tbuckley/cabot-search huggingface dataset:
Cardiovascular Importance of Hyperglycemia and Hypoglycemia
Authors: Ivan Tkáč
Journal: Diabetes Care (2013)

For addressing the question of cardiovascular importance of hypoglycemia, it is important to clarify its context. First, hypoglycemia is a result of treatment of hyperglycemia by oral insulin secretagogues or insulin. Chronic hyperglycemia usually expressed by HbA1c level is considered a risk factor for cardiovascular disease, although this epidemiological association does not necessarily mean the existence of causal association, so the possibility cannot be excluded that HbA1c may be only a marker of atherosclerotic vascular disease. Thus, in the present review the evidence related to hyperglycemia and hypoglycemia as factors contributing to the development of cardiovascular events will be discussed and the main following issues will be addressed: The relationship of hyperglycemia to cardiovascular disease will be documented based on analysis of epidemiological and clinical interventional studies. Furthermore, the evidence will be summarized that hypoglycemic episodes contribute to the development of cardiovascular events in patients with type 2 diabetes treated by hypoglycemia-inducing drugs. Finally, it will be demonstrated how the conclusions from the described studies translated in practical recommendations for personalized treatment of type 2 diabetes.

### Is hyperglycemia related to cardiovascular disease?

The evidence about a relationship between hyperglycemia and cardiovascular disease comes from epidemiological studies and epidemiological post hoc analyses of clinical trials. For consideration of a biological variable, e.g., HbA1c, as a cardiovascular risk factor, it is important to analyze its relationship with cardiovascular disease also outside the diabetic range. The epidemiological study European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) included 4,662 men and 5,570 women. Relative risks for cardiovascular disease (nonfatal or fatal coronary heart disease and strokes) adjusted for age and risk factors were calculated after 6-year follow-up period. An increase in HbA1c of 1% (11 mmol/mol) was associated with relative risk for cardiovascular disease of 1.21 (95% CI 1.13–1.29 for males and 1.11–1.31 for females; …
Glucocorticoid receptor β and histone deacetylase 1 and 2 expression in the airways of severe asthma
Authors: Claire A Butler, Stephen McQuaid, Cliff C Taggart, Sinead Weldon, Richard Carter, Grzegorz Skibinski, Timothy J Warke, David F Choy, Lorcan P McGarvey, Peter Bradding, Joe R Arron, Liam G Heaney
Journal: Thorax (2011)

<h3>Rationale</h3> Upregulation of glucocorticoid receptor β (GRβ) has been implicated in steroid resistance in severe asthma, although previous studies are conflicting. GRβ has been proposed as a dominant negative isoform of glucocorticoid receptor α (GRα) but it has also been suggested that GRβ can cause steroid resistance via reduced expression of histone deacetylase 2 (HDAC2), a key regulator of steroid responsiveness in the airway. <h3>Objectives</h3> To examine GRβ, GRα, HDAC1 and HDAC2 expression at transcript and protein levels in bronchial biopsies from a large series of patients with severe asthma, and to compare the findings with those of patients with mild to moderate asthma and healthy volunteers. <h3>Methods</h3> Bronchoscopic study in two UK centres with real-time PCR and immunohistochemistry performed on biopsies, western blotting of bronchial epithelial cells and immunoprecipitation with anti-GRβ antibody. <h3>Measurements and main results</h3> Protein and mRNA expression for GRα and HDAC2 did not differ between groups. GRβ mRNA was detected in only 13 of 73 samples (seven patients with severe asthma), however immunohistochemistry showed widespread epithelial staining in all groups. Western blotting of bronchial epithelial cells with GRβ antibody detected an additional 'cross-reacting' protein, identified as clathrin. HDAC1 expression was increased in patients with severe asthma compared with healthy volunteers. <h3>Conclusions</h3> GRβ mRNA is expressed at low levels in a minority of patients with severe asthma. HDAC1 and HDAC2 expression was not downregulated in severe asthma. These data do not support upregulated GRβ and resultant reduced HDAC expression as the principal mechanism of steroid resistance in severe asthma. Conflicting GRβ literature may be explained in part by clathrin cross-reactivity with commercial antibodies.
A Randomized Phase I and Pharmacological Trial of Sequences of 1,3-bis(2-Chloroethyl)-1-Nitrosourea and Temozolomide in Patients with Advanced Solid Neoplasms
Authors: Lisa A. Hammond, John R. Eckardt, John G. Kuhn, Stanton L. Gerson, Tom Johnson, Lon Smith, Ronald L. Drengler, Elizabeth Campbell, Geoffrey R. Weiss, Daniel D. Von Hoff, Eric K. Rowinsky
Journal: Clinical Cancer Research (2004)

