” BMA conference told
Authors: Rebecca Coombes
Journal: BMJ (2004)

The BMA is to tackle ministers over concerns that NHS reforms are creating conditions in which international companies—chiefly from the United States—can intervene and run areas of health care.

A conference this week to debate the NHS Improvement Plan, published in June, heard fears that the new “payment by results” financial system, whereby hospitals are paid per patient according to a fixed tariff, could see units close if they failed to compete on price with alternative provision in the private sector.

Many delegates said they were doubtful whether the changes were in the interest of patient choice, as the government claimed.

Barbara Wood, joint chair of the BMA's Patient Liaison Group, said patients did not necessarily want a choice …
Isolation of modified ubiquitin as a neutrophil chemotaxis inhibitor from uremic patients.
Authors: G Cohen, M Rudnicki, W H Hörl
Journal: Journal of the American Society of Nephrology (1998)

Uremic toxins are factors that accumulate in the serum and peritoneal cavity of uremic patients. They are responsible for a variety of functional disturbances and also contribute to the increased risk of infection by interfering with essential functions of the unspecific immune response. From the peritoneal effluent of peritoneal dialysis (PD) patients, a peptide was isolated by applying three different chromatographic methods. This peptide inhibits the chemotactic movement of polymorphonuclear leukocytes (PMNL) in an in vitro assay in a concentration-dependent, nonreversible manner, and therefore belongs to the group of uremic toxins. Amino acid sequencing showed that the isolated peptide has the same amino terminal sequence as ubiquitin. The peptide also reacted with anti-ubiquitin antibodies in a Western blot experiment, but had a more acidic isoelectric point than ubiquitin. By using affinity chromatography, anti-ubiquitin antibody binding fractions were isolated from all PD and hemodialysis (HD) patients investigated. These fractions contained the same acidic band and also significantly inhibited PMNL chemotaxis. Ubiquitin per se had no effect on PMNL chemotaxis. Therefore, it is concluded that from PD and HD patients a modified form of ubiquitin was isolated, and this modification was responsible for its inhibitory effect.
Effect of Variation of Transmural Pressure on the Frequency Response of Isolated Segments of Canine Carotid Arteries
Authors: KENNETH J. HUTCHISON
Journal: Circulation Research (1974)

The frequency-response curve of isolated canine arterial segments at transmural pressures between 140 and 40 mm Hg showed an initial constant-amplitude portion over the lower frequency range followed by one or two major amplitude peaks (resonances) at higher frequencies. At lower transmural pressures, the response was more damped and resonances were infrequent. The amplitude of the flat portion of the curve increased as transmural pressure was decreased, and thus the dynamic modulus of elasticity calculated at 10 Hz decreased. The static modulus behaved in a similar fashion, but it was always lower than the dynamic modulus. The resonances shifted to lower frequencies as transmural pressure was decreased, and thus the dynamic modulus of elasticity calcuwall stiffness. Two series of five arteries each were examined; in one series the arteries were mounted with a fixed 50% longitudinal elongation and in the other series they were mounted with variable, mean 85%, longitudinal elongations. The difference between the two series suggests that increasing longitudinal elongation markedly increases the frequency shift induced by transmural pressure of one of the resonances and may result in coincidence of the two resonances at a given transmural pressure which varies from artery to artery.
Enteromegaly and cardiomegaly in Chagas disease
Authors: F. Koberle
Journal: Gut (1963)

Chagas disease due to a trypanosome infection may lead to extensive destruction of ganglion cells in the peripheral autonomic system and may result in gross enlargement of the oesophagus, colon, and heart. From studies on nerve cell counts it is concluded that the number of ganglion cells in the oesophagus must be reduced to less than half to produce functional disturbances in the oesophagus and to one tenth to produce a megaoesophagus. Problems of terminology are discussed.
Noninvasive Molecular Imaging of Hypoxia in Human Xenografts: Comparing Hypoxia-Induced Gene Expression with Endogenous and Exogenous Hypoxia Markers
Authors: Fuqiu He, Xuelong Deng, Bixiu Wen, Yueping Liu, Xiaorong Sun, Ligang Xing, Akiko Minami, Yunhong Huang, Qing Chen, Pat B. Zanzonico, C. Clifton Ling, Gloria C. Li
Journal: Cancer Research (2008)

