tbuckley/cabot-search huggingface dataset:
Withdrawal of sibutramine in Europe
Authors: G. Williams
Journal: BMJ (2010)

Another sign that there is no magic bullet to treat obesity

The therapeutic cupboard containing antiobesity drugs has never been well stocked. The European Medicines Agency (EMA) recently decided that sibutramine must follow the example of rimonabant, withdrawn last year because of safety concerns.1 This leaves just one drug—orlistat—to face the rising tide of obesity across the continent. The demise of sibutramine carries both irony and wider messages for the management of obesity.

Sibutramine fell at the crucial hurdle of cardiovascular risk. Arterial disease—which leads ultimately to myocardial ischaemia, heart failure, and stroke—affects most obese people to some degree and is their major cause of death.2 Much evidence suggests that weight loss decreases morbidity and mortality associated with cardiovascular disease,3 and this is an important justification for all antiobesity measures, including drugs. Unfortunately for sibutramine, an interim analysis of the SCOUT (Sibutramine Cardiovascular Outcome Trial) study found that the drug increased morbidity from cardiovascular disease.1

The odds were always stacked against sibutramine, because cardiovascular risk is embedded in its mechanism of action. Sibutramine acts centrally to reduce food intake; it inhibits the presynaptic reuptake and degradation of serotonin and noradrenaline, thus enhancing the appetite suppressing actions of both neurotransmitters. …
Physical Activity and Weight Gain Over 20 Years
Authors: Sarah Jolley, Brian Porter, John Amory
Journal: JAMA (2011)

To the Editor: Dr Hankinson and colleagues reported on the relationship of activity and body mass index (BMI) over 20 years in a large, ethnically diverse cohort of young to middle-aged adults participating in the CARDIA study. Weight gain is a major underlying risk factor for mortality secondary to the development of diabetes, heart disease, and cancer. In their analysis, being in the highest tertile of activity was associated with a reduction in the rate of increase in both BMI and waist circumference. However, individuals in this highest activity tertile still experienced significant increases in both BMI and waist circumference over time. In their study, was there an activity level that was associated with no increase in BMI or waist circumference? If so, that level of activity might actually prevent increases in BMI during the transition from young adulthood to middle age. Did that activity level differ by sex or race? Also, was there an ideal ratio of activity to caloric intake at which the observed increases in BMI were minimized? Such information would be useful in counseling young adults about the level of activity needed to maintain a healthy weight and minimize the risk of obesity-related morbidity and mortality.
Etanercept monotherapy in patients with psoriasis: A summary of safety, based on an integrated multistudy database
Authors: Alice B. Gottlieb, Craig L. Leonardi, Bernard S. Goffe, Jean-Paul Ortonne, Peter C.M. van der Kerkhof, Ralph Zitnik, Arline Nakanishi, Angelika Jahreis
Journal: Journal of the American Academy of Dermatology (2006)
Defective development of NK1.1+ T-cell antigen receptor αβ+ cells in zeta-associated protein 70 null mice with an accumulation of NK1.1+CD3− NK-like cells in the thymus
Authors: Kazuya Iwabuchi, Chikako Iwabuchi, Saori Tone, Daisuke Itoh, Noriko Tosa, Izumi Negishi, Kazumasa Ogasawara, Toshimitsu Uede, Kazunori Onoé
Journal: Blood (2001)
The ER-Luminal Domain of the HCMV Glycoprotein US6 Inhibits Peptide Translocation by TAP
Authors: Kwangseog Ahn, Albrecht Gruhler, Begona Galocha, Thomas R Jones, Emmanuel J.H.J Wiertz, Hidde L Ploegh, Per A Peterson, Young Yang, Klaus Früh
Journal: Immunity (1997)
Dysadherin can enhance tumorigenesis by conferring properties of stem-like cells to hepatocellular carcinoma cells
Authors: Jeong-Ran Park, Ran-Ju Kim, Yoo-Kyung Lee, Soo-Rim Kim, Kyung-Jin Roh, Seung Hyun Oh, Gu Kong, Kyung-Sun Kang, Jeong-Seok Nam
Journal: Journal of Hepatology (2010)
Bilirubin Mono- and diglucuronide formation by human liverIn vitro: Assay by high-pressure liquid chromatography
Authors: Jayanta Roy Chowdhury, Namita Roy Chowdhury, George Wu, Rivka Shouval, Irwin M. Arias
Journal: Hepatology (1981)

