tbuckley/cabot-search huggingface dataset:
Nuclear medicine from A career hot spot: nuclear medicine
Authors: L. Prvulovich
Journal: BMJ (1997)

Like many nuclear medicine specialists, I discovered nuclear medicine quite late in my career while working towards an MD as a research registrar in cardiology. My project used nuclear medicine techniques to examine left ventricular remodelling after myocardial infarction. Four years later and with an MD, I decided to train in nuclear medicine and I have never regretted it. I enjoy all aspects of nuclear medicine but have made use of my cardiac training by developing my interest in nuclear cardiology both clinically and for research. Cardiology on call, with its stream of emergency patients often requiring acute intervention, is, how- ever, a thing of the past.

Limited undergraduate teaching as well as regional differences in the provision and use of nuclear medicine services mean that many junior doctors have only a limited awareness of what nuclear medicine can offer in terms of patient management and as a career. Few actively contemplate a career in nuclear medicine until research projects introduce them to nuclear medicine techniques.

Nuclear medicine has held the status of an independent specialty since 1989 and is concerned with the administration of unsealed radioactive substances to patients for diagnosis, therapy, or research. Departments of nuclear medicine exist in most teaching hospitals and within an increasing number of district general hospitals.

The range of nuclear medicine procedures is wide among both adults and children. Examples of common diagnostic procedures include ventilation- perfusion lung scanning for pulmonary embolism, bone scanning in benign and malignant disease, and myocardial perfusion studies in ischaemic heart disease as well as renography in the investigation of renal function and morphology. A recent survey indicated that the number of imaging studies is rising at an annual rate of about 7%. Most patients are …
Genetic Risk Assessment and <i>BRCA</i> Mutation Testing for Breast and Ovarian Cancer Susceptibility: Systematic Evidence Review for the U.S. Preventive Services Task Force
Authors: Heidi D. Nelson, Laurie Hoyt Huffman, Rongwei Fu, Emily L. Harris
Journal: Annals of Internal Medicine (2005)

Background: Clinically significant mutations of BRCA1 and BRCA2 genes are associated with increased susceptibility for breast and ovarian cancer. Although these mutations are uncommon, public interest in testing for them is growing. Purpose: To determine benefits and harms of screening for inherited breast and ovarian cancer susceptibility in the general population of women without cancer presenting for primary health care in the United States. Data Sources: MEDLINE (1966 to 1 October 2004), Cochrane Library databases, reference lists, reviews, Web sites, and experts. Study Selection: Eligibility was determined by inclusion criteria specific to key questions about risk assessment, genetic counseling, mutation testing, prevention interventions, and potential adverse effects. Data Extraction: After review of studies, data were extracted, entered into evidence tables, and summarized by using descriptive or statistical methods. Study quality was rated by using predefined criteria. Data Synthesis: Tools assessing risks for mutations and referral guidelines have been developed; their accuracy, effectiveness, and adverse effects in primary care settings are unknown. Risk assessment, genetic counseling, and mutation testing did not cause adverse psychological outcomes, and counseling improved distress and risk perception in the highly selected populations studied. Intensive cancer screening studies are inconclusive. Chemoprevention trials indicate risk reduction for breast cancer in women with varying levels of risk, as well as increased adverse effects. Observational studies of prophylactic surgeries report reduced risks for breast and ovarian cancer in mutation carriers. Limitations: No data describe the range of risk associated with BRCA mutations, genetic heterogeneity, and moderating factors; studies conducted in highly selected populations contain biases; and information on adverse effects is incomplete. Conclusions: A primary care approach to screening for inherited breast and ovarian cancer susceptibility has not been evaluated, and evidence is lacking to determine benefits and harms for the general population.
Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma
Authors: J. Bellmunt, S.A. Mullane, L. Werner, A.P. Fay, M. Callea, J.J. Leow, M.E. Taplin, T.K. Choueiri, F.S. Hodi, G.J. Freeman, S. Signoretti
Journal: Annals of Oncology (2015)
Risk Factors for Abnormal Developmental Trajectories in Young Children With Congenital Heart Disease
Authors: Kathleen A. Mussatto, Raymond Hoffmann, George Hoffman, James S. Tweddell, Laurel Bear, Yumei Cao, Jena Tanem, Cheryl Brosig
Journal: Circulation (2015)

