tbuckley/cabot-search huggingface dataset:
Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals.
Authors: A Meyer, R Buhl, S Kampf, H Magnussen
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Idiopathic pulmonary fibrosis (IPF) is characterized by a huge alveolar oxidant burden and a deficiency of glutathione, a major antioxidant, in the pulmonary epithelial lining fluid (ELF). Therefore, a rational therapeutic strategy is to increase lung glutathione to augment the pulmonary antioxidant protective screen. To evaluate this concept, different doses of N-acetylcysteine (NAC), a glutathione precursor, were administered intravenously to eight patients with pulmonary fibrosis and six control subjects. In patients, bronchoalveolar lavage fluid (BALF) total glutathione increased significantly from 0.99 +/- 0.25 microM to 1.79 +/- 0.37 microM within 3 h following 1.8 g NAC, whereas 4.8 g NAC had no additional effect (1.47 +/- 0.34 microM). In the control subjects, NAC did not significantly alter BALF total glutathione (baseline: 0.79 +/- 0.17 microM, 600 mg NAC: 0.92 +/- 0.33 microM, 1.8 g NAC: 1.39 +/- 0.41 microM, 4.8 g NAC: 1.33 +/- 0.46 microM). The same was true in ELF, 1.8 g NAC significantly raised ELF total glutathione in patients from 186 +/- 47 microM to near normal levels (373 +/- 103 microM), with no further increase following 4.8 g NAC (293 +/- 62 microM). In the control subjects, ELF total glutathione remained unchanged independent of the NAC dose (baseline: 342 +/- 91 microM, 600 mg NAC: 385 +/- 135 microM, 1.8 g NAC: 633 +/- 220 microM, 4.8 g NAC: 646 +/- 263 microM). The increases in total glutathione were almost entirely due to increased levels of reduced glutathione, the form functional as an antioxidant. No adverse effects were noted.(ABSTRACT TRUNCATED AT 250 WORDS)
An NMR Metabolomics Approach for the Diagnosis of Leptomeningeal Carcinomatosis
Authors: Hye Rim Cho, He Wen, Young Jin Ryu, Yong Jin An, Hyo Cheol Kim, Woo Kyung Moon, Moon Hee Han, Sunghyouk Park, Seung Hong Choi
Journal: Cancer Research (2012)

Leptomeningeal carcinomatosis (LC) is the third most common metastatic complication of the central nervous system. However, the current modalities to reliably diagnose this condition are not satisfactory. Here, we report a preclinical proof of concept for a metabolomics-based diagnostic strategy using a rat LC model incorporating glioma cells that stably express green fluorescent protein. Cytologic diagnoses gave 66.7% sensitivity for the 7-day LC group and 0% for the 3-day LC group. MR imaging could not diagnose LC at these stages. In contrast, nuclear magnetic resonance-based metabolomics on cerebrospinal fluid detected marked differences between the normal and LC groups. Predictions based on the multivariate model provided sensitivity, specificity, and overall accuracy of 88% to 89% in both groups for LC diagnosis. Further statistical analyses identified lactate, acetate, and creatine as specific for the 7-day LC group, with glucose a specific marker of the normal group. Overall, we showed that the metabolomics approach provided both earlier and more accurate diagnostic results than cytology and MR imaging in current use.
Postinterferon α-fetoprotein elevation and risk of hepatocellular carcinoma development after sustained virological response: Cause or results?
Authors: Hidenori Toyoda, Takashi Kumada, Toshifumi Tada
Journal: Hepatology (2014)

