tbuckley/cabot-search huggingface dataset:
Peptic ulceration, gastric secretion, and renal transplantation.
Authors: G D Chisholm, A D Mee, G Williams, J E Castro, J H Baron
Journal: BMJ (1977)

Fifty-four patients on haemodialysis for chronic renal failure underwent renal transplantation. Basal and maximum acid output and the incidence of peptic ulcer before transplantation were not significantly different from those of controls. But after renal transplantation the incidence of symptoms of peptic ulcer was high (22%) and four out of six patients who developed gastrointestinal bleeding died from this complication. In men peak acid output was significantly increased after renal transplantation and was associated with a 30% incidence of symptoms of peptic ulcer compared with 10% in women, who showed no significant change in mean basal or peak acid output. Peptic ulceration after transplantation was not associated with steroid dosage, hyperparathyroidism, or the height of blood urea concentrations. Given criteria of a history of dyspepsia, abnormal barium meal findings, or gastric hypersecretion, it was not possible to identify patients at risk from peptic ulceration or life-threatening complications after renal transplantation. Thus the routine screening of these patients for peptic ulcer has no practical value, and the incidence of fatal complications is not high enough to justify routine prophylactic anti-ulcer surgery aimed at reducing acid secretion before renal transplantation.
Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation.
Authors: H He, F J Giordano, R Hilal-Dandan, D J Choi, H A Rockman, P M McDonough, W F Bluhm, M Meyer, M R Sayen, E Swanson, W H Dillmann
Journal: Journal of Clinical Investigation (1997)

The Ca2+ ATPase of the sarcoplasmic reticulum (SERCA2) plays a dominant role in lowering cytoplasmic calcium levels during cardiac relaxation and reduction of its activity has been linked to delayed diastolic relaxation in hypothyroid and failing hearts. To determine the contractile alterations resulting from increased SERCA2 expression, we generated transgenic mice overexpressing a rat SERCA2 transgene. Characterization of a heterozygous transgenic mouse line (CJ5) showed that the amount of SERCA2 mRNA and protein increased 2. 6-fold and 1.2-fold, respectively, relative to control mice. Determination of the relative synthesis rate of SERCA2 protein showed an 82% increase. The mRNA levels of some of the other genes involved in calcium handling, such as the ryanodine receptor and calsequestrin, remained unchanged, but the mRNA levels of phospholamban and Na+/Ca2+ exchanger increased 1.4-fold and 1.8-fold, respectively. The increase in phospholamban or Na+/Ca2+ exchanger mRNAs did not, however, result in changes in protein levels. Functional analysis of calcium handling and contractile parameters in isolated cardiac myocytes indicated that the intracellular calcium decline (t1/2) and myocyte relengthening (t1/2) were accelerated by 23 and 22%, respectively. In addition, the rate of myocyte shortening was also significantly faster. In isolated papillary muscle from SERCA2 transgenic mice, the time to half maximum postrest potentiation was significantly shorter than in negative littermates. Furthermore, cardiac function measured in vivo, demonstrated significantly accelerated contraction and relaxation in SERCA2 transgenic mice that were further augmented in both groups with isoproterenol administration. Similar results were obtained for the contractile performance of myocytes isolated from a separate line (CJ2) of homozygous SERCA2 transgenic mice. Our findings suggest, for the first time, that increased SERCA2 expression is feasible in vivo and results in enhanced calcium transients, myocardial contractility, and relaxation that may have further therapeutic implications.
Linear mucosal defects: a characteristic endoscopic finding of lansoprazole-associated collagenous colitis
Authors: E. Nomura, H. Kagaya, K. Uchimi, T. Noguchi, S. Suzuki, M. Suzuki, H. Onodera, H. Tateno
Journal: Endoscopy (2010)

Collagenous colitis is a distinct clinicopathologic entity characterized by chronic watery diarrhea and, histologically, by the subepithelial deposition of collagen [1] [2]. Some luminal antigens, including nonsteroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs), particularly lansoprazole, are thought to contribute to the development of collagenous colitis. On endoscopy, collagenous colitis usually shows no or minimal nonspecific abnormalities. However, a recent report showed that "linear mucosal defects", including mucosal tears and sharp longitudinal ulcers, are characteristic colonoscopic findings of lansoprazole-associated collagenous colitis [3]. We report a case of lansoprazole-associated collagenous colitis that showed multiple linear mucosal defects in the colon.
Induction of nitric oxide synthase by cyclic AMP in rat vascular smooth muscle cells.
Authors: T Imai, Y Hirata, K Kanno, F Marumo
Journal: Journal of Clinical Investigation (1994)

