tbuckley/cabot-search huggingface dataset:
Biliary lipid composition in idiopathic bile acid malabsorption
Authors: M Fracchia, S Pellegrino, P Secreto, A Pera, G Galatola
Journal: Gut (1998)

Chronic diarrhoea is the clinical hallmark of patients presenting with idiopathic bile acid malabsorption. Its pathogenesis is unknown; colonic water secretion can be induced by dihydroxy bile acids, but it is not known whether enrichment of the bile acid pool with these bile acids occurs in such patients. Furthermore, bile acid malabsorption is known to affect biliary lipid composition, but no information is available for the idiopathic type.To verify: (a) whether diarrhoea in patients with idiopathic bile acid malabsorption is associated with enrichment of the bile acid pool with dihydroxy bile acids; and (b) whether supersaturation with cholesterol of duodenal bile occurs in such patients as a result of chronic bile acid depletion.Thirteen patients with idiopathic bile acid malabsorption diagnosed according to abnormal 75SeHCAT test and absence of other organic diseases, and 23 control subjects.Bile rich duodenal fluid was collected during intravenous ceruletide infusion in the fasting state. Biliary lipids were analysed by enzymatic assays and bile acids by high performance liquid chromatography.Patients with idiopathic bile acid malabsorption had a cholesterol saturation index similar to controls. Bile acid composition showed only a decrease in percentage cholic acid (29 (2)% versus 36 (2)%; p<0.05); the dihydroxy:trihydroxy bile acid ratio was similar to controls.Patients with idiopathic bile acid malabsorption do not have an increased risk of forming cholesterol gallstones. The mechanism of diarrhoea does not seem to depend on an enrichment of the bile acid pool with dihydroxy bile acids.
Differential expression of VASP in normal lung tissue and lung adenocarcinomas
Authors: L Dertsiz
Journal: Thorax (2005)

<b>Background:</b> Vasodilator stimulated phosphoprotein (VASP) is associated with focal adhesions and is thought to have an important role in actin filament assembly and cell motility. We hypothesise that an increase in the expression of VASP is involved in the progression and invasion of lung adenocarcinomas in parallel to tumour progression. A study was undertaken to analyse VASP expression in normal lung tissue and lung adenocarcinomas. <b>Methods:</b> Human lung tissues with adenocarcinomas (n = 26) were used. Normal lung tissue specimens (n = 14) were taken from areas a standard distance (3 cm) from resected adenocarcinomas of patients who underwent surgical lung resection. Adenocarcinomas were classified according to pathological staging and histopathological grades. Tissues were stained for VASP using immunohistochemistry. <b>Results:</b> Normal lung pneumocytes showed no VASP expression while alveolar macrophages had the strongest immunoreactivity for VASP. Bronchial epithelium (surface epithelium, goblet cells) and bronchial gland cells had a very weak immunoreactivity for VASP. Adenocarcinomas had significantly greater VASP expression than normal epithelium (p&lt;0.001). Moreover, VASP expression in adenocarcinomas increased significantly with more advanced tumour stage (p&lt;0.001). <b>Conclusions:</b> The spatial and differential expression of VASP in normal lung tissue and lung adenocarcinomas suggests that it is likely to be involved in the differentiation of normal lung cells to adenocarcinomas. The significant increase in the expression of VASP in adenocarcinomas in parallel to pathological staging suggests that it may regulate the invasive behaviour of lung adenocarcinomas as adenocarcinoma invasion is increased in more advanced tumours.
Functional Knockout of the Transient Outward Current, Long-QT Syndrome, and Cardiac Remodeling in Mice Expressing a Dominant-Negative Kv4 α Subunit
Authors: Dianne M. Barry, Haodong Xu, Richard B. Schuessler, Jeanne M. Nerbonne
Journal: Circulation Research (1998)

