tbuckley/cabot-search huggingface dataset:
Effect of cold preservation on intracellular calcium concentration and calpain activity in rat sinusoidal endothelial cells
Authors: Aravinda G. Upadhya, Stefan A. Topp, Richard S. Hotchkiss, John Anagli, Steven M. Strasberg
Journal: Hepatology (2003)

This study was performed to determine the role of intracellular calcium concentration and calpain activity on the cellular events that occur in rat sinusoidal endothelial cells (SEC) in the cold. Intracellular calcium concentrations were measured in isolated cold preserved rat SEC. Dantrolene or 1,2-bis(o-Aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA-AM) was added in some studies. In other studies, calpain activity and m-calpain and μ-calpain expression were measured during cold preservation in the presence or absence of calpain inhibitors. The effect of addition of dantrolene to preservation solutions on function of whole livers after preservation was determined. Cold preservation caused an increase in intracellular calcium concentration first detected at 1 hour of preservation. This was associated with cell rounding and actin disassembly. Dantrolene and BAPTA-AM prevented the increase in intracellular calcium concentration and reduced cell rounding and actin disassembly. Cold preservation also resulted in increased calpain activity and expression on SEC. Calpain expression was reduced by dantrolene. Calpain inhibitors N-acetyl-leu-leu-norleucinal (ALLN) and N-acetyl-leu-leu-methioninal (ALLM) reduced calpain activity and expression and restored SEC cell shape and actin morphology. Dantrolene improved function of livers preserved in Eurocollins (EC) solution when tested on the isolated perfused rat liver (IPRL). In conclusion, exposure of SEC to cold results sequentially in elevated intracellular calcium concentration, increased calpain activity, and actin disassembly.
'Proper to the duty of a chirurgeon': Ambroise Pare and sixteenth century paediatric surgery
Authors: A N Williams, J Williams
Journal: Journal of the Royal Society of Medicine (2004)

Ambroise Pare ´rose from humble origins to become surgeon to four kings of France.Though he is remembered mainly for his work as a military surgeon and for his advocacy of podalic version, his contribution to surgery was far greater than this. 1 In France his works were a mainstay of surgical practice for 250 years.To illustrate his contributions to paediatric surgery we have translated excerpts from the 1849 facsimile copy of his Oeuvres of 1585, 2 particularly the seventeenth book which deals with the means and artificial devices used to treat those who have natural defects or defects caused by an accident.We also borrow from the posthumous English translation by Thomas Johnson, 1633, edited in the 1950s by Geoffrey Keynes. 3are ´'s aim was to raise the reputation of surgery to honour and esteem.He wrote: 'Five things are proper to the dutie of a chirurgeon.To take away that which is superfluous, to restore to their places such things as are displaced, to separate those things which are joined together, to joyne that which is divided, and to supply the defects of nature.' 3 '. . .one must not make varus and valgus children walk until the joints are well strengthened, so that they do not dislocate.
GDF15/MIC-1 Functions As a Protective and Antihypertrophic Factor Released From the Myocardium in Association With SMAD Protein Activation
Authors: Jian Xu, Thomas R. Kimball, John N. Lorenz, David A. Brown, Asne R. Bauskin, Raisa Klevitsky, Timothy E. Hewett, Samuel N. Breit, Jeffery D. Molkentin
Journal: Circulation Research (2006)

Here we identified growth-differentiation factor 15 (GDF15) (also known as MIC-1), a secreted member of the transforming growth factor (TGF)-beta superfamily, as a novel antihypertrophic regulatory factor in the heart. GDF15 is not expressed in the normal adult heart but is induced in response to conditions that promote hypertrophy and dilated cardiomyopathy. To elucidate the function of GDF15 in the heart, we generated transgenic mice with cardiac-specific overexpression. GDF15 transgenic mice were normal but were partially resistant to pressure overload-induced hypertrophy. Expression of GDF15 in neonatal cardiomyocyte cultures by adenoviral-mediated gene transfer antagonized agonist-induced hypertrophy in vitro. Transient expression of GDF15 outside the heart by intravenous adenoviral delivery, or by direct injection of recombinant GDF15 protein, attenuated ventricular dilation and heart failure in muscle lim protein gene-targeted mice through an endocrine effect. Conversely, examination of Gdf15 gene-targeted mice showed enhanced cardiac hypertrophic growth following pressure overload stimulation. Gdf15 gene-targeted mice also demonstrated a pronounced loss in ventricular performance following only 2 weeks of pressure overload stimulation, whereas wild-type controls maintained function. Mechanistically, GDF15 stimulation promoted activation of SMAD2/3 in cultured neonatal cardiomyocytes. Overexpression of SMAD2 attenuated cardiomyocyte hypertrophy similar to GDF15 treatment, whereas overexpression of the inhibitory SMAD proteins, SMAD6/7, reversed the antihypertrophic effects of GDF15. These results identify GDF15 as a novel autocrine/endocrine factor that antagonizes the hypertrophic response and loss of ventricular performance, possibly through a mechanism involving SMAD proteins.
Cyclooxygenase-2 (COX-2)–Independent Anticarcinogenic Effects of Selective COX-2 Inhibitors
Authors: Sabine Grösch, Thorsten Jürgen Maier, Susanne Schiffmann, Gerd Geisslinger
Journal: JNCI Journal of the National Cancer Institute (2006)