By measurements of NO2-/NO3- (NOx) production and Northern blot analysis, we studied the effects of a membrane-permeable cAMP derivative, 8-bromo-cAMP, on the expression of inducible nitric oxide synthase (iNOS) gene and the synthesis of NOx in cultured rat vascular smooth muscle cells (VSMCs). 8-bromo-cAMP stimulated NOx production and increased steady-state levels of iNOS mRNA in rat VSMC in a time- and dose-dependent manner. NG-monomethyl-L-arginine, a NOS inhibitor, completely blocked the 8-bromo-cAMP-induced NOx production, whose effect was partially, but significantly reversed by an excess L-arginine, but not by D-arginine. Compounds that increase intracellular cAMP levels (cholera toxin, forskolin, and 3-isobutyl-1-methylxanthine), all stimulated NOx production. Dexamethasone inhibited the stimulated NOx production, as well as the induction of iNOS mRNA by cAMP. Both actinomycin D and cycloheximide completely blocked the stimulated NOx production by cAMP. Actinomycin D abolished the cAMP-induced iNOS mRNA, whereas cycloheximide remarkably increased iNOS mRNA levels in the presence and absence of 8-bromo-cAMP (superinduction). Actinomycin D, but not dexamethasone, completely abolished the cycloheximide-induced iNOS mRNA. The half-life of cAMP-induced iNOS mRNA was approximately 2 h, whereas no decay in the cycloheximide-induced iNOS mRNA was observed during 12 h. These results demonstrate that iNOS gene is upregulated by cAMP and the superinduction of iNOS mRNA is attributable to increased mRNA stability in rat VSMC.
Efficient Hepatic Delivery and Expression from a Recombinant Adeno-associated Virus 8 Pseudotyped α1-Antitrypsin Vector
Authors: Thomas J. Conlon, Travis Cossette, Kirsten Erger, Young-Kook Choi, Tracy Clarke, Marda Scott-Jorgensen, Sihong Song, Martha Campbell-Thompson, James Crawford, Terence R. Flotte
Journal: Molecular Therapy (2005)

α1-Antitrypsin (AAT) deficiency is a single-gene disorder in which a mutation in the AAT (approved symbol SERPINA1) gene (PI*Z) leads to misfolding of the protein, loss of the protective antiprotease effect of AAT for the lungs, and a toxic effect on hepatocytes. Optimal therapy for AAT deficiency will require a high percentage of hepatocyte transduction to be effective for liver and lung disease. Recently, rAAV genomes pseudotyped with capsids from serotypes 7 and 8 showed efficient hepatic transduction. We hypothesized that upon portal vein injection to target hepatocytes, serotype 8 would better transduce target cells and therefore express hAAT in both a greater percentage of cells and greater amounts. AAV2 and pseudotyped vectors for serotypes 1, 5, and 8 carrying the human AAT transgene were injected at 1 × 1010 particle doses into C57Bl/6 mice. Circulating hAAT from AAV2/8-injected animals showed a 2-log advantage over AAV2 and 3-log increase over AAV2/1 and 5 for the 24-week study. Most significantly, up to 40% of total liver cells stained positive for the transgene in AAV2/8 subjects while remaining primarily episomal. Therefore, pseudotyped AAV8 provides a vehicle to infect a high percentage of hepatocytes stably and thereby express therapeutic molecules to modify AAT PiZ transcripts.
Coffee consumption as trigger for insulin dependent diabetes mellitus in childhood.
Authors: J Tuomilehto, E Tuomilehto-Wolf, E Virtala, R LaPorte
Journal: BMJ (1990)

Hepatocellular carcinoma is a frequent complication of liver cirrhosis, and patients usually die from gastrointestinal bleeding, cachexia, or liver failure. The clinical healing of our patient's hepatocellular carcinoma may have been related to the severe haemor rhagic shock. Because of its high metabolic require? ments neoplastic tissue is more sensitive than normal tissue to a sudden reduction of the blood and oxygen supply. The fiver receives a dual blood supply from the hepatic artery and the portal vein, whereas hepatomas are fed predominantly by the hepatic artery.2 Surgical procedures such as transcatheter arterial chemo embolisation3 and ligation of the hepatic artery branch4 have therefore been proposed to induce anoxia of the tumour when hepatectomy cannot be performed. The haemorrhage probably produced optimal conditions to kill neoplastic cells without damaging normal tissues. The sensitivity of hepatocellular carcinoma to a reduc? tion in blood supply would therefore seem to be confirmed by this case history.
Inhibition of hereditary hepatitis and liver tumor development in Long-Evans cinnamon rats by the copper-chelating agent trientine dihydrochloride
Authors: K Sone
Journal: Hepatology (1996)