We read with interest the article by Asahina et al.,1 which clearly demonstrated a higher incidence of hepatocellular carcinoma (HCC) in patients with higher levels of α-fetoprotein (AFP) after interferon-based antiviral therapy. There was a surprisingly high incidence of HCC (almost 50%) in patients who achieved sustained virological response (SVR) but whose postinterferon (IFN) AFP levels were higher than 20 ng/mL. There are two distinct patterns of HCC development after SVR. In one pattern, HCC develops after the eradication of hepatitis C virus (HCV). This pattern is associated with the residual potential for hepatocarcinogenesis after SVR, which may be signaled by elevated AFP after IFN. The other pattern involves HCC that was too minute to be detected before and just after IFN treatment, but grew enough to be visualized on imaging studies during post-SVR follow-up. Previous studies of HCC tumor volume doubling time suggest that some minute HCC tumors would take several years to be detected by imaging modalities.2 Some patients who achieved SVR, therefore, might have had minute, undetectable HCC at the time of SVR. Although the authors described excluding patients with HCC based on imaging studies, such modalities always have limitations in their ability to detect minute HCC (for example, <5 mm in diameter). In particular, the ability of imaging modalities to detect minute HCC was unsatisfactory during the earlier part of the study period (1990s). Their Fig. 2F suggests a specific feature in the cumulative incidence curves for HCC based on post-IFN AFP levels in patients with SVR. Among patients who did not achieve SVR, the incidence of HCC continued to increase gradually according to the number of years after SVR. This includes patients with high post-IFN AFP levels, whose HCC incidence curves were similar to incidence curves stratified by post-IFN ALT levels. In contrast, in patients with SVR, cumulative HCC incidence curves according to post-IFN AFP levels were different. The incidence of HCC in patients with post-IFN AFP ≥20 ng/mL and with post-IFN AFP ≥10 ng/mL and <20 ng/mL increased rapidly until 3 to 4 years after SVR, with only a few patients developing HCC thereafter. This feature could be due to the detection of preexisting minute HCC after SVR. Was the post-IFN AFP elevation observed in these patients a marker of enhanced hepatocarcinogenesis or an existing HCC? It will be difficult to determine whether elevated levels of AFP were produced by HCC without visible HCC on imaging studies. It would be interesting to check the fucosylated fraction of AFP (AFP-L3), a more specific marker that has been reported as a marker of minute HCC,3 if post-IFN AFP-L3 data were available. Hidenori Toyoda, M.D., Ph.D. Takashi Kumada, M.D., Ph.D. Toshifumi Tada, M.D. Department of Gastroenterology Ogaki Municipal Hospital Ogaki, Gifu, Japan
P01.23 * NEUROTENSIN PROMOTES THE PROGRESSION OF MALIGNANT GLIOMA THROUGH NTSR1 AND IMPACTS THE PROGNOSIS OF GLIOMA PATIENTS
Authors: L. Yi, M. Xu, L. Xu, H. Feng, H. Cui
Journal: Neuro-Oncology (2014)

BACKGROUND: Neurotensin (NTS) functions as a neuromodulator and induces cellular proliferation and migration in various solid tumors. However, whether NTS can promote the progression of malignant glioma and its prognostic significance for glioma patients remain unclear. METHODS: NTS and its high-affinity receptor (NTSR1) expression levels in clinical glioma samples were detected by immunohistochemistry and immunobloting. The prognostic analysis in glioma patients were conducted online by R2 microarray analysis and the visualization platform. The proliferation of glioma cells were evaluated by CCK8 and BrdU incorporation assay. The celluar invasiveness were tested by wound healing model and the Matrigel transwell assay. A neutralizing antibody to NTS, NTSR1-selective antagonist SR48692 and NTSR1-siRNA were used to suppress the NTS stimulation. Erk1/2 phosphorylation was tested by immunobloting. The orthotopic glioma implantation model was established to examine the role of NTS and NTSR1 in the progression of glioma in vivo. RESULTS: Positive correlations were shown between the expression levels of NTS and NTSR1 with the pathological grade of gliomas. The high levels of NTS and NTSR1 expression indicate a worse prognosis in glioma patients. The proliferation and invasiveness of glioma cells could be enhanced by NTS stimulation and impaired by the inhibition of NTSR1 functions. NTS stimulated Erk1/2 phosphorylation in glioma cells, which could be reversed by treatment with SR48692 or NTSR1-siRNA. In vivo experiments showed that therapy with SR48692 significantly prolonged the survival length of glioma-bearing mice and inhibited glioma cell invasiveness in vivo. CONCLUSIONS: NTS promotes the proliferation and invasion of glioma via the activation of NTSR1 and its downstream signaling molecules, resulting in Erk1/2 phosphorylation. High levels of NTS and NTSR1 expression predict a bad prognosis in glioma patients.
Critical role of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of inflammation-driven dermal fibrosis in a mouse model of systemic sclerosis
Authors: Jérôme Avouac, Muriel Elhai, Michal Tomcik, Barbara Ruiz, Manuel Friese, Melanie Piedavent, Marco Colonna, Gunter Bernhardt, André Kahan, Gilles Chiocchia, Jörg H W Distler, Yannick Allanore
Journal: Annals of the Rheumatic Diseases (2012)

