tbuckley/cabot-search huggingface dataset:
Intestinal vasodilation by epoxyeicosatrienoic acids: arachidonic acid metabolites produced by a cytochrome P450 monooxygenase.
Authors: K G Proctor, J R Falck, J Capdevila
Journal: Circulation Research (1987)

Purified synthetic products from the cytochrome P450 pathway of arachidonate metabolism were applied to the intestinal serosa. Arteriolar blood flow was calculated using video microscopy. After a steady-state baseline, a bolus containing 10-60 micrograms 14,15-epoxyeicosatrienoic acid/ml (14,15-EET) had no detectable effect on blood flow. However, 25 +/- 3 micrograms 11,12-EET/ml and 36 +/- 2 micrograms 8,9-EET/ml caused increases (134 +/- 8% and 127 +/- 6%) that were similar to those elicited by 8 +/- 2 micrograms adenosine/ml (138 +/- 12%). Furthermore, the increases (275 +/- 38%) produced by 32 +/- 6 micrograms 5,6-EET/ml exceeded those elicited (160 +/- 10%) by a similar concentration (27 +/- 3 micrograms/ml) of adenosine. Thus, a structure-activity relationship is suggested. Nevertheless, these values probably underestimate the potency of the EETs because the vasoactivity was reduced by contact with water. The activity of the cyclooxygenase pathway seemed to limit the formation of vasoactive quantities of EETs, or other nonprostanoids, from exogenous arachidonate in the serosa but not the mucosa. A bolus (1.3 +/- 0.2 mg/ml) or continuous application (122 +/- 45 micrograms/ml) of arachidonate caused blood flow increases (236 +/- 14% or 229 +/- 27%) that were almost eliminated (129 +/- 5% or 121 +/- 9%) by a cyclooxygenase inhibitor; the residual response was abolished by a cytochrome P450 inhibitor. However, cytochrome P450 inhibitors alone did not attenuate the arachidonate response. In contrast, a continuous application of 194 micrograms arachidonate/ml to the mucosa caused a markedly smaller blood flow increase (119 +/- 8%) and cyclooxygenase inhibitors potentiated (132 +/- 8%), rather than reduced, this response. We conclude that EETs are a labile class of vasodilators with a potency comparable to adenosine in the intestinal microcirculation. Indirect evidence suggests regional differences in the formation of vasoactive quantities of arachidonate metabolites within the intestinal wall.
Impact of inflammatory bowel disease and ursodeoxycholic acid therapy on small-duct primary sclerosing cholangitis
Authors: Phunchai Charatcharoenwitthaya, Paul Angulo, Felicity B. Enders, Keith D. Lindor
Journal: Hepatology (2007)

A longitudinal, cohort study was performed to characterize the clinical features of patients with small-duct primary sclerosing cholangitis (PSC) occurring with and without inflammatory bowel disease (IBD) and to determine the influence of IBD and the effect of ursodeoxycholic acid (UDCA) therapy on the course of the liver disease. Forty-two patients with small-duct PSC (14 women and 28 men; mean age, 36.7 ± 13.3 years) were followed for up to 24.9 years. At presentation, prevalence of signs of liver disease (none versus 35%, P = 0.002), gastroesophageal varices (5% versus 30%, P = 0.03), and stage III/IV disease (9% versus 45%, P = 0.008) were lower in those with IBD versus those without IBD. During follow-up, 6 patients underwent liver transplantation, and another died of cirrhosis. Using the Cox proportional hazard analysis, concomitant IBD was not associated with liver death or transplant, whereas the revised Mayo risk score for PSC was the only prognostic factor associated with liver-related outcomes (relative risk, 6.47; 95% confidence interval, 1.75-137.5). UDCA (13-15 mg/kg/day) therapy for an average of 40 months showed biochemical improvement ( P &lt; 0.001) in UDCA-treated patients, while no significant change occurred in untreated patients. UDCA therapy had no effect on delaying progression of disease (relative risk, 0.95; 95% confidence interval, 0.38-2.36). Conclusion: Small-duct PSC often is recognized at an early stage in patients with IBD; however, IBD has no impact on long-term prognosis. Although UDCA therapy improves liver biochemistries, it may not delay disease progression during the short period of treatment. (Hepatology 2008.)
Prevention of autoimmune diabetes in non-obese diabetic mice by treatment with a class II major histocompatibility complex-blocking peptide.
Authors: U Hurtenbach, E Lier, L Adorini, Z A Nagy
Journal: The Journal of Experimental Medicine (1993)

