tbuckley/cabot-search huggingface dataset:
Mutagenicity and Potential Carcinogenicity of Thiopurine Treatment in Patients with Inflammatory Bowel Disease
Authors: Truc Nguyen, Pamela M. Vacek, Patrick O'Neill, Richard B. Colletti, Barry A. Finette
Journal: Cancer Research (2009)

The thiopurines azathioprine and 6-mercaptopurine (6-MP) are effective immune modulators and cytotoxic agents extensively used in the treatment of autoimmune diseases, graft rejection, and cancer. There is compelling epidemiologic evidence that thiopurine treatment increases the risk for a variety of tumors by mechanisms that are unclear. We investigated the in vivo mutagenicity of long-term thiopurine treatment by determining the frequency and spectra of somatic mutation events at the hypoxanthine phosphoribosyltransferase (HPRT) locus in peripheral T lymphocytes as well as the prevalence of mutant clonal proliferation in a cross-sectional analysis of data from 119 children and adults with inflammatory bowel disease (IBD). ANOVA and regression were performed to assess relationships among the frequency and spectra of HPRT mutations with disease, duration of illness, duration of treatment, and total therapeutic dose of azathioprine and 6-MP. We observed a significant increase in the frequency of somatic mutations in 56 subjects treated with thiopurines for IBD compared with 63 subjects not treated with thiopurines. This increase was related to both total dose (P < 0.001) and duration of treatment (P < 0.001). Comparative mutation spectra analysis of 1,020 mutant isolates revealed a significant increase in the proportion of all transitions (P < 0.001), particularly G:C to A:T transitions (P < 0.001). Combined analyses of two signatures for mutant clonality, HPRT mutation, and T-cell receptor beta CDR3 region unique gene sequence also showed a significant thiopurine-dependent increase in mutant cell clonal proliferation (P < 0.001). These findings provide in vivo evidence for mutation induction as a potential carcinogenic mechanism associated with chronic thiopurine intervention.
Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis inob/ob mice
Authors: Xiaokun Ding, Neeraj K. Saxena, Songbai Lin, Narita Gupta, Frank A. Anania
Journal: Hepatology (2005)

Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning problem in hepatology, and is associated with insulin resistance. Exendin-4 is a peptide agonist of the glucagon-like peptide (GLP) receptor that promotes insulin secretion. The aim of this study was to determine whether administration of Exendin-4 would reverse hepatic steatosis in ob/ob mice. Ob/ob mice, or their lean littermates, were treated with Exendin-4 [10 μg/kg or 20 μg/kg] for 60 days. Serum was collected for measurement of insulin, adiponectin, fasting glucose, lipids, and aminotransferase concentrations. Liver tissue was procured for histological examination, real-time RT-PCR analysis and assay for oxidative stress. Rat hepatocytes were isolated and treated with GLP-1. Ob/ob mice sustained a reduction in the net weight gained during Exendin-4 treatment. Serum glucose and hepatic steatosis was significantly reduced in Exendin-4 treated ob/ob mice. Exendin-4 improved insulin sensitivity in ob/ob mice, as calculated by the homeostasis model assessment. The measurement of thiobarbituric reactive substances as a marker of oxidative stress was significantly reduced in ob/ob-treated mice with Exendin-4. Finally, GLP-1–treated hepatocytes resulted in a significant increase in cAMP production as well as reduction in mRNA expression of stearoyl-CoA desaturase 1 and genes associated with fatty acid synthesis; the converse was true for genes associated with fatty acid oxidation. In conclusion, Exendin-4 appears to effectively reverse hepatic steatosis in ob/ob mice by improving insulin sensitivity. Our data suggest that GLP-1 proteins in liver have a novel direct effect on hepatocyte fat metabolism. (HEPATOLOGY 2006;43:173–181.)
Acute renal failure after infusion of gelatins.
Authors: S. F. Hussain, P. J. Drew
Journal: BMJ (1989)

Women recruited 86 Chlamydia negative (46 normal at vaginal examination) 12 Chlamydia positive (2 normal at vaginal examination) 5 Chlamydia test unsatisfactory (0 normal at vaginal examination) 11 Treated* I Untreated 79 Termination of pregnancyt 11 Termination I Termination 5 Termination 2 Infected after termination 0 Infected after termination I Infected after termination 2 Infected after termination 0 Chlamydia positive at onset of infection I Chlamydia positive at onset of infection I Chlamydia positive at onset of infection*Erythromycin stearate 500 mg four times a day for 10 days or doxycycline 200 mg daily for 10 days.tlnfection was defined clinically as any four of the following: temperature >38'C, increased vaginal bleeding, increased vaginal discharge, tendcr adnexial mass, and tenderness of the uterus or parametrium.
Interactions of bombesin and substance P at the feline lower esophageal sphincter.
Authors: J C Reynolds, M R Dukehart, A Ouyang, S Cohen
Journal: Journal of Clinical Investigation (1986)