A novel in vivo experimental strategy, involving cell type-specific expression of a dominant-negative K+ channel pore-forming alpha subunit, was developed and exploited to probe the molecular identity of the cardiac transient outward K+ current (I(to)). A point mutation (W to F) was introduced at position 362 in the pore region of Kv4.2 to produce a nonconducting mutant (Kv4.2W362F) subunit. Coexpression of Kv4.2W362F with Kv4.2 (or Kv4.3) attenuates the wild-type currents, and the effect is subfamily specific; ie, Kv4.2W362F does not affect heterologously expressed Kv1.4 currents. With the use of the alpha-myosin heavy chain promoter to direct cardiac-specific expression, several lines of Kv4.2W362F transgenic mice were generated. Electrophysiological recordings reveal that I(to) is selectively eliminated in ventricular myocytes isolated from transgenic mice expressing Kv4.2W362F, thereby demonstrating directly that the Kv 4 subfamily underlies I(to) in the mammalian heart. Functional knockout of I(to) leads to marked increases in action potential durations in ventricular myocytes and to prolongation of the QT interval in surface ECG recordings. In addition, a novel rapidly activating and inactivating K+ current, which is not detectable in myocytes from nontransgenic littermates, is evident in Kv4.2W362F-expressing ventricular cells. Importantly, these results demonstrate that electrical remodeling occurs in the heart when the expression of endogenous K- channels is altered.
Clinical Significance of<i>TROP2</i>Expression in Colorectal Cancer
Authors: Takahiro Ohmachi, Fumiaki Tanaka, Koshi Mimori, Hiroshi Inoue, Katsuhiko Yanaga, Masaki Mori
Journal: Clinical Cancer Research (2006)

Abstract Purpose and Experimental Design: To identify cancer-related genes, the expression profiles of colorectal cancer cells and normal epithelial cells were examined and compared using laser microdissection and cDNA microarray analysis. From these combined techniques, several cancer-related genes, including TROP2, were identified. TROP2 is known as a calcium signal transducer and is highly expressed in several types of tumors. However, no studies have investigated the significance of TROP2 expression in colorectal cancer. Thus, the expression status of TROP2 was investigated in 74 colorectal cancer samples by quantitative real-time reverse transcription-PCR and immunohistochemical studies. Results: Laser microdissection and cDNA microarray analysis showed that there were 84 overexpressed genes in cancer cells. One of the highly overexpressed genes was TROP2. Quantitative real-time reverse transcription-PCR showed that TROP2 expression in cancer samples was significantly higher than in normal samples (P &amp;lt; 0.001). The samples were divided into high (n = 26) and low (n = 48) TROP2 expression groups. The cases with high TROP2 expression showed a higher frequency of liver metastasis (P = 0.005) and more cancer-related death (P = 0.046). Those cases also had an inclination of deeper depth of invasion (P = 0.064) and more lymph node metastasis (P = 0.125). Interestingly, the patients with high TROP2 expression tumors had poorer prognosis (P = 0.0036). Multivariate analysis showed that TROP2 expression status was an independent prognostic factor (relative risk, 2.38; 95% confidence interval, 1.29-4.74; P &amp;lt; 0.01). Conclusion: TROP2 is one of the cancer-related genes that correlates with biological aggressiveness and poor prognosis of colorectal cancer. Thus, TROP2 is a possible candidate gene for diagnosis and molecular target therapy of colorectal cancer.
Responses of Cardiac Protein Kinase C Isoforms to Distinct Pathological Stimuli Are Differentially Regulated
Authors: Yasuchika Takeishi, Thunder Jalili, Nancy A. Ball, Richard A. Walsh
Journal: Circulation Research (1999)

Abstract —Currently at least 11 protein kinase C (PKC) isoforms have been identified and may play different roles in cell signaling pathways leading to changes in cardiac contractility, the hypertrophic response, and tolerance to myocardial ischemia. The purpose of the present study was to test the hypothesis that responses of individual PKC isoforms to distinct pathological stimuli were differentially regulated in the adult guinea pig heart. Isolated hearts were perfused by the Langendorff method and were exposed to ischemia, hypoxia, H 2 O 2 , or angiotensin II. Hypoxia and ischemia induced translocation of PKC isoforms α, β 2 , γ, and ζ, and H 2 O 2 translocated PKC isoforms α, β 2 , and ζ. Angiotensin II produced translocation of α, β 2 , ε, γ, and ζ isoforms. Inhibition of phospholipase C with tricyclodecan-9-yl-xanthogenate (D609) blocked hypoxia-induced (α, β 2 , and ζ) and angiotensin II–induced (α, β 2 , γ, and ζ) translocation of PKC isoforms. Inhibition of tyrosine kinase with genistein blocked translocation of PKC isoforms by hypoxia (β 2 and ζ) and by angiotensin II (β 2 ). By contrast, neither D609 nor genistein blocked H 2 O 2 -induced translocation of any PKC isoform. We conclude that hypoxia-induced activation of PKC isoforms is mediated through pathways involving phospholipase C and tyrosine kinase, but oxidative stress may activate PKC isoforms independently of Gαq-phospholipase C coupling and tyrosine kinase signaling. Because oxidative stress may directly activate PKC, and PKC activation appears to be involved in human heart failure, selective inhibition of the PKC isoforms may provide a novel therapeutic strategy for the prevention and treatment of this pathological process.
Evidence for Multiple Mechanisms in Human Ventricular Fibrillation
Authors: Martyn P. Nash, Ayman Mourad, Richard H. Clayton, Peter M. Sutton, Chris P. Bradley, Martin Hayward, David J. Paterson, Peter Taggart
Journal: Circulation (2006)