Nonsteroidal antiinflammatory drugs (NSAIDs) appear to reduce the risk of developing cancer. One mechanism through which NSAIDs act to reduce carcinogenesis is to inhibit the activity of cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in various cancer tissues. Overexpression of COX-2 increases cell proliferation and inhibits apoptosis. However, selective COX-2 inhibitors can also act through COX-independent mechanisms. In this review, we describe the COX-2-independent molecular targets of these COX-2 inhibitors and discuss how these targets may be involved in the anticarcinogenic activities of these selective COX-2 inhibitors. We also compare the concentrations of these inhibitors used in in vitro and in vivo experiments and discuss the implications of the in vitro studies for clinical management of cancer with these drugs.
A Hypermutable Insert in an Immunoglobulin Transgene Contains Hotspots of Somatic Mutation and Sequences Predicting Highly Stable Structures in the RNA Transcript
Authors: Ursula Storb, Emily L. Klotz, John Hackett, Karen Kage, Grazyna Bozek, Terence E. Martin
Journal: The Journal of Experimental Medicine (1998)

Immunoglobulin (Ig) genes expressed in mature B lymphocytes can undergo somatic hypermutation upon cell interaction with antigen and T cells. The mutation mechanism had previously been shown to depend upon transcription initiation, suggesting that a mutator factor was loaded on an RNA polymerase initiating at the promoter and causing mutations during elongation (Peters, A., and U. Storb. 1996. Immunity. 4:57–65). To further elucidate this process we have created an artificial substrate consisting of alternating EcoRV and PvuII restriction enzyme sites (EPS) located within the variable (V) region of an Ig transgene. This substrate can easily be assayed for the presence of mutations in DNA from transgenic lymphocytes by amplifying the EPS insert and determining by restriction enzyme digestion whether any of the restriction sites have been altered. Surprisingly, the EPS insert was mutated many times more frequently than the flanking Ig sequences. In addition there were striking differences in mutability of the different nucleotides within the restriction sites. The data favor a model of somatic hypermutation where the fine specificity of the mutations is determined by nucleotide sequence preferences of a mutator factor, and where the general site of mutagenesis is determined by the pausing of the RNA polymerase due to secondary structures within the nascent RNA.
Clinical, Socioeconomic, and Lifestyle Parameters Associated With Erectile Dysfunction Among Diabetic Men
Authors: Ofra Kalter-Leibovici, Julio Wainstein, Arnona Ziv, Ilana Harman-Bohem, Havi Murad, Itamar Raz
Journal: Diabetes Care (2005)