Abstract Tumor hypoxia is important in the development and treatment of human cancers. We have developed a novel xenograft model for studying and imaging of hypoxia-induced gene expression. A hypoxia-inducible dual reporter herpes simplex virus type 1 thymidine kinase and enhanced green fluorescence protein (HSV1-TKeGFP), under the control of hypoxia response element (9HRE), was stably transfected into human colorectal HT29 cancer cells. Selected clones were further enriched by repeated live cell sorting gated for hypoxia-induced eGFP expression. Fluorescent microscopy, fluorescence-activated cell sorting, and radioactive substrate trapping assays showed strong hypoxia-induced expression of eGFP and HSV1-tk enzyme in the HT29-9HRE cells in vitro. Sequential micropositron emission tomography (PET) imaging of tumor-bearing animals, using the hypoxic cell tracer 18F-FMISO and the reporter substrate 124I-FIAU, yielded similar tumor hypoxia images for the HT29-9HRE xenograft but not in the parental HT29 tumor. Using autoradiography and IHC, detailed spatial distributions in tumor sections were obtained and compared for the following hypoxia-associated biomarkers in the HT29-9HRE xenograft: 124I-FIAU, 18F-FMISO, Hoechst (perfusion), lectin-TRITC (functional blood vessels), eGFP, pimonidazole, EF5, and CA9. Intratumoral distributions of 124I-FIAU and 18F-FMISO were similar, and eGFP, pimonidazole, EF5, and CA9 colocalized in the same areas but not in well-perfused regions that were positive for Hoechst and lectin-TRITC. In enabling the detection of hypoxia-induced molecular events and mapping their distribution in vivo with serial noninvasive positron emission tomography imaging, and multiple variable analysis with immunohistochemistry and fluorescence microscopy, this human xenograft model provides a valuable tool for studying tumor hypoxia and in validating existing and future exogenous markers for tumor hypoxia. [Cancer Res 2008;68(20):8597–606]
25-Hydroxyvitamin D Levels Inversely Associate with Risk for Developing Coronary Artery Calcification
Authors: Ian H. de Boer, Bryan Kestenbaum, Abigail B. Shoben, Erin D. Michos, Mark J. Sarnak, David S. Siscovick
Journal: Journal of the American Society of Nephrology (2009)

Vitamin D deficiency associates with increased risk for cardiovascular events and mortality, but the mechanism driving this association is unknown. Here, we tested whether circulating 25-hydroxyvitamin D concentration associates with coronary artery calcification (CAC), a measure of coronary atherosclerosis, in the Multi-Ethnic Study of Atherosclerosis. We included 1370 participants: 394 with and 976 without chronic kidney disease (estimated GFR <60 ml/min per 1.73 m(2)). At baseline, CAC was prevalent among 723 (53%) participants. Among participants free of CAC at baseline, 135 (21%) developed incident CAC during 3 yr of follow-up. Lower 25-hydroxyvitamin D concentration did not associate with prevalent CAC but did associate with increased risk for developing incident CAC, adjusting for age, gender, race/ethnicity, site, season, physical activity, smoking, body mass index, and kidney function. Further adjustment for BP, diabetes, C-reactive protein, and lipids did not alter this finding. The association of 25-hydroxyvitamin D with incident CAC seemed to be stronger among participants with lower estimated GFR. Circulating 1,25-dihydroxyvitamin D concentrations among participants with chronic kidney disease did not significantly associate with prevalent or incident CAC in adjusted models. In conclusion, lower 25-hydroxyvitamin D concentrations associate with increased risk for incident CAC. Accelerated development of atherosclerosis may underlie, in part, the increased cardiovascular risk associated with vitamin D deficiency.
The Epidermal Growth Factor Receptor Pathway: A Model for Targeted Therapy
Authors: Maurizio Scaltriti, José Baselga
Journal: Clinical Cancer Research (2006)

Abstract The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase receptor that is frequently expressed in epithelial tumors. The EGFR was the first receptor to be proposed as a target for cancer therapy, and after 2 decades of intensive research, there are several anti-EGFR agents available in the clinic. Recent advances in our understanding in the mechanisms of receptor activation and function, discovery of primary and secondary EGFR somatic mutations, as well as a new generation of anti-EGFR agents provide new leads on the clinical targeting of this receptor and may serve as a model for strategies aimed at targeting other receptors.
Biological rationale for the use of DNA methyltransferase inhibitors as new strategy for modulation of tumor response to chemotherapy and radiation
Authors: Giovanni L Gravina, Claudio Festuccia, Francesco Marampon, Vladimir M Popov, Richard G Pestell, Bianca M Zani, Vincenzo Tombolini
Journal: Molecular Cancer (2010)