The role of antigen presentation as a possible mechanism underlying major histocompatibility complex (MHC) association of autoimmune disease has been studied in non-obese diabetic (NOD) mice. By screening for inhibition of antigen presentation to NOD T cell hybridoma, we have selected a synthetic peptide, yTYTVHAAHAYTYt (small letters denote D amino acids), that efficiently blocks antigen presentation by the NOD class II MHC molecule A alpha g7A beta g7 (Ag7) in vitro. The inhibition is MHC selective, in that it does not affect antigen presentation by the E(d) and E(k) molecules, and has only a marginal effect on presentation by the A(d) molecule. This peptide also inhibits the priming for Ag7-restricted T cell responses in vivo, and prevents the spontaneous development of diabetes in female NOD mice, when administered chronically from 3 wk of age on. Chronic treatment with a control peptide, KMKMVHAAHAKMKM, that fails to bind to Ag7 has no effect on the disease. These data indicate that antigen presentation by the Ag7 molecule plays a pivotal role in the induction of autoimmune diabetes. Furthermore, the results demonstrate that interference with antigen presentation by a class II molecule can prevent the onset of spontaneous autoimmune disease associated with the same molecule.
Telomerase Transcriptional Targeting of Inducible Bax/TRAIL Gene Therapy Improves Gemcitabine Treatment of Pancreatic Cancer
Authors: Séverine Wack, Soukaina Rejiba, Céline Parmentier, Marc Aprahamian, Amor Hajri
Journal: Molecular Therapy (2007)

Currently, gemcitabine is approved as the first-line therapy for patients with locally advanced or metastatic pancreatic cancer. Unfortunately, because of pre-existing or acquired chemoresistance of most of the tumor cells, gemcitabine has failed to significantly improve the outcome for pancreatic carcinoma patients. The present study explored the possibility of sensitizing pancreatic cancer to gemcitabine chemotherapy by combining the chemotherapy with the proapoptotic genes Bax and TNF-related apoptosis-inducing ligand (TRAIL). We designed two tetracycline-inducible recombinant adenoviruses using the human telomerase reverse transcriptase (hTERT) promoter for transcriptional apoptogene targeting. Our data showed that treatment with the adenoviral systems resulted in high-level expression of Bax and TRAIL genes directly related to apoptosis induction, leading to a significant sensitization of resistant pancreatic tumor cells. Furthermore, treatment with Bax and TRAIL adenoviruses plus a suboptimal dose of gemcitabine resulted in significant tumor regression and prolongation of the experimental animal';s life, in contrast to the weak retardation in tumor growth observed when gemcitabine alone was used. Additionally, using an orthotopic tumor model, we showed the usefulness of a non-invasive whole-body optical imaging for real-time evaluation of therapeutic efficacy. Together, these findings suggest that hTERT-targeted proapoptotic gene expression in combination with gemcitabine may be a potential therapeutic strategy for treatment of pancreatic adenocarcinoma.
Acute renal failure due to acetaminophen ingestion
Authors: P Blakely, B R McDonald
Journal: Journal of the American Society of Nephrology (1995)

