tbuckley/cabot-search huggingface dataset:
Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation
Authors: Laure Guenin-Macé, Romain Veyron-Churlet, Maria-Isabel Thoulouze, Guillaume Romet-Lemonne, Hui Hong, Peter F. Leadlay, Anne Danckaert, Marie-Thérèse Ruf, Serge Mostowy, Chiara Zurzolo, Philippe Bousso, Fabrice Chrétien, Marie-France Carlier, Caroline Demangel
Journal: Journal of Clinical Investigation (2013)

Mycolactone is a diffusible lipid secreted by the human pathogen Mycobacterium ulcerans, which induces the formation of open skin lesions referred to as Buruli ulcers. Here, we show that mycolactone operates by hijacking the Wiskott-Aldrich syndrome protein (WASP) family of actin-nucleating factors. By disrupting WASP autoinhibition, mycolactone leads to uncontrolled activation of ARP2/3-mediated assembly of actin in the cytoplasm. In epithelial cells, mycolactone-induced stimulation of ARP2/3 concentrated in the perinuclear region, resulting in defective cell adhesion and directional migration. In vivo injection of mycolactone into mouse ears consistently altered the junctional organization and stratification of keratinocytes, leading to epidermal thinning, followed by rupture. This degradation process was efficiently suppressed by coadministration of the N-WASP inhibitor wiskostatin. These results elucidate the molecular basis of mycolactone activity and provide a mechanism for Buruli ulcer pathogenesis. Our findings should allow for the rationale design of competitive inhibitors of mycolactone binding to N-WASP, with anti-Buruli ulcer therapeutic potential.
Exhausted or just sleeping: Awakening virus-specific responses in chronic hepatitis C virus infection
Authors: Nicole A.W. Wood, May La Linn, David G. Bowen, Kris Kowdley, Geoffrey McCaughan, Christian Trautwein
Journal: Hepatology (2011)

Having successfully developed mechanisms to evade immune clearance, hepatitis C virus (HCV) establishes persistent infection in approximately 75%–80% of patients. In these individuals, the function of HCV-specific CD8+ T cells is impaired by ligation of inhibitory receptors, the repertoire of which has expanded considerably in the past few years. We hypothesized that the coexpression of the negative regulatory receptors T cell immunoglobulin and mucin domain–containing molecule 3 (Tim-3) and programmed death 1 (PD-1) in HCV infection would identify patients at risk of developing viral persistence during and after acute HCV infection. The frequency of PD-1−Tim-3− HCV-specific CTLs greatly outnumbered PD-1+Tim-3+ CTLs in patients with acute resolving infection. Moreover, the population of PD-1+Tim-3+ T cells was enriched for within the central memory T cell subset and within the liver. Blockade of either PD-1 or Tim-3 enhanced in vitro proliferation of HCV-specific CTLs to a similar extent, whereas cytotoxicity against a hepatocyte cell line that expressed cognate HCV epitopes was increased exclusively by Tim-3 blockade. These results indicate that the coexpression of these inhibitory molecules tracks with defective T cell responses and that anatomical differences might account for lack of immune control of persistent pathogens, which suggests their manipulation may represent a rational target for novel immunotherapeutic approaches.
Mammographic screening and mortality from breast cancer: the Malmo mammographic screening trial.
Authors: I. Andersson, K. Aspegren, L. Janzon, T. Landberg, K. Lindholm, F. Linell, O. Ljungberg, J. Ranstam, B. Sigfusson
Journal: BMJ (1988)

