tbuckley/cabot-search huggingface dataset:
Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver
Authors: Evita van de Steeg, Viktor Stránecký, Hana Hartmannová, Lenka Nosková, Martin Hřebíček, Els Wagenaar, Anita van Esch, Dirk R. de Waart, Ronald P.J. Oude Elferink, Kathryn E. Kenworthy, Eva Sticová, Mohammad al-Edreesi, A.S. Knisely, Stanislav Kmoch, Milan Jirsa, Alfred H. Schinkel
Journal: Journal of Clinical Investigation (2012)

Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.
Breast Radiotherapy after Lumpectomy — No Longer Always Necessary
Authors: Ian E. Smith, Gillian M. Ross
Journal: New England Journal of Medicine (2004)

Breast-conserving surgery followed by radiotherapy is the standard of care for women with small breast cancers who wish to avoid mastectomy. This approach achieves good local control, does not disturb the women's body image or impair survival,1 and has been an important step forward in the management of this disease.Several trials have compared breast-conserving surgery plus postoperative radiotherapy with breast-conserving surgery alone, and all have shown an increased risk of local recurrence if radiotherapy is omitted but no difference in survival. One of the largest of these trials, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 study, . . .
Fungal spores: hazardous to health?
Authors: W G Sorenson
Journal: Environmental Health Perspectives (1999)

Fungi have long been known to affect human well being in various ways, including disease of essential crop plants, decay of stored foods with possible concomitant production of mycotoxins, superficial and systemic infection of human tissues, and disease associated with immune stimulation such as hypersensitivity pneumonitis and toxic pneumonitis. The spores of a large number of important fungi are less than 5 microm aerodynamic diameter, and therefore are able to enter the lungs. They also may contain significant amounts of mycotoxins. Diseases associated with inhalation of fungal spores include toxic pneumonitis, hypersensitivity pneumonitis, tremors, chronic fatigue syndrome, kidney failure, and cancer.
283. Suppression of Inflammatory Pathways Selectively Induced by Oncolytic Viruses Enhances Viral Oncolysis
Authors: Giulia Fulci, Laura M. Breymann, Elizabeth J. Fontana, Davide Gianni, Hiroaki Wakimoto, Ralph Weissleder, Robert Lee, Quing Liu, Antonio E. Chiocca
Journal: Molecular Therapy (2005)

Top of pageAbstract
Oncolytic viruses (OV) generate intratumoral progeny viruses that propagate the oncolytic effect throughout tumor cells in vitro. However, the generation of progeny viruses in vivo is suppressed by the host innate immune responses. We have demonstrated that, in rats harboring gliomas, pretreatment with cyclophosphamide (CPA), enhances OV replication. The use of CPA in viral therapy is limited by its broad immune-suppressive activity and toxicity. Our aim is to identify specific factors responsible for limiting OV survival in tumors in order to design pharmacological means that enhance OV replication in a selective fashion.

We have used rats pretreated with either CPA or PBS to deliver OV intratumorally (CPA-/OV+ and CPA+/OV+) and analyze the immune pathways that are associated with viral proliferation. Our data show that OV has the same capacity to infect tumor cells in both CPA pre-treated and non pre-treated rats. After cell infection, OV increases the intratumoral levels of IFNg, a known inducer of macrophage/monocyte/microglia in the brain. This phenomenon is associated with a reduction of intratumoral viral titers within 76 hours from OV injection. In CPA pre-treated rats, IFNg levels remain low, macrophage intratumoral infiltration is suppressed and viral oncolysis is increased within 76 hours from OV injection. Pharmacologic depletion of macrophages enhances OV oncolysis and suppresses macrophage-induced immune responses in the tumor. Broad comparative analysis of gene expression in tumors of rats CPA-/OV+ and CPA+/OV+ using Affymetrix rat genome arrays has identified seven other molecular targets that are downstream effectors of IFNg-induced inflammation and are associated with viral proliferation.