Bilirubin diglucuronide, the major pigment in human bile is formed in two steps. Bilirubin is converted to bilirubin monoglucuronide by transfer of the glucuronosyl moiety of uridine diphosphoglucuronic acid catalyzed by the microsomal enzyme, uridine diphosphoglucuronate glucuronosyl transferase (UDP glucuronyl transferase, EC 2.4.1.17). Bilirubin monoglucuronide is converted to bilirubin diglucuronide in vitro by two enzymatic mechanisms: (a) UDP glucuronyl transferase-mediated transfer of a second mole of glucuronic acid form UDP-glucuronic acid to bilirubin monoglucuronide; (b) dismutation of 2 moles of bilirubin monoglucuronide to 1 mole of bilirubin diglucuronide and 1 mole of unconjugated bilirubin, catalyzed by bilirubin monoglucuronide dismutase (bilirubin glucuronoside glucuronosyl transferase EC 2.4.1.95). Assay methods for the three enzymatic mechanisms in human liver homogenate by high-pressure liquid chromatography analysis of underivatized bilirubin tetrapyrroles have been developed. UDP glucuronyl transferase was activated in five human liver homogenates with digitonin, Triton X-100, or UDP- N -acetylglucosamine. Greatest activation was observed with Triton X-100. The pH optimum for conversion of bilirubin to bilirubin monoglucuronide was 7.4, and UDP glucuronyl transferase activity was 625 ± 51 nmoles per 20 min per gm liver. At high initial bilirubin concentrations (342 μ M ), the product of UDP glucuronyl transferase assay with bilirubin as substrate was predominantly bilirubin monoglucuronide. At lower initial bilirubin concentrations (6.5 to 34 μ M ), up to 15% bilirubin diglucuronide was formed. Glucuronyl transferase-mediated UDP glucuronic acid-dependent conversion of bilirubin monoglucuronide to diglucuronide was assayed using UDP- 14 -C-glucuronic acid. The pH optimum was 7.4, and the rate was 21 ± 7 nmoles per gm liver per 20 min. The rate of bilirubin diglucuronide formation by enzymatic dismutation of bilirubin monoglucuronide was 470 ± 112 nmoles per gm liver per min. The pH optimum was 6.6. The products of enzymatic dismutation were of the IXα configuration.
Abstract 5462: Enhancing efficacy of drugs by targeting CXCR2 receptor signaling for the treatment of malignant breast cancer
Authors: Bhawna Sharma, Dhananjay Nawandar, Michelle L. Varney, Kalyan C. Nannuru, Rakesh K. Singh
Journal: Cancer Research (2010)

Abstract Breast cancer is the second most common cause of cancer death in women in the United States after lung cancer and is responsible for more than 40,000 deaths each year. Many challenges exist in the current management of advanced stage breast cancer as there are fewer recognized therapeutic strategies, often due to therapy resistance. Recent reports suggest that malignant cells that survive initial chemo- and radiation therapy often express inflammatory cytokines, which provides survival benefit making tumors resistant to further chemotherapy. The specific objective of the study is to develop strategy to manipulate chemokine-chemokine receptor network for effective therapy with limited toxicity against drug-resistant breast cancer. We investigated whether modulation of CXCR2-dependent signaling in malignant mammary tumor enhances therapeutic efficacy of chemotherapy drugs. We used mammary tumor cells expressing different levels of CXCR2 (Cl66-wt and Cl66-shCXCR2) and examined their response to Paclitaxel and Doxorubicin. We observed significant enhancement of paclitaxel and doxorubicin-mediated toxicity at concentrations 5 and 10nM in Cl66-shCXCR2 cells as compared to Cl66-wt cells. Moreover, the expression of CXCL1, a CXCR2 ligand, was increased in paclitaxel and doxorubicin treated mammary tumor cells. Paclitaxel and doxorubicin induced CXCL-1 levels was significantly lower in Cl66-shCXCR2 cells as compared to Cl66-wt cells. In vivo studies using wild type and knockdown cells showed no significant difference in the tumor growth. However, we observed a difference in the tumor growth between wild type and knockdown tumors in mice treated with 10mg/kg concentration of paclitaxel for 3 weeks after starting the treatment. When these studies were further extended there wasn't any difference between the two groups. Furthermore, we extended these studies using human breast cancer cell lines (MDA-MB231, MDA-MET, and SKBR3). MDA-MB231 and MDA-MET are triple negative and considered to be more metastatic and drug resistant than SKBR3 which is HER2-over expressing cell line. We observed differential expression of CXCR2 and its ligands in these cells. Our observation also showed significant difference in the paclitaxel and doxorubicin-mediated inhibitory response in MDA-MB231 and MDA-MET cells as compared to SKBR3 cells. Together these studies demonstrate that manipulating CXCR2-dependent activity in malignant breast cancer cells significantly enhanced therapeutic efficacy of paclitaxel and doxorubicin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5462.
Modulation of protein kinase C by taurolithocholic acid in isolated rat hepatocytes
Authors: Ulrich Beuers, Irmelin Probst, Carol Soroka, James L. Boyer, Gerd A. Kullak-Ublick, Gustav Paumgartner
Journal: Hepatology (1999)