STUDY OBJECTIVE--To determine whether mortality from breast cancer could be reduced by repeated mammographic screening. DESIGN--Birth year cohorts of city population separately randomised into study and control groups. SETTING--Screening clinic outside main hospital. PATIENTS--Women aged over 45; 21,088 invited for screening and 21,195 in control group. INTERVENTIONS--Women in the study group were invited to attend for mammographic screening at intervals of 18-24 months. Five rounds of screening were completed. Breast cancer was treated according to stage at diagnosis. END POINT--Mortality from breast cancer. MEASUREMENTS AND MAIN RESULTS--All women were followed up and classed at end point as alive without breast cancer, alive with breast cancer, dead from breast cancer, or dead from other causes. Cause of death was taken from national mortality registry and for patients with breast cancer was validated independently. Mean follow up was 8.8 years. Altogether 588 cases of breast cancer were diagnosed in the study group and 447 in the control group; 99 v 94 women died of all causes and 63 v 66 women died of breast cancer (no significant difference; relative risk 0.96 (95% confidence interval 0.68 to 1.35)). In the study group 29% more women aged less than 55 died of breast cancer (28 v 22; relative risk 1.29 (0.74 to 2.25)). More women in the study group died from breast cancer in the first seven years; after that the trend reversed, especially in women aged greater than or equal to 55 at entry. Overall, women in the study group aged greater than or equal to 55 had a 20% reduction in mortality from breast cancer (35 v 44; relative risk 0.79 (0.51 to 1.24)). OTHER FINDINGS--In the study group 100 (17%) cancers appeared in intervals between screenings and 107 (18%) in non-attenders; 51 of these women died from breast cancer. Cancers classed as stages II-IV comprised 33% (190/579) of cancers in the study group and 52% (231/443) in the control group. CONCLUSIONS--Invitation to mammographic screening may lead to reduced mortality from breast cancer, at least in women aged 55 or over.
Medical students face uncertain future
Authors: J. Westall
Journal: BMJ (1998)

Over 100 preclinical students at Sheffield University were told last month that they could not continue their medical studies as planned owing to the financial crisis in South East Asia.

The students, most of whom are Malaysian, are taking part in a pioneering scheme under which they spend their first two preclinical years at Sheffield University and then complete their training at a new medical school in Ipoh, Malaysia. The partnership, known as the Asean Sheffield Medical College, …
New Insights Into Diabetic Polyneuropathy
Authors: Michael Polydefkis
Journal: JAMA (2003)

Patients with complaints of numbness, tingling, and dysesthesias in the toes and feet are frequently referred to neurologists. Often, the only objective evidence for peripheral nerve dysfunction in these patients is limited to small-caliber sensory nerve fibers. On examination these patients may have reduced distal pinprick sensation, and distal leg skin biopsies show loss of small-caliber nerve fibers. Studies focusing on small-caliber nerve fibers have led to a growing impression that neuropathy can be associated with early diabetes or impaired glucose tolerance (IGT). Often, neuropathy can be the presenting symptom of either diabetes or IGT. Furthermore, the oral glucose tolerance test appears to be a more sensitive measure of glucose dysmetabolism in these patients than levels of fasting blood glucose or glycated hemoglobin. Patients with IGT-associated neuropathy may represent an attractive target population for future regenerative studies given that their neuropathy is less severe and presumably more easily reversed than neuropathy occurring in patients with diabetes.Historically, small-caliber fibers have not been extensively evaluated due to a lack of objective measures. Several measures to evaluate these fibers are emerging, including skin biopsy with visualization of epidermal nerve fibers. The accessibility of epidermal nerve fibers makes them an attractive target for nerve injury models, which have potential for development as novel outcome measures. Such approaches may address some of the challenges of past diabetic polyneuropathy trials.
Carcinoma of the breast. Occurence after treatment with melphalan for multiple myeloma
Authors: R. Bell
Journal: JAMA (1976)

IT HAS been advocated that adjuvant cytotoxic chemotherapy with melphalan after mastectomy may be the preferred form of management of primary carcinoma of the breast with pathologically positive axillary nodes. 1 We report two patients treated with melphalan in whom carcinoma of the breast subsequently developed.  Report of Cases  Case 1.—  A 68-year-old woman had back pain in January 1974. A diagnosis of multiple myeloma was made based on a monoclonal peak on serum protein electrophoresis, a total protein value of 11.3 gm/100 ml, and a bone marrow aspirate that showed 60% plasma cells. The patient was treated with intermittent doses of melphalan and prednisolone. 2   In April 1975, obstructive jaundice developed. A liver biopsy specimen showed evidence of extrahepatic biliary obstruction. A percutaneous transhepatic cholangiogram showed dilated hepatic ducts, with complete obstruction in the common bile duct. At laparotomy, a carcinoma of the head of the pancreas was found;
'Sticky' neutrophils, pathergic arthritis, and response to heparin in pyoderma gangrenosum complicating ulcerative colitis.
Authors: A D Dwarakanath, L G Yu, C Brookes, D Pryce, J M Rhodes
Journal: Gut (1995)