OBJECTIVE—Erectile dysfunction is frequently observed in diabetes. The current study aims to assess the association of a comprehensive set of clinical, socioeconomic, and lifestyle parameters with erectile dysfunction in diabetic men. RESEARCH DESIGN AND METHODS—Participants were randomly selected from male patients (age &amp;gt;18 years) treated in 26 diabetes clinics in Israel. Participants completed a self-reported questionnaire on demographic, socioeconomic, and lifestyle characteristics and on erectile function, using the IIEF-15 (International Index of Erectile Function). Information on diabetes type, duration, treatment, and control; microvascular complications and cardiovascular disease; drug therapy; blood pressure; and lipid levels was also obtained. RESULTS—Information on erectile function was obtained in 1,040 patients. Their mean age was 57 years, and their median diabetes duration was 8 years (range &amp;lt;1–50). Normal erectile function was found in 13.5% of the patients and severe erectile dysfunction in 30.1%. The characteristics found to be significantly associated with erectile dysfunction [associations presented as adjusted odds ratio (95% CI)] were: patient’s age (5-year increments): 1.38 (1.29–1.48); diabetes duration (5-year increments): 1.16 (1.07–1.26); current HbA1c level (1% increment): 1.10 (1.01–1.19); any microvascular disease: 1.43 (1.09–1.88); cardiovascular disease: 1.78 (1.27–2.48); and diuretic treatment: 1.78 (1.09–2.91). Leisure time and work-related physical activity and consumption of small amounts of alcohol were found to be protective: 0.51 (0.36–0.72) and 0.70 (0.51–0.97), respectively. CONCLUSIONS—In diabetic men, erectile dysfunction severity increases with age and diabetes duration, poor glycemic control, presence of microvascular complications, diuretic treatment, and cardiovascular disease. Physical activity and alcohol intake may be protective. These findings can guide clinicians in taking preventive measures and undertaking early screening and treatment in high-risk patients.
Plasma levels of soluble interleukin 2 receptor, soluble CD30, interleukin 10 and B cell activator of the tumour necrosis factor family during follow-up in vasculitis associated with proteinase 3-antineutrophil cytoplasmic antibodies: associations with disease activity and relapse
Authors: J-S F Sanders, M G Huitma, C G M Kallenberg, C A Stegeman
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objectives:</b> To evaluate whether T cell activation, as reflected by levels of soluble interleukin 2 receptor (sIL2R), soluble CD30 (sCD30), IL-10 and B cell activator of the tumour necrosis factor family (BAFF) at diagnosis and during initial follow-up, is predictive for persistent or renewed antineutrophil cytoplasmic antibody (ANCA) positivity and clinical relapse in patients with vasculitis associated with proteinase 3-antineutrophil cytoplasmic antibodies (PR3-ANCA). <b>Methods:</b> 87 Patients with PR3-ANCA-associated vasculitis and at least 2 years of follow-up were included in the study. At diagnosis, and at 3, 6, 12, 18 and 24 months after diagnosis, cytoplasmic ANCA titres were detected by indirect immunofluorescence (IIF), and PR3-ANCA, sIL2R, sCD30, IL-10 and BAFF levels were assessed by ELISA. 31 healthy volunteers provided plasma samples for comparison. Levels of immune markers were related to ANCA positivity and relapse during follow-up. <b>Results:</b> Plasma levels of sIL2R, sCD30 and BAFF were higher in patients than in controls at all time points. Plasma levels of sIL2R, sCD30 and IL-10 were higher at diagnosis and relapse than during remission. At 18 months, sCD30 (p&lt;0.001) and sIL2R levels (p = 0.01) were significantly higher in PR3-ANCA-positive patients (detected by ELISA) than in PR3-ANCA-negative patients. ANCA-positive patients detected by ELISA or IIF at 24 months had significantly higher plasma sCD30 levels (p = 0.02 and p = 0.03, respectively) than ANCA-negative patients. <b>Conclusion:</b> Increased T cell activation in patients with ANCA-associated vasculitis in remission during and after immunosuppressive treatment is associated with persistent or renewed ANCA positivity.
Selective Tropism of Seneca Valley Virus for Variant Subtype Small Cell Lung Cancer
Authors: J. T. Poirier, Irina Dobromilskaya, Whei F. Moriarty, Craig D. Peacock, Christine L. Hann, Charles M. Rudin
Journal: JNCI Journal of the National Cancer Institute (2013)

We assessed the efficacy of Seneca Valley virus (SVV-001), a neuroendocrine cancer-selective oncolytic picornavirus, in primary heterotransplant mouse models of small cell lung cancer (SCLC), including three lines each of classic and variant SCLC. Half-maximal effective concentrations for cell lines derived from three variant heterotransplants ranged from 1.6×10(-3) (95% confidence interval [CI] = 1×10(-3) to 2.5×10(-3)) to 3.9×10(-3) (95% CI = 2.8×10(-3) to 5.5×10(-3)). Sustained tumor growth inhibition in vivo was only observed in variant lines (two-sided Student t test, P < .005 for each). Doses of 10(14) vp/kg were able to completely and durably eradicate tumors in a variant SCLC heterotransplant model in two of six mice. Gene expression profiling revealed that permissive lines are typified by lower expression of the early neurogenic transcription factor ASCL1 and, conversely, by higher expression of the late neurogenic transcription factor NEUROD1. This classifier demonstrates a sensitivity of .89, specificity of .92, and accuracy of .91. The NEUROD1 to ASCL1 ratio may serve as a predictive biomarker of SVV-001 efficacy.
Valosin-Containing Protein Phosphorylation at Ser784 in Response to DNA Damage
Authors: Mark Livingstone, Hong Ruan, Jessica Weiner, Karl R. Clauser, Peter Strack, Shengfang Jin, Amy Williams, Heidi Greulich, James Gardner, Monica Venere, Tamara A. Mochan, Richard A. DiTullio, Katarina Moravcevic, Vassilis G. Gorgoulis, Anne Burkhardt, Thanos D. Halazonetis
Journal: Cancer Research (2005)