The protein kinase C (PKC) family of isoenzymes plays a key role in the regulation of hepatocellular secretion. The hydrophobic and cholestatic bile acid, taurolithocholic acid (TLCA), acts as a potent Ca ++ agonist in isolated hepatocytes. However, its effect on PKC isoforms has not been elucidated. Here we investigate the effects of TLCA at low micromolar concentrations on the distribution of PKC isoforms and on membrane–associated PKC activity. The distribution of PKC isoforms was determined in isolated rat hepatocytes in short–term culture using Western blotting and immunofluorescence techniques. PKC activity was measured radiochemically. TLCA (10 μmol/L) induced selective translocation of ε–PKC by 47.9% ± 20.5% ( P &lt; .02 vs. controls; n = 7), but not of α–, δ–, and ζ–PKC to the hepatocellular membranes, whereas the phorbol ester, phorbol 12–myristate 13–acetate (PMA) (1 μmol/L) caused translocation of all mobile isoforms, α–, δ–, and ε–PKC, as shown by immunoblotting. Immunofluorescence studies demonstrated selective translocation of ε–PKC to the canalicular membranes of isolated rat hepatocyte couplets by TLCA (10 μmol/L), but predominant translocation to intracellular and basolateral membranes by PMA (1 μmol/L). Both TLCA (10 μmol/L) and PMA (1 μmol/L) stimulated membrane–bound PKC activity by 60.5% ± 45.8% ( P &lt; .05 vs. controls; n = 5) and 72.4% ± 37.2% ( P &lt; .05; n = 5), respectively. TLCA at lower concentrations (5 μmol/L) was less effective. Because activation of ε–PKC has been associated with impairment of vesicle–mediated targeting and insertion of membrane proteins in secretory cells, it is attractive to speculate that TLCA reduces bile secretory capacity of the liver cell by activation of ε–PKC at the canalicular membrane
Finding Effective Treatment for Impaired Physicians
Authors: Rebecca Voelker
Journal: JAMA (1994)

ALMOST TWO DECADES after acknowledging that some physicians become addicted to alcohol and other drugs, the Federation of State Medical Boards is refining policies aimed at providing impaired physicians with effective treatment. The federation broached the topic of physician impairment in the late 1970s by recommending that all state medical licensing boards have the power to take disciplinary action based on impairment, not harm to patients. But by the mid 1980s, federation officials felt a revision was in order. In addition to developing a brief definition of impairment, the federation recommended that state boards be able to direct their licensees into treatment programs and encourage treatment by exempting reporting requirements for those who complied with treatment provisos. Now, says James Winn, MD, the federation's executive vice president, it's time to refine existing policies. The goal is "to define not only the elements which are essential to model [treatment] programs, but
Recovery From Acute Subdural Hematoma
Authors: Stanley A. Shatsky
Journal: JAMA (1979)

<h3>To the Editor.—</h3> It was gratifying to see what M. Seth Hockman, MD, said (241:2783, 1979) regarding the successful neurological recovery of a 49-year-old patient with a panhemispheric acute subdural hematoma. We believe, however, that his point— what the present standard of neurosurgical practice is—must be much more strongly made to the medical community. The author's first statement, "the development of fixed pupils following transtentorial herniation is such an ominous prognostic sign that only rarely have reports appeared that cite recovery from it," should be taken quite literally, that simply there have been few reports of recovery. This is not at all to say that the great majority of practicing neurosurgeons have not accumulated numerous patients who have recovered. As US Army staff neurosurgeons, we have in the past two years had five patients recover from neurological deterioration as bad as or even worse than that described. The most recent
Optimization of adenoviral vectors to direct highly amplified prostate-specific expression for imaging and gene therapy
Authors: Makoto Sato, Mai Johnson, Liqun Zhang, Baohui Zhang, Kim Le, Sanjiv S Gambhir, Michael Carey, Lily Wu
Journal: Molecular Therapy (2003)

