tbuckley/cabot-search huggingface dataset:
25 year trends in first time hospitalisation for acute myocardial infarction, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity: a Danish nationwide cohort study
Authors: M. Schmidt, J. B. Jacobsen, T. L. Lash, H. E. Botker, H. T. Sorensen
Journal: BMJ (2012)

<b>Objectives</b> To examine 25 year trends in first time hospitalisation for acute myocardial infarction in Denmark, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity. <b>Design</b> Nationwide population based cohort study using medical registries. <b>Setting</b> All hospitals in Denmark. <b>Subjects</b> 234&nbsp;331 patients with a first time hospitalisation for myocardial infarction from 1984 through 2008. <b>Main outcome measures</b> Standardised incidence rate of myocardial infarction and 30 day and 31–365 day mortality by sex. Comorbidity categories were defined as normal, moderate, severe, and very severe according to the Charlson comorbidity index, and were compared by means of mortality rate ratios based on Cox regression. <b>Results</b> The standardised incidence rate per 100&nbsp;000 people decreased in the 25 year period by 37% for women (from 209 to 131) and by 48% for men (from 410 to 213). The 30 day, 31–365 day, and one year mortality declined from 31.4%, 15.6%, and 42.1% in 1984–8 to 14.8%, 11.1%, and 24.2% in 2004–8, respectively. After adjustment for age at time of myocardial infarction, men and women had the same one year risk of dying. The mortality reduction was independent of comorbidity category. Comparing patients with very severe versus normal comorbidity during 2004–8, the mortality rate ratio, adjusted for age and sex, was 1.96 (95% CI 1.83 to 2.11) within 30 days and 3.89 (3.58 to 4.24) within 31–365 days. <b>Conclusions</b> The rate of first time hospitalisation for myocardial infarction and subsequent short term mortality both declined by nearly half between 1984 and 2008. The reduction in mortality occurred for all patients, independent of sex and comorbidity. However, comorbidity burden was a strong prognostic factor for short and long term mortality, while sex was not.
Developing and Validating a Risk Score for Lower-Extremity Amputation in Patients Hospitalized for a Diabetic Foot Infection
Authors: Benjamin A. Lipsky, John A. Weigelt, Xiaowu Sun, Richard S. Johannes, Karen G. Derby, Ying P. Tabak
Journal: Diabetes Care (2011)

Diabetic foot infection is the predominant predisposing factor to nontraumatic lower-extremity amputation (LEA), but few studies have investigated which specific risk factors are most associated with LEA. We sought to develop and validate a risk score to aid in the early identification of patients hospitalized for diabetic foot infection who are at highest risk of LEA.Using a large, clinical research database (CareFusion), we identified patients hospitalized at 97 hospitals in the U.S. between 2003 and 2007 for culture-documented diabetic foot infection. Candidate risk factors for LEA included demographic data, clinical presentation, chronic diseases, and recent previous hospitalization. We fit a logistic regression model using 75% of the population and converted the model coefficients to a numeric risk score. We then validated the score using the remaining 25% of patients.Among 3,018 eligible patients, 21.4% underwent an LEA. The risk factors most highly associated with LEA (P < 0.0001) were surgical site infection, vasculopathy, previous LEA, and a white blood cell count >11,000 per mm(3). The model showed good discrimination (c-statistic 0.76) and excellent calibration (Hosmer-Lemeshow, P = 0.63). The risk score stratified patients into five groups, demonstrating a graded relation to LEA risk (P < 0.0001). The LEA rates (derivation and validation cohorts) were 0% for patients with a score of 0 and ~50% for those with a score of ≥21.Using a large, hospitalized population, we developed and validated a risk score that seems to accurately stratify the risk of LEA among patients hospitalized for a diabetic foot infection. This score may help to identify high-risk patients upon admission.
Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor–induced epithelial‐mesenchymal transition
Authors: Zhi‐Chao Wang, Qiang Gao, Jie‐Yi Shi, Wei‐Jie Guo, Liu‐Xiao Yang, Xin‐Yang Liu, Long‐Zi Liu, Li‐Jie Ma, Meng Duan, Ying‐Jun Zhao, Yong‐Na Wu, Dong‐Mei Gao, Xiao‐Ying Wang, Guo‐Ming Shi, Zhen‐Bin Ding, Ai‐Wu Ke, Qi‐Qun Tang, Ya Cao, Jian Zhou, Jia Fan
Journal: Hepatology (2015)