The purpose of this study was to determine the interactions between bombesin and substance P at the feline lower esophageal sphincter (LES). Intraluminal pressures were recorded using a fixed, perfused catheter assembly. Myoelectrical activity was recorded using bipolar Ag-AgCl serosal electrodes. Bombesin, i.v., gave a dose-dependent increase in LES pressure and electronically counted spike activity. The threshold dose was 10(-7) g/kg, while the maximal dose, 10(-5) g/kg, increased LES pressure by 65.5 +/- 14.8 mmHg. The neuroantagonist, tetrodotoxin, decreased the LES response to bombesin by 74.1% +/- 7.9% (P less than 0.05), but had no significant effect on the LES response to substance P. The sphincteric response to bombesin was not inhibited by bilateral cervical vagotomy, atropine, propranolol, or phentolamine (P less than 0.10). Bombesin tachyphylaxis abolished the LES response to bombesin but had no effect on the response to substance P. Conversely, substance P tachyphylaxis completely abolished the LES response to bombesin (P less than 0.001). The substance P antagonist [D-Pro2, D-Trp7,9]substance P also significantly inhibited the LES response to bombesin (P less than 0.05). Acidification of the distal esophagus with 2.0 ml of 0.1 N HCl increased LES pressure by 32.5 +/- 5.2 mmHg (P less than 0.02). The LES response to acid was inhibited by bombesin tachyphylaxis (maximal pressure response, 4.7 +/- 2.1 mmHg, P less than 0.01 compared with control acid response). The tachyphylaxis techniques were specific for the peptides giving no effect on the LES responses to phenylephrine, bethanechol, or pentagastrin. We drew the following conclusions: (a) bombesin increased feline LES pressure via nonvagal neural pathways that were insensitive to adrenergic or cholinergic antagonists; (b) bombesin may be involved in the enteric pathways that mediate the feline LES response to distal esophageal acidification; and (c) substance P mediates the effect of bombesin at the LES and is a neurotransmitter in the LES response to acidification.
Methyldopa and propranolol or practolol in moderate hypertension.
Authors: J C Petrie, D B Galloway, T A Jeffers, H R Millar, M C Smith, R A Wood, J A Lewis, W T Simpson
Journal: BMJ (1976)

The effect of a low dose of methyldopa combined with (a) a non-selective and (b) a selective beta-adrenoceptor antagonist was studied in a double-blind crossover trial in 24 carefully selected patients with moderate hypertension (mean initial lying blood pressure 189/117 mm Hg). Each patient received methyldopa 750 mg/day, propranolol 240 mg/day, practolol 600 mg/day, methyldopa 750 mg/day combined with propranolol 240 mg/day, methyldopa 750 mg/day combined with practolol 600 mg/day, and placebo for four weeks each according to a random sequence. After four weeks of therapy the most effective treatment, methyldopa combined with propranolol, reduced lying and standing blood pressures by 36-5/21-4 mm Hg and 44-7/25 mm Hg respectively. Thic combination had similar effects to those of the combination of methyldopa with the cardioselective agent practolol except that it reduced lying diastolic pressure further. The combination was more effective than either treatment alone. No significant differences were found between the effects of propranolol, practolol, or methyldopa at the doses used.
Enteric-coated aspirin overdose and gastric perforation.
Authors: R J Farrand, J H Green, C Haworth
Journal: BMJ (1975)

Increase in serum cholesterol during phenytoin treatmentLong-term treatment with phenytoin is often accompanied by various metabolic and endocrine abnormalities.Particular attention has been paid to effects on pancreatic p-cells, where it inhibits the release of insulin and suppresses the response of plasma insulin to various stimuli.I Phenytoin also influences thyroid function, reducing serum levels of thyroid hormones and increasing thyroid-stimulating hormone.2Since serum lipid levels are increased in both insulin deficiency and thyroid hypofunction a prospective study of serum lipids, glucose tolerance, and insulin response in patients on phenytoin has been carried out. Patients, methods, and resultsEleven formerly untreated patients with epilepsy aged 15-58 years were studied before the institution of phenytoin treatment and 3, 6, 9, and 12 months afterwards.Their weights ranged from 89% to 116% of normal, and their serum cholesterol and triglyceride levels ranged from 4-7 to 9-4
Recent advances in the isolation of liver cells
Authors: Gianfranco Alpini, John O. Phillips, Benjamin Vroman, Nicholas F. Larusso
Journal: Hepatology (1994)