Children with congenital heart disease are at risk for developmental delay. This study sought to identify early risk factors for abnormal developmental trajectories in children with congenital heart disease.Children with congenital heart disease at high risk for developmental delay, without known genetic abnormality, and with ≥3 assessments by the use of the Bayley Scales of Infant and Toddler Development, Third Edition, were studied. Logistic regression was used to assess the impact of patient and clinical factors on cognitive, language, and motor score trajectories; classified as: average or improved if all scores were ≥85 (<1 standard deviation below the mean) or increased to ≥85 and never decreased; or abnormal if all scores were <85, fell to <85 and never improved, or fluctuated above and below 85. Data on 131 children with 527 Bayley Scales of Infant and Toddler Development, Third Edition assessments were analyzed. Subject age was 5.5 to 37.4 months. Overall, 56% had cognitive, language, and motor development in the average range. Delays occurred in single domains in 23%. Multiple domains were delayed in 21%. More cardiac surgeries, longer hospital stay, poorer linear growth, and tube feeding were associated with worse outcomes in all domains (P<0.05). In the multivariable model, the need for tube feeding was a risk factor for having an abnormal developmental trajectory (odds ratio, 5.1-7.9). Minority race and lack of private insurance had significant relationships with individual domains.Longitudinal developmental surveillance identified early factors that can help quantify the risk of developmental delay over time. Strategies to improve modifiable factors and early therapeutic intervention can be targeted to children at highest risk.
Catecholamine stimulation is associated with impaired myocardial O2 utilization in heart failure
Authors: L Nikolaidis
Journal: Cardiovascular Research (2002)

To investigate the effect of alpha,beta(1) and beta(2) adrenergic receptor (AR) stimulation on coronary hemodynamics, myocardial oxygen consumption (M(v)O(2)) and metabolic substrate preference in advanced dilated cardiomyopathy (DCM).We studied 19 conscious, instrumented dogs with pacing-induced DCM. We evaluated systemic, coronary hemodynamics and M(v)O(2) in response to norepinephrine (NOR, 0.05-0.4 microg/kg per min), dobutamine (DOB, 1-10 microg/kg per min), phenylephrine (PHE, 1-5 microg/kg per min) and isoproterenol (ISO, 0.05-0.4 microg/kg per min) alone or in the presence of metoprolol (ISO+MET). Experiments were conducted in control state and in advanced DCM, 4-5 weeks after the initiation of pacing.Contractile responses (LV dP/dt) to catecholamines were desensitized and accompanied by a parallel decrease in heart rate-adjusted myocardial O(2) consumption (M(v)O(2/beat)), when alpha(PHE) or beta(1) (DOB) or both alpha/beta(1) (NOR) AR were stimulated in DCM. This was due to impaired transmyocardial (Ao-Cs) O(2) extraction rather than limitations in CBF responses. There was an associated shift in myocardial metabolism, evidenced by an increased preference for glycolytic substrates (Respiratory Quotient) following administration of any of these three adrenergic agonists in DCM. Combined beta(1)/beta(2) stimulation with ISO or beta(2)-AR stimulation (ISO+MET) in DCM resulted in greater M(v)O(2/beat), [(Ao-Cs) O(2)] extraction, and decreases in myocardial RQ consistent with a shift toward oxidation of FFA.The impairment in contractile responses to dobutamine and norepinephrine in DCM is associated with impaired myocardial O(2) extraction, and a shift toward a preference for glycolysis. A different myocardial metabolic pattern suggestive of increased oxidation of FFA with increased myocardial O(2) extraction was observed in the presence of combined beta(1)/beta(2) stimulation with isoproterenol or beta(2) stimulation (ISO+MET). These data suggest that beta(2)-AR stimulation in DCM shifts substrate preference toward FFA oxidation associated with greater M(v)O(2) requirements. These findings identify a putative metabolic effect of beta(2) -AR in DCM that may be deleterious.
Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal vitamin D receptor modulators
Authors: Y. Ma
Journal: Journal of Clinical Investigation (2006)