These data indicate that, selective temporary repression of inflammation leads to efficient viral replication and uncovers specific molecular targets that could be used to increase viral therapy.
Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis
Authors: None Gupta, None Gupta
Journal: British Journal of Dermatology (1998)

We examined the prevalence of depression (measured by the Carroll Rating Scale for Depression, CRSD), wishes to be dead and acute suicidal ideation among 480 patients with dermatological disorders that may be cosmetically disfiguring, i.e. non-cystic facial acne (n = 72; 5.6% suicidal ideation), alopecia areata (n = 45; 0% suicidal ideation), atopic dermatitis (n = 146; 2.1% suicidal ideation) and psoriasis (79 outpatients, 2.5% suicidal ideation and 138 inpatients, 7.2% suicidal ideation). Analysis of variance revealed that the severely affected psoriasis inpatients (mean +/- SD total body surface area affected: 52 +/- 23.4%) had the highest (P < 0.05) CRSD score, followed by the patients with mild to moderate acne; both scores were in the range for clinical depression (CRSD score > 10). The 5.6-7.2% prevalence of active suicidal ideation among the psoriasis and acne patients was higher than the 2.4-3.3% prevalence reported among general medical patients. Our findings highlight the importance of recognizing psychiatric comorbidity, especially depression, among dermatology patients and indicate that in some instances even clinically mild to moderate disease such as non-cystic facial acne can be associated with significant depression and suicidal ideation.
Caesarean delivery rates and pregnancy outcomes: the 2005 WHO global survey on maternal and perinatal health in Latin America
Authors: José Villar, Eliette Valladares, Daniel Wojdyla, Nelly Zavaleta, Guillermo Carroli, Alejandro Velazco, Archana Shah, Liana Campodónico, Vicente Bataglia, Anibal Faundes, Ana Langer, Alberto Narváez, Allan Donner, Mariana Romero, Sofia Reynoso, Karla Simônia de Pádua, Daniel Giordano, Marius Kublickas, Arnaldo Acosta
Journal: The Lancet (2006)
Myocardial function and coronary blood flow response to acute ischemia in chronic canine diabetes.
Authors: B Haider, S S Ahmed, C B Moschos, H A Oldewurtel, T J Regan
Journal: Circulation Research (1977)

To examine the influence of preexistent diabetes mellitus on left ventricular performance and coronary blood flow responses to acute ischemia, mild normoglycemic diabetes was induced in nine mongrel dogs after three doses of alloxan, (20 mg/kg, iv), at monthly intervals. Hemodynamic measurements and coronary blood flow (85Kr clearance) were obtained before and after the onset of ischemia. This was produced by occlusion of the proximal left anterior descending coronary artery via a balloon-type catheter in nine intact anesthetized diabetic dogs and 10 nondiabetic dogs. During the 1st hour of ischemia in the diabetic group, the end-diastolic pressure rose from 7 +/- 1.1 (mean +/- SE) mm Hg to 23.8 +/- 2.3 without a significant increase of end-diastolic volume. In controls end-diastolic pressure rose from 8.6 +/- 1.1 mm Hg to 15.3 +/- 1.4, and end-diastolic volume was significantly increased, so that the ratio of end-diastolic pressure and volume was significantly higher in the diabetic group (P less than 0.005). Although indices of contractility did not differ, stroke volume and work reductions were significantly greater in diabetics, despite the fact that coronary blood flow was reduced to a similar extent. Size of the ischemic areas appeared comparable as judged by distribution of dye injected distal to the occlusion. Since potassium loss and sodium gain in the inner and outer layers of ischemic tissue did not differ between the two groups, the intensity of ischemia seemed similar. Glycogenolysis was unimpaired in the diabetic ischemic muscle but triglyceride levels remained elevated. Morphologically the diabetic myocardium was characterized by a diffuse accumulation of periodic acid-Schiff-positive glycoprotein in the interstitium, which was thought to limit diastolic filling of the ischemic ventricle and to contribute to the substantial reduction of ventricular performance.
Clinical Dermatology: A Color Guide to Diagnosis and Therapy
Authors: Christopher P. Crotty
Journal: JAMA (1991)