The development of new and refined separation techniques--including FACS, FFE, CFE and isopyknic gradients--has had a profound impact on the ability of investigators to isolate specific cell types from the liver. Although some of these techniques, such as FFE, may be of limited preparative value, they are nonetheless important analytical tools that detect subtle differences among cell subpopulations. The isolation of highly purified preparations of liver cells in large yields requires the use of more conventional purification methods such as CFE and isopyknic centrifugation. Immunological approaches represent a key development for the isolation of specific liver cell types, especially when they are used in combination with other techniques. Excellent, reliable and relatively simple techniques now exist to isolate highly purified preparations of hepatocytes, cholangiocytes, KCs, SCs, FSC, myofibroblasts and pit cells. Additional work is necessary to refine techniques for the isolation of dendritic cells and lymphocytes.
Diagnostic and prognostic value of Mycobacterium tuberculosis complex specific interferon gamma release assay in patients with tuberculous meningitis
Authors: Mukund R. Vidhate, Maneesh Kumar Singh, Ravindra Kumar Garg, Rajesh Verma, Rakesh Shukla, Madhu Mati Goel, Annu Makker, Amita Jain
Journal: Journal of Infection (2011)
Complementary modes of action of tissue-type plasminogen activator and pro-urokinase by which their synergistic effect on clot lysis may be explained.
Authors: R Pannell, J Black, V Gurewich
Journal: Journal of Clinical Investigation (1988)

Tissue plasminogen activator (t-PA) and/or pro-urokinase (pro-UK) induced lysis of standard 125I-fibrin clots suspended in plasma was studied. Doses were kept below the concentration at which a nonspecific effect was seen, i.e., where fibrinogenolysis and major plasminogen consumption were observed. Small amounts of t-PA potentiated clot lysis by pro-UK by attenuating the lag phase characteristic of pro-UK, and causing a much earlier transition to the rapid phase of lysis. Similar promotion of the fibrinolytic effect of pro-UK was obtained when clots were pretreated with UK or with a little plasmin (less than 1% clot lysis). Promotion by plasmin was nullified by a subsequent treatment of the clot with carboxypeptidase B, indicating that the plasmin effect was related to the exposure of carboxy terminal lysine residues on fibrin. These lysine termini, absent in undegraded fibrin, are known to be essential for the high affinity binding of plasminogen to fibrin. In contrast, clot lysis by t-PA was unaffected by plasmin pretreatment and little affected by carboxypeptidase B treatment of the fibrin substrate. Therefore, plasminogen bound to lysine termini on fibrin, although found to be essential for pro-UK, did not appear to serve as a substrate for t-PA. Selective activation of fibrin bound plasminogen has been attributed to the conformational change in Glu-plasminogen that occurs as a result of binding. The present findings suggest that this conformational change occurs when plasminogen is bound to a terminal lysine but not to an internal lysine. Plasminogen bound to the latter site on fibrin was activated by t-PA and therefore is involved in the ternary complex. This initiates lysis of the undegraded clot and exposes the plasminogen binding sites required by pro-UK. By their complementary activation of fibrin bound plasminogen, t-PA followed by pro-UK induces efficient and synergistic fibrinolysis, whereas each is relatively inefficient when used alone.
Granular Cell Tumor in Upper GI-tract Endoscopy Five Cases of Esophageal Location
Authors: E. Bayerdörffer, R. Ottenjann
Journal: Endoscopy (1986)