Vitamin D receptor (VDR) ligands are therapeutic agents for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. VDR ligands also show immense potential as therapeutic agents for autoimmune diseases and cancers of skin, prostate, colon, and breast as well as leukemia. However, the major side effect of VDR ligands that limits their expanded use and clinical development is hypercalcemia that develops as a result of the action of these compounds mainly on intestine. In order to discover VDR ligands with less hypercalcemia liability, we sought to identify tissue-selective VDR modulators (VDRMs) that act as agonists in some cell types and lack activity in others. Here, we describe LY2108491 and LY2109866 as nonsecosteroidal VDRMs that function as potent agonists in keratinocytes, osteoblasts, and peripheral blood mononuclear cells but show poor activity in intestinal cells. Finally, these nonsecosteroidal VDRMs were less calcemic in vivo, and LY2108491 exhibited more than 270-fold improved therapeutic index over the naturally occurring VDR ligand 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in an in vivo preclinical surrogate model of psoriasis.
Skin carotenoid levels are not associated with risk of nonmelanoma skin cancer: Response to “Supplement use and the risk of cutaneous squamous cell carcinoma”
Authors: Kristen C. Corey, Marisa Kardos Garshick, Voraphat Dejsuphong, Xinaida T. Lima, Alexandra B. Kimball
Journal: Journal of the American Academy of Dermatology (2012)
Mechanical load on the ventilatory muscles during an incremental cycle ergometer test
Authors: T Wanke, D Formanek, G Schenz, W Popp, H Gatol, H Zwick
Journal: European Respiratory Journal (1991)

An incremental cycle ergometer test performed with a total of 40 healthy subjects (25 male, 15 female) was used to study the mechanical load on the ventilatory muscles. The parameters for the mechanical load on the ventilatory muscles are the time integral of the oesophageal pressure and the mean oesophageal pressure change per time unit (dPoe/dTI) of each breathing manoeuvre. The pressure-time integral is the area delimited by the oesophageal pressure trace and the inspiratory time axis. It is expressed as a fraction of the product of the subject's maximum oesophageal pressure (Poe(max)) and total breath cycle duration (TTOT). This parameter is called oesophageal tension time index (TTIoe). The relationship between minute ventilation and these two parameters during ergometer test showed gender-specific variations because of the differences between men and women as to anthropometric data, lung function parameters and maximum ventilatory muscle strength. Moreover, the dPoe/dTI values significantly depend on the breathing frequency. The present study has provided evidence that, in general, the TTIoe and dPoe/dTI values in terms of a specific minute ventilation (VE) are higher in women than in men. Parameters for the mechanical load on the ventilatory muscles regarding the level of pressure to be generated as well as the duration and velocity of muscle contraction should therefore also allow for the gender of the patients.
CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity
Authors: Lillian Cruz-Orengo, David W. Holman, Denise Dorsey, Liang Zhou, Penglie Zhang, Melissa Wright, Erin E. McCandless, Jigisha R. Patel, Gary D. Luker, Dan R. Littman, John H. Russell, Robyn S. Klein
Journal: The Journal of Experimental Medicine (2011)

Loss of CXCL12, a leukocyte localizing cue, from abluminal surfaces of the blood–brain barrier occurs in multiple sclerosis (MS) lesions. However, the mechanisms and consequences of reduced abluminal CXCL12 abundance remain unclear. Here, we show that activation of CXCR7, which scavenges CXCL12, is essential for leukocyte entry via endothelial barriers into the central nervous system (CNS) parenchyma during experimental autoimmune encephalomyelitis (EAE), a model for MS. CXCR7 expression on endothelial barriers increased during EAE at sites of inflammatory infiltration. Treatment with a CXCR7 antagonist ameliorated EAE, reduced leukocyte infiltration into the CNS parenchyma and parenchymal VCAM-1 expression, and increased abluminal levels of CXCL12. Interleukin 17 and interleukin 1β increased, whereas interferon-γ decreased, CXCR7 expression on and CXCL12 internalization in primary brain endothelial cells in vitro. These findings identify molecular requirements for the transvascular entry of leukocytes into the CNS and suggest that CXCR7 blockade may have therapeutic utility for the treatment of MS.
THE COMPARATIVE EFFECTS OF SMALL INTRAVENOUS DOSES OF EPINEPHRINE UPON ARTERIAL PRESSURE AND PULSE RATE IN NORMOTENSIVE SUBJECTS AND IN HYPERTENSIVE PATIENTS BEFORE AND AFTER THORACOLUMBAR SYMPATHECTOMY
Authors: Walter E. Judson, James W. Culbertson, Clarence M. Tinsley, Julius Litter, Robert W. Wilkins
Journal: Journal of Clinical Investigation (1950)
Pomalidomide and Lenalidomide Induce p21WAF-1 Expression in Both Lymphoma and Multiple Myeloma through a LSD1-Mediated Epigenetic Mechanism
Authors: Laure Escoubet-Lozach, I-Lin Lin, Kristen Jensen-Pergakes, Helen A. Brady, Anita K. Gandhi, Peter H. Schafer, George W. Muller, Peter J. Worland, Kyle W.H. Chan, Dominique Verhelle
Journal: Cancer Research (2009)