Trientine dihydrochloride (trientine) is an alternative medicinal copper chelating agent for patients with Wilson's disease of penicillamine intolerance. We examined the effects of trientine on the spontaneous development of hepatitis and hepatic tumors, by its short-term and long-term administration to Long-Evans cinnamon (LEC) rats with an accumulation of copper in the liver, as animal models of Wilson's disease. Male rats were given trientine in their drinking water at 1500 ppm for 18 weeks, from 6 weeks to 24 weeks of age in short-term experiment, and 1500 ppm for 27 weeks then 750 ppm for 52 weeks, from 8 to 87 weeks of age in the long-term experiment. Development of hepatitis was observed in the control LEC rats at 18 weeks of age. They had high levels of plasma transaminases (glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GPT]), and on pathological examination, hepatocyte destruction was observed. Histological findings revealed that short-term administration of trientine inhibited the development of hepatitis remarkably. The plasma GOT and GPT levels of treated animals were only slightly higher than those of normal LEA (Long-Evans with agouti coat color) rats, a sibling line of LEC rats. Copper levels in the liver were decreased by a maximum of 50 percent. In the long-term administration of trientine, the incidence of hepatic cell carcinoma (HCC) in the treated rats was 67 percent that of the untreated LEC rats, and the number of HCCs per rat in the treated group was 0.7 +/- 0.5, being significantly lower as compared with 4.7 +/- 3.5 in the untreated rats. Additionally, the development of cholangiofibrosis in LEC rats was completely prevented by long-term administration of the agent. The copper level in the liver of treated rats was reduced by 33 percent at 87 weeks of age. Development of HCC in LEC rats might be partly, but not totally, because of copper accumulation. No effects on the levels of copper, iron, or zinc in the liver of LEA rats was detected, and no adverse effects were detected in either LEC or LEA rats after both short- and long-term administration of trientine in drinking water.
Acute magnesium poisoning as a complication of chronic intermittent haemodialysis.
Authors: J. R. Govan, C. A. Porter, J. G. Cook, B. Dixon, J. A. Traffor
Journal: BMJ (1968)

Magnesium chloride is a normal constituent of dialysate solutions used for the haemodialysis of patients with end-stage renal disease.The concentration used in this centre is 1.5 mEq/litre.This communication describes the effects of an excessively high level of 15 mEq/l.Previous to August 1967 our dialysate solutions were made up in the hospital dispensary as a 4-litre concentrate which was diluted to 120 litres with softened tap-water before use.The final solution is checked on a conductivity meter before beginning haemodialysis.In August 1967, owing to increasing demand on the hospital dispensary due to rapid growth in the size of the unit, we decided to obtain dialysate concentrates from a commercial supplier.Before using the new dialysate solution sodium, potassium, and chloride estimations were performed in our own laboratory.The public analyst later confirmed the above findings but also found that the diluted concentrate contained 15 mEq of magnesium per litre.Six patients were dialysed * Senior House Officer.
Key role of myosin light chain (MLC) kinase-mediated MLC2a phosphorylation in the ?-adrenergic positive inotropic effect in human atrium
Authors: M GRIMM, P HAAS, B WILLIPINSKISTAPELFELDT, W ZIMMERMANN, T RAU, K PANTEL, M WEYAND, T ESCHENHAGEN
Journal: Cardiovascular Research (2004)