Hepatocellular carcinoma (HCC) is the third‐most lethal cancer worldwide. Understanding the molecular pathogenesis of HCC recurrence and metastasis is the key to improve patients’ prognosis. In this study, we report that protein tyrosine phosphatase receptor S (PTPRS) is significantly down‐regulated in nearly 80% of HCCs, and its expression negatively correlates with aggressive pathological features, such as larger tumor size and advanced stage. In addition, PTPRS deficiency is independently associated with shorter survival and increased recurrence in patients, although 16.7% of HCCs show intratumor heterogeneous expression of PTPRS. Restoration of wild‐type, but not mutant, PTPRS expression significantly inhibits HCC cell migration and invasion in vitro as well as lung metastasis in vivo , whereas knockdown of its expression significantly promotes invasion and metastasis. Notably, PTPRS‐regulated HCC invasiveness is accompanied by typical changes of epithelial‐mesenchymal transition (EMT). Moreover, PTPRS forms a complex with epithermal growth factor receptor (EGFR) and regulates its tyrosine residues’ phosphorylation. Ectopic expression of EGFR reverses the metastasis‐inhibiting effects of PTPRS, whereas silencing of EGFR or inhibiting phosphorylation of key molecules in EGFR downstream pathways reinhibits EMT and metastasis caused by PTPRS down‐regulation. Meanwhile, promoter hypermethylation of PTPRS is frequently detected in HCC samples and cell lines. Treatment with a demethylation agent, 5‐aza‐2′‐deoxycytidine, recovers PTPRS expression in a dose‐dependent manner. Conclusions : Epigenetic inactivation of PTPRS may increase phosphorylation and activity of EGFR signaling to promote EMT and metastasis in HCC. (H epatology 2015;62:1201‐1214)
Production of Wnt Inhibitors by Myeloma Cells: Potential Effects on Canonical Wnt Pathway in the Bone Microenvironment
Authors: Nicola Giuliani, Francesca Morandi, Sara Tagliaferri, Mirca Lazzaretti, Gaetano Donofrio, Sabrina Bonomini, Roberto Sala, Marcellina Mangoni, Vittorio Rizzoli
Journal: Cancer Research (2007)

Osteoblast impairment occurs within multiple myeloma cell infiltration into the bone marrow. Canonical Wnt signaling activation in osteoprogenitor cells is involved in osteoblast formation through the stabilization of dephosphorylated beta-catenin and its nuclear translocation. The effects of multiple myeloma cells on Wnt signaling in human mesenchymal/osteoprogenitor cells are unclear. In 60 multiple myeloma patients checked, we found that among the Wnt inhibitors, Dickkopf-1 and secreted frizzled-related protein-3 were produced by multiple myeloma cells. However, although multiple myeloma cells or multiple myeloma bone marrow plasma affected expression of genes in the canonical Wnt signaling and inhibited beta-catenin stabilization in murine osteoprogenitor cells, they failed to block the canonical Wnt pathway in human mesenchymal or osteoprogenitor cells. Consistently, Wnt3a stimulation in human osteoprogenitor cells did not blunt the inhibitory effect of multiple myeloma cells on osteoblast formation. Consequently, despite the higher Wnt antagonist bone marrow levels in osteolytic multiple myeloma patients compared with nonosteolytic ones, beta-catenin immunostaining was not significantly different. Our results support the link between the production of Wnt antagonists by multiple myeloma cells and the presence of bone lesions in multiple myeloma patients but show that myeloma cells do not inhibit canonical Wnt signaling in human bone microenvironment.
Effect of apoproteins on hepatic uptake of triglyceride emulsions in the rat.
Authors: F Shelburne, J Hanks, W Meyers, S Quarfordt
Journal: Journal of Clinical Investigation (1980)

The addition of apoprotein E isolated from human very low density lipoproteins to both rat lymph chylomicrons and a triglyceride emulsion significantly increased the hepatic uptake of these particles in a nonrecycling isolated rat liver perfusion system. The cleared triglyceride was removed without apparent hydrolysis by the hepatocyte. When lymph chylomicrons were loaded with both Apo E and Apo C proteins by exposure to rat plasma, no increment in hepatic clearance was observed. Sequential evalutions of the influence of the C apoproteins on the hepatic clearance of both emulsions and chylomicrons revealed that the CIII (CIII-1) protein had a pronounced inhibitory effect on hepatic removal. The inhibition was observed for both Apo E-enriched chylomicrons and those containing little of this apoprotein.
Recent Studies on the Structure and Function of Multisubstrate Flavin-Containing Monooxygenases
Authors: D M Ziegler
Journal: The Annual Review of Pharmacology and Toxicology (1993)