Objective To investigate the contribution of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of dermal fibrosis on gene inactivation and targeted molecular strategies. Methods Human skin expression of DNAM-1 was determined by immunohistochemistry. Mice deficient for DNAM-1 (dnam1 −/− ) and wild-type controls (dnam1 +/+ ) were injected with bleomycin or NaCl. Infiltrating leucocytes, T cells, B cells and monocytes were quantified and inflammatory cytokines were measured in lesional skin of dnam1 −/− and dnam1 +/+ mice. The anti-fibrotic potential of a DNAM-1 neutralising monoclonal antibody (mAb) was evaluated in the mouse model of bleomycin-induced dermal fibrosis. Results Overexpression of DNAM-1 was detected in the skin of patients with SSc (systemic sclerosis). Dnam1 −/− mice were protected from bleomycin-induced dermal fibrosis with reduction of dermal thickening (75±5%, p=0.03), hydroxyproline content (46±8%, p=0.04) and myofibroblast counts (39±5%, p=0.01). Moreover, the number of T cells was significantly decreased in lesional skin of dnam1 −/− mice (69±15%, p=0.0007). Dnam1 −/− mice also displayed decreased levels of TNF-α and IL-6 in lesional skin. Consistent with the gene inactivation strategy, treatment of mice with DNAM-1 neutralising mAb prevented dermal fibrosis induced by bleomycin with reduction of dermal thickness (64±6%, p=0.002), hydroxyproline content (61±8%, p=0.004) and myofibroblast counts (83±12%, p=0.002). Conclusions An inactivation gene strategy showed that DNAM-1 exerts profibrotic effects by controlling T cell activation and cytokine release. A molecular targeted strategy confirmed that DNAM-1 neutralising mAb has potent antifibrotic properties, supporting the hypothesis that inhibition of DNAM-1 might be a promising new approach for the treatment of SSc and potentially other related fibrotic diseases.
miR-133b, a muscle-specific microRNA, is a novel prognostic marker that participates in the progression of human colorectal cancer via regulation of CXCR4 expression
Authors: Fang-Ting Duan, Feng Qian, Ke Fang, Kang-Yu Lin, Wen-Tao Wang, Yue-Qin Chen
Journal: Molecular Cancer (2013)

Abstract Background MicroRNA-133b (miR-133b), which is a muscle-specific microRNA, has been reported to be downregulated in human colorectal carcinoma (CRC) when compared to adjacent non-tumor tissue. However, its diagnostic value and role in CRC have yet to be described. CXC chemokine receptor-4 (CXCR4), which participates in multiple cell processes such as cell invasion-related signaling pathways, was predicted to be a potential target of miR-133b. The aim of this study was to investigate the associations and functions of miR-133b and CXCR4 in CRC initiation and invasion. Methods Mature miR-133b and CXCR4 expression levels were detected in 31 tumor samples and their adjacent, non-tumor tissues from patients with CRC, as well as in 6 CRC cell lines, using real-time quantitative RT-PCR (qRT-PCR). Luciferase reporter assays and Western blots were used to validate CXCR4 as a putative target gene of miR-133b. Regulation of CXCR4 expression by miR-133b was assessed using qRT-PCR and Western blot analysis, and the effects of exogenous miR-133b and CXCR4 on cell invasion and migration were evaluated in vitro using the SW-480 and SW-620 CRC cell lines. Results A significant downregulation of miR-133b was observed in 93.55% of CRC tissues, and the expression of miR-133b was much lower in metastatic tumors (stage C and D, stratified by the Modified Dukes Staging System) than in primary tumors (stage A and B). In contrast, CXCR4 protein expression significantly increased in 52.63% of CRC samples, and increased CXCR4 expression in CRC was associated with advanced tumor stage. CXCR4 was shown to be a direct target of miR-133b by luciferase reporter assays, and transfection of miR-133b mimics inhibited invasion and stimulated apoptosis of SW-480 and SW-620 CRC cells. Conclusions Our study demonstrated that downregulated miR-133b contributed to increased cell invasion and migration in CRC by negatively regulating CXCR4. These findings may be significant for the development of therapy target for CRC.
Interferon alpha treatment and endocrine disease
Authors: W. B. Chan, C. C. Chow, C. S. Cockram
Journal: Journal of the Royal Society of Medicine (2003)