Epigenetic modifications play a key role in the patho-physiology of many tumors and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. DNA methyltransferase (DNMT) inhibitors represent a promising class of epigenetic modulators. Research performed yielded promising anti-tumorigenic activity for these agents in vitro and in vivo against a variety of hematologic and solid tumors. These epigenetic modulators cause cell cycle and growth arrest, differentiation and apoptosis. Rationale for combining these agents with cytotoxic therapy or radiation is straightforward since the use of DNMT inhibitor offers greatly improved access for cytotoxic agents or radiation for targeting DNA-protein complex. The positive results obtained with these combined approaches in preclinical cancer models demonstrate the potential impact DNMT inhibitors may have in treatments of different cancer types. Therefore, as the emerging interest in use of DNMT inhibitors as a potential chemo- or radiation sensitizers is constantly increasing, further clinical investigations are inevitable in order to finalize and confirm the consistency of current observations.The present article will provide a brief review of the biological significance and rationale for the clinical potential of DNMT inhibitors in combination with other chemotherapeutics or ionizing radiation. The molecular basis and mechanisms of action for these combined treatments will be discussed herein.
Drug points: Gabapentin induced cholestasis
Authors: C. E Richardson
Journal: BMJ (2002)

our results are representative.The MONICA project is well known and well regarded among the people in this part of Sweden, where it has been running since 1985, and the great willingness to give consent to genetic research emphasises the importance of close researcher-participant interaction.We conclude that (a) it is feasible to obtain individual consent for genetic research many years after blood was donated; (b) people's readiness to contribute to genetic research is high, at least in the framework of a carefully conducted study that is well known to the population; and (c) consent is given nearly as often for industrial genetic research as for academic genetic research, provided that the blood samples are anonymised and an ethics committee has approved the research.
ECMO in adults for severe respiratory failure finally comes of age: just in time?
Authors: S J Finney, J J Cordingley, M J D Griffiths, T W Evans
Journal: Thorax (2010)

The idea of employing cardiopulmonary bypass technology as a means of oxygenating (extracorporeal membrane oxygenation (ECMO)) or removing carbon dioxide (ECCO2R) in patients with acute respiratory failure (ARF) was first assessed in randomised controlled trials in the 1970s and 1980s.1 2 Poor rates of survival and major complications, particularly massive haemorrhage, led to most intensivists believing that ECMO was inappropriate in adults. A small number of centres worldwide—including that in Leicester, UK—continued to refine the use of ECMO in small numbers of adult patients whom it proved impossible to oxygenate by conventional means. Following the publication of their case series with improved results,3 Peek and colleagues embarked upon a randomised controlled trial of conventional ventilation or ECMO in patients with severe ARF (CESAR), the results of which have just been reported.4

Patients (n=766) were screened for inclusion over a 5-year period and those with potentially reversible severe ARF (defined as a Murray score >3 or …
Decreased expression of TGF- type II receptor in bronchial glands of smokers with COPD
Authors: S Baraldo
Journal: Thorax (2005)

<b>Background:</b> The role of transforming growth factor-β<sub>1</sub> (TGF-β<sub>1</sub>) in chronic obstructive pulmonary disease is still controversial, but it has been proposed that it may protect from mucus hypersecretion since it is able to downregulate mucin production. A study was undertaken to investigate the expression of TGF-β<sub>1</sub> and its type II receptor (TGF-β RII) in the bronchial glands of smokers with COPD. <b>Methods:</b> The expression of TGF-β<sub>1</sub> and TGF-β RII were examined immunohistochemically in the bronchial glands of 24 smokers undergoing lung resection for solitary peripheral nodules: 12 with airflow limitation (smokers with COPD) and 12 with normal lung function. <b>Results:</b> The expression of TGF-β<sub>1</sub> in bronchial glands was similar in the two groups of subjects while that of TGF-β RII was lower in smokers with COPD than in smokers with normal lung function (p = 0.004). TGF-β RII expression was inversely correlated with the values of Reid's index, a measure of gland size (p = 0.02, <i>r</i> = −0.50). <b>Conclusions:</b> In the bronchial glands of smokers with COPD there is decreased expression of TGF-β RII which is associated with bronchial gland enlargement. These findings support the view that the absence of TGF-β signalling may induce structural changes in the bronchial glands which, in turn, may promote mucus hypersecretion.