Abstract Purpose: O 6-alkylguanine-DNA alkyltransferase (AGAT) is modulated by methylating agents, which, in turn, abrogates nitrosourea resistance in preclinical studies. The feasibility of administering various sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TEM) in patients with advanced solid neoplasms was evaluated in this Phase I and pharmacological study to assess this premise in the clinical setting. The study also sought to determine the maximum tolerated dose (MTD) levels of BCNU and TEM as a function of Seq, to characterize the pharmacokinetic (PK) behavior of TEM administered both before and after BCNU, assess AGAT fluctuations in peripheral blood mononuclear cells (PBMCs), and seek preliminary evidence of anticancer activity. Experimental Design: Sixty-three patients were randomized to receive treatment with oral TEM daily on days 1–5 and BCNU administered i.v., either on day 1 before TEM [Sequence (Seq) B→T] or day 5 after TEM (Seq T→B). Treatment was repeated every 6 weeks. Blood sampling for PK studies was performed on both days 1 and 5 of course one. PBMCs were sampled to evaluate major sequence-dependent effects on AGAT levels. Results: Neutropenia and thrombocytopenia were the principal dose-limiting toxicities of the BCNU/TEM regimen. These effects were more prominent in patients receiving Seq T→B, resulting in a much lower MTD of 80/100 mg/m2/day compared with 150/110 mg/m2/day for Seq B→T. Notable antitumor activity was observed in patients with glioblastoma multiforme, sarcoma, and ovarian carcinoma. No sequence-dependent PK effects were noted to account for sequence-dependent toxicological effects. At the MTD level, AGAT activity in PBMCs decreased 3-fold, on average, and AGAT fluctuations did not appear to be sequence-dependent. Conclusions: The principal toxicities of the BCNU/TEM regimen were neutropenia and thrombocytopenia, which were consistent and predictable, albeit sequence-dependent. Seq T→B was substantially more myelosuppressive, resulting in disparate MTDs and dose levels recommended for subsequent disease-directed evaluations (150/110 and 80/100 mg/m2/day for Seq B→T and T→B, respectively). Sequence-dependent differences in TEM PK do not account for this clinically relevant magnitude of sequence-dependent toxicity. The characteristics of the myelosuppressive effects of BCNU/TEM, the paucity of severe nonhematological toxicities, and antitumor activity at tolerable doses warrant disease-directed evaluations on this schedule.
The rise and fall of surgery for the "floating" kidney
Authors: D. L McWhinnie, D. N H Hamilton
Journal: BMJ (1984)

The latter half of the nineteenth century produced a remarkable expansion of surgical practice. Although most of these new techniques and concepts were soundly based, others, such as the movable or floating kidney, were later ridiculed and discredited.In Glasgow Royal Infirmary during the 48 years from 1880, when movable kidney was first mentioned in the annual reports of the hospital, to 1928 472 patients (89% female) were diagnosed as suffering from the condition. Nearly half of them (216) underwent operation and the operative mortality was low. In the first decade of this century an average of 18 cases a year were admitted to the wards of the infirmary. From 1915 to 1920 the number of cases dropped, as did the proportion undergoing operation, but in the 1920s the numbers increased again.In common with other ineffective treatments for imaginary diseases, operations for the movable kidney simply faded away in Britain in the 1930s.
Reversing Hepatocellular Carcinoma Progression by Using Networked Biological Therapies
Authors: Richard J. Epstein, Thomas W. Leung
Journal: Clinical Cancer Research (2007)