The interferons are a group of proteins with antiviral activity, growth regulatory properties, and a wide variety of immunomodulatory activities. There is evidence that, when interferon α is used therapeutically in chronic hepatitis B and C and in certain malignancies,1-5 it can precipitate or exacerbate autoimmune endocrine diseases, especially of the thyroid gland.6 In this review we examine the published information on such unwanted effects.
The Circadian Clock Modulates Renal Sodium Handling
Authors: Svetlana Nikolaeva, Sylvain Pradervand, Gabriel Centeno, Vlasta Zavadova, Natsuko Tokonami, Marc Maillard, Olivier Bonny, Dmitri Firsov
Journal: Journal of the American Society of Nephrology (2012)

The circadian clock contributes to the control of BP, but the underlying mechanisms remain unclear. We analyzed circadian rhythms in kidneys of wild-type mice and mice lacking the circadian transcriptional activator clock gene. Mice deficient in clock exhibited dramatic changes in the circadian rhythm of renal sodium excretion. In parallel, these mice lost the normal circadian rhythm of plasma aldosterone levels. Analysis of renal circadian transcriptomes demonstrated changes in multiple mechanisms involved in maintaining sodium balance. Pathway analysis revealed the strongest effect on the enzymatic system involved in the formation of 20-HETE, a powerful regulator of renal sodium excretion, renal vascular tone, and BP. This correlated with a significant decrease in the renal and urinary content of 20-HETE in clock-deficient mice. In summary, this study demonstrates that the circadian clock modulates renal function and identifies the 20-HETE synthesis pathway as one of its principal renal targets. It also suggests that the circadian clock affects BP, at least in part, by exerting dynamic control over renal sodium handling.
Post-marketing surveillance of adverse reactions to new medicines.
Authors: A B Wilson
Journal: BMJ (1977)

The occurrence of the oculomucocutaneous syndrome with practololl has led to a wide debate on the need to review current procedures and to consider new methods for more quickly recognising and, if possible, quantifying unusual and low frequency adverse reactions to new medicines. The Committee on Safety of Medicines (CSM) is considering the situation and is planning to consult the professions, the phar maceutical industry, and other interested parties before advising on what action may be necessary. I Adverse reactions that occur with any new medicine after marketing fall into two classes, either foreseeable or unforesee able, in the light of the total evidence that has been accumulated up to the stage of marketing approval. What steps are now taken to minimise the risk to the patient for each class of adverse response ?
Functional gastrointestinal disorders: psychological, social, and somatic features
Authors: E J Bennett, C Piesse, K Palmer, C-A Badcock, C C Tennant, J E Kellow
Journal: Gut (1998)

Background —Psychological, social, and extraintestinal (somatic) disturbances are prominent features of functional gastrointestinal disorders (FGID); little attention, however, has been given to differences in the nature of these disturbances in the various FGID subgroups. Aims —(1) To determine whether psychological, social, and extraintestinal factors are associated with specific FGID, and/or with the overall severity and extent of FGID disturbance (the number of coexistent FGID subgroups present in any individual); and (2) to determine whether chronic social stressors link gastrointestinal, extraintestinal, and emotional symptomatologies in FGID. Patients —One hundred and eighty eight outpatients, fulfilling standard criteria for one or more functional gastroduodenal or functional bowel disorders. Methods —Utilising detailed and objective interview and questionnaire methods, detailed gastrointestinal, extraintestinal, psychological, and social data were collected. Results —Chronic stressors and extraintestinal and emotional symptomatologies were prominent features of functional dyspepsia (FD) and irritable bowel syndrome (IBS) alone. These particular features were, however, highly specific for particular FD and/or IBS subgroups. The chronic threat component of social stressors predicted the nature and extent of multisystem (gastrointestinal, extraintestinal, and emotional) symptomatology. Conclusions —Notable differences between the various FGID subgroups support the symptom based classification of FGID. Chronic stressor provoked psychological and extraintestinal disturbance is most specific for the FD-IBS group of syndromes.
Tbx5 Is Required for Avian and Mammalian Epicardial Formation and Coronary Vasculogenesis
Authors: Nata Y.S.-G. Diman, Gabriel Brooks, Boudewijn P.T. Kruithof, Olivier Elemento, J.G. Seidman, Christine E. Seidman, Craig T. Basson, Cathy J. Hatcher
Journal: Circulation Research (2014)