Gene expression-based imaging coupled to gene therapy will permit the prediction of therapeutic outcome. A significant challenge for successful gene therapy is to achieve a high-level of specific gene expression; however, tissue-specific promoters are weak. We postulate that if the weak activity of tissue-specific promoters can be amplified to the levels of strong viral promoters, which have been successful in preclinical scenarios, while retaining specificity, the therapeutic index of gene therapy can be greatly augmented. With this in mind, we developed a two-step transcriptional activation (TSTA) system. In this two-tiered system, a modified prostate-specific antigen promoter was employed to drive a potent synthetic transcriptional activator, GAL4-VP2. This, in turn, activated the expression of a GAL4-dependent reporter or therapeutic gene. Here we demonstrate that recombinant adenoviral vectors (Ads) in which we have incorporated prostate-targeted TSTA expression cassettes retain cell specificity and androgen responsiveness in cell culture and in animal models, as measured by noninvasive optical bioluminescence imaging. We investigated the mechanism of TSTA in different adenoviral configurations. In one configuration, both the activator and the reporter components are inserted into a single Ad (AdTSTA-FL). The activity of AdTSTA-FL exceeds that of a cytomegalovirus promoter-driven vector (AdCMV-FL), while maintaining tissue specificity. When the activator and reporter components are placed in two separate Ads, androgen induction is more robust than for the single AdTSTA-FL. Based on these findings, we hope to refine the TSTA Ads further to improve the efficacy and safety of prostate cancer gene therapy.
CLINICAL PREDICTORS OF CORONARY ARTERY CALCIFICATION IN END-STAGE RENAL DISEASE PATIENTS: THE PACE (PREDICTORS OF ARRHYTHMIC AND CARDIOVASCULAR RISK IN END-STAGE RENAL DISEASE) STUDY
Authors: Tiago A. Magalhaes, Patricia B. Rizzi, Lucy Meoni, Bernard Jaar, Steve Sozio, Michelle Estrella, Wen-Hong Kao, Miguel Santaularia-Tomas, Joao A. Lima, Rulan S. Parekh
Journal: Journal of the American College of Cardiology (2013)
Improved prediction of the minimal phototoxic dose in PUVA therapy
Authors: A. SAKUNTABHAI, J.N.S. MATTHEWS, P.M. FARR
Journal: British Journal of Dermatology (1994)

Journal Article Improved prediction of the minimal phototoxic dose in PUVA therapy Get access A. SAKUNTABHAI, A. SAKUNTABHAI Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne NEI 4LP, U.K. Search for other works by this author on: Oxford Academic Google Scholar J.N.S. MATTHEWS, J.N.S. MATTHEWS Department of Medical Statistics, University of Newcastle upon Tyne Search for other works by this author on: Oxford Academic Google Scholar P.M. FARR P.M. FARR Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne NEI 4LP, U.K. Dr P.M. Farr. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 130, Issue 5, 1 May 1994, Pages 604–609, https://doi.org/10.1111/j.1365-2133.1994.tb13107.x Published: 01 May 1994 Article history Accepted: 29 October 1993 Published: 01 May 1994
The St Vincent's potentially inappropriate medicines study: development of a disease‐specific consensus list and its evaluation in ambulatory heart failure care
Authors: Margaret Bermingham, Mary Ryder, Bronagh Travers, Nuala Edwards, Lorraine Lalor, Deirdre Kelly, Joseph Gallagher, Rory O'Hanlon, Kenneth McDonald, Mark Ledwidge
Journal: European Journal of Heart Failure (2014)
Anti-Tubular Basement-Membrane (TBM) Nephritis
Authors: Robert T. McCluskey
Journal: New England Journal of Medicine (1975)

Despite a distinctive immunofluorescence picture, anti-TBM antibody accumulation in human renal disease was recorded only after descriptions of experimental models of anti-TBM disease. Immunization of guinea pigs or certain strains of rats with appropriate renal tubular basement-membrane (TBM) preparations in adjuvant results in severe renal disease, characterized by tubular damage and interstitial inflammation.1 2 3 The immunofluorescence findings are highly characteristic: completely continuous ("linear") accumulation of IgG, and usually of C3, is seen along the TBM (both proximal and distal). (Immunization of rabbits or rats with soluble extracts of kidney or exogenous antigens may also lead to immune-complex deposition along the TBM; . . .
1132-161 Electrocardiographic type of intraventricular conduction disturbances does not predict mechanical dyssynchrony assessed by tissue synchronization imaging
Authors: Takuya Hasegawa, Satoshi Nakatani, Takeshi Maruo, Yoshio Yasumura, Masakazu Yamagishi, Masafumi Kitakaze, Kunio Miyatake
Journal: Journal of the American College of Cardiology (2004)
Fatal airway obstruction in infectious mononucleosis.
Authors: J A Burton
Journal: BMJ (1986)

