tbuckley/cabot-search huggingface dataset:
A Major Role for hERG in Determining Frequency of Reentry in Neonatal Rat Ventricular Myocyte Monolayer
Authors: Luqia Hou, Makarand Deo, Philip Furspan, Sandeep V. Pandit, Sergey Mironov, David S. Auerbach, Qiuming Gong, Zhengfeng Zhou, Omer Berenfeld, José Jalife
Journal: Circulation Research (2010)

Rationale: The rapid delayed rectifier potassium current, I Kr , which flows through the human ether-a-go-go-related (hERG) channel, is a major determinant of the shape and duration of the human cardiac action potential (APD). However, it is unknown whether the time dependency of I Kr enables it to control APD, conduction velocity (CV), and wavelength (WL) at the exceedingly high activation frequencies that are relevant to cardiac reentry and fibrillation. Objective: To test the hypothesis that upregulation of hERG increases functional reentry frequency and contributes to its stability. Methods and Results: Using optical mapping, we investigated the effects of I Kr upregulation on reentry frequency, APD, CV, and WL in neonatal rat ventricular myocyte (NRVM) monolayers infected with GFP (control), hERG ( I Kr ), or dominant negative mutant hERG G628S. Reentry frequency was higher in the I Kr -infected monolayers (21.12±0.8 Hz; n=43 versus 9.21±0.58 Hz; n=16; P &lt;0.001) but slightly reduced in G628S-infected monolayers. APD 80 in the I Kr -infected monolayers was shorter (&gt;50%) than control during pacing at 1 to 5 Hz. CV was similar in both groups at low frequency pacing. In contrast, during high-frequency reentry, the CV measured at varying distances from the center of rotation was significantly faster in I Kr -infected monolayers than controls. Simulations using a modified NRVM model predicted that rotor acceleration was attributable, in part, to a transient hyperpolarization immediately following the AP. The transient hyperpolarization was confirmed experimentally. Conclusions: hERG overexpression dramatically accelerates reentry frequency in NRVM monolayers. Both APD and WL shortening, together with transient hyperpolarization, underlies the increased rotor frequency and stability.
Use of the SINBAD Classification System and Score in Comparing Outcome of Foot Ulcer Management on Three Continents
Authors: Paul Ince, Zulfiqarali G. Abbas, Janet K. Lutale, Abdul Basit, Syed Mansoor Ali, Farooq Chohan, Stephan Morbach, Jörg Möllenberg, Fran L. Game, William J. Jeffcoate
Journal: Diabetes Care (2008)

To compare populations with and outcomes of diabetic foot ulcers managed in the U.K., Germany, Tanzania, and Pakistan and to explore the use of a new score of ulcer type in comparing outcomes among different countries.Data from a series of 449 patients with diabetic foot ulcers managed in the U.K. were used to evaluate the new simplified system of classification and to derive an aggregate score. The use of the score was then explored using data from series managed in Germany (n = 239), Tanzania (n = 479), and Pakistan (n = 173).A highly significant difference was found in time to healing between ulcers of increasing score in the U.K. series (Kruskal-Wallis test; P = 0). When data from all centers were examined, a step-up in days to healing was noted for those with scores of >or=3 (out of 6). Examination of baseline variables contributing to outcome revealed the following differences among centers: ischemia, ulcer area, and depth contributing to outcome in the U.K.; ischemia, area, depth, and infection in Germany; depth, infection, and neuropathy in Tanzania; and depth alone in Pakistan.Any system of classification designed for general implementation must encompass all the variables that contribute to outcome in different communities. Adoption of a simple score based on these variables, the Site, Ischemia, Neuropathy, Bacterial Infection, and Depth (SINBAD) score, may prove useful in predicting ulcer outcome and enabling comparison among different centers.
Metabolic Syndrome and Incident Diabetes
Authors: Earl S. Ford, Chaoyang Li, Naveed Sattar
Journal: Diabetes Care (2008)

OBJECTIVE—Our objective was to perform a quantitative review of prospective studies examining the association between the metabolic syndrome and incident diabetes. RESEARCH DESIGN AND METHODS—Using the title terms “diabetes” and “metabolic syndrome” in PubMed, we searched for articles published since 1998. RESULTS—Based on the results from 16 cohorts, we performed a meta-analysis of estimates of relative risk (RR) and incident diabetes. The random-effects summary RRs were 5.17 (95% CI 3.99–6.69) for the 1999 World Health Organization definition (ten cohorts); 4.45 (2.41–8.22) for the 1999 European Group for the Study of Insulin Resistance definition (four cohorts); 3.53 (2.84–4.39) for the 2001 National Cholesterol Education Program definition (thirteen cohorts); 5.12 (3.26–8.05) for the 2005 American Heart Association/National Heart, Lung, and Blood Institute definition (five cohorts); and 4.42 (3.30–5.92) for the 2005 International Diabetes Federation definition (nine cohorts). The fixed-effects summary RR for the 2004 National Heart, Lung, and Blood Institute/American Heart Association definition was 5.16 (4.43–6.00) (six cohorts). Higher number of abnormal components was strongly related to incident diabetes. Compared with participants without an abnormality, estimates of RR for those with four or more abnormal components ranged from 10.88 to 24.4. Limited evidence suggests fasting glucose alone may be as good as metabolic syndrome for diabetes prediction. CONCLUSIONS—The metabolic syndrome, however defined, has a stronger association with incident diabetes than that previously demonstrated for coronary heart disease. Its clinical value for diabetes prediction remains uncertain.
Human Placental Cytotrophoblasts Attract Monocytes and Cd56bright Natural Killer Cells via the Actions of Monocyte Inflammatory Protein 1α
Authors: Penelope M. Drake, Michael D. Gunn, Israel F. Charo, Chia-Lin Tsou, Yan Zhou, Ling Huang, Susan J. Fisher
Journal: The Journal of Experimental Medicine (2001)

During human pregnancy, the specialized epithelial cells of the placenta (cytotrophoblasts) come into direct contact with