tbuckley/cabot-search huggingface dataset:
Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics
Authors: C DEZFULIAN, N RAAT, S SHIVA, M GLADWIN
Journal: Cardiovascular Research (2007)

The anion nitrite (NO(2)(-)) constitutes a biochemical reservoir for nitric oxide (NO). Nitrite reduction to NO may be catalyzed by hemoglobin, myoglobin or other metal-containing enzymes and occurs at increasing rates under conditions of physiologic hypoxia or ischemia. A number of laboratories have now demonstrated in animal models the ability of nitrite to provide potent cytoprotection following focal ischemia-reperfusion (IR) injury of the heart, liver, brain, and kidney. While the mechanism of nitrite-mediated cytoprotection remains to be fully characterized, the release of nitrite-derived NO following IR appears to be central to this mechanism. The evidence of nitrite-mediated cytoprotection against IR injury in multiple animal models opens the door to potential therapeutic opportunities in human disease. Here we review the mechanisms for nitrite formation in blood and tissue, its metabolic equilibrium with NO, nitrate, and NO-modified proteins, the evidence supporting nitrite-mediated cytoprotection, and the potential mechanisms driving cytoprotection, and we explore the opportunities for the therapeutic application of nitrite for human disease.
Biologic and Clinical Characteristics of Breast Cancer With Single Hormone Receptor–Positive Phenotype
Authors: Emad A. Rakha, Maysa E. El-Sayed, Andrew R. Green, E. Claire Paish, Desmond G. Powe, Julia Gee, Robert I. Nicholson, Andrew H.S. Lee, John F.R. Robertson, Ian O. Ellis
Journal: Journal of Clinical Oncology (2007)

Purpose Response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PgR) status. It is usually easier to decide treatment strategies in cases of double-positive/-negative phenotypes than in single-positive tumors. Patients and Methods We have examined a large and well-characterized series of primary invasive breast carcinoma (1,944 cases) with long-term clinical follow-up and hormone therapy data. Patients were stratified according to ER and PgR expression and the study was focused on the single-positive groups (ER–/PgR+ and ER+/PgR–), to assess their main features and evaluate any prognostic and predictive difference between them and compare them with the double-positive/-negative tumors. Results ER+/PgR–tumors were found more frequently in elderly, postmenopausal women. The majority were grade 2 ductal/no specific type carcinomas. There was no difference between the two groups with regard to lymph node stage. Survival analyses showed no difference between the two groups in terms of disease-free interval and overall survival. However, when compared with the double-negative phenotype, ER+/PgR–showed an association with better outcome but no such survival advantage was detected in case of ER–/PgR+ tumors. In the group of patients with ER+ tumors who received adjuvant hormonal therapy, absence of PgR (ER+/PgR–) was an independent predictor of development of recurrence and shorter survival and, hence, poorer response to hormonal therapy. Conclusion ER+/PgR–and ER–/PgR+ tumors are biologically and clinically distinct groups of breast cancer that may require different treatment strategies with ER–/PgR+ exhibiting more aggressive behavioral characteristics.
Missed and Delayed Diagnoses in the Ambulatory Setting: A Study of Closed Malpractice Claims
Authors: Tejal K. Gandhi, Allen Kachalia, Eric J. Thomas, Ann Louise Puopolo, Catherine Yoon, Troyen A. Brennan, David M. Studdert
Journal: Annals of Internal Medicine (2006)

Although missed and delayed diagnoses have become an important patient safety concern, they remain largely unstudied, especially in the outpatient setting.To develop a framework for investigating missed and delayed diagnoses, advance understanding of their causes, and identify opportunities for prevention.Retrospective review of 307 closed malpractice claims in which patients alleged a missed or delayed diagnosis in the ambulatory setting.4 malpractice insurance companies.Diagnostic errors associated with adverse outcomes for patients, process breakdowns, and contributing factors.A total of 181 claims (59%) involved diagnostic errors that harmed patients. Fifty-nine percent (106 of 181) of these errors were associated with serious harm, and 30% (55 of 181) resulted in death. For 59% (106 of 181) of the errors, cancer was the diagnosis involved, chiefly breast (44 claims [24%]) and colorectal (13 claims [7%]) cancer. The most common breakdowns in the diagnostic process were failure to order an appropriate diagnostic test (100 of 181 [55%]), failure to create a proper follow-up plan (81 of 181 [45%]), failure to obtain an adequate history or perform an adequate physical examination (76 of 181 [42%]), and incorrect interpretation of diagnostic tests (67 of 181 [37%]). The leading factors that contributed to the errors were failures in judgment (143 of 181 [79%]), vigilance or memory (106 of 181 [59%]), knowledge (86 of 181 [48%]), patient-related factors (84 of 181 [46%]), and handoffs (36 of 181 [20%]). The median number of process breakdowns and contributing factors per error was 3 for both (interquartile range, 2 to 4).Reviewers were not blinded to the litigation outcomes, and the reliability of the error determination was moderate.Diagnostic errors that harm patients are typically the result of multiple breakdowns and individual and system factors. Awareness of the most common types of breakdowns and factors could help efforts to identify and prioritize strategies to prevent diagnostic errors.
Diabetes-Induced Vascular Hypertrophy Is Accompanied by Activation of Na <sup>+</sup> -H <sup>+</sup> Exchange and Prevented by Na <sup>+</sup> -H <sup>+</sup> Exchange Inhibition
Authors: Karin Jandeleit-Dahm, Katherine M. Hannan, Caroline A. Farrelly, Terri J. Allen, Jon R. Rumble, Richard E. Gilbert, Mark E. Cooper, Peter J. Little
Journal: Circulation Research (2000)