Mechanisms of the positive inotropic response to alpha(1)-adrenergic stimulation in the heart remain poorly understood, but recent evidence in rat papillary muscle suggests an important role of regulatory myosin light chain (MLC2) phosphorylation. This study investigated alpha(1)-adrenergic contractile effects and the role of MLC kinase (MLCK)-dependent phosphorylation of MLC2 in human atrial muscle strips.Force measurement was performed on electrically stimulated atrial muscle strips (n=140; 20 hearts) in the presence of the beta-blocker nadolol. MLC2a phosphorylation was determined by 2D-polyacrylamide gel electrophoresis and Western blotting of muscle strips that were immediately freeze-clamped following force measurements.The alpha(1)-agonist phenylephrine (PE; 0.3-100 microM) exerted a concentration-dependent, monophasic, sustained positive inotropic effect (86% above basal) that was accompanied by an 80% increase in MLC2a phosphorylation. Desinhibition of MLC phosphatase by the Rho kinase inhibitor Y-27632 (10 microM) reduced the effect of PE by 16%. The MLCK inhibitor wortmannin (10 microM) completely abolished both the PE-induced increase in force and MLC2a phosphorylation. The structurally unrelated MLCK inhibitor ML-7 (10 microM) had similar effects. Neither Y-27632 nor wortmannin or ML-7 affected beta-adrenergic force stimulation. In contrast to our findings in atrial muscle strips, we observed no increase in MLC2v phosphorylation after PE in human ventricular muscle strips and wortmannin failed to inhibit PE-induced force of contraction.alpha(1)-Adrenergic receptors mediate a prominent increase in contractile force in human atria that depends on MLCK activity and is accompanied by an increase in MLC2 phosphorylation.
Points: Poverty and ideology
Authors: A. Scott-Samuel
Journal: BMJ (1983)

December, p 1617) of a patient in whom atenolol treatment apparently precipitated renal artery thrombosis.Recent reports suggest that the angiotensin converting enzyme inhibitor captopril may cause the same complication in patients with pre-existing renal artery stenosis.Oelkers' has described two patients with renovascular hypertension who developed renal artery occlusion during treatment with captopril, and, according to Hollenberg,' about 10% of patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney developed rapidly progressive renal failure during the first few weeks of treatment with captopril.Half of these patients recovered renal function with a reduction in dosage of captopril.No details of the remaining patients were given, but one might speculate that some or all of them may also have developed renal artery thrombosis.
Community-based study of acne vulgaris in adolescents in Singapore
Authors: H-H. Tan, A.W.H. Tan, T. Barkham, X-Y. Yan, M. Zhu
Journal: British Journal of Dermatology (2007)

Journal Article Community‐based study of acne vulgaris in adolescents in Singapore Get access H‐H. Tan, H‐H. Tan Department of Dermatology, National Skin Centre, 1 Mandalay Road, Singapore 308205 *Department of Microbiology, Tan Tock Seng Hospital, Singapore †Centre for Epidemiology and Research, National Healthcare Group, Singapore Correspondence: Hiok‐Hee Tan. E‐mail: hhtan@nsc.gov.sg Search for other works by this author on: Oxford Academic Google Scholar A.W.H. Tan, A.W.H. Tan Department of Dermatology, National Skin Centre, 1 Mandalay Road, Singapore 308205 *Department of Microbiology, Tan Tock Seng Hospital, Singapore †Centre for Epidemiology and Research, National Healthcare Group, Singapore Search for other works by this author on: Oxford Academic Google Scholar T. Barkham, T. Barkham Department of Dermatology, National Skin Centre, 1 Mandalay Road, Singapore 308205 *Department of Microbiology, Tan Tock Seng Hospital, Singapore †Centre for Epidemiology and Research, National Healthcare Group, Singapore Search for other works by this author on: Oxford Academic Google Scholar X‐Y. Yan, X‐Y. Yan Department of Dermatology, National Skin Centre, 1 Mandalay Road, Singapore 308205 *Department of Microbiology, Tan Tock Seng Hospital, Singapore †Centre for Epidemiology and Research, National Healthcare Group, Singapore Search for other works by this author on: Oxford Academic Google Scholar M. Zhu M. Zhu Department of Dermatology, National Skin Centre, 1 Mandalay Road, Singapore 308205 *Department of Microbiology, Tan Tock Seng Hospital, Singapore †Centre for Epidemiology and Research, National Healthcare Group, Singapore Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 157, Issue 3, 1 September 2007, Pages 547–551, https://doi.org/10.1111/j.1365-2133.2007.08087.x Published: 01 September 2007
Nuclear Medicine: A Clinical Introduction
Authors: J. Wyke
Journal: Gut (1980)