Acetaminophen is the most commonly reported drug overdose in the United States. Acute renal failure occurs in less than 2% of all acetaminophen poisonings and 10% of severely poisoned patients. At the therapeutic dosages, acetaminophen can be toxic to the kidneys in patients who are glutathione depleted (chronic alcohol ingestion, starvation, or fasting) or who take drugs that stimulate the P-450 microsomal oxidase enzymes (anticonvulsants). Acute renal failure due to acetaminophen manifests as acute tubular necrosis (ATN). ATN can occur alone or in combination with hepatic necrosis. The azotemia of acetaminophen toxicity is typically reversible, although it may worsen over 7 to 10 days before the recovery of renal function occurs. In severe overdoses, renal failure coincides with hepatic encephalopathy and dialysis may be required. Recognition of acetaminophen nephropathy requires the following: (1) a thorough drug history, including over-the-counter medications such as Tylenol or Nyquil; (2) knowledge of the risk factors that lessen its margin of safety at therapeutic ingestions, i.e., alcoholism; and (3) consideration of acetaminophen in the differential diagnosis of patients who present with combined hepatic dysfunction and ATN.
Relationship Between Risk Factors and Mortality in Type 1 Diabetic Patients in Europe
Authors: Sabita S. Soedamah-Muthu, Nish Chaturvedi, Daniel R. Witte, Lynda K. Stevens, Massimo Porta, John H. Fuller
Journal: Diabetes Care (2008)

The purpose of this study was to examine risk factors for mortality in patients with type 1 diabetes.Baseline risk factors were measured in the EURODIAB Prospective Cohort Study with 2,787 type 1 diabetic patients (51% men and 49% women) recruited from 16 European countries. Mortality data were collected during a 7-year follow-up.There was an annual mortality rate of 5 per 1,000 person-years in patients with type 1 diabetes (mean age at baseline 33 years, range 15-61 years); of the total 2,787 subjects, 102 died. The final multivariable model contained age at baseline (standardized hazard ratio 1.78 [95% CI 1.44-2.20]), A1C (1.18 [0.95-1.46]), waist-to-hip ratio (WHR) (1.32 [1.14-1.52]), pulse pressure (1.33 [1.13-1.58]), and non-HDL cholesterol (1.33 [1.12-1.60]) as risk factors for all-cause mortality. Macroalbuminuria (2.39 [1.19-4.78]) and peripheral (1.88 [1.06-3.35]) and autonomic neuropathy (2.40 [1.32-4.36]) were the most important risk markers for mortality. Similar risk factors were found for all-cause, non-cardiovascular disease (CVD), unknown-cause, and CVD mortality.Important risk factors for the increased total and non-CVD mortality in type 1 diabetic patients are age, WHR, pulse pressure, and non-HDL cholesterol. Microvascular complications from macroalbuminuria and peripheral and autonomic neuropathy are strong risk markers for future mortality exceeding the effect of the traditional risk factors.
Preoperative screening for metastases in lung cancer.
Authors: M F Muers
Journal: Thorax (1994)