Abstract —Vascular disease often involves vessel hypertrophy with underlying cellular hypertrophy or hyperplasia. Experimental diabetes stimulates hypertrophy of the rat mesenteric vasculature, and we investigated the hypothesis that this hypertrophy is associated with activation of Na + -H + exchange (NHE) activity. We measured the NHE activity in isolated, intact blood vessels from control and streptozotocin-induced diabetic adult rats using concurrent myography and fluorescence spectroscopy. The role of inhibiting NHE activity in preventing the development of the mesenteric hypertrophy in streptozotocin-diabetic rats was investigated by administration of cariporide (100 mg/kg body weight per day in 3 doses by gavage) after induction of diabetes and subsequently determining vessel weight and structure. The weight of the mesenteric vasculature was not increased 1 week after streptozotocin treatment but was significantly increased by an average of 56% at 3 weeks. NHE activity in mesenteric arteries showed an enhanced maximal velocity ( V max ) in diabetic vessels at 1 and 3 weeks (0.246±0.006 and 0.238±0.007 versus 0.198±0.007 pH U/min) with no change in the apparent K m . Moreover, NHE-1 mRNA in mesenteric arterioles at 3 weeks after streptozotocin treatment was increased by &gt;60% (55.8±6.4 versus 91.3±12.3 fg). Administration of cariporide significantly reduced mesenteric vascular weight, the wall/lumen ratio, and mesenteric extracellular matrix accumulation in the diabetic animals. Our study shows that diabetes in vivo correlates with elevated NHE activity and mRNA in the mesenteric vasculature and furthermore that inhibition of this system prevents the hypertrophic response. These data suggest that NHE may be a target for therapeutic modulation of vascular changes in diabetes.
A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study
Authors: J. R. Le Gall
Journal: JAMA (1993)

<h3>Objective.</h3> —To develop and validate a new Simplified Acute Physiology Score, the SAPS II, from a large sample of surgical and medical patients, and to provide a method to convert the score to a probability of hospital mortality. <h3>Design and Setting.</h3> —The SAPS II and the probability of hospital mortality were developed and validated using data from consecutive admissions to 137 adult medical and/or surgical intensive care units in 12 countries. <h3>Patients.</h3> —The 13 152 patients were randomly divided into developmental (65%) and validation (35%) samples. Patients younger than 18 years, burn patients, coronary care patients, and cardiac surgery patients were excluded. <h3>Outcome Measure.</h3> —Vital status at hospital discharge. <h3>Results.</h3> —The SAPS II includes only 17 variables: 12 physiology variables, age, type of admission (scheduled surgical, unscheduled surgical, or medical), and three underlying disease variables (acquired immunodeficiency syndrome, metastatic cancer, and hematologic malignancy). Goodness-of-fit tests indicated that the model performed well in the developmental sample and validated well in an independent sample of patients (<i>P</i>=.883 and<i>P</i>=.104 in the developmental and validation samples, respectively). The area under the receiver operating characteristic curve was 0.88 in the developmental sample and 0.86 in the validation sample. <h3>Conclusion.</h3> —The SAPS II, based on a large international sample of patients, provides an estimate of the risk of death without having to specify a primary diagnosis. This is a starting point for future evaluation of the efficiency of intensive care units. (<i>JAMA</i>. 1993;270:2957-2963)
Myc-Transformed Epithelial Cells Down-Regulate Clusterin, Which Inhibits Their Growth <b> <i>in Vitro</i> </b> and Carcinogenesis <b> <i>in Vivo</i> </b>
Authors: Andrei Thomas-Tikhonenko, Isabelle Viard-Leveugle, Michael Dews, Philippe Wehrli, Cinzia Sevignani, Duonan Yu, Stacey Ricci, Wafik el-Deiry, Bruce Aronow, Gürkan Kaya, Jean-Hilaire Saurat, Lars E. French
Journal: Cancer Research (2004)