<i>Clinical Dermatology</i>, by Thomas P. Habif, MD, provides an excellent introduction to dermatology for nondermatologists. For practicing dermatologists, the summaries are valuable. Also, the brief reviews of common and uncommon skin diseases provide a quick refresher course and superb patient-education material. Twenty-seven chapters cover, among other subjects, topical therapy and topical corticosteroids. The chapter on dermatologic surgical procedures gives an up-to-date, albeit superficial, review, including proper punch and shave biopsy techniques. In addition, the brief summaries of Mohs micrographic surgery, dermabrasion, dermal implants, lasers, and liposuction are well done and informative. One of the more useful aspects of this textbook is the appendix and dermatologic formulary, which give helpful lists, including sources of salicylates, dyes, and benzoic acid, and summarize commonly used medications. In addition, there is a section on adverse drug interactions, a rapid reference in dealing with commonly used medications. Probably the most impressive contribution of the book
Abstract 3812: Deguelin as a novel therapeutic agent for Herceptin resistant breast cancers
Authors: Rajeshwari Mehta, Fatouma Alimirah, Akash Gupta, Amit Kalra, Rajendra Mehta
Journal: Cancer Research (2012)

Human breast cancers overexpressing HER-2 are generally highly aggressive. Current therapeutic strategies to target HER-2 signaling pathway with antibodies or small molecule tyrosine kinase inhibitors have shown impressive success in the management of these tumor types, although most women exhibit short term response to these therapies. Acquired resistance to HER-2 target drugs, especially Herceptin is a major challenge to clinicians. Patients receiving Herceptin therapy invariably recur and most often with highly aggressive tumors. Thus identifying new drugs which target multiple molecular pathways is desired to treat Herceptin resistant breast cancer. Using paired HER-2 overexpressing parental Herceptin responsive (BT-474) and its Herceptin resistant variant cells (BT-474HR) we showed that acquired resistance to Herceptin is associated with enhanced expression of HER-2, EGFR, CyclinD1, P-AKT (Ser-473), PI-3K, JAB1 proteins and decreased expression of nuclear pten and p27 proteins. These results are similar to those observed in recurrent breast tumors in patients following Herceptin treatment. Deguelin, a natural product derivative of rotenoids and has been shown to inhibit growth of diverse cancer types. Deguelin is a known AKT inhibitor, however its efficacy is never tested in breast cancers resistant to Herceptin which express high levels of p-AKT. We examined effect of Deguelin on HER-2 overexpressing BT-474 BT-474-HRcells. Deguelin inhibited growth of both, BT-474 and BT-474HR cells in concentration (0-250nM) and time dependent (24-72h) manner. There was a 40-50%- inhibition of both BT474and BT-474HR cells at 25nM Deguelin treatment at 72h. Deguelin decreased cell surface expression of HER-2 in both these cell lines. In parental BT-474 cells both Herceptin 5-10ug/ml and Deguelin down regulated HER-2 expression, but only Deguelin reduced HER-2 (125-250nM) over expression in both BT-474 and BT-474HR cells. Down regulation of HER-2 following Deguelin treatment was associated with simultaneous down regulation of nuclear accumulation of cyclin D1, and JAB1, and p-AKT (Ser-473) proteins and up regulation of nuclear p27 and p53in both BT-474 and BT474 HR cells. These results suggest that Deguelin inhibits growth of both HER-2 overexpressing and those resistant to Herceptin therapy breast cancer cells. Effect of Deguelin appears to be mediated through down regulation of HER-2, PI3K AKT, JAB1, Cyclin D1, and p27 pathway. Our preliminary results warrant further investigation into Deguelin as a potential therapeutic agent for Herceptin resistant breast cancers. (This work was supported by NCI CA140321.)Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3812. doi:1538-7445.AM2012-3812
EFFECT OF FEEDING MODALITY ON GROWTH: A REPORT FROM THE NATIONAL PEDIATRIC CARDIOLOGY QUALITY IMPROVEMENT COLLABORATE
Authors: Garick Hill, Nancy Rudd, Peter Bartz, David Hehir, Michele Frommelt, Julie Slicker, Jena Tanem, Katherine Frontier, Katie Trapp, Qun Xiang, Tao Wang, James Tweddell, Nancy Ghanayem
Journal: Journal of the American College of Cardiology (2013)
"THE REWARDS OF GOVERNMENT SERVICE"
Authors: James C. Pryor
Journal: JAMA (1926)