In a pilot study by field-screening in two different sauna baths, a day-sauna and a night-sauna, 318 homosexual men were investigated for syphilis and hepatitis B surface antigen (HBsAg) and its antibody (anti-HBs). Of the 134 visitors to the day-sauna 35.1% were seroreactive for syphilis, four (3%) carried HBsAg, and 95 (70.9%) anti-HBs. Of the 184 visitors to the night-sauna 33.2% were seroreactive for syphilis, 16 (8.7%), carried HBsAg, and 97 (52.7%) anti-HBs. The correlation between seroreactivity for syphilis and the presence of HBsAg amd anti-HBs was statistically significant.
Pesticides and Atopic and Nonatopic Asthma among Farm Women in the Agricultural Health Study
Authors: Jane A. Hoppin, David M. Umbach, Stephanie J. London, Paul K. Henneberger, Greg J. Kullman, Michael C. R. Alavanja, Dale P. Sandler
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Risk factors for asthma among farm women are understudied.We evaluated pesticide and other occupational exposures as risk factors for adult-onset asthma.Studying 25,814 farm women in the Agricultural Health Study, we used self-reported history of doctor-diagnosed asthma with or without eczema and/or hay fever to create two case groups: patients with atopic asthma and those with nonatopic asthma. We assessed disease-exposure associations with polytomous logistic regression.At enrollment (1993-1997), 702 women (2.7%) reported a doctor's diagnosis of asthma after age 19 years (282 atopic, 420 nonatopic). Growing up on a farm (61% of all farm women) was protective for atopic asthma (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.43-0.70) and, to a lesser extent, for nonatopic asthma (OR, 0.83; 95%CI, 0.68-1.02; P value for difference = 0.008). Pesticide use was almost exclusively associated with atopic asthma. Any use of pesticides on the farm was associated only with atopic asthma (OR, 1.46; 95% CI, 1.14-1.87). This association with pesticides was strongest among women who had grown up on a farm. Women who grew up on farms and did not apply pesticides had the lowest overall risk of atopic asthma (OR, 0.41; 95% CI, 0.27-0.62) compared with women who neither grew up on farms nor applied pesticides. A total of 7 of 16 insecticides, 2 of 11 herbicides, and 1 of 4 fungicides were significantly associated with atopic asthma; only permethrin use on crops was associated with nonatopic asthma.These findings suggest that pesticides may contribute to atopic asthma, but not nonatopic asthma, among farm women.
PRC1 and Suv39h specify parental asymmetry at constitutive heterochromatin in early mouse embryos
Authors: Mareike Puschendorf, Rémi Terranova, Erwin Boutsma, Xiaohong Mao, Kyo-ichi Isono, Urszula Brykczynska, Carolin Kolb, Arie P Otte, Haruhiko Koseki, Stuart H Orkin, Maarten van Lohuizen, Antoine H F M Peters
Journal: Nature Genetics (2008)
Experts launch Europe-wide drive to highlight dangers of alcohol
Authors: A. O'Dowd
Journal: BMJ (2012)

An international team of scientists has launched a drive to highlight the dangers of excessive drinking, which is thought to cause one in every eight deaths in people aged 15 to 64 years in Europe.

The importance of raising awareness of dangerous drinking and promoting health over the interests of the drinks industry is emphasised in a new policy briefing paper published on 16 May.1

The paper comes from a group called the Addiction and Lifestyles in Contemporary Europe—Reframing Addictions Project (ALICE RAP), a European Union network of more than 150 researchers from a range of disciplines who study various aspects of addiction.

It says that people in Europe drink more than twice the world’s …
Phase I Trial of Histone Deacetylase Inhibition by Valproic Acid Followed by the Topoisomerase II Inhibitor Epirubicin in Advanced Solid Tumors: A Clinical and Translational Study
Authors: Pamela Münster, Douglas Marchion, Elona Bicaku, Morgen Schmitt, Ji Hyun Lee, Ronald DeConti, George Simon, Mayer Fishman, Susan Minton, Chris Garrett, Alberto Chiappori, Richard Lush, Daniel Sullivan, Adil Daud
Journal: Journal of Clinical Oncology (2007)