Abstract Effective treatment of malignant carcinomas requires identification of proteins regulating epithelial cell proliferation. To this end, we compared gene expression profiles in murine colonocytes and their c-Myc-transformed counterparts, which possess enhanced proliferative potential. A surprisingly short list of deregulated genes included the cDNA for clusterin, an extracellular glycoprotein without a firmly established function. We had previously demonstrated that in organs such as skin, clusterin expression is restricted to differentiating but not proliferating cell layers, suggesting a possible negative role in cell division. Indeed, its transient overexpression in Myc-transduced colonocytes decreased cell accumulation. Furthermore, clusterin was down-regulated in rapidly dividing human keratinocytes infected with a Myc-encoding adenovirus. Its knockdown via antisense RNA in neoplastic epidermoid cells enhanced proliferation. Finally, recombinant human clusterin suppressed, in a dose-dependent manner, DNA replication in keratinocytes and other cells of epithelial origin. Thus, clusterin appears to be an inhibitor of epithelial cell proliferation in vitro. To determine whether it also affects neoplastic growth in vivo, we compared wild-type and clusterin-null mice with respect to their sensitivity to 7, 12-dimethylbenz(a)anthracene /12-Otetradecanoylphorbol-13-acetate (DMBA/TPA)-induced skin carcinogenesis. We observed that the mean number of papillomas/mouse was higher in clusterin-null animals. Moreover, these papillomas did not regress as readily as in wild-type mice and persisted beyond week 35. The rate of progression toward squamous cell carcinoma was not altered, although those developing in clusterin-null mice were on average better differentiated. These data suggest that clusterin not only suppresses epithelial cell proliferation in vitro but also interferes with the promotion stage of skin carcinogenesis.
Experience with a gastrointestinal marker (51CrCl3) in a combined study of ileal function using 75SeHCAT and 58CoB12 measured by whole body counting.
Authors: T Smith, I Bjarnason
Journal: Gut (1990)

Introduction of a radioactive gastrointestinal marker (51CrCl3) into a combined study (75SeHCAT + 58CoB12) of ileal function by whole body counting has been undertaken. The technique was assessed in 23 subjects (15 patients with inflammatory bowel disease, six on non-steroidal anti-inflammatory drugs for rheumatoid arthritis, and two normal subjects). Mean (SD) 51CrCl3 retention was only 4.1 (6.0)% on day 4, and was similar on day 7 in subjects given a second dose of 51CrCl3 on day 4. Only one subject had more than 20% of 51CrCl3 retention after four days. A 51CrCl3 correction method adequately corrected for colonic hold up of 58CoB12, when compared with final equilibrium values of 58CoB12 retention. Use of the non-absorbed 58CoB12 fraction as a gastrointestinal marker gave good agreement with the 51CrCl3 method in correcting 75SeHCAT values. In all subjects studied, corrections for colonic retention of 75SeHCAT on day 4, were small (less than 7% of dose) and did not affect the assessment of any subject. In conclusion, an additional gastrointestinal marker such as 51CrCl3 is unnecessary in our combined study since that role can be effected, when indicated by the non-absorbed 58CoB12 fraction.
Biological dust exposure in the workplace is a risk factor for chronic obstructive pulmonary disease
Authors: Melanie Matheson, Geza Benke, Joan Raven, Malcolm Sim, H Kromhout, R Vermeulen, David Johns, E Walters, Michael Abramson
Journal: Thorax (2005)