The mechanisms that sustain ventricular fibrillation (VF) in the human heart remain unclear. Experimental models have demonstrated either a periodic source (mother rotor) or multiple wavelets as the mechanism underlying VF. The aim of this study was to map electrical activity from the entire ventricular epicardium of human hearts to establish the relative roles of these mechanisms in sustaining early human VF. In 10 patients undergoing cardiac surgery, VF was induced by burst pacing, and 20 to 40 seconds of epicardial activity was sampled (1 kHz) with a sock containing 256 unipolar contact electrodes connected to a UnEmap system. Signals were interpolated from the electrode sites to a fine regular grid (100x100 points), and dominant frequencies (DFs) were calculated with a fast Fourier transform with a moving 4096-ms window (10-ms increments). Epicardial phase was calculated at each grid point with the Hilbert transform, and phase singularities and activation wavefronts were identified at 10-ms intervals. Early human VF was sustained by large coherent wavefronts punctuated by periods of disorganized wavelet behavior. The initial fitted DF intercept was 5.11 +/- 0.25 (mean +/- SE) Hz (P < 0.0001), and DF increased at a rate of 0.018 +/- 0.005 Hz/s (P < 0.01) during VF, whereas combinations of homogeneous, heterogeneous, static, and mobile DF domains were observed for each of the patients. Epicardial reentry was present in all fibrillating hearts, typically with low numbers of phase singularities. In some cases, persistent phase singularities interacted with multiple complex wavelets; in other cases, VF was driven at times by a single reentrant wave that swept the entire epicardium for several cycles. Our data support both the mother rotor and multiple wavelet mechanisms of VF, which do not appear to be mutually exclusive in the human heart.
Helicobacters are indigenous to the human stomach: duodenal ulceration is due to changes in gastric microecology in the modern era
Authors: M J BLASER
Journal: Gut (1998)

Peptic ulcer disease has been considered to be a “disease of civilisation”.1 Yet Helicobacter pylori , which now is believed to play a critical role in this illness,2 3 has probably been part of the human biota since time immemorial,4 and peptic (especially duodenal) ulceration seems to have become epidemic in humans at a time when H pylori was loosening its firm grip on the human stomach. These phenomena seem contradictory. It is the aim of this paper to describe the elements of the apparent paradox, and to consider several alternative explanations. Resolution of this question has substantial implications for human medicine.

The human body is the home of countless microbes5which usually are called the “normal flora”. Indigenous biota is a better term than normal flora, since bacteria are not plants,6 and normal is difficult to define. The major habitats of the indigenous biota include the gastrointestinal and upper respiratory tracts, the vagina, and the skin, and each niche shares several characteristics (table 1). In each locale, multiple different ecological niches are present. For example, the lumen of the colon is characterised by notable variation in redox potential, and each niche has predominant organisms. The predominant biota of the skin is anaerobic,7 a phenomenon that indicates the multiplicity of ecological niches present. The indigenous biota is acquired early in life, and there often is a succession of organisms as local microenvironments change. Examples of this phenomenon include the changes in the colonic and oral biota accompanying weaning and the eruption of teeth, respectively.8 The biota are numerous, with 103 to 1011 organisms per gram at each site. The colonising microbes are diverse. Bacteria predominate, but fungi and protozoans also are present. In several locales, many different species are present, although …
Ribozyme Oligonucleotides Against Transforming Growth Factor-β Inhibited Neointimal Formation After Vascular Injury in Rat Model
Authors: Kei Yamamoto, Ryuichi Morishita, Naruya Tomita, Takashi Shimozato, Hironori Nakagami, Akira Kikuchi, Motokuni Aoki, Jitsuo Higaki, Yasufumi Kaneda, Toshio Ogihara
Journal: Circulation (2000)