Five cases of esophageal granular cell tumor are reported with characteristics similar to those of benign tumors described previously. In contrast to previous reports these tumors are suitable for removal by endoscopic means, provided they are small and are strictly submucosal in location. This view is further supported by the still open discussion as to histogenesis, and the contradictory opinions on its biological significance. Owing to the increasingly widespread use of fiberoptic instruments the diagnosis "granular cell tumor" will become more common. The diagnosis must always be confirmed histologically. Since the tumor may invade adjacent tissue, or even show a tendency to malignant degeneration in late stages, endoscopic removal seems necessary.
Hypertonic Saline Nasal Provocation Stimulates Nociceptive Nerves, Substance P Release, and Glandular Mucous Exocytosis in Normal Humans
Authors: JAMES N. BARANIUK, MUSHTAQ ALI, ATSUSHI YUTA, SHEEN-YIE FANG, KRISTINA NARANCH
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Hypertonic saline (HTS) induces bronchoconstriction. Potential mechanisms were evaluated in a human nasal provocation model. Aliquots of normal saline (1 × NS, 100 μ l) and higher concentrations (3 × NS, 6 × NS, 12 × NS, 24 × NS) were sprayed into one nostril at 5-min intervals. Lavage fluids were collected from the ipsilateral and contralateral sides to determine the concentrations of specific mucus constituents. Nasal cavity air-space volume was assessed by acoustic rhinometry (AcRh). The distribution of substance-P-preferring neurokinin-1 (NK-1) receptor mRNA was assessed by in situ reverse transcriptase–polymerase chain reaction. Unilateral HTS induced unilateral dose-dependent increases in sensations of pain, blockage, and rhinorrhea, the weights of recovered lavage fluids, and concentrations of total protein, lactoferrin, mucoglycoprotein markers, and substance P. Contralateral, reflex-mediated effects were minor. There were no changes in IgG or AcRh measurements. NK-1 receptor mRNA was localized to submucosal glands. HTS caused pain with unilateral substance P release. The presumed nociceptive nerve efferent axon response led to glandular exocytosis, presumably through actions on submucosal gland NK-1 receptors. Vascular processes, including plasma exudation, filling of venous sinusoids, and mucosal edema were not induced in these normal subjects.
A man with hypertension and two murmurs
Authors: S. C. G. Rison, T. P. Locke, E. Rosenthal, S. Gandhi
Journal: BMJ (2012)

A 34 year old white man was referred by his general practitioner to our cardiology clinic with hypertension and a six month history of intermittent lower midsternal chest pain. The pain radiated to the left side of his back and was unrelated to physical exertion. He also reported two episodes of sudden onset dyspnoea, which lasted a few minutes, occurred at rest, and was not associated with chest pain or cardiac symptoms. He had not experienced such symptoms previously. His exercise tolerance was normal.

On examination, he was comfortable at rest. His heart rate was regular, at 80 beats/min. He had a large volume “collapsing” pulse, a prominent carotid pulse, and bounding peripheral pulses. His jugular venous pressure was not raised. There was no radioradial delay but radiofemoral delay was noted. His blood pressure was 210/70 mm Hg. The apex beat was visible and displaced 3 cm left of the midclavicular line in the fifth intercostal space. A left parasternal heave was noted. On auscultation, a loud early diastolic murmur and a systolic murmur were heard. Examination of the respiratory, abdominal, and neurological systems was unremarkable. Figure 1⇓ shows his chest radiograph.



Fig 1 Posteroanterior chest radiograph 





### 1 On the basis of the clinical findings and chest radiograph, what diagnoses can be made?

#### Short answer

Rib notching (fig 2⇓), cardiomegaly, loss of aortic knuckle, systolic hypertension, and systolic murmur are consistent with coarctation of the aorta; the widened pulse pressure, loud early diastolic murmur, and prominent carotid pulse suggest aortic valve regurgitation. The aortic valve is bicuspid, thus prone to regurgitation, in 20-85% of patients with coarctation.



Fig 2 Posteroanterior chest radiograph showing characteristic inferior rib notching (Roesler’s sign, red …
Dilated Cardiomyopathy Associated With Deficiency of the Cytoskeletal Protein Metavinculin
Authors: Masato Maeda, Emma Holder, Brian Lowes, Scott Valent, Roger D. Bies
Journal: Circulation (1997)

Background The cytoskeleton plays an important role in maintaining cell structure and integrity. Defects in cytoskeletal proteins can cripple cell strength and may cause cardiomyopathy. We analyzed heart tissues from subjects with dilated cardiomyopathy for abnormalities in the cardiac cytoskeleton. Metavinculin, a cardiac isoform of the cytoskeletal protein vinculin, connects actin microfilaments to the intercalated disk and membrane costameres of the heart. Methods and Results Metavinculin and vinculin transcripts and protein were analyzed by polymerase chain reaction (PCR) and Western blotting. Thirty-three human heart specimens were studied, including 5 normal controls, 4 subjects with ischemic cardiomyopathy, 1 with X-linked cardiomyopathy, and 23 with idiopathic dilated cardiomyopathy (IDC). PCR of cardiac cDNA detected absence of the metavinculin transcript in cardiac tissue from a subject with IDC. PCR of genomic DNA showed that the metavinculin exon was present but not utilized in the cardiac transcript. Western blot analysis demonstrated absence of metavinculin protein in the heart from this subject. Immunostaining of cardiac vinculin in this heart showed disorganized intercalated disk structures. Metavinculin deficiency was associated with normal cardiac expression of the cytoskeletal proteins vinculin, α-actinin, and dystrophin. Normal metavinculin expression in the other heart specimens suggests that the defect is specific in the IDC subject identified. Conclusions These results demonstrate an association between metavinculin deficiency and dilated cardiomyopathy due to a defect in alternative mRNA splicing.
Coarctation of the Aorta Associated with Patent Ductus Arteriosus
Authors: JACK C. COOLEY, JOHN W. KIRKLIN, O. THERON CLAGETT, JAMES D. DUSHANE, HOWARD B. BURCHELL, EARL H. WOOD
Journal: Circulation (1956)