This is the first examination of sensory receptive properties and associated electrophysiological properties <i>in vivo</i> of dorsal root ganglion (DRG) neurons that express the TTX-resistant sodium channel Na<sub>v</sub>1.9 (NaN). Intracellular recordings in lumbar DRGs in Wistar rats enabled units with dorsal root C-, Aδ-, or Aα/β-fibers to be classified as nociceptive, low-threshold mechanoreceptive (LTM), or unresponsive. Intracellular dye injection enabled subsequent immunocytochemistry for Na<sub>v</sub>1.9-like immunoreactivity (Na<sub>v</sub>1.9-LI). Na<sub>v</sub>1.9-LI was expressed selectively in nociceptive-type (C- and A-fiber nociceptive and C-unresponsive) units. Of the nociceptive units, 64, 54, and 31% of C-, Aδ-, and Aα/β-fiber units, respectively, were positive for Na<sub>v</sub>1.9-LI. C-unresponsive units were included in the nociceptive-type group on the basis of their nociceptor-like membrane properties; 91% were positive. Na<sub>v</sub>1.9-LI was undetectable in Aδ- or Aα/β-fiber LTM units and in one C-LTM unit. Na<sub>v</sub>1.9-LI intensity was correlated negatively with soma size and conduction velocity in nociceptive units and with conduction velocity in C-fiber units. There was a positive correlation with action potential rise time in nociceptive-type units with membrane potentials equal to or more negative than –50 mV. The data provide direct evidence that Na<sub>v</sub>1.9 is expressed selectively in (but not in all) C- and A-fiber nociceptive-type units and suggest that Na<sub>v</sub>1.9 contributes to membrane properties that are typical of nociceptive neurons.
History of Kidney Stones and the Risk of Coronary Heart Disease
Authors: Pietro Manuel Ferraro, Eric N. Taylor, Brian H. Eisner, Giovanni Gambaro, Eric B. Rimm, Kenneth J. Mukamal, Gary C. Curhan
Journal: JAMA (2013)

<h3>Importance</h3> Kidney stone disease is common and may be associated with an increased risk of coronary heart disease (CHD). Previous studies of the association between kidney stones and CHD have often not controlled for important risk factors, and the results have been inconsistent. <h3>Objective</h3> To examine the association between a history of kidney stones and the risk of CHD in 3 large prospective cohorts. <h3>Design, Setting, and Participants</h3> A prospective study of 45 748 men and 196 357 women in the United States without a history of CHD at baseline who were participants in the Health Professionals Follow-up Study (HPFS) (45 748 men aged 40-75 years; follow-up from 1986 to 2010), Nurses' Health Study I (NHS I) (90 235 women aged 30-55 years; follow-up from 1992 to 2010), and Nurses' Health Study II (NHS II) (106 122 women aged 25-42 years; follow-up from 1991 to 2009). The diagnoses of kidney stones and CHD were updated biennially during follow-up. <h3>Main Outcomes and Measures</h3> Coronary heart disease was defined as fatal or nonfatal myocardial infarction (MI) or coronary revascularization. The outcome was identified by biennial questionnaires and confirmed through review of medical records. <h3>Results</h3> Of a total of 242 105 participants, 19 678 reported a history of kidney stones. After up to 24 years of follow-up in men and 18 years in women, 16 838 incident cases of CHD occurred. After adjusting for potential confounders, among women, those with a reported history of kidney stones had an increased risk of CHD than those without a history of kidney stones in NHS I (incidence rate [IR], 754 vs 514 per 100 000 person-years; multivariable hazard ratio [HR], 1.18 [95% CI, 1.08-1.28]) and NHS II (IR, 144 vs 55 per 100 000 person-years; multivariable HR, 1.48 [95% CI, 1.23-1.78]). There was no significant association in men (IR, 1355 vs 1022 per 100 000 person-years; multivariable HR, 1.06 [95% CI, 0.99-1.13]). Similar results were found when analyzing the individual end points (fatal and nonfatal MI and revascularization). <h3>Conclusions and Relevance</h3> Among the 2 cohorts of women, a history of kidney stones was associated with a modest but statistically significantly increased risk of CHD; there was no significant association in a separate cohort of men. Further research is needed to determine whether the association is sex-specific.
Improved Oral Delivery of <i>N</i>-(4-Hydroxyphenyl)Retinamide with a Novel LYM-X-SORB Organized Lipid Complex
Authors: Barry J. Maurer, Ondrej Kalous, David W. Yesair, Xiaqin Wu, Jitka Janeba, Vanessa Maldonado, Vazgen Khankaldyyan, Tomas Frgala, Bee-Chun Sun, R. Travis McKee, Stephen W. Burgess, Walter A. Shaw, C. Patrick Reynolds
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] is a cytotoxic retinoid that suffers from a wide interpatient variation in bioavailability when delivered orally in a corn oil capsule. The poor bioavailability of the capsule formulation may have limited responses in clinical trials, and the large capsules are not suitable for young children. To support the hypothesis that a novel organized lipid matrix, LYM-X-SORB, can increase the oral bioavailability of fenretinide, fenretinide in LYM-X-SORB matrix and in a powderized LYM-X-SORB formulation was delivered to mice. Experimental Design: Fenretinide was delivered orally to mice as the contents of the corn oil capsule, in LYM-X-SORB matrix (4-HPR/LYM-X-SORB matrix) or in a LYM-X-SORB matrix powderized with sugar and flour (4-HPR/LYM-X-SORB oral powder). Levels of 4-HPR, and its principal metabolite, N-(4-methoxyphenyl)retinamide, were assayed in plasma and tissues. Results: In a dose-responsive manner, from 120 to 360 mg/kg/d, delivery to mice of 4-HPR in LYM-X-SORB matrix, or as 4-HPR/LYM-X-SORB oral powder, increased 4-HPR plasma levels up to 4-fold (P &amp;lt; 0.01) and increased tissue levels up to 7-fold (P &amp;lt; 0.01) compared with similar doses of 4-HPR delivered using capsule contents. Metabolite [N-(4-methoxyphenyl)retinamide] levels mirrored 4-HPR levels. Two human neuroblastoma murine xenograft models showed increased survival (P &amp;lt; 0.03), when treated with 4-HPR/LYM-X-SORB oral powder, confirming the bioactivity of the formulation. Conclusions: 4-HPR/LYM-X-SORB oral powder is a novel, oral drug delivery formulation, suitable for pediatric use, which warrants further development for the delivery of fenretinide in the treatment of cancer. A phase I clinical trial in pediatric neuroblastoma is in progress.
Von willebrand factor (VIII<sub>VWF</sub>) in lyophilized factor VIII concentrates
Authors: Miles J. McCue, Arthur D. Brossoit, Daniel J. Marmer, David R. Head
Journal: American Journal of Hematology (1980)