Pyoderma gangrenosum is strongly associated with inflammatory bowel disease and exhibits pathergy, occurring at sites of previous minor trauma. A patient is presented with a 21 year history of extensive ulcerative colitis, who developed pyoderma gangrenosum and arthralgia while receiving high dose corticosteroids for active ulcerative colitis. The arthralgia exhibited pathergy affecting particularly the left temporomandibular joint, which was stressed by an asymmetric bite, and the left elbow, which had been fractured many years previously. This prompted the hypothesis that neutrophils in this condition may be marginated, as a result of increased stickiness of either the neutrophil or the vascular endothelium. The introduction of heparin therapy was associated with rapid resolution of the arthralgia, pyoderma gangrenosum, and ulcerative colitis.
The Usefulness of the Dynamic Phase in Pertechnetate Thyroid Imaging for Solitary Hypofunctioning Nodules
Authors: PETER S. KLIEGER, GEORGE A. WILSON, BENNETT S. GREENSPAN
Journal: Clinical Nuclear Medicine (1992)

One hundred patients, each with a solitary thyroid nodule detected by clinical palpation, underwent three-phase Tc-99m pertechnetate thyroid imaging. The degree of perfusion of the thyroid nodule was classified as hypoperfused, euperfused, or hyperperfused compared to the remainder of the gland by a consensus of three nuclear medicine physicians. The nodules were subsequently biopsied, and the degree of perfusion of the nodules was correlated with their histologic diagnosis. Twenty-two nodules were classified as hyperperfused, 64 as euperfused, and 14 as hypoperfused. Malignancy rates of the hyperperfused, euperfused, and hypoperfused nodules were 36%, 31% and 0%, respectively. This seems to indicate that malignant thyroid nodules demonstrate a degree of perfusion at least equal to or greater than the rest of the thyroid gland. Conversely, none of the hypoperfused nodules was found to be malignant. The perfusion phase of thyroid imaging may provide useful clinical information regarding possible malignancy of a thyroid nodule.
Targeting of GSK3β promotes imatinib-mediated apoptosis in quiescent CD34+ chronic myeloid leukemia progenitors, preserving normal stem cells
Authors: Giovanni Reddiconto, Claudia Toto, Ilaria Palamà, Simone De Leo, Emanuela de Luca, Serena De Matteis, Luciana Dini, Carlo Gambacorti Passerini, Nicola Di Renzo, Michele Maffia, Addolorata Maria Luce Coluccia
Journal: Blood (2012)
Immunofluorescent Studies in Renal Biopsies in Pre-eclampsia
Authors: O. M. Petrucco, N. M. Thomson, J. R. Lawrence, M. W. Weldon
Journal: BMJ (1974)

Renal biopsies were performed on 11 patients considered clinically and histologically to have pre-eclampsia. Immunofluorescent studies with fluorescein-labelled anti-IgG, IgA, IgM, and IgE complement, albumin, fibrin, and fibrinogen were carried out on the tissue obtained. Significant correlation was obtained between the clinical severity of the disease and the density and pattern of IgM and IgG deposition. Complement was found in glomeruli in severe cases, while complement deposition in the walls of afferent and efferent arterioles was a constant finding. These findings support the concept that an immunological mechanism may be responsible for the renal lesions in pre-eclampsia. If immunity does play a part in the pathogenesis of pre-eclampsia, possible mechanisms include the involvement of histocompatibility antigens and cross-reactivity of fetal and maternal tissues. Renal fibrin deposition in pre-eclampsia may be secondary to an immune process, an occurrence well-described in other forms of glomerulonephritis in man and other species.
Contact Allergy to Mace
Authors: Claude A. Frazier
Journal: JAMA (1976)

THE RIOTS and disruptions of the 1960s turned the attentions of police forces around the country to effective methods of crowd control. Tear gas, developed before World War II, had long been a popular method of dispersing and subduing the unruly because of its capacity to temporarily disable without inflicting permanent or serious injury. A lacrimator, tear gas irritates the mucous membranes of the eyes, causing painful smarting and profuse enough tearing to guarantee impaired vision. Among the tens of thousands of American soldiers who experienced the "gas chamber drill" of having to don their gas masks quickly while clouds of tear gas were pumped into a sealed tent or room, a few cases of sensitivity reactions have been reported. Kissin and Mazer<sup>1</sup>detail the case of an aviation cadet in whom itching and an erythematous eruption of the hands and trunk developed on his second exposure to tear
Detection of Penicillin Hypersensitivity With Penicilloyl-Polylysine
Authors: Michael W. Rytel, Franklin M. Klion, Thomas R. Arlander, Lloyd F. Miller
Journal: JAMA (1963)

