tbuckley/cabot-search huggingface dataset:
Buffering Capacity and Size of siRNA Polyplexes Influence Cytokine Levels
Authors: Qixin Leng, Szu-Ting Chou, Puthupparampil V Scaria, Martin C Woodle, A James Mixson
Journal: Molecular Therapy (2012)

Induction of cytokines by small interfering RNA (siRNA) polyplexes has been a significant concern of researchers attempting to minimize the toxicity of this promising therapy. Although cationic carriers of siRNA are known to increase cytokine levels, few systematic studies have been done to determine what properties of the carrier are important to modulate cytokines. Because branched histidine-lysine (HK) peptides are effective carriers of siRNA and their sequence can be readily modified, we selected this class of carrier to determine which sequences of the peptide were important for cytokine induction. With the use of peripheral blood mononuclear cells (PBMCs), the HK peptide with a higher number of histidines (H3K(+H)4b) in complex with siRNA induced lower levels of cytokines compared with other HK (e.g., H2K4b, H3K4b, H3K(+N)4b) siRNA nanoplexes. Notably, these peptides' siRNA polyplexes showed a similar pattern of cytokine induction when injected intravenously in a mouse model, i.e., the HK with higher content of histidines induced cytokines the least. As indicated by the pH-sensitive dye within acidic endosomes, the greater pH-buffering capacity of H3K(+H)4b compared with other HK peptides may explain why cytokine levels were reduced. In addition to buffering capacity, the size of HK polyplexes markedly influenced cytokine production. Induction of cytokines by small interfering RNA (siRNA) polyplexes has been a significant concern of researchers attempting to minimize the toxicity of this promising therapy. Although cationic carriers of siRNA are known to increase cytokine levels, few systematic studies have been done to determine what properties of the carrier are important to modulate cytokines. Because branched histidine-lysine (HK) peptides are effective carriers of siRNA and their sequence can be readily modified, we selected this class of carrier to determine which sequences of the peptide were important for cytokine induction. With the use of peripheral blood mononuclear cells (PBMCs), the HK peptide with a higher number of histidines (H3K(+H)4b) in complex with siRNA induced lower levels of cytokines compared with other HK (e.g., H2K4b, H3K4b, H3K(+N)4b) siRNA nanoplexes. Notably, these peptides' siRNA polyplexes showed a similar pattern of cytokine induction when injected intravenously in a mouse model, i.e., the HK with higher content of histidines induced cytokines the least. As indicated by the pH-sensitive dye within acidic endosomes, the greater pH-buffering capacity of H3K(+H)4b compared with other HK peptides may explain why cytokine levels were reduced. In addition to buffering capacity, the size of HK polyplexes markedly influenced cytokine production.
Maple-Syrup-Urine Disease
Authors: Derrick Lonsdale, David H. Barber
Journal: New England Journal of Medicine (1964)

MAPLE-syrup-urine disease is now well documented as being an inborn error of metabolism.1 The purpose of this paper is to present another case of the disease in an infant boy, together with his family pedigree and a report of the emergency measures taken to arrest the fatal course of the disease. Further studies2 on leucine loading of the immediate members of the family have been reported.Case ReportA 12-day-old male infant was examined at the Cleveland Clinic on October 24, 1963, because of continuous convulsions for 6 days. Pregnancy, labor and delivery had been normal and full term, and . . .
XXIII. The Automobile Makes an Impact
Authors: Lester S. King
Journal: JAMA (1984)

In 1882 the young doctor just starting in practice was advised, as soon as his circumstances permitted, to get a horse and buggy. These would show that his practice was growing, and "anyone can ride into a full practice much quicker than he can walk into one." However, the young physician was enjoined never to "let a bony horse and seedy or unsuitable kind of carriage" stand in front of his office for "hours at a time, as if to advertise both your poverty and your paucity of practice."<sup>1</sup> Within the next 20 years the position of the horse and buggy was undergoing a profound reevaluation. A new mode of transportation was emerging from a long gestation, to become a thriving infant with a great future. Inventors in France had taken the lead. In 1895, in a 727-mile race, nine of 22 entries crossed the finish line. In America the
Nonanticoagulant Heparin Prevents Coronary Endothelial Dysfunction After Brief Ischemia-Reperfusion Injury in the Dog
Authors: Peter C. Kouretas, Young D. Kim, Paul A. Cahill, Adam K. Myers, Lam N. To, Yi-Ning Wang, James V. Sitzmann, Robert L. Hannan
Journal: Circulation (1999)