Interest in the oxidation of xenobiotics catalyzed by flavin-containing monooxygenases has expanded dramatically over the past decade. Studies on their exceptional substrate range, wide tissue distribution, and the existence of multiple forms are perhaps the major developments that have stimulated recent work on these enzymes. In addition, the reports by Smith and his associates on the polymorphism of the N-oxygenation of trimethylamine (1) and nicotine (2) in humans apparently due to a genetic defect in one or more of the flavin-containing monooxygenases has fueled further interest in the role of these enzymes in the metabolism of xenobiotics. This review focuses primarily on recent work on the number of isoforms (based largely on differences in primary structures deduced from cDNAs) present in major organs of entry, possible methods for estimating substrate specificity and activity of different isoforms in crude tissue preparations, and methods for manipUlating hepatic concentration (activity) of flavin-containing monooxygenases with dietary xenobiotics. The latter work, while still in very early stages, will undoubtedly have a significant impact on this area of drug metabolism by providing a convenient model for assessing the effect of changes in the concentration of these enzymes on the metabolism of a specific
Pregnancy Among Patients With Chronic Myeloid Leukemia Treated With Imatinib
Authors: Patricia Ault, Hagop Kantarjian, Susan O'Brien, Stefan Faderl, Miloslav Beran, Mary Beth Rios, Charles Koller, Francis Giles, Michael Keating, Moshe Talpaz, Jorge Cortes
Journal: Journal of Clinical Oncology (2006)

Imatinib has potential teratogenicity in animals, but the effect of exposure to imatinib during conception and pregnancy in humans is not known.The records of all patients with chronic myeloid leukemia (CML) treated with imatinib were reviewed. We report the experience on 19 pregnancies involving 18 patients (10 females and eight males) who conceived while receiving imatinib for the treatment of CML.All female patients discontinued therapy immediately on recognition of pregnancy. Three pregnancies (involving two female patients and one male patient) ended in spontaneous abortion, and one patient had an elective abortion. All other pregnancies were uneventful. Two of the 16 babies had minor abnormalities at or shortly after birth (hypospadias in one baby and rotation of small intestine in one baby) that were surgically repaired. All babies have continued normal growth and development. Among female patients who interrupted therapy, five of nine in complete hematologic remission (CHR) at the time of treatment interruption eventually lost CHR, and six experienced an increase in Philadelphia chromosome-positive metaphases. At a median of 18 months after resuming therapy with imatinib, eight patients had a cytogenetic response (complete in three patients).Although there is no evidence that a brief exposure to imatinib during conception and pregnancy adversely affects the developing fetus, most patients lose their response after treatment interruption. Patients receiving imatinib should be advised to practice adequate contraception.
Endogenous Activation of Mitochondrial K <sub>ATP</sub> Channels Protects Human Failing Myocardium From Hydroxyl Radical–Induced Stunning
Authors: Christoph Maack, Ewtim R. Dabew, Mathias Hohl, Hans-Joachim Schäfers, Michael Böhm
Journal: Circulation Research (2009)

During reperfusion of ischemic myocardium, a burst of hydroxyl radicals (OH) induces contractile dysfunction ("myocardial stunning"), and OH in the plasma of patients after myocardial infarction predict the development of heart failure. The effects of OH on myocardial function in patients with heart failure; however, have never been assessed. Furthermore, although ATP-dependent K+ channels (K(ATP) channels) are implicated in myocardial protection during ischemia/reperfusion ("ischemic preconditioning"), their role in heart failure has hardly been elucidated.To investigate the effects of OH on cardiac contractile function in human failing myocardium, and to clarify the role of K(ATP) channels during this response.In isolated left ventricular trabeculae of nonfailing hearts, OH (produced by Fe3+-nitrilotriacetic acid and H2O2) induced substantial systolic and diastolic dysfunction, whereas in failing myocardium, stunning was virtually absent. Although in failing myocardium, protein expression of sarcolemmal K(ATP) channels (Kir6.2/SUR2) was approximately 2-fold upregulated, their blockade with HMR-1098 did not impair contractile function in the presence of OH. In contrast, when blocking mitochondrial K(ATP) channels during OH exposure (with 5-HD), failing myocardium developed contractile dysfunction to a degree that was comparable to H-induced stunning in nonfailing myocardium without K(ATP) channel blockade.Human failing left ventricular myocardium is resistant to OH-induced stunning, and this resistance is related to endogenous activation of putative mitochondrial K(ATP) channels. Given that certain sulfonylurea drugs that also block mitochondrial K(ATP) channels (eg, glibenclamide) are frequently used for the treatment of diabetes, our results imply that in patients with heart failure and diabetes, these drugs may impair left ventricular function during ischemia/reperfusion.
Inhibition of thyrotropin response to thyrotropin-releasing hormone by small quantities of thyroid hormones
Authors: Peter J. Snyder, Robert D. Utiger
Journal: Journal of Clinical Investigation (1972)