According to recent concepts, the haptenes responsible for penicillin hypersensitivity are penicillin derivatives rather than the penicillin molecule itself. Penicilloyl-polylysine has been administered as a skin test to 1,022 naval recruits to determine correlation between skin reactions and systemic penicillin allergy. Individuals allergic to penicillin had a 35% incidence of positive skin reactions compared to an incidence of 6.8% in nonallergic recruits. A strongly positive skin test carried an almost ninefold greater risk of occurrence of a systemic reaction following penicillin treatment than did a negative skin test. The test was reproducible and penicilloyl-polylysine in the dosages employed was nonsensitizing.
Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland.
Authors: R Donghi, A Longoni, S Pilotti, P Michieli, G Della Porta, M A Pierotti
Journal: Journal of Clinical Investigation (1993)

The p53 gene was analyzed in tumor specimens obtained from 52 patients with various types of carcinoma of the thyroid gland by a combined molecular and immunocytochemical approach. The histologic types included 37 well-differentiated papillary and follicular carcinomas, 8 poorly differentiated, and 7 undifferentiated carcinomas. The p53 gene was shown to be unaffected in all differentiated tumors by single-strand conformation polymorphism analysis. However, in two out of eight (25%) of poorly differentiated carcinomas and five out of seven (71%) undifferentiated carcinomas, p53 mutations were identified and subsequently characterized by DNA sequencing. One undifferentiated carcinoma displayed two areas with varying degrees of differentiation. The comparative analysis of the p53 gene, in both the more and the less differentiated area of this tumor, clearly showed that the p53 mutation was confined to the latter component of the tumor specimen. These results indicate that mutations of the p53 gene are associated with the most aggressive histologic types of thyroid tumors, such as the undifferentiated carcinoma and, to a certain extent, the poorly differentiated carcinoma, and that the alterations of this gene represent a late genetic event in human thyroid carcinogenesis.
Technetium-99m Red Blood Cell Blood-pool Imaging in Functional Asplenia Due to Leukemic Infiltration
Authors: JAMES H.K. YOO, JOSEPH A. ORZEL, JAMES W. BAGNALL, FREDERICK L. WEILAND
Journal: Clinical Nuclear Medicine (1986)

Tc-99m labeled RBC blood-pool and Tc-99m sulfur colloid imaging were performed in a patient with chronic myelogenous leukemia (CML) in blast crisis. Functional asplenia was demonstrated on the sulfur colloid study despite intact organ perfusion as demonstrated by blood-pool imaging. Tc-99m RBC blood-pool imaging appears to be an ideal noninvasive technique to document intact spleen perfusion in functional asplenia.
FDG PET/CT Showing Erythema Nodosum Associated With Tuberculous Lymphadenitis
Authors: Xiaohua Chen, Hankui Lu, Yunchao Gao
Journal: Clinical Nuclear Medicine (2013)

Erythema nodosum (EN) is histopathologically an acute septal panniculitis of subcutaneous adipose lobule. It can be either idiopathic or secondary to various underlying conditions. A female patient with EN underwent FDG PET/CT to search underlying cause. The images showed enlarged lymph nodes in the mediastinum with moderately elevated FDG uptake and multifocal increased FDG uptake over her lower extremities. The patient’s condition was subsequently diagnosed with EN associated with mediastinal tuberculous lymphadenitis based on skin biopsy, tuberculin skin test, and treatment response.
ACHIEVED LIPOPROTEIN LEVELS AND REGRESSION OF CORONARY ATHEROSCLEROSIS WITH HIGH DOSE STATIN THERAPY: INSIGHTS FROM SATURN
Authors: Stephen J. Nicholls, Christie Ballantyne, Phillip Barter, M. Chapman, Raimund Erbel, Peter Libby, Joel Raichlen, Kiyoko Uno, Rishi Puri, Yu Kataoka, Kathy Wolski, Steven Nissen
Journal: Journal of the American College of Cardiology (2012)
Control of Endothelial Targeting and Intracellular Delivery of Therapeutic Enzymes by Modulating the Size and Shape of ICAM-1-targeted Carriers
Authors: Silvia Muro, Carmen Garnacho, Julie A Champion, John Leferovich, Christine Gajewski, Edward H Schuchman, Samir Mitragotri, Vladimir R Muzykantov
Journal: Molecular Therapy (2008)