Holt-Oram syndrome is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. Overexpression of Tbx5 in the chick proepicardial organ impaired coronary blood vessel formation. However, the potential activity of Tbx5 in the epicardium itself, and the role of Tbx5 in mammalian coronary vasculogenesis, remains largely unknown.To evaluate the consequences of altered Tbx5 gene dosage during proepicardial organ and epicardial development in the embryonic chick and mouse.Retroviral-mediated knockdown or upregulation of Tbx5 expression in the embryonic chick proepicardial organ and proepicardial-specific deletion of Tbx5 in the embryonic mouse (Tbx5(epi-/)) impaired normal proepicardial organ cell development, inhibited epicardial and coronary blood vessel formation, and altered developmental gene expression. The generation of epicardial-derived cells and their migration into the myocardium were impaired between embryonic day (E) 13.5 to 15.5 in mutant hearts because of delayed epicardial attachment to the myocardium and subepicardial accumulation of epicardial-derived cells. This caused defective coronary vasculogenesis associated with impaired vascular smooth muscle cell recruitment and reduced invasion of cardiac fibroblasts and endothelial cells into myocardium. In contrast to wild-type hearts that exhibited an elaborate ventricular vascular network, Tbx5(epi-/-) hearts displayed a marked decrease in vascular density that was associated with myocardial hypoxia as exemplified by hypoxia inducible factor-1α upregulation and increased binding of hypoxyprobe-1. Tbx5(epi-/-) mice with such myocardial hypoxia exhibited reduced exercise capacity when compared with wild-type mice.Our findings support a conserved Tbx5 dose-dependent requirement for both proepicardial and epicardial progenitor cell development in chick and in mouse coronary vascular formation.
Asymptomatic Liver Cell Adenomas
Authors: William L. Ramseur
Journal: JAMA (1978)

THERE has been a substantial increase in the frequency of adenomas of the liver in young women in the last few years. A large number of these women have been taking long-term oral contraceptives. With increased awareness of this problem, more asymptomatic women are being detected. The opinion concerning the surgical approach for an asymptomatic intrahepatic adenoma has varied mainly because of the lack of information regarding its natural history, the uncertainty of resolution after hormone withdrawal, and the fear of spontaneous hemorrhage. The evidence correlating oral contraceptive use and the onset of liver tumors has been circumstantial, and there have been reports of these tumors occurring in patients who do not take oral contraceptives. This case, in addition to others described recently showing tumor regression following the withdrawal of oral contraceptive use, lends more support to the etiologic role of oral contraceptives in these tumors. <h3>Report of a Case</h3>
Elevated Serum Ferritin Concentrations in a Glucose-Impaired Population and in Normal Glucose Tolerant First-Degree Relatives in Familial Type 2 Diabetic Pedigrees
Authors: Yan Ren, Haoming Tian, Xiujun Li, Jinzhong Liang, Guizhi Zhao
Journal: Diabetes Care (2004)

Two large epidemiological studies have recently reported a strong association between elevated serum ferritin concentration and increased risk for diabetes (1,2). Moreover, other studies have revealed the relationship among excess ferritin, coronary heart disease, and insulin resistance and have therefore renewed interest in ferritin as a risk factor for diabetes.

This study further investigates the association between ferritin metabolism and different status of glucose tolerance, including 121 type 2 diabetic subjects, 86 impaired glucose tolerant (IGT) subjects, 58 normal glucose tolerant (NGT) first-degree relatives in type 2 diabetic pedigrees, and 85 healthy control subjects. All patients underwent an oral glucose tolerance test (OGTT) and insulin release tests after 8 h of fasting, and blood levels of ferritin, HbA1c, glucose, insulin, C-peptide, and lipids were measured. Serum ferritin levels were measured with the radioimmunoassay kit (Beijing …
US GPs are unhappy, underpaid, deluged by paperwork, and want to retire, study says
Authors: J. Hopkins Tanne
Journal: BMJ (2008)

Primary care doctors in the United States are unhappy, a survey has found. The non-profit making Physicians’ Foundation received almost 12 000 responses from a survey of 270 000 primary care doctors and more than 50 000 specialists, a response rate of less than 4%.

Although 78% of the doctors who responded think that there is a shortage of primary care doctors, half of them plan to reduce the number of patients they see or to stop practising in the next three years. This is bad news when the new administration under President Barack Obama seeks to increase the availability of health care.

“Combine these statistics with recent studies showing that medical schools are graduating fewer and fewer students …
TCTAP A-168 Five-year Clinical Follow-up of Long Paclitaxel Drug Eluting Stents
Authors: Karthik Tummala, Vijay Maniyal, Rajiv Chandrashekaran, Natarajan Kumaraswamy, Rajesh Thachitodiyl, Prakash Kamath
Journal: Journal of the American College of Cardiology (2014)