Abstract The liver is distinguished from other tissues by (a) its detoxifying function, (b) its resistance to apoptosis, and (c) its regenerative response to damage. Hepatocellular carcinoma arises when chronic insults, such as hepatitis or iron overload, constitutively activate this regenerative program. Here, we propose that the proliferative response of the liver to damage underlies the resistance of hepatocellular carcinoma to cytotoxic therapy, and that hepatocellular carcinoma growth should therefore be more readily controlled by using a networked combination of noncytotoxic interventions to interrupt the damage-inducible regenerative pathway. To this end, hepatocellular carcinoma boasts a wealth of potential drug targets, including viral replication, the antiapoptotic immunosuppressant α-fetoprotein, hepatic iron overload, inflammatory signaling, extracellular proteases, and growth factors. By blocking these positive feedback loops in parallel, and so returning the host environment to a more normal state, epigenetic repression of tumor-suppressor gene function may be reversed and tumor dormancy restored. Noncytotoxic maneuvers that short circuit damage resistance loops may thus represent an indirect form of gene therapy meriting incorporation into hepatocellular carcinoma clinical trials.
International variation in the prevalence of COPD (The BOLD Study): a population-based prevalence study
Authors: A Sonia Buist, Mary Ann McBurnie, William M Vollmer, Suzanne Gillespie, Peter Burney, David M Mannino, Ana MB Menezes, Sean D Sullivan, Todd A Lee, Kevin B Weiss, Robert L Jensen, Guy B Marks, Amund Gulsvik, Ewa Nizankowska-Mogilnicka
Journal: The Lancet (2007)
Cognitive Disorders and Dementia in CKD
Authors: Jean-Marc Bugnicourt, Olivier Godefroy, Jean-Marc Chillon, Gabriel Choukroun, Ziad A. Massy
Journal: Journal of the American Society of Nephrology (2013)

Epidemiologic data suggest that individuals at all stages of CKD have a higher risk of developing cognitive disorders and dementia. This risk is generally explained by the high prevalence of both symptomatic and subclinical ischemic cerebrovascular lesions. However, other potential mechanisms, including direct neuronal injury by uremic toxins, could also be involved, especially in the absence of obvious cerebrovascular disease. We discuss the prevalence and characteristics of cognitive disorders and dementia in patients with CKD, brain imaging findings, and traditional and nontraditional risk factors. Understanding the pathophysiologic interactions between renal impairment and brain function is important in order to minimize the risk for future cognitive impairment.
An incidental finding in a 34-year-old male under investigation for haemoptysis
Authors: D. Pinot, D. Breen, J-M. Peloni, J-Y. Gaubert, H. Dutau, D. Vervloet
Journal: European Respiratory Journal (2009)

A 34-yr-old male presented with a 1-week history of a productive cough associated with small volume haemoptysis.This was preceded by a 3-month history of a chronic nonproductive cough and 6 kg weight loss.He denied chest pain, fever or night sweats.He admitted to increasing fatigue, but denied arthalgia, myalgia or skin rash.His past medical history was noncontributory.The patient worked in the construction industry and smoked 20 cigarettes per day.He admitted to illicit drug usage, both cannabis and cocaine on a regular basis.
Randomized, Placebo-Controlled, Double-Blinded Chemoimmunotherapy Clinical Trial in a Pet Dog Model of Diffuse Large B-cell Lymphoma
Authors: Laura Marconato, Patrick Frayssinet, Nicole Rouquet, Stefano Comazzi, Vito Ferdinando Leone, Paola Laganga, Federica Rossi, Massimo Vignoli, Lorenzo Pezzoli, Luca Aresu
Journal: Clinical Cancer Research (2013)