Abstract The response of eukaryotic cells to DNA damage includes the activation of phosphatidylinositol-3 kinase–related kinases (PIKK), such as ATM, ATR, and DNA-dependent protein kinase (DNA-PK). These three kinases have very similar substrate specificities in vitro, but in vivo, their substrates overlap only partially. Several in vivo substrates of ATM and ATR have been identified and almost all of them are involved in DNA damage–induced cell cycle arrest and/or apoptosis. In contrast, few in vivo substrates of DNA-PK have been identified. These include histone H2AX and DNA-PK itself. We identify here valosin-containing protein (VCP) as a novel substrate of DNA-PK and other PIKK family members. VCP is phosphorylated at Ser784 within its COOH terminus, a region previously shown to target VCP to specific intracellular compartments. Furthermore, VCP phosphorylated at Ser784 accumulated at sites of DNA double-strand breaks (DSBs). VCP is a protein chaperone that unfolds and translocates proteins. Its phosphorylation in response to DNA damage and its recruitment to sites of DNA DSBs could indicate a role of VCP in DNA repair.
Writing About Emotional Experiences Reduces β-Agonist Use in Patients with Asthma - 3-Month Follow Up of a Randomised Controlled Trial
Authors: H.E. Smith, C.J. Jones, A. Theadom, R. Horne, R. Bowskill, M. Hankins, A.J. Frew
Journal: Journal of Allergy and Clinical Immunology (2009)
Treatment with cyclosporin switching to hydroxychloroquine in patients with rheumatoid arthritis
Authors: W-U Kim
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVE</h3> To investigate the therapeutic benefit of cyclosporin A (CSA) switching to hydroxychloroquine (HCQ) in patients with rheumatoid arthritis (RA). <h3>METHODS</h3> Thirty four patients with RA who displayed residual inflammation and disability despite partial responses to prior maximal tolerated doses of methotrexate, were included. All were treated with a staged approach using CSA for 24 weeks to induce clinical improvement, followed by HCQ for 16 weeks to maintain the improvement. Seven ACR core set measures were evaluated every four to eight weeks. <h3>RESULTS</h3> During a 40 week open trial, 27/34 patients completed the study. CSA treatment significantly reduced the tender joints score, swollen joints score, visual analogue pain scale, patient9s or doctor9s global assessment, patient9s self assessed disability, and C reactive protein. Compared with the time of entry into the trial, patients who switched from CSA to HCQ still possessed significantly lower levels of most variables, determined at 28, 32, and 40 weeks. According to the ACR 20% improvement definition, 15/27 (56%) patients had improved at 24 weeks after CSA treatment, and 14/27 (52%) remained improved at 16 weeks after the change to HCQ. Frequent side effects, such as hypertrichosis, gastrointestinal trouble, and hypertension, were noted during CSA treatment, but most of these disappeared after switching to HCQ. The mean levels of blood pressure and serum creatinine were significantly increased during CSA treatment, but returned to normal after changing to HCQ. <h3>CONCLUSIONS</h3> The data suggest that CSA switching to HCQ treatment may be an effective strategy for patients with RA partially responding to methotrexate, particularly those with toxicity due to CSA.
Obstructive Sleep Apnea and the Recurrence of Atrial Fibrillation
Authors: Ravi Kanagala, Narayana S. Murali, Paul A. Friedman, Naser M. Ammash, Bernard J. Gersh, Karla V. Ballman, Abu S. M. Shamsuzzaman, Virend K. Somers
Journal: Circulation (2003)