<h3>To the Editor:</h3> —In the editorial (The Journal, January 23, p. 278) entitled "The Trend of Veterans' Relief Legislation: State Medicine," the following sentence conveys a bad impression and should be modified: "The rewards of government service are not now generally such as to attract the type of men who seek to become physicians or to hold them after they have once entered the service." That the government services do not offer a favorable field for the professional money maker is admitted. It is not, however, admitted that "men who seek to become physicians" are not attracted to the navy (I speak for that branch of government service only) by the guaranteed (if too small) salary; by the opportunity for doing scientific work; by the generously supplied equipment; by the opportunity for travel, with its professional and cultural advantages; by the opportunity to do postgraduate work at government expense at
Failing sick doctors
Authors: T. Bewley
Journal: BMJ (1995)

Medical staffdid have input to unitEDrrOR,-In their paper on a midwife managed delivery unit V A Hundley and colleagues state that "there is no input to the midwives unit by medical staff."'In table IV, however, they state that 246 women received epidural or spinal anaes- thesia during their stay in the unit.This implies that the women benefited from a 24 hour obstetric anaesthesia service.A recent survey of patients' knowledge showed that at least 21% of patients are unaware that their anaesthetist is a doctor.2Surely this does not also apply to our obstetric and midwifery colleagues.
AUTOIMMUNE INJURY OF SQUAMOUS EPITHELIUM BY PEMPHIGUS AUTOANTIBODIES
Authors: Esperanza Avalos, H. Patel, G. J. Anhalt, L. A. Diaz
Journal: British Journal of Dermatology (1984)

Journal Article AUTOIMMUNE INJURY OF SQUAMOUS EPITHELIUM BY PEMPHIGUS AUTOANTIBODIES Get access Esperanza Avalos, Esperanza Avalos Immunodermatology Unit, Department of Dermatology, The Johns Hopkins University, Baltimore, Maryland 21205, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar H. Patel, H. Patel Immunodermatology Unit, Department of Dermatology, The Johns Hopkins University, Baltimore, Maryland 21205, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar G. J. Anhalt, G. J. Anhalt Immunodermatology Unit, Department of Dermatology, The Johns Hopkins University, Baltimore, Maryland 21205, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar L. A. Diaz L. A. Diaz Immunodermatology Unit, Department of Dermatology, The Johns Hopkins University, Baltimore, Maryland 21205, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 111, Issue 3, 1 September 1984, Pages 359–365, https://doi.org/10.1111/j.1365-2133.1984.tb04735.x Published: 01 September 1984
IMPACT OF VESSEL CALCIFICATION ON INTIMAL COVERAGE AFTER PACLITAXEL-COATED NITINOL DRUG-ELUTING STENT (ZILVER-PTX) IMPLANTATION IN THE SUPERFICIAL FEMORAL ARTERY
Authors: Masashi Fukunaga, Kenichi Fujii, Kojiro Miki, Hiroto Tamaru, Takahiro Imanaka, Mitsumasa Ohyanagi, Tohru Masuyama
Journal: Journal of the American College of Cardiology (2014)
Successful treatment of transient acquired factor X deficiency by plasmapheresis with concomitant intravenous immunoglobulin and steroid therapy
Authors: S.V. Smith, D.K. Liles, G.C. White, M.E. Brecher
Journal: American Journal of Hematology (1998)