Inhibition of thyrotropin (TSH) release by chronic treatment with small quantities of triiodothyronine (T(3)) and thyroxine (T(4)) was evaluated by determining the serum TSH response to thyrotropin-releasing hormone (TRH) in normal subjects and hypothyroid patients. Response to TRH was determined before treatment and after each dosage of a synthetic combination of T(3) + T(4) had been given for 3-4 wk. Treatment of eight normal subjects with 15 mug T(3) + 60 mug T(4) reduced the maximum increase in serum TSH above baseline (maximum DeltaTSH) by 76% in response to 400 mug TRH and by 87% in response to 25 mug TRH. The average serum T(3) level during a 24 hr period in normal subjects who had been taking 15 mug T(3) + 60 mug T(4) for 3-4 wk was 129+/-10 ng/100 ml (mean +/-SEM), well within the normal range, 70-150 ng/100 ml, although higher than the pretreatment level, 98+/-7 ng/100 ml. The average serum T(4) level was unchanged from the pretreatment level. Treatment of the same subjects with 30 mug T(3) + 120 mug T(4) reduced the maximum DeltaTSH further.Six patients with primary hypothyroidism were treated, sequentially, with 15 + 60, 22.5 + 90, and 30 mug T(3) + 120 mug T(4). For each patient there was one increase in dosage of 7.5 mug T(3) + 30 mug T(4) which abruptly converted a maximum DeltaTSH that was greater than, or at the upper limit of, normal to one that was subnormal. Concurrent with these six abrupt changes in TSH response, the mean serum T(3) level increased only from 105+/-5 to 129+/-9 ng/100 ml, and the mean serum T(4) level increased only from 4.9+/-0.8 to 6.3+/-0.5 mug/100 ml. These data demonstrate the extreme sensitivity of TRH-induced TSH release to inhibition by the chronic administration of quantities of T(3) + T(4) which do not raise serum T(3) and T(4) levels above the normal ranges.
Protein Engineering for Cardiovascular Therapeutics
Authors: Steven M. Jay, Richard T. Lee
Journal: Circulation Research (2013)

A number of new and innovative approaches for repairing damaged myocardium are currently undergoing investigation, with several encouraging results. In addition to the progression of stem cell-based approaches and gene therapy/silencing methods, evidence continues to emerge that protein therapeutics may be used to directly promote cardiac repair and even regeneration. However, proteins are often limited in their therapeutic potential by short local half-lives and insufficient bioavailability and bioactivity, and many academic laboratories studying cardiovascular diseases are more comfortable with molecular and cellular biology than with protein biochemistry. Protein engineering has been used broadly to overcome weaknesses traditionally associated with protein therapeutics and has the potential to specifically enhance the efficacy of molecules for cardiac repair. However, protein engineering as a strategy has not yet been used in the development of cardiovascular therapeutics to the degree that it has been used in other fields. In this review, we discuss the role of engineered proteins in cardiovascular therapies to date. Further, we address the promise of applying emerging protein engineering technologies to cardiovascular medicine and the barriers that must be overcome to enable the ultimate success of this approach.
ISOLATION OF ENTERIC BACILLI FROM SEWAGE AND WATER AND ITS BEARING ON EPIDEMIOLOGY
Authors: W. J. Wilson
Journal: BMJ (1933)