Background —Coronary endothelial dysfunction after brief ischemia-reperfusion (IR) remains a clinical problem. We investigated the role of heparin and N -acetylheparin, a nonanticoagulant heparin derivative, in modulating coronary endothelial function after IR injury, with an emphasis on defining the role of the nitric oxide (NO)–cGMP pathway in the heparin-mediated effect. Methods and Results —Male mongrel dogs were surgically instrumented, and the effects of both bovine heparin and N -acetylheparin on coronary endothelial vasomotor function, expressed as percent change from baseline flow after acetylcholine challenge, were studied after 15 minutes of regional ischemia of the left anterior descending artery (LAD) followed by 120 minutes of reperfusion. In dogs treated with placebo (saline), coronary vasomotor function was significantly ( P ≤0.03) decreased after 15 and 30 minutes of reperfusion (65±12% and 73±12%) compared with preischemia (103±6%). In contrast, the vasodilatory response to the endothelium-independent vasodilator sodium nitroprusside was maintained during reperfusion. Preischemic administration of both bovine heparin and N -acetylheparin (6.0 mg/kg IV) preserved coronary endothelial function throughout reperfusion. In a parallel group of dogs, nitrate/nitrite (NOx) and cGMP levels in the LAD were measured after treatment and during 15-minute reperfusion. Preischemic administration of N -acetylheparin caused a significant increase in basal NOx and cGMP levels compared with saline controls. Pretreatment with N -acetylheparin also caused a significant increase in NOx and cGMP levels in the LAD after 15 minutes of reperfusion compared with IR alone. Conclusions —These results suggest that heparin preserves coronary endothelial function after brief IR injury by a mechanism independent of its anticoagulant activity and that the effect of heparin may be mediated in part by activation of the NO-cGMP pathway.
Abstract 4629: Expression of cancer-associated proliferating cell nuclear antigen (caPCNA) in various stages and types of neoplasia (breast, cervix, colon, gastric, lung, ovary, thyroid, and uterus)
Authors: George E. Sandusky, Karla John, Patty Gulley, Katie Carr, Liang Cheng, Linda H. Malkas, Robert Hickey
Journal: Cancer Research (2010)

Abstract Novel immunohistochemistry biomarkers that target specific cellular proteins that are either uniquely or primarily expressed by cancer cells are being developed. One of these biomarkers, caPCNA, [the cancer associated isoform of PCNA] may be useful as an aide for distinguishing early stage neoplasia from hyperplasia in clinical cases that are often difficult to interpret. The caPCNA isoform appears to be expressed almost exclusively in a large variety of cancer cells and at all Stages [1 to 4] of the disease. It is not consistently observed in most normal adjacent tissues. This study analyzed the expression of caPCNA, by immunohistochemistry (IHC) using an automated Ventana immunostaining platform. In the present study, IHC was performed on neutral buffered formalin fixed paraffin embedded tissues obtained from various pathology labs. Evaluation of carcinomas (120 cases) from various organs and clinical stages as well as normal adjacent tissue was performed. Immunostaining was localized in tumor cells only to the cell nucleus. CaPCNA expression was seen in 10 of 10 cervical Ca, 20 of 20 colon Ca, 10 of 10 thyroid Ca, 10 of 10 gastric Ca, 10 of 10 ovarian Ca, 25 of 25 breast Ca, 10 of 10 lung Ca, 11 of 12 uterine Ca, and 15 of 15 DCIS Ca. On a normal tissue panel, caPCNA immunostaining was seen in macrophages, syncytial trophoblasts in the placenta, GI tract crypt epithelial cells, and scattered staining in the basilar layer of the skin. Immunostaining of normal macrophages and most of the other reactive cell types was abolished by removal of the heavy chain of the primary antibody during creation of an Fab2' fragment of the anti-caPCNA antibody. In summary, the present results illustrate the localization of caPCNA at all stages, in many different types of neoplasms. CaPCNA may therefore be a useful biomarker for early stage cancer diagnosis and potentially maybe a predictor of patient outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4629.
Preemptive Olmesartan for the Delay or Prevention of Microalbuminuria in Diabetes
Authors: Julie R. Ingelfinger
Journal: New England Journal of Medicine (2011)