Background —Because the mechanisms of atherosclerosis or restenosis after angioplasty have been postulated to involve an increase in transforming growth factor (TGF)-β, a selective decrease in TGF-β may have therapeutic value. Thus, we used the ribozyme strategy to actively cleave the targeted gene to selectively inhibit TGF-β expression. Methods and Results —We constructed ribozyme oligonucleotides (ONs) targeted to the sequence of the TGF-β gene that shows 100% homology among the human, rat, and mouse species. The specificity of ribozyme against TGF-β gene was confirmed by selective inhibition of TGF-β mRNA in cultured vascular smooth muscle cells as well as balloon-injured blood vessels in vivo. Importantly, the marked decrease in TGF-β resulted in significant inhibition of neointimal formation after vascular injury in a rat carotid artery model ( P &lt;0.01), whereas DNA-based control ONs and mismatched ribozyme ONs did not have any inhibitory effect on neointimal formation. Inhibition of neointimal formation was accompanied by (1) a reduction in collagen synthesis and mRNA expression of collagen I and III and (2) a significant decrease in DNA synthesis as assessed by proliferating cell nuclear antigen staining. Moreover, we modified ribozyme ONs containing phosphorothioate DNA and RNA targeted to the TGF-β gene. Of importance, modified ribozyme ONs showed a further reduction in TGF-β expression. Conclusions —Overall, this study provides the first evidence that selective blockade of TGF-β resulted in inhibition of neointimal formation, accompanied by a reduction in collagen synthesis and DNA synthesis in a rat model. We anticipate that modification of ribozyme ON pharmacokinetics will facilitate the potential clinical utility of the ribozyme strategy.
Endogenous collagen peptide activation of CD1d-restricted NKT cells ameliorates tissue-specific inflammation in mice
Authors: Yawei Liu, Anna Teige, Emma Mondoc, Saleh Ibrahim, Rikard Holmdahl, Shohreh Issazadeh-Navikas
Journal: Journal of Clinical Investigation (2010)

NKT cells in the mouse recognize antigen in the context of the MHC class I-like molecule CD1d and play an important role in peripheral tolerance and protection against autoimmune and other diseases. NKT cells are usually activated by CD1d-presented lipid antigens. However, peptide recognition in the context of CD1 has also been documented, although no self-peptide ligands have been reported to date. Here, we have identified an endogenous peptide that is presented by CD1d to activate mouse NKT cells. This peptide, the immunodominant epitope from mouse collagen type II (mCII707-721), was not associated with either MHC class I or II. Activation of CD1d-restricted mCII707-721-specific NKT cells was induced via TCR signaling and classical costimulation. In addition, mCII707-721-specific NKT cells induced T cell death through Fas/FasL, in an IL-17A-independent fashion. Moreover, mCII707-721-specific NKT cells suppressed a range of in vivo inflammatory conditions, including delayed-type hypersensitivity, antigen-induced airway inflammation, collagen-induced arthritis, and EAE, which were all ameliorated by mCII707-721 vaccination. The findings presented here offer new insight into the intrinsic roles of NKT cells in health and disease. Given the results, endogenous collagen peptide activators of NKT cells may offer promise as novel therapeutics in tissue-specific autoimmune and inflammatory diseases.
A Single Dose of Vitamin D Enhances Immunity to Mycobacteria
Authors: Adrian R. Martineau, Robert J. Wilkinson, Katalin A. Wilkinson, Sandra M. Newton, Beate Kampmann, Bridget M. Hall, Geoffrey E. Packe, Robert N. Davidson, Sandra M. Eldridge, Zoë J. Maunsell, Sandra J. Rainbow, Jacqueline L. Berry, Christopher J. Griffiths
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Vitamin D was used to treat tuberculosis (TB) in the preantibiotic era. Prospective studies to evaluate the effect of vitamin D supplementation on antimycobacterial immunity have not previously been performed.To determine the effect of vitamin D supplementation on antimycobacterial immunity and vitamin D status.A double-blind randomized controlled trial was conducted in 192 healthy adult TB contacts in London, United Kingdom. Participants were randomized to receive a single oral dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks.The primary outcome measure was assessed with a functional whole blood assay (BCG-lux assay), which measures the ability of whole blood to restrict luminescence, and thus growth, of recombinant reporter mycobacteria in vitro; the readout is expressed as a luminescence ratio (luminescence postinfection/baseline luminescence). IFN-gamma responses to the Mycobacterium tuberculosis antigens early secretory antigenic target-6 and culture filtrate protein 10 were determined with a second whole blood assay. Vitamin D supplementation significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro compared with placebo (mean luminescence ratio at follow-up, 0.57, vs. 0.71, respectively; 95% confidence interval for difference, 0.01-0.25; p=0.03) but did not affect antigen-stimulated IFN-gamma secretion.A single oral dose of 2.5 mg vitamin D significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro without affecting antigen-stimulated IFN-gamma responses. Clinical trials should be performed to determine whether vitamin D supplementation prevents reactivation of latent TB infection. Clinical trial registered with www.clinicaltrials.gov (NCT 00157066).
Breaking Bad News: Learning Through Experience
Authors: Stephanie J. Arnold, Bogda Koczwara
Journal: Journal of Clinical Oncology (2006)