Cytotoxic T lymphocytes play a central role in the control of persistent human CMV (HCMV) infection and reactivation. In healthy virus carriers, the specific CD8<sup>+</sup> CTL response is almost entirely directed against the virion tegument protein pp65 and/or the 72-kDa major immediate early protein, IE1. Studies that included a large panel of HCMV<sup>+</sup> donors suggested that immunorelevance of pp65 and IE1 was directly related with individual HLA haplotype difference. Nevertheless, there are no data on the incidence of HCMV natural polymorphism on virus-specific CTL responses. To assess the impact of IE1 polymorphism on CTL response, we have sequenced in 103 clinical isolates the DNA region corresponding to IE1<sub>315–324</sub>, an immunodominant epitope presented by HLA-A*0201 molecules. Seven peptidic variants were found with extensive difference in their frequencies. The response of four HLA-A*0201-restricted anti-IE1 T lymphocyte clones, which were previously generated from one donor against autologous B lymphoblastoid cells expressing a recombinant clinical variant of IE1, was then evaluated using target cells loaded with mutant synthetic peptides or expressing rIE1 variants. One of four clones, which have been sorted 19 times among 22 clones targeted against IE1<sub>315–324</sub>, recognized six of the seven tested variant epitopes. All three other clones showed distinct reactivity patterns to target cells loaded with the different mutant peptides or expressing IE1 variants. Therefore, in the HLA-A2 context, clonal expansions of anti-IE1 memory CTLs may confer a protection against HCMV successive infections and reactivations by killing cells presenting most of the naturally occurring IE1<sub>315–324</sub> epitope variants.
P1-04-05: T-DM1 and Pertuzumab as New Tools for HER2 Specific Antibody-Therapy Against Breast Cancer Stem Cells in HER2−Positive Mammary Carcinoma.
Authors: A Honig, J Diessner, J Dietl, J Wischhusen
Journal: Cancer Research (2011)

Abstract Trastuzumab (Herceptin®) has significantly improved the overall survival of patients with HER2−positive breast cancer. The efficacy of this treatment depends significantly on antibody-dependent cell mediated cytotoxicity (ADCC). However, while trastuzumab can direct NK cells towards tumor cells and thereby promote tumor cell lysis, spheroid-forming tumor-initiating cells are largely spared. Consequently, populations of surviving cells showed greatly enhanced clonogenicity in vitro and tumorigenicity in vivo. Low HER2 levels and reduced expression of activating NK cell ligands provide likely explanations for the escape of these cells from HER2−directed NK cell-dependent therapies. Moreover, recent data show that unproductive interactions between immune cells and cancer cells can induce a process called “epithelial-to-mesenchymal transition” (EMT) which enables previously differentiated cancer cells to acquire stem cell-like properties as evidenced by a CD44highCD24low breast cancer stem cell signature and aldehyde dehydrogenase positivity. We thus investigated whether new HER2−specific antibodies could enhance NK-cell mediated target cell lysis or inhibit the induction of tumor stem cells. The antibody pertuzumab also binds to the HER2−receptor. It inhibits homo- and heterodimerization of the HER2 receptor with other member of the HER family, in particular the dimerization of HER2/HER3 receptors. We were able to show that the combination of trastuzumab and pertuzumab leads to increased antibody-binding on breast cancer cells and breast cancer stem cells, resulting in enhanced ADCC. This correlates with the clinically observed synergy between trastuzumab and pertuzumab as observed for example in the Neosphere trial, a neoadjuvant study for HER2−positive breast cancer. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate which combines trastuzumab with the tubulin inhibitor maytansine. Interestingly, treatment with T-DM1 largely prevented the NK cell-dependent induction of the EMT markers Twist and Snail and the characteristic downregulation of E-cadherin. Thus, T-DM1 apparently interferes with EMT and may hence prevent the re-induction of the stem cell phenotype. In line with the presumed effect against cancer stem cells, T-DM1 significantly attenuated the clonogenic potential of FACS-sorted trastuzumab-unresponsive cancer stem cells. Accordingly, our data show that these new therapeutics may be more effective against cancer stem cells and thereby promise a more sustained treatment of HER2−positive breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-05.
Acquired Toxoplasmosis
Authors: Donald E. Kayhoe, Leon Jacobs, Henry K. Beye, Norman B. McCullough
Journal: New England Journal of Medicine (1957)

THE first published cases of acquired toxoplasmosis in man were reported in 19401 and 1941.2 , 3 Since then approximately 55 additional cases have appeared in the medical literature in English. In many of these the parasite was not isolated or was found only after the death of the patient. Of 14 cases of acquired toxoplasmosis ending fatally1 2 3 4 5 6 7 8 9 10 11 12 the organism was recovered by animal inoculation in only 4.2 , 3 , 11 , 12 Since the diagnosis is often made late in the disease, few patients have been studied extensively, and little is known of the efficacy of treatment. Recently, pyrimethamine (2:4′-diamino-5-[4′-chlorphenyl]-6-ethyl pyrimidine)¶ and triple sulfonamides have been . . .