BRITISHunderstanding of them.Kurzrok, 13 for example, has shown that whereas in cases of artificial menopause by radio-destruction or removal of the ovaries the ovarian hormones are necessarily absent, in cases of spontaneous menopause these hormones may or may not be absent.Manifestly, it is only where they are absent that their therapeutic injection can be expected to do good.Many papers have been published in the last two or three years on the treatment of menopausal symptoms.by oestrin- containing substances in which there is no evidence of uniform success, just as in earlier years there was the same discrepancy of results in the use of the solid and largely inert ovarian extracts.The psychical factor in the menopause is probably as important as in dysmenor- rhoea, and must always be taken into account in estima- ting the success of any trea,tment, especially treatment by hypodermic injections.But, when all is said and done, it is certain that if only patients whose urine showed an absence of oestrin were treated by oestrin therapy, the results would be more uniform, the treatment would be rationalized, and our understanding of the real physiology of the menopause would be increased.
Cholesterol and bile acid balance in Macaca fascicularis. Effects of alfalfa saponins.
Authors: M R Malinow, W E Connor, P McLaughlin, C Stafford, D S Lin, A L Livingston, G O Kohler, W P McNulty
Journal: Journal of Clinical Investigation (1981)

We determine the effects of alfalfa top saponins on cholesterol and bile acid balance in eight cynomolgus macaques (Macaca fascicularis). The monkeys ate semipurified food containing cholesterol with or without added saponins. The saponins decreased cholesterolemia without changing the levels of high density lipoprotein-cholesterol; hence, they reduced the total cholesterol/high density lipoprotein-cholesterol ratio. Furthermore, they decreased intestinal absorption of cholesterol, increased fecal excretion of endogenous and exogenous neutral steroids and bile acids, and decreased the percent distribution of fecal deoxycholic and lithocholic acids. The fecal excretion of fat was also slightly increased, but steatorrhea did not occur. We saw no signs of toxicity in the monkeys after 6 or 8 wk of saponin ingestion. The data suggest that alfalfa top saponins may be of use in the treatment of patients with hypercholesterolemia, but long-term studies on possible toxicity are needed before this therapy can be recommended for humans.
Inactivating<i>PAPSS2</i>Mutations in a Patient with Premature Pubarche
Authors: Cees Noordam, Vivek Dhir, Joanne C. McNelis, Florian Schlereth, Neil A. Hanley, Nils Krone, Jan A. Smeitink, Roel Smeets, Fred C.G.J. Sweep, Hedi L. Claahsen-van der Grinten, Wiebke Arlt
Journal: New England Journal of Medicine (2009)

Dehydroepiandrosterone (DHEA) sulfotransferase, known as SULT2A1, converts the androgen precursor DHEA to its inactive sulfate ester, DHEAS [corrected], thereby preventing the conversion of DHEA to an active androgen. SULT2A1 requires 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for catalytic activity. We have identified compound heterozygous mutations in the gene encoding human PAPS synthase 2 (PAPSS2) in a girl with premature pubarche, hyperandrogenic anovulation, very low DHEAS levels, and increased androgen levels. In vitro coincubation of human SULT2A1 and wild-type or mutant PAPSS2 proteins confirmed the inactivating nature of the mutations. These observations indicate that PAPSS2 deficiency is a monogenic adrenocortical cause of androgen excess.
Acetazolamide Improves Central Sleep Apnea in Heart Failure
Authors: Shahrokh Javaheri
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Acetazolamide is a mild diuretic and a respiratory stimulant. It is used to treat periodic breathing at high altitude.To determine the therapeutic efficacy of acetazolamide on central sleep apnea associated with heart failure.Twelve male patients with stable systolic heart failure whose initial polysomnograms showed more than 15 episodes per hour of apnea and hypopnea participated in the study. The patients were randomized to a double-blind cross-over protocol with acetazolamide or placebo, taken 1 h before bedtime for six nights with 2 wk of washout.Polysomnography, pulmonary function tests, arterial blood gases, and left ventricular ejection fraction were obtained initially along with a sleep questionnaire, history, and physical examination. Baseline measurements were repeated at the end of each arm.There were no significant differences between parameters at baseline and placebo. In comparing placebo with acetazolamide, the hourly number of episodes of central apnea (49 +/- 28 vs. 23 +/- 21 [mean +/- SD]; p = 0.004) and the percentage of total sleep time spent below an arterial oxyhemoglobin saturation of 90% (19 +/- 32 vs. 6 +/- 13%; p = 0.01) decreased significantly. Acetazolamide improved subjective perception of overall sleep quality (p = 0.003), feeling rested on awakening (p = 0.007), daytime fatigue (p = 0.02), and falling asleep unintentionally during daytime (p = 0.002).In patients with heart failure, administration of a single dose of acetazolamide before sleep improves central sleep apnea and related daytime symptoms.