To determine the safety, toxicity, and maximum-tolerated dose of a sequence-specific combination of the histone deacetylase inhibitor (HDACi), valproic acid (VPA), and epirubicin in solid tumor malignancies and to define the clinical feasibility of VPA as an HDACi.Patients were treated with increasing doses of VPA (days 1 through 3) followed by epirubicin (day 3) in 3-week cycles. The study evaluated pharmacokinetic and pharmacodynamic end points, toxicities, and tumor response.Forty-eight patients were enrolled, and 44 received at least one cycle of therapy. Patients (median age, 54 years; range, 39 to 78 years) received the following doses of VPA: 15, 30, 45, 60, 75, 90, 100, 120, 140, and 160 mg/kg/d. Dose-limiting toxicities were somnolence (n = 1), confusion (n = 3), and febrile neutropenia (n = 1). No exacerbation of epirubicin-related toxicities was observed. Partial responses were seen across different tumor types in nine patients (22%), and stable disease/minor responses were seen in 16 patients (39%), despite a median number of three prior regimens (range, zero to 10 prior regimens). Patients received a median number of four treatment cycles (range, one to 10 cycles), and treatment was stopped after reaching maximal epirubicin doses rather than progression in 13 (32%) of 41 patients patients. Total and free VPA plasma concentrations increased linearly with dose and correlated with histone acetylation in peripheral-blood mononuclear cells.The maximum-tolerated dose and recommended phase II dose was VPA 140 mg/kg/d for 48 hours followed by epirubicin 100 mg/m2. Sustained plasma concentrations of VPA exceeding those required for in vitro synergy were achieved with acceptable toxicity. Noteworthy antitumor activity was observed in heavily pretreated patients and historically anthracycline-resistant tumors.
Medical Management of Venous Thrombosis
Authors: S Wessler
Journal: Annual Review of Medicine (1976)

Deep venous thrombosis of the lower extremities is a common age-related phenome­ non manifest by focal intravascular coagulation in which the mechanism is obscure, the clinical recognition elusive, the recurrence rate high, and mortality unpredict­ able. The urgency of the physician's concern with deep venous thrombosis clearly lies in the intimate but variable association between thrombi in peripheral veins and death from embolization of these thrombi to the pulmonary arteries-thus the rubric, venous thromboembolism. Venous thromboembolism is a ubiquitous and frequently lethal complication (50,000 deaths annually) of a broad spectrum of medical and surgical diseases and of sedentary living. Its hazard to a productive life has been masked by a lack of awareness of its true incidence and by the fact that it is not itself a disease, but rather a complication of a host of major disease states. Recent data have documented its remarkable scope, its increasing prevalence in our society, its mechanism of action at the molecular level, and most importantly, have provided new methods of pri­ mary prophylaxis that are now available for general use by physicians and surgeons. In short, venous thromboembolism has become a largely preventable complication of disease (1). Anticoagulants, particularly heparin and the coumarin compounds, are the main­ stay of the therapeutic armamentarium in the prophylaxis of venous thromboembol­ ism. Current interest has focused on the newer applications of heparin, particularly at the onset of the risk of intravascular coagulation, while coumarins maintain their value mainly in long-term prophylaxis. Thrombolytic therapy may have an acces­ sory role in the management of massive pulmonary emboli. The practical usefulness of venoms remains to be established, and evidence is not yet available that platelet antiaggregating agents are therapeutic in venous disease. Finally, a variety of physi-
Increased Glucose Uptake and Oxidation in Mouse Hearts Prevent High Fatty Acid Oxidation but Cause Cardiac Dysfunction in Diet-Induced Obesity
Authors: Jie Yan, Martin E. Young, Lei Cui, Gary D. Lopaschuk, Ronglih Liao, Rong Tian
Journal: Circulation (2009)

Shift of myocardial substrate preference has been observed in many chronic diseases such as diabetes and heart failure. This study was undertaken to elucidate the mechanisms underlying the chronic substrate switch in adult hearts and to determine the functional consequences of the switch.Transgenic mice with cardiac-specific overexpression of the insulin-independent glucose transporter GLUT1 (TG) were used to increase intracellular glucose in cardiac myocytes. A high-fat diet was used to increase the fatty acid supply to the heart. High-fat diet induced a 40% increase in fatty acid oxidation in wild-type hearts, whereas glucose oxidation was decreased to 30% of the control. In contrast, glucose oxidation was >2-fold higher in TG hearts, and the high-fat diet failed to upregulate fatty acid oxidation in these hearts. Glucose induced changes in the expression of multiple metabolic genes, including peroxisome proliferator-activated receptor-alpha (decreased by 51%), 3-oxoacid CoA transferase (decreased by 67%), and acetyl-CoA carboxylase (increased by 4-fold), resulting in a remodeling of the metabolic network to favor a shift of substrate preference toward glucose. Although TG mice on a normal diet maintained normal cardiac energetics and function, the inability to upregulate myocardial fatty acid oxidation in TG mice fed a high-fat diet resulted in increased oxidative stress in the heart, activation of p38 mitogen-activated protein kinase, and contractile dysfunction.We have demonstrated that chronic increases in myocardial glucose uptake and oxidation reduce the metabolic flexibility and render the heart susceptible to contractile dysfunction.
Severe hypocalcaemia after being given intravenous bisphosphonate
Authors: Rajesh Peter, Vinita Mishra, William D Fraser
Journal: BMJ (2004)