Patients with either type 1 or type 2 diabetes mellitus are at high risk for chronic kidney disease, which is usually first evident with the onset of microalbuminuria. There is overall consensus that agents that block the renin–angiotensin system — particularly angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) — slow the progression of chronic kidney disease in patients with diabetes who already have microalbuminuria. Long-term trials with losartan (the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL] trial)1 and irbesartan2 showed that ARBs slowed the course of diabetic nephropathy in patients with baseline evidence of renal . . .
Speckle-Tracking Radial Strain Reveals Left Ventricular Dyssynchrony in Patients With Permanent Right Ventricular Pacing
Authors: Laurens F. Tops, Matthew S. Suffoletto, Gabe B. Bleeker, Eric Boersma, Ernst E. van der Wall, John Gorcsan, Martin J. Schalij, Jeroen J. Bax
Journal: Journal of the American College of Cardiology (2007)
Emmett's Clinical Urography: An Atlas and Textbook of Roentgenologic Diagnosis
Authors: James F. Martin
Journal: JAMA (1978)

This fourth edition of<i>Emmett's Clinical Urography</i>brings up to date a well-recognized, highly regarded textbook of diagnosis in diseases encountered in clinical urology. This revision, in three volumes, is intended as a complete treatise on urographic diagnosis suitable as a textbook for the student or a reference book and atlas for the busy practitioner. The authors have presented a monumental work. The material presented in all chapters is beautifully illustrated and composed for easy first-time reading. The roentgenographic material is nicely correlated with the clinical problems. There has been considerable revision of the overall format, with the addition of three attractive new chapters. Chapter 5 discusses sonography and computerized tomography (CT). A great deal of fine clinical material is presented in both sections, but there is a need for more detailed labeling of anatomic structures in both the normal and the abnormal, and an attempt at correlation of the
Public health decisions: the laboratory's role in the Lorain County, Ohio, investigation.
Authors: Robert H Hill, Susan Head, Dana B Barr, Carol Rubin, Emilio Esteban, Samuel E Baker, Sandra Bailey, Larry L Needham
Journal: Environmental Health Perspectives (2002)

In 1994 officials from the Ohio Department of Health reported that some residents of Lorain County, Ohio, possibly had been exposed to methyl parathion (MP), a highly toxic restricted-use pesticide. The U.S. Centers for Disease Control and Prevention (CDC) assisted in the investigation by providing epidemiologic and laboratory support to the state and local health departments. Although the initial investigation found MP inside the homes, it was unclear if the residents were exposed. CDC used a new biological monitoring method to measure urinary p-nitrophenol (PNP), the metabolite of MP. This biological monitoring measures the internal dose from exposure to toxic chemicals from all routes. Laboratory analyses demonstrated that the urine of residents contained moderate to high levels of PNP, with median, mean, and highest reported concentrations of 28, 240, and 4,800 g/L, respectively, thus confirming exposure of the residents. Almost 80% of the residents had urinary PNP concentrations above the 95th percentile of the reference range concentrations. This information, combined with other analytical results of air and wipe tests, guided public health officials' decisions about the potential risk in each household. In this article we illustrate the laboratory's role in providing information to assist in making these public health decisions. Furthermore, it illustrates how a multidisciplinary team from various governmental agencies worked together to protect the public's health.
Bile Salts as Atypical Surfactants and Solubilizers
Authors: Pasupati Mukerjee, Yoshikiyo Moroi, Moriyasu Murata, Alex Y. S. Yang
Journal: Hepatology (1984)