The combination of patent ductus arteriosus and coarctation of the aorta poses special anatomic, physiologic and surgical problems. An experience with 14 such cases is presented, which suggests that pulmonary hypertension occurs frequently in these cases. Physiologic data in cases having coarctation of the aorta, patent ductus arteriosus and pulmonary hypertension that underwent cardiac catheterization are presented. Clinical, anatomic, physiologic and surgical implications of this combination are discussed.
Different immune mechanisms leading to autoimmunity in primary sclerosing cholangitis and autoimmune chronic active hepatitis of childhood
Authors: Glorgina Mieli-Vergani, Ava Lobo-Yeo, Barbara M. McFarlane, Ian G. McFarlane, Alex P. Mowat, Diego Vergani
Journal: Hepatology (1989)

Children with primary sclerosing cholangitis or autoimmune chronic active hepatitis have similar high levels of immunoglobulin G and non-organ-specific autoantibodies and may have similar histological features. To investigate a possible immunopathogenesis of primary sclerosing cholangitis, we have studied a series of regulatory and/or effector immune mechanisms in eight children with primary sclerosing cholangitis, comparing them to 14 children with autoimmune chronic active hepatitis and 24 healthy children as controls. Antibodies to a liver membrane protein preparation were found in all children with autoimmune chronic active hepatitis tested and in seven of eight with primary sclerosing cholangitis, whereas antibodies against the hepatic asialoglycoprotein receptor were present in three of six patients with autoimmune chronic active hepatitis and in two of the eight with primary sclerosing cholangitis. Lymphocyte cytotoxicity values to autologous hepatocytes were similarly elevated in primary sclerosing cholangitis (median: 50%; range: 38 to 83%) and in autoimmune chronic active hepatitis (median: 52%; range 37 to 87%) compared to controls (median: 8%; range: 0 to 27%) (p&lt;0.01 for both). In contrast, T suppressor cell number and function were normal in patients with primary sclerosing cholangitis (median: 23%; range: 19 to 28%; and median: 54%; range: 44 to 61%), but significantly decreased in patients with autoimmune chronic active hepatitis (median: 15%; range: 9 to 21%; and median: 9%; range: −40 to +21%) when compared to controls (median: 24%; range: 16 to 29%; and median: 53%; range: 8 to 77%) (p&lt;0.01 for both). While the percentage of T lymphocytes expressing the activation marker HLA-DR was similarly increased in primary sclerosing cholangitis (median: 5%; range: 2 to 6%) and in autoimmune chronic active hepatitis (median: 5%; range: 1 to 10%) compared to controls (median: 3%; range: 1 to 5%, p&lt;0.01 for both), the percentage of T lymphocytes expressing interleukin 2 receptors was greatly increased in autoimmune chronic active hepatitis (median: 19%; range: 12 to 22%) but normal in primary sclerosing cholangitis (median: 0%; range: 0 to 1%). These data suggest that liver-damaging effector mechanisms are similar in primary sclerosing cholangitis and autoimmune chronic active hepatitis but that factors leading to autoimmunity differ. Whereas in autoimmune chronic active hepatitis. autoimmunity probably derives from defective T-dependent immune regulation, in primary sclerosing cholangitis it could result from B lymphocyte activation bypassing T cells.
Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma
Authors: Dirk Hose, Thierry Rème, Tobias Meissner, Jérôme Moreaux, Anja Seckinger, Joe Lewis, Vladimir Benes, Axel Benner, Michael Hundemer, Thomas Hielscher, John D. Shaughnessy, Bart Barlogie, Kai Neben, Alwin Krämer, Jens Hillengass, Uta Bertsch, Anna Jauch, John De Vos, Jean-François Rossi, Thomas Möhler, Jonathon Blake, Jürgen Zimmermann, Bernard Klein, Hartmut Goldschmidt
Journal: Blood (2009)
Utility of peripheral blood for cytogenetic and mutation analysis in myelodysplastic syndrome
Authors: Azim M. Mohamedali, Heba Alkhatabi, Austin Kulasekararaj, Sneha Shinde, Syed Mian, Farooq Malik, Alexander E. Smith, Joop Gäken, Ghulam J. Mufti
Journal: Blood (2013)