Bisphosphonates are increasingly used to treat metabolic bone disease and as prophylaxis against metastatic bone cancer.1 2 Zoledronic acid is a new intravenous bisphosphonate licensed to treat hypercalcaemia of malignancy, but it has been used off licence as prophylaxis for metastatic cancer, bone pain, treatment of osteoporosis, and Paget's disease of the bone. Zoledronic acid is 100 to 1000 times more potent than disodium pamidronate or oral alendronic acid, risedronate sodium, sodium clodronate, or disodium etidronate. A randomised controlled trial found that zoledronic acid is more effective than disodium pamidronate in treating hypercalcaemia of malignancy.3 Zoledronic acid does not cause the gastrointestinal side effects associated with oral bisphosphonates, but increased potency carries a higher risk of hypocalcaemia. We have recent experience of patients becoming hypocalcaemic after doctors gave intravenous bisphosphonates.

### Case 1

A 49 year old man with transitional cell carcinoma of the bladder received chemotherapy with cisplatin, methotrexate, and vinblastine after resection of a tumour. His prechemotherapy adjusted calcium was normal. Despite four cycles of chemotherapy every two weeks he had bone pain due to metastases. Doctors gave him 4 mg of zoledronic acid and intravenous diamorphine after diclofenac sodium and co-proxamol failed to relieve his symptoms. His adjusted calcium six days before being given zoledronic acid was low (table).

View this table:

Serum analyte concentrations in patents given bisphosphonates



Three days after being given intravenous zoledronic acid, he had tetanic spasms and paraesthesia. Trousseau's sign was positive and an electrocardiogram showed a long QT interval—474 ms (RR < 440 ms). His adjusted calcium …
Localisation of endothelin like immunoreactivity in adult and developing human gut.
Authors: C Escrig, A E Bishop, H Inagaki, G Moscoso, K Takahashi, I M Varndell, M A Ghatei, S R Bloom, J M Polak
Journal: Gut (1992)

The distribution of immunoreactivity for the potent vasoconstrictor endothelin-1 was studied in adult and developing human gut using antisera to endothelin-1 (1-21) and the C terminus of big endothelin-1. The coexistence of these peptides with other neuropeptides was investigated using comparative immunocytochemistry. Endothelin-1 like immunoreactivity was detected in extracts of adult (range 20-60 fmol/g wet weight) and fetal (33 fmol/g) gastrointestinal tract and was shown by chromatography to be the predominant isoform of endothelin present in both. It was localised by immunocytochemistry to ganglion cells in the submucous and myenteric plexuses and to scattered nerves, whereas big endothelin-1 like immunoreactivity was found in the submucous plexus only. Colocalisation studies showed immunoreactivity for both endothelin-1 and vasoactive intestinal peptide in the same ganglion cells of the submucous plexus. Although endothelin-1 immunoreactivity was not detected by immunocytochemistry in the fetal human gut until the 32nd week of gestation, big endothelin-1 was found as early as 11 weeks in the developing neural structures and epithelial cells. The latter were shown to be endocrine cells by their immunoreactivity for chromogranin. Our results indicate that endothelin is a neuropeptide found in adult human gut which shows transient expression in endocrine cells during development.