We tested the hypothesis that patients with untreated obstructive sleep apnea (OSA) would be at increased risk for recurrence of atrial fibrillation (AF) after cardioversion.We prospectively obtained data on history, echocardiogram, ECG, body mass index, hypertension, diabetes, NYHA functional class, ejection fraction, left atrial appendage velocity, and medications in patients with AF/atrial flutter referred for DC cardioversion. Forty-three individuals were identified as having OSA on the basis of a previous sleep study. Data regarding the use of continuous positive airway pressure (CPAP) and recurrence of AF were obtained for 39 of these patients. Follow-up data were also obtained in 79 randomly selected postcardioversion patients (controls) who did not have any previous sleep study. Twenty-seven of the 39 OSA patients either were not receiving any CPAP therapy (n=25) or were using CPAP inappropriately (n=2). Recurrence of AF at 12 months in these 27 patients was 82%, higher than the 42% recurrence in the treated OSA group (n=12, P=0.013) and the 53% recurrence (n=79, P=0.009) in the 79 control patients. Of the 25 OSA patients who had not been treated at all, the nocturnal fall in oxygen saturation was greater (P=0.034) in those who had recurrence of AF (n=20) than in those without recurrence (n=5).Patients with untreated OSA have a higher recurrence of AF after cardioversion than patients without a polysomnographic diagnosis of sleep apnea. Appropriate treatment with CPAP in OSA patients is associated with lower recurrence of AF.
Quality of Life in Good Prognosis Patients With Metastatic Germ Cell Cancer: A Prospective Study of the European Organization for Research and Treatment of Cancer Genitourinary Group/Medical Research Council Testicular Cancer Study Group (30941/TE20)
Authors: Sophie D. Fosså, Ronald de Wit, J. Trevor Roberts, Peter M. Wilkinson, Pieter H.M. de Mulder, Graham M. Mead, Pat Cook, Linda de Prijck, Sally Stenning, Neil K. Aaronson, Andrew Bottomley, Laurence Collette
Journal: Journal of Clinical Oncology (2003)

To describe global quality of life (GLQL) in patients with metastatic testicular cancer (TC) treated with four different schedules of bleomycin, etoposide, and cisplatin (BEP) chemotherapy (four v three cycles given over 5 v 3 days).Quality-of-life data were prospectively collected in 666 patients with metastatic TC entered into the European Organization for Research and Treatment of Cancer (EORTC) Trial 30941/United Kingdom Medical Research Council Trial TE20, using the EORTC Quality-of-Life Questionnaire C30 and a TC module. Data were analyzed by a mixed effects model and by evaluation of clinically relevant changes at 2 years.The pattern of GLQL changes was similar in the four groups. Two years after chemotherapy, 36% of patients displayed improved GLQL as compared with baseline, whereas GLQL had deteriorated in 13%. At 3 months, patients receiving the 3-day regimen experienced increased gastrointestinal (GI) toxicity more than those receiving the 5-day regimen, with the difference reaching the level of clinical relevance (>or = 10-point change) if four cycles were given. The 3-day schedule increased the 2-year risk of tinnitus, with clinical relevance demonstrated after four cycles. Long-term peripheral neuropathy and Raynaud-like phenomena were not associated with the number of cycles or days per cycle. At 2 years, Raynaud-like phenomena, tinnitus, or reduced hearing were reported by 21% to 26% of the patients.Because of the excess of acute GI toxicity and the increased risk of tinnitus after the 3-day regimen, we recommend the 5-day regimen if four cycles of BEP are planned. If only three cycles are to be given, then the 3-day regimen is acceptable, even given the increased risk of nausea/vomiting at 3 months.
Lipid peroxidation in rats chronically fed ethanol.
Authors: J P Teare, S M Greenfield, D Watson, N A Punchard, N Miller, C A Rice-Evans, R P Thompson
Journal: Gut (1994)

Chronic alcohol consumption induces cytochrome P450IIE1, enabling habitual abusers to consume far greater quantities of alcohol than normal subjects. This pathway of metabolism leads to the production of free radical species, which cause tissue damage through peroxidation of cell membranes. Groups of Wistar rats of equal male: female ratio (n = 24) were fed alcohol by gavage twice daily to achieve a dosage of 15 g/kg body weight. Mean peak blood alcohol concentrations of 186 mg% were produced in males and 156 mg% in females. The animals were allowed free access to standard laboratory chow and water. Control animals were pair-fed to the alcoholic group and fed isocaloric glucose by gavage. Groups of animals were killed between 9 and 11 am on consecutive mornings, after nocturnal feeding, since it has previously been shown that fasting rapidly depletes hepatic glutathione concentrations. Hepatic glutathione was measured by a spectrophotometric enzymatic recycling procedure. As a marker of lipid peroxidation hepatic malonaldehyde (MDA) was measured by high performance liquid chromatography. Hepatic MDA was increased in the alcoholic group (p < 0.001), as was total hepatic glutathione (p < 0.0001). Plasma concentrations of alpha-tocopherol were increased in the alcoholic group, but ascorbic acid and superoxide dismutase values were not affected. No sex differences were detected. The increased MDA production in the alcohol group is strong evidence that lipid peroxidation is a mechanism of alcoholic tissue damage. The rise in hepatic glutathione may be an adaptive response to free radical production that protects the rat against tissue damage.