Scott, I have found that listening to each upper lung area is a reliable guide of tube placement in the trachea or, for that matter, right mainstem bronchus.This allows gentle easing back of the tube above the carina even without radiographic help.It is inappropriate to give to endotracheal intu- bation a mystique which might lead to its not being used on the very patients who need it most.
Mortality among residents of shelters, rooming houses, and hotels in Canada: 11 year follow-up study
Authors: S. W Hwang, R. Wilkins, M. Tjepkema, P. J O'Campo, J. R Dunn
Journal: BMJ (2009)

<b>Objective</b> To examine mortality in a representative nationwide sample of homeless and marginally housed people living in shelters, rooming houses, and hotels. <b>Design</b> Follow-up study. <b>Setting</b> Canada 1991-2001. <b>Participants</b> 15 100 homeless and marginally housed people enumerated in 1991 census. <b>Main outcome measures</b> Age specific and age standardised mortality rates, remaining life expectancies at age 25, and probabilities of survival from age 25 to 75. Data were compared with data from the poorest and richest income fifths as well as with data for the entire cohort <b>Results</b> Of the homeless and marginally housed people, 3280 died. Mortality rates among these people were substantially higher than rates in the poorest income fifth, with the highest rate ratios seen at younger ages. Among those who were homeless or marginally housed, the probability of survival to age 75 was 32% (95% confidence interval 30% to 34%) in men and 60% (56% to 63%) in women. Remaining life expectancy at age 25 was 42 years (42 to 43) and 52 years (50 to 53), respectively. Compared with the entire cohort, mortality rate ratios for men and women, respectively, were 11.5 (8.8 to 15.0) and 9.2 (5.5 to 15.2) for drug related deaths, 6.4 (5.3 to 7.7) and 8.2 (5.0 to 13.4) for alcohol related deaths, 4.8 (3.9 to 5.9) and 3.8 (2.7 to 5.4) for mental disorders, and 2.3 (1.8 to 3.1) and 5.6 (3.2 to 9.6) for suicide. For both sexes, the largest differences in mortality rates were for smoking related diseases, ischaemic heart disease, and respiratory diseases. <b>Conclusions</b> Living in shelters, rooming houses, and hotels is associated with much higher mortality than expected on the basis of low income alone. Reducing the excessively high rates of premature mortality in this population would require interventions to address deaths related to smoking, alcohol, and drugs, and mental disorders and suicide, among other causes.
THE EPIDEMIOLOGY OF A RABBIT RESPIRATORY INFECTION
Authors: Leslie T. Webster
Journal: The Journal of Experimental Medicine (1924)

The onset of spontaneous snuffles in rabbits at The Rockefeller Institute is preceded by the appearance in the nasal passages of Bacterium lepisepticum. The active stages of snuffles infection are associated with the presence in these passages of large numbers of this bacterium. Spontaneous recovery from snuffles is associated with a diminution in number or a disappearance of these bacteria from the nasal passages. Various experimental procedures reduce the resistance of rabbits to spontaneous snuffles.
Rhabdomyolysis Induced by Psychotropic Drugs
Authors: Hayato Kaida, Masatoshi Ishibashi, Hidemi Nishida, Kenkichi Baba, Naofumi Hayabuchi
Journal: Clinical Nuclear Medicine (2005)

A 41-year-old man experienced continuous convulsions, unconsciousness, and a high temperature. His laboratory findings revealed an increase in serum creatine phosphokinase, serum myoglobulin, and urinary myoglobulin levels. He had taken many psychotropic drugs as treatment for schizophrenia and was very dehydrated. Because a diagnosis of rhabdomyolysis was suspected, Tc-99m HMDP bone scintigraphy was performed. It showed diffusely increased soft tissue uptake in his shoulder girdles, vertebral area, psoas iliac muscles, and gluteofemoral muscles, leading to a diagnosis of rhabdomyolysis. Bone scintigraphy is useful in making an early diagnosis and evaluating the location and degree of muscle injury in rhabdomyolysis.
Hypertension, the Potassium Ion and Impaired Carbohydrate Tolerance
Authors: Jerome W. Conn
Journal: New England Journal of Medicine (1965)

AS the subject for this lecture, I have chosen to discuss some fascinating clinical and biologic relations existing between the three elements in the title. At the present time, I am actively engaged in studying these relations, for I believe that they will prove to have important bearing upon the interpretation and management of decreased carbohydrate tolerance in a large number of patients. Later, I shall show some preliminary and, as yet, unpublished data dealing with an important mechanism by which carbohydrate tolerance is impaired in a large number of people. But it would be well, first, to indicate whence . . .