Abstract Lenalidomide and pomalidomide have both been evaluated clinically for their properties as anticancer agents, with lenalidomide being available commercially. We previously reported that both compounds cause cell cycle arrest in Burkitt's lymphoma and multiple myeloma cell lines by increasing the level of p21WAF-1 expression. In the present study, we unravel the molecular mechanism responsible for p21WAF-1 up-regulation using Namalwa cells as a human lymphoma model. We show that the increase of p21WAF-1 expression is regulated at the transcriptional level through a mechanism independent of p53. Using a combination of approaches, we show that several GC-rich binding transcription factors are involved in pomalidomide-mediated up-regulation of p21WAF-1. Furthermore, we report that p21WAF-1 up-regulation is associated with a switch from methylated to acetylated histone H3 on p21WAF-1 promoter. Interestingly, lysine-specific demethylase-1 (LSD1) silencing reduced both pomalidomide and lenalidomide up-regulation of p21WAF-1, suggesting that this histone demethylase is involved in the priming of the p21WAF-1 promoter. Based on our findings, we propose a model in which pomalidomide and lenalidomide modify the chromatin structure of the p21WAF-1 promoter through demethylation and acetylation of H3K9. This effect, mediated via LSD1, provides GC-rich binding transcription factors better access to DNA, followed by recruitment of RNA polymerase II and transcription activation. Taken together, our results provide new insights on the mechanism of action of pomalidomide and lenalidomide in the regulation of gene transcription, imply possible efficacy in p53 mutated and deleted cancer, and suggest new potential clinical uses as an epigenetic therapy. [Cancer Res 2009;69(18):7347–56]
Altered kinetics of nonhomologous end joining and class switch recombination in ligase IV–deficient B cells
Authors: Li Han, Kefei Yu
Journal: The Journal of Experimental Medicine (2008)

Immunoglobulin heavy chain class switch recombination (CSR) is believed to occur through the generation and repair of DNA double-strand breaks (DSBs) in the long and repetitive switch regions. Although implied, the role of the major vertebrate DSB repair pathway, nonhomologous end joining (NHEJ), in CSR has been controversial. By somatic gene targeting of DNA ligase IV (Lig4; a key component of NHEJ) in a B cell line (CH12F3) capable of highly efficient CSR in vitro, we found that NHEJ is required for efficient CSR. Disruption of the Lig4 gene in CH12F3 cells severely inhibits the initial rate of CSR and causes a late cell proliferation defect under cytokine stimulation. However, unlike V(D)J recombination, which absolutely requires NHEJ, CSR accumulates to a substantial level in Lig4-null cells. The data revealed a fast-acting NHEJ and a slow-acting alterative end joining of switch region breaks during CSR.
Glucocorticoid Excess Induces Superoxide Production in Vascular Endothelial Cells and Elicits Vascular Endothelial Dysfunction
Authors: Takahiko Iuchi, Masashi Akaike, Takao Mitsui, Yasushi Ohshima, Yasumi Shintani, Hiroyuki Azuma, Toshio Matsumoto
Journal: Circulation Research (2003)

Glucocorticoid (GC) excess often elicits serious adverse effects on the vascular system, such as hypertension and atherosclerosis, and effective prophylaxis for these complications is limited. We sought to reveal the mechanism underlying GC-induced vascular complications. Responses in forearm blood flow to reactive hyperemia in 20 GC-treated patients were significantly decreased to 43±8.9% (mean±SEM) from the values obtained before GC therapy (130±14%). An administration of vitamin C almost normalized blood flow responses. In human umbilical vein endothelial cells (HUVECs), production of hydrogen peroxide was increased up to 166.5±3.3% of control values by 10 −7 mol/L dexamethasone (DEX) treatment ( P &lt;0.01). Concomitant with DEX-induced hydrogen peroxide production, intracellular amounts of peroxynitrite significantly increased and those of nitric oxide (NO) decreased, respectively ( P &lt;0.01). Immunoblotting analysis using anti-nitrotyrosine antibody showed that peroxynitrite formation was increased in DEX-treated HUVECs. Using inhibitors against metabolic pathways for generation of reactive oxygen species (ROS), we identified that the major production sources of ROS by DEX treatment were mitochondrial electron transport chain, NAD(P)H oxidase, and xanthine oxidase. These findings suggest that GC excess causes overproduction of ROS and thereby perturbs NO availability in the vascular endothelium, leading to vascular complications in patients with GC excess.
Anti‐leukemic potential of methyl‐cobalamin inactivation by nitrous oxide
Authors: J. Abels, A. C. M. Kroes, A. A. M. Ermens, J. Van Kapel, M. Schoester, L. J. M. Spijkers, J. Lindemans
Journal: American Journal of Hematology (1990)