Recent research has suggested that self-association of bile salts does not follow the micellar pattern of self-association exhibited by typical flexible chain surfactants and detergents. A working model for the self-association of bile salts is proposed. It includes a mild degree of cooperativity in the early stages of the growth of aggregates and coexistence of a number of aggregates of different aggregation numbers. The polydispersity implies an increase in the average aggregation number with increasing concentration of the bile salt. Bile salts can be purified by foam fractionation. Surface tension data for sodium cholate are in agreement with the above qualitative model of self-association. An isoextraction method is useful for estimating monomer activities. Results for sodium deoxycholate suggest little self-association in dilute solutions and a mildly cooperative self-association at higher concentrations. A comparative study of the interactions of the fluorescent probe, 2-p-toluidinyl-naphthalene-6-sulfonate, with sodium alkyl sulfates and sodium deoxycholate indicates that bile salts may differ significantly from classical micellar systems in their solubilization characteristics also. The evidence suggests strongly that a specific adduct formation with an optimum number of bile salt anions may be important in solubilization brought about by the rigidity and the complex shape of the bile salt anions.
Unresolved questions of chromocholangioscopy with methylene blue
Authors: I. Maetani
Journal: Endoscopy (2008)

We have read the article of Hoffman et al. with interest [1]. They reported usefulness of chromocholangioscopy with methylene blue [1]. In the article, the authors state that their study is the first to use chromocholangioscopy with methylene blue. However, we have already reported a paper with the same concept in 1996 [2], although we assessed this issue by percutaneous cholangioscopy. In our paper, we clearly mentioned the difference of methylene blue staining properties based on types of biliary epithelia: normal, metaplasia, or cancer. The cancerous epithelia stained significantly less often than either the normal (P < 0.000005) or the metaplastic (P < 0.001) epithelia [2] according to our study using frozen sections of biopsied specimens. In addition, our investigation revealed that this stain was truly absorbed by biliary epithelium [2]. The paper written by Hoffman et al. [1] concluded that methylene-blue-aided cholangioscopy was beneficial in order to guess which epithelia is lining the surface of the bile duct, which is similar to our findings.
Particulate Matter–Induced Airway Hyperresponsiveness Is Lymphocyte Dependent
Authors: Vanessa Saunders, Patrick Breysse, Jennifer Clark, Alyssa Sproles, Melissa Davila, Marsha Wills-Karp
Journal: Environmental Health Perspectives (2010)

Exposure to airborne particulate matter (PM), a major component of air pollution, has been associated with increases in both exacerbations of and hospitalizations for asthma. We have previously shown that exposure to ambient PM collected in urban Baltimore (AUB) induces airway hyperresponsiveness (AHR), eosinophilic and neutrophilic inflammation, and the recruitment of T cells. However, the mechanism(s) by which it induces these features of asthma remains unknown.We investigated whether T lymphocytes play a role in AUB-induced AHR.We compared the effects of AUB exposure on the allergic phenotype in wild-type (WT) BALB/c mice and in mice deficient in recombinase-activating gene-1 (Rag1-/-) that lack mature lymphocytes.We found that exposure of WT mice to AUB induced AHR concomitant with increases in the numbers of bronchoalveolar lavage (BAL) fluid lymphocytes, eosinophils, neutrophils, and mucus-containing cells in the lungs of WT mice. Interestingly, we show for the first time that these effects were associated with significant elevations in interleukin (IL)-17A, IL-17F, and T-helper 2 cell (TH2) (IL-13, IL-5) cytokine levels in lung cells, as well as reductions in the levels of the suppressive cytokine IL-10. Interestingly, Rag1-/- mice failed to develop AUB-induced AHR; however, AUB-induced BAL fluid cellularity, and mucus cell changes were only partially inhibited in Rag1-/- mice.Taken together, our results suggest that AUB exposure increases the pathophysiological features of asthma via activation of lymphocyte-dependent pathways. These results provide a plausible biological mechanism for the strong association between PM exposure and the increased severity of asthma.
Effect of theophylline on membrane potential and contractile force in hamster diaphragm muscle in vitro.
Authors: S Esau
Journal: Journal of Clinical Investigation (1986)