Two patients with no history of previous bleeding diatheses presented with active bleeding from multiple body sites, declining hemoglobin levels, and markedly prolonged prothrombin times (PT) and activated partial thromboplastin times (aPTT) with incomplete correction on PT mix assays. Both patients demonstrated a severe deficiency of factor X (F.X) (<1%; reference range 60–150%). F.X levels and bleeding were refractory to multiple transfusions of fresh frozen plasma (FFP) in both patients. In contrast, daily therapeutic plasma exchange (PLEX) with concomitant administration of intravenous immunoglobulin (IV IgG) and steroids produced a rapid increase in F.X levels with cessation of bleeding, followed by stabilization and normalization of F.X levels and progressive correction of coagulation times. Neither patient has demonstrated a recurrence of the bleeding tendency following discontinuation of steroid therapy. These patients had transient acquired F.X deficiency, a rare coagulopathy, which can result in a lethal bleeding diathesis. An IgG inhibitor that selectively inhibited F.X activation in Russell's viper venom or tissue factor/F.VIIa assays was demonstrated in one patient's pretreatment plasma. Previous treatment of hemorrhage in transient acquired F.X deficiency has been prothrombin complex and/or activated clotting concentrates, which can be associated with transient hypercoagulable states. This is the first reported use of PLEX in transient acquired F.X deficiency. PLEX is safe, efficacious, and rapidly restores hemostasis in this rare acquired bleeding disorder. Am. J. Hematol. 57:245–252, 1998. © 1998 Wiley-Liss, Inc.
Particulate Air Pollution, Progression, and Survival after Myocardial Infarction
Authors: Antonella Zanobetti, Joel Schwartz
Journal: Environmental Health Perspectives (2007)

Several studies have examined the effect of particulate pollution (PM) on survival in general populations, but less is known about susceptible groups. Moreover, previous cohort studies have been cross-sectional and subject to confounding by uncontrolled differences between cities.We investigated whether PM was associated with progression of disease or reduced survival in a study of 196,000 persons from 21 U.S. cities discharged alive following an acute myocardial infarction (MI), using within-city between-year exposure to PM. We constructed city-specific cohorts of survivors of acute MI using Medicare data between 1985 and 1999, and defined three outcomes on follow-up: death, subsequent MI, and a first admission for congestive heart failure (CHF). Yearly averages of PM(10) (particulate matter with aerodynamic diameter < 10 microm) were merged to the individual annual follow-up in each city. We applied Cox's proportional hazard regression model in each city, with adjustment for individual risk factors. In the second stage of the analysis, the city-specific results were combined using a meta-regression.We found significant associations with a hazard ratio for the sum of the distributed lags of 1.3 [95% confidence interval (CI), 1.2-1.5] for mortality, a hazard ratio of 1.4 (95% CI, 1.2-1.7) for a hospitalization for CHF, and a hazard ratio of 1.4 (95% CI, 1.1-1.8) for a new hospitalization for MI per 10 microg/m(3) PM(10).This is the first long-term study showing a significant association between particle exposure and adverse post-MI outcomes in persons who survived an MI.
Lung mucociliary clearance in rheumatoid disease.
Authors: P P Sutton, N Kadir, D Pavia, N F Sheahan, S W Clarke
Journal: Annals of the Rheumatic Diseases (1982)

Lung mucociliary clearance rates were measured in 11 patients with rheumatoid disease and found to be unaltered when compared with those of a group of matched control subjects. The results are discussed in relation to the increased incidence of respiratory infection in patients with rheumatoid disease and also to the recently reported finding of increased airways obstruction in these patients.
Viral Hepatitis Type B Presenting With Seizure
Authors: Benjamin R. Brooks
Journal: JAMA (1977)

NEUROLOGICAL signs and symptoms may rarely herald the onset of infectious hepatitis.<sup>1,2</sup>Seizures as a presenting sign are exceedingly rare. Four cases of convulsions preceding or coincident with the onset of the icteric phase of infectious hepatitis have been documented,<sup>3,4</sup>and one case of status epilepticus has recently been reported.<sup>4</sup>None of these cases were shown to be associated with hepatitis type B surface antigen(HB<sub>s</sub>Ag)-positive viral hepatitis. A patient with viral hepatitis type B was recently admitted to this hospital after a generalized tonic-clonic seizure. Focal EEG changes remitted during the convalescent stage of his illness, and the patient has remained free of clinical or EEG evidence of seizures during a four-year period of observation. <h3>Report of a Case</h3> A 21-year-old, right-handed male construction worker was admitted to the Massachusetts General Hospital after a tonic-clonic convulsion lasting approximately two minutes unassociated with tongue-biting or incontinence.