Endocytosis in endothelial cells (ECs) is important for many biomedical applications, including drug delivery by nano- and microscale carriers. However, little is known about how carrier geometry influences endothelial drug targeting, intracellular trafficking, and effects. We studied this using prototype polymer carriers of various sizes (0.1-10 mum) and shapes (spheres versus elliptical disks). Carriers were targeted to intercellular adhesion molecule 1 (ICAM-1), a transmembrane glycoprotein that is upregulated in many pathologies and used as a target for intraendothelial drug delivery. ECs internalized anti-ICAM-coated carriers of up to several microns in size via cell adhesion molecule-mediated endocytosis. This pathway is distinct from caveolar and clathrin endocytosis that operate for submicron-size objects. Carrier geometry was found to influence endothelial targeting in the vasculature, and the rate of endocytosis and lysosomal transport within ECs. Disks had longer half-lives in circulation and higher targeting specificity in mice, whereas spheres were endocytosed more rapidly. Micron-size carriers had prolonged residency in prelysosomal compartments, beneficial for endothelial antioxidant protection by delivered catalase. Submicron carriers trafficked to lysosomes more readily, optimizing effects of acid sphingomyelinase (ASM) enzyme replacement in a model of lysosomal storage disease. Therefore, rational design of carrier geometry will help optimize endothelium-targeted therapeutics.
PROGNOSTIC VALUE OF NEGATIVE ADENOSINE STRESS PERFUSION CARDIAC MAGNETIC RESONANCE WITH LATE GADOLINIUM ENHANCEMENT IN INTERMEDIATE CARDIOVASCULAR RISK PATIENTS
Authors: James D. Richardson, Angela Bertaso, Dennis Wong, Adam J. Nelson, Hussam Tayeb, Angelo Carbone, Benjamin K. Dundon, Payman Molaee, Kerry Williams, Matthew I. Worthley, Karen Teo, Stephen G. Worthley
Journal: Journal of the American College of Cardiology (2011)
Clinical Experience with Angiotensin II in the Treatment of Shock
Authors: Francesco del Greco
Journal: JAMA (1961)

The effects of using angiotensin in the treatment of shock from various causes were studied in 21 patients. The blood pressure returned to normal in every instance excepting 6 patients who were moribund when treatment was begun. Of 6 patients who were in advanced bacteremic shock and whose prognosis was considered hopeless, 4 survived as did one with severe shock associated with postoperative intracranial bleeding and two with severe barbiturate poisoning. Angiotensin was also used in treating 10 patients in whom hypotension appeared in the course of dialysis by an artificial kidney. Six survived. In this series of cases angiotensin produced no side effects of any sort.
Competition, Regulation, and Hospital Costs, 1982 to 1986
Authors: James C. Robinson
Journal: JAMA (1988)

We used data on 5490 nonfederal, short-term general hospitals to evaluate the relative effectiveness of regulatory and market-oriented cost-control policies on hospital cost inflation between 1982 and 1986. All-payer rate-regulation programs reduced inflation rates by 16.3% in Massachusetts, 15.4% in Maryland, and 6.3% in New York, compared with the control hospitals in 43 states with neither all-payer rate regulation nor an aggressive market-oriented strategy. New Jersey hospitals experienced a rate of cost inflation similar to the control hospitals. Given the effectiveness of its regulatory program in the 1970s, however, New Jersey began and ended the period from 1982 to 1986 with the lowest costs, controlling for wages and patient mix. California's market-oriented cost-control policy reduced inflation rates by 10.1%. Hospitals with large percentages of patients insured by Medicare's prospective payment system experienced cost inflation rates 16.1% lower than hospitals with small percentages of Medicare patients. Investor-owned hospitals experienced rates of cost increase 11.6% higher than private nonprofit hospitals and 15.0% higher than public hospitals.
Binding of IgE from peanut allergic sera to the major peanut allergens, Ara h 1 and Ara h 2: Comparison of IgE immunoblots to a functional assay
Authors: G.W. Palmer, D.A. Dibbern, A.W. Burks, G.A. Bannon, S.A. Bock, S.C. Dreskin
Journal: Journal of Allergy and Clinical Immunology (2003)