Active immunotherapy is a promising antitumoral strategy; however its use in combination with chemotherapy in dogs with large B-cell lymphoma (DLBCL) remains largely untested. Heat shock proteins (HSP) bind the small peptides they chaperone (HSPPC), allowing for immunization of the host against a large repertoire of tumor-associated antigens. Hydroxylapatite vehicles HSPPCs and acts as an immunologic adjuvant. The aim of this study was to show that an autologous vaccine with hydroxylapatite and tumor-derived HSPPCs is safe and therapeutically effective in dogs with DLBCL.Nineteen dogs with naturally occurring DLBCL were entered into a prospective randomized placebo-controlled double-blinded trial of HSPPCs-hydroxylapatite plus chemotherapy versus chemotherapy alone. Endpoints included time to progression (TTP), lymphoma-specific survival (LSS), and incidence of toxicoses.Median first TTP after randomization to the vaccine arm was 304 days versus 41 days for the control arm (P = 0.0004). There was also a statistically significant difference in duration of second remission between the two groups (P = 0.02). Median LSS was 505 days for the vaccinated dogs versus 159 days for the unvaccinated dogs (P = 0.0018). Six vaccinated dogs achieved molecular remission, as shown by clonal immunoglobulin H (IgH) rearrangement. Toxicoses were comparable between the two treatment arms.The results of this trial demonstrate that the autologous vaccine tested here is safe and efficacious in prolonging TTP and LSS in dogs with DLBCL when used in combination with dose-intense chemotherapy. On the basis of these results, additional evaluation of this novel therapeutic strategy is warranted in human DLBCL.
Intratumoral Injection of Dendritic Cells Engineered to Secrete Interleukin-12 by Recombinant Adenovirus in Patients With Metastatic Gastrointestinal Carcinomas
Authors: Guillermo Mazzolini, Carlos Alfaro, Bruno Sangro, Esperanza Feijoó, Juan Ruiz, Alberto Benito, Iñigo Tirapu, Ainhoa Arina, Josu Sola, Maite Herraiz, Felipe Lucena, Cristina Olagüe, José Subtil, Jorge Quiroga, Ignacio Herrero, Belén Sádaba, Maurizio Bendandi, Cheng Qian, Jesús Prieto, Ignacio Melero
Journal: Journal of Clinical Oncology (2004)

To evaluate the feasibility and safety of intratumoral injection of autologous dendritic cells (DCs) transfected with an adenovirus encoding interleukin-12 genes (AFIL-12) for patients with metastatic gastrointestinal carcinomas. Secondarily, we have evaluated biologic effects and antitumoral activity.Seventeen patients with metastatic pancreatic (n = 3), colorectal (n = 5), or primary liver (n = 9) malignancies entered the study. DCs were generated from CD14+ monocytes from leukapheresis, cultured and transfected with AFIL-12 before administration. Doses from 10 x 10(6) to 50 x 10(6) cells were escalated in three cohorts of patients. Patients received up to three doses at 21-day intervals.Fifteen (88%) and 11 of 17 (65%) patients were assessable for toxicity and response, respectively. Intratumoral DC injections were mainly guided by ultrasound. Treatment was well tolerated. The most common side effects were lymphopenia, fever, and malaise. Interferon gamma and interleukin-6 serum concentrations were increased in 15 patients after each treatment, as well as peripheral blood natural killer activity in five patients. DC transfected with AFIL-12 stimulated a potent antibody response against adenoviral capsides. DC treatment induced a marked increase of infiltrating CD8+ T lymphocytes in three of 11 tumor biopsies analyzed. A partial response was observed in one patient with pancreatic carcinoma. Stable disease was observed in two patients and progression in eight patients, with two of the cases fast-progressing during treatment.Intratumoral injection of DC transfected with an adenovirus encoding interleukin-12 to patients with metastatic gastrointestinal malignancies is feasible and well tolerated. Further studies are necessary to define and increase clinical efficacy.
Red flags to screen for malignancy and fracture in patients with low back pain
Authors: Aron Downie, Christopher M Williams, Nicholas Henschke, Mark J Hancock, Raymond W J G Ostelo, Henrica C W de Vet, Petra Macaskill, Les Irwig, Maurits W van Tulder, Bart W Koes, Christopher G Maher
Journal: British Journal of Sports Medicine (2014)

What are the best red flags to indicate the possibility of fracture or malignancy in patients presenting with low back pain in primary, secondary, or tertiary care?Older age, prolonged corticosteroid use, severe trauma, and presence of a contusion or abrasion increase the likelihood of spinal fracture (likelihood was higher with multiple red flags); a history of malignancy increases the likelihood of spinal malignancy.
A Comparative Study of Efficacy of Salbutamol via Metered Dose Inhaler (MDI) with Volumatic Spacer and via Dry Powder Inhaler (DPI), Easyhaler, to Nebulization in Mild to Moderate Severity Acute Asthma Exacerbation in Children
Authors: C SIRIKUL, K CHUMPAKDEE, M VANGVEERAVONG
Journal: Journal of Allergy and Clinical Immunology (2008)
Chemotherapy and Targeted Therapy for Women With Human Epidermal Growth Factor Receptor 2–Negative (or unknown) Advanced Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline
Authors: Ann H. Partridge, R. Bryan Rumble, Lisa A. Carey, Steven E. Come, Nancy E. Davidson, Angelo Di Leo, Julie Gralow, Gabriel N. Hortobagyi, Beverly Moy, Douglas Yee, Shelley B. Brundage, Michael A. Danso, Maggie Wilcox, Ian E. Smith
Journal: Journal of Clinical Oncology (2014)