Abstract Several (14) commercially prepared, lyophilized Factor VIII concentrates were assayed for VIII AHF , VIII Ag , and VIII VWF . Significant levels of VIII Ag (immunologic) and VIII VWF (von Willebrand Factor) were present in addition to VIII AHF (Functional VIII, Antihemophilic Factor, Factor VIII coagulant activity). An average of 0.95 units of VIII VWF (range 0.47–1.7) were present for every 1.0 unit of VIII AHF (as stated on the manufacturer's label). We suggest that the various lyophilized preparations of Factor VIII concentrate available could be assayed for VIII VWF and should be tested therapeutically in patients with von Willebrand disease.
Angiotensin II-dependent persistent podocyte loss from destabilized glomeruli causes progression of end stage kidney disease
Authors: Akihiro Fukuda, Larysa T. Wickman, Madhusudan P. Venkatareddy, Yuji Sato, Mahboob A. Chowdhury, Su Q. Wang, Kerby A. Shedden, Robert C. Dysko, Jocelyn E. Wiggins, Roger C. Wiggins
Journal: Kidney International (2011)
Single Photon Emission Computed Tomography of Pulmonary Emboli and Venous Thrombi Using Anti–D-Dimer
Authors: Timothy A. Morris, James J. Marsh, Peter G. Chiles, Ronald G. Konopka, Craig A. Pedersen, Peter F. Schmidt, Michael Gerometta
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Previous attempts to diagnose thromboemboli using radiolabeled antibodies and nuclear medicine imaging have been disappointing. We present the results of experiments with intravenous technetium-99m-labeled deimmunized antifibrin Fab' fragments to diagnose thromboemboli using single photon emission computed tomography (SPECT), a highly sensitive scintigraphic imaging technique. Pulmonary emboli (PEs) and lower extremity deep vein thrombi (DVTs) were formed in five dogs, then technetium-99m-labeled Fab' ( approximately 400 mg, approximately 260 MBq) were injected via forelimb veins. Thoracic and lower extremity SPECT scans were performed at 2-hour intervals after antibody infusion to visualize the thromboemboli. Four hours after antibody infusion, all PEs and DVTs of mass 0.4 g or greater were clearly visualized on SPECT scans as 'hot spots' within the lungs and legs, respectively. PEs (0.48 +/- 0.09 g) were intensely radiolabeled, yielding clot/blood radioactivity ratios of 22.8 +/- 5.6. DVTs (0.45 +/- 0.31 g) also had high clot/blood ratios (11.7 +/- 2.6). Infusion of these radiolabeled antibody fragments, combined with SPECT, produces clear images of PEs and DVTs within a clinically feasible time frame. The technique reliably identified even peripheral thromboemboli of relatively small size, which are difficult to diagnose with currently available imaging techniques, and may enable imaging of PEs, DVTs, or both in the same patient.