Abstract Myelo‐cytotoxicity of extended nitrous oxide (N 2 O) inhalation was described almost forty years ago and then incidentally applied already with temporary success for suppressing leukemia. In 1948 the accompanying megaloblastic maturation arrest was explained by inactivation of the methylcobalamin coenzyme and subsequent folate deficiency. We studied the anti‐leukemic effect of N 2 O on a transplantable acute leukemia in B(rown) N(orway) rats. Progression of this B,N,M(yelocytic)L(eukemia) was measured as spleen and liver weights, and leukemic blood cell counts. The deoxyuridine (dU)‐suppression test provided in vitro indication of the functional folate activity of leukemic cells. Breathing of N 2 O‐oxygen considerably reduced but did not eradicate, BNML‐proliferation. Addition of anti‐metabolites, interfering with some enzyme in the folate metabolism beyond the methylcobalamin co‐enzyme dependent methionine synthase step, acted at least synergistically. The anti‐leukemic effect of cycloleucine, which reduces S‐adenosyl‐methionine synthesis by inactivation of methionine adenosyltransferase, was moderate but became much stronger with N 2 O inhalation. Methotrexate, a potent anti‐leukemic agent by inhibiting tetrahydrofolate (THF) generation through inactivation of di‐HF reductase, became highly anti‐BNML, even in low dosage when combined with or preceded by N 2 O. 5‐Fluorouracil, which inhibits methylene‐THF dependent thymidilate synthase, itself was surprisingly anti‐BNML, but also became much more potent with previous or concomittant N 2 O exposure. Preliminary dU‐suppression test results with human acute leukemia cells, exposed to N 2 O and/or folate antagonists in vitro, correlated well with the in vivo BNML‐experiments. Combining the anticobalamin activity of N 2 O with an anti‐folate therefore seems to be a promising chemotherapeutic approach.
Lubrication of synovial membrane.
Authors: E L Radin, I L Paul, D A Swann, E S Schottstaedt
Journal: Annals of the Rheumatic Diseases (1971)

A 6 year old boy with clinical and radiological features of pycnodysostosis is described. In addition to pycnodysostosis he had a myelophthisic type of anaemia suggesting an overlap with osteopetrosis.
Isoproterenol-Induced Myocardial Infarction in Rats
Authors: JACK SAROFF, BERNARD C. WEXLER
Journal: Circulation Research (1970)

Mature male rats with isoproterenol-induced myocardial infarction and normal controls were injected intravenously with [1, 2- 3 H] corticosterone ( 3 H corticosterone). Blood and tissue samples (liver, brain, adrenal glands, "normal" and necrotic areas of the heart) were collected 15, 30, and 45 minutes after tracer injection. Gross and histopathological changes were noted. The metabolic clearance rate of corticosterone was greater for the experimental group (11.9 liter/day) than in the normal group (8.4 liter/day). The production rate of corticosterone was approximately 4.45 mg/day for both groups of animals. The percent serum protein-binding of corticosterone was lowered from a normal of 70.3 to 56.7 in the group with cardiac necrosis. The data indicated that during myocardial infarction there was a decrease in the synthesis or availability of the corticosteroid-binding globulin. The increased uptake of 3 H corticosterone by the adrenal glands reflected the increased adrenal glandular steroid metabolism as well as depletion of its corticosterone reserve in animals during the stress of cardiac necrosis. There was a greater uptake of 3 H corticosterone by the hearts and brains of the animals with myocardial infarction; but during the acute phase of infarction, there was no selective uptake of 3 H corticosterone by necrotic vs. normal-appearing areas of the heart.