To identify optimal chemo- and targeted therapy for women with human epidermal growth factor 2 (HER2)- negative (or unknown) advanced breast cancer.
A Rare Adult Cause of Dizziness
Authors: Francy Shu, Robert Oberle, Emily Herndon, Kimmo Hatanpaa, James Battiste, Steven Vernino
Journal: JAMA Neurology (2014)

A 55-year-old man was seen with progressively worsening dizziness over 10 months. The initial assessment with unremarkable laboratory and imaging studies suggested a peripheral vestibular disorder. He was then lost to follow-up but later was seen with worsening ataxia. Additional imaging studies showed subtle parenchymal lesions in the posterior fossa. The differential diagnoses included nutritional deficiencies, autoimmune disorders, systemic malignancies, and intracranial tumors. The final diagnosis was confirmed by a biopsy.
Gene Expression Profiles of Luteal Phase Fallopian Tube Epithelium from <i>BRCA</i> Mutation Carriers Resemble High-Grade Serous Carcinoma
Authors: Alicia A. Tone, Heather Begley, Monika Sharma, Joan Murphy, Barry Rosen, Theodore J. Brown, Patricia A. Shaw
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To identify molecular alterations potentially involved in predisposition to adnexal serous carcinoma (SerCa) in the nonmalignant fallopian tube epithelium (FTE) of BRCA1/2 mutation carriers, given recent evidence implicating the distal FTE as a common source for SerCa. Experimental Design: We obtained and compared gene expression profiles of laser capture microdissected nonmalignant distal FTE from 12 known BRCA1/2 mutation carriers (FTEb) and 12 control women (FTEn) during the luteal and follicular phase, as well as 13 high-grade tubal and ovarian SerCa. Results: Gene expression profiles of tubal and ovarian SerCa specimens were indistinguishable by unsupervised cluster analysis and significance analysis of microarrays. FTEb samples as a group, and four individual FTEb samples from the luteal phase in particular, clustered closely with SerCa rather than normal control FTE. Differentially expressed genes from these four samples relative to other FTEb samples, as well as differentially expressed genes in all FTEb luteal samples relative to follicular samples, were mapped to the I2D protein-protein interaction database, revealing a complex network affecting signaling pathways previously implicated in tumorigenesis. Two candidates, disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) and Ski-like (SKIL), were further validated by real-time reverse transcription–PCR and tissue arrays. FTEb luteal and SerCa samples expressed higher levels of oncogenic SKIL and decreased levels of tumor suppressor DAB2, relative to FTEb follicular samples. Conclusions: These findings support a common molecular pathway for adnexal SerCa and implicate factors associated with the luteal phase in predisposition to ovarian cancer in BRCA mutation carriers.
Isotopic studies of therapeutic anticoagulation with a coagulating enzyme
Authors: W. R. Bell, E. Regoeczi
Journal: Journal of Clinical Investigation (1970)

The kinetics of the depletion of plasma fibrinogen were studied in seven patients who received fibrinogen-(131)I 1 hr before an intravenous injection of the coagulating enzyme (CE) derived from the venom of the pit viper, Agkistrodon rhodostoma. Disappearance of the clottable radioactivity labeled fibrinogen from the circulation conformed to an exponential decay with an average half-life of 0.85 hr. The mean clearance rate for protein-bound radioactivity, composed of fibrinogen and it's split products, was 12% of the intravascular pool per hour. The breakdown products of fibrin produced by CE inhibited polymerization of fibrin in vitro. Studies in five patients performed between the 3rd and 10th day following the administration of CE revealed that the absolute catabolic rates of fibrinogen were subnormal initially, but gradually increased as the fibrinogen concentration returned to normal. In rabbits, after the administration of CE, regeneration of the fibrinogen pool was markedly prolonged. This delayed regeneration time was not influenced by an excess of antivenene, but rapid regeneration to pretreatment values of plasma fibrinogen was immediately initiated by stimulating fibrinogen synthesis with subcutaneous turpentine.