She sits in bed, propped up by two pillows, wearing a white hospital gown, staring out of the window. Her fingers pick at something—is it a tissue? —listlessly, distractedly. I’ve been told to see her and “get a history.” I’m nervous—she doesn’t look well and certainly is in no cheerful mood to talk. But I do as I’m told, and approach her with a smile: “Hello, I’m a medical student; do you mind chatting to me about why you’re in the hospital?” She turns and wearily looks me up and down— was my cheerfulness too forced? “Oh, I suppose so, if you must. Not much else for me to do, is there?” So I pull up a chair and we get started. Dianne tells me that she noticed a lump on her neck some weeks ago, and dismissed it at first, thinking, “must have knocked myself on something,” but when it didn’t go away, she visited her local doctor. Before she knew it, he ordered some tests, and had her admitted to the hospital overnight for a lymph node biopsy. And here she was—it was midmorning—anxiously awaiting her test results. “They said it could be lymphoma,” she told me, “which is a death sentence, isn’t it? My friend’s mother had a blood cancer a couple of years ago, and it was horrible—all her hair fell out, she was so sick. Those last few months. . .she was in so much pain.” And then she burst into tears. “I’m going to die of cancer,” Dianne sobbed, “I’m so young, I have two children. What is my husband going to do? And what about work—I can’t afford to take time off!” Desperately, I offered up the box of tissues by her bed— wanting to get out of the room and feeling completely helpless. “Time out! Let’s leave it there for a minute. Tell me, Dianne, how are you feeling?” Our moderator cut in. “And you, Stephanie, what do you think about the way you approached this patient?” I was in a simulation. Dianne no longer had a lump and had wiped away her tears, revealing the actor beneath. “I felt blocked,” said the actor. “Your offering me a tissue was an indication that you didn’t want to listen to my problems, you just wanted me to stop crying!” I agreed, but for different reasons—I had no idea how to help a very distressed patient deal with terribly bad news and was actually very upset myself. WHY IS BREAKING BAD NEWS SO DIFFICULT?
The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats
Authors: Tatsuya Morimoto, Yoichi Sunagawa, Teruhisa Kawamura, Tomohide Takaya, Hiromichi Wada, Atsushi Nagasawa, Masashi Komeda, Masatoshi Fujita, Akira Shimatsu, Toru Kita, Koji Hasegawa
Journal: Journal of Clinical Investigation (2008)

Hemodynamic overload in the heart can trigger maladaptive hypertrophy of cardiomyocytes. A key signaling event in this process is nuclear acetylation by histone deacetylases and p300, an intrinsic histone acetyltransferase (HAT). It has been previously shown that curcumin, a polyphenol responsible for the yellow color of the spice turmeric, possesses HAT inhibitory activity with specificity for the p300/CREB-binding protein. We found that curcumin inhibited the hypertrophy-induced acetylation and DNA-binding abilities of GATA4, a hypertrophy-responsive transcription factor, in rat cardiomyocytes. Curcumin also disrupted the p300/GATA4 complex and repressed agonist- and p300-induced hypertrophic responses in these cells. Both the acetylated form of GATA4 and the relative levels of the p300/GATA4 complex markedly increased in rat hypertensive hearts in vivo. The effects of curcumin were examined in vivo in 2 different heart failure models: hypertensive heart disease in salt-sensitive Dahl rats and surgically induced myocardial infarction in rats. In both models, curcumin prevented deterioration of systolic function and heart failure–induced increases in both myocardial wall thickness and diameter. From these results, we conclude that inhibition of p300 HAT activity by the nontoxic dietary compound curcumin may provide a novel therapeutic strategy for heart failure in humans.