Theophylline enhances the force of diaphragmatic contraction and delays fatigue. The mechanism is not known, but recent evidence suggests it may act at the cell membrane. To test this hypothesis, we studied the effect of theophylline on resting membrane potential and tension in hamster diaphragm cells. Muscle strips were obtained from five adult hamsters and placed in Krebs solution, aerated with 95% O2, 5% CO2. Resting membrane potential was measured using 3-M KCl-filled glass microelectrodes; 15-22 fibers in each strip were sampled. Force frequency curves (twitch to 100 Hz) were obtained. The muscle bath was then changed to one containing 100 mg/liter (0.55) theophylline. Resting membrane potential was -76 +/- 3 mV (mean +/- S.D.) in Krebs solution and increased to -85 +/- 3 mV (P less than 0.01) with added theophylline. Tension increased from 5% (at 100 Hz) to 20% (at 10 Hz) with theophylline. Hyperpolarization indicates an increase in intracellular to extracellular potassium concentration. Net potassium outflow occurs with each contraction, causing the cell membrane to become depolarized with repeated contractions, ultimately leading to fatigue. The hyperpolarization of the skeletal muscle cell membrane observed with theophylline may play an important role in prolonging time to fatigue.
EARLY FIRST TRIMESTER FETAL ECHOCARDIOGRAPHY: IDENTIFICATION OF CARDIAC STRUCTURES BY 2D IMAGING AND COLOR DOPPLER FROM SIX WEEKS GESTATION
Authors: Darren Hutchinson, Angela McBrien, Lisa Howley, Yuka Yamamoto, Akiko Hirose, Terek Motan, Venu Jain, Winnie Savard, Lisa K. Hornberger
Journal: Journal of the American College of Cardiology (2013)
Book Review The Corrosion of Medicine: Can the Profession Reclaim Its Moral Legacy? By John Geyman. 344 pp. Monroe, ME, Common Courage Press, 2008. $24.95. 978-1-56751-384-4 Worried Sick: A Prescription for Health in an Overtreated America By Nortin M. Hadler. 353 pp. Chapel Hill, University of North Carolina Press, 2008. $28. 978-0-8078-3187-8
Authors: Steffie Woolhandler, David U. Himmelstein
Journal: New England Journal of Medicine (2008)
Shedding of Distinct Cryptic Collagen Epitope (HU177) in Sera of Melanoma Patients
Authors: Bruce Ng, Jan Zakrzewski, Melanie Warycha, Paul J. Christos, Dean F. Bajorin, Richard L. Shapiro, Russell S. Berman, Anna C. Pavlick, David Polsky, Madhu Mazumdar, Anthony Montgomery, Leonard Liebes, Peter C. Brooks, Iman Osman
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Extracellular matrix remodeling during tumor growth plays an important role in angiogenesis. Our preclinical data suggest that a newly identified cryptic epitope (HU177) within collagen type IV regulates endothelial and melanoma cell adhesion in vitro and angiogenesis in vivo. In this study, we investigated the clinical relevance of HUI77 shedding in melanoma patient sera. Experimental Design: Serum samples from 291 melanoma patients prospectively enrolled at the New York University Medical Center and 106 control subjects were analyzed for HU177 epitope concentration by a newly developed sandwich ELISA assay. HU177 serum levels were then correlated with clinical and pathologic parameters. Results: Mean HU177 epitope concentration was 5.8 ng/mL (range, 0-139.8 ng/mL). A significant correlation was observed between HU177 concentration and nodular melanoma histologic subtype [nodular, 10.3 ± 1.6 ng/mL (mean ± SE); superficial spreading melanoma, 4.5 ± 1.1 ng/mL; all others, 6.1 ± 2.1 ng/mL; P = 0.01 by ANOVA test]. Increased HU177 shedding also correlated with tumor thickness (≤1.00 mm, 3.8 ± 1.1 ng/mL; 1.01-3.99 mm, 8.7 ± 1.3 ng/mL; ≥4.00 mm, 10.3 ± 2.4 ng/mL; P = 0.003 by ANOVA). After multivariate analysis controlling for thickness, the correlation between higher HU177 concentration and nodular subtype remained significant (P = 0.03). The mean HU177 epitope concentration in control subjects was 2.4 ng/mL. Conclusions: We report that primary melanoma can induce detectable changes in systemic levels of cryptic epitope shedding. Our data also support that nodular melanoma might be biologically distinct compared with superficial spreading type melanoma. As targeted interventions against cryptic collagen epitopes are currently undergoing phase I clinical trial testing, these findings indicate that patients with nodular melanoma may be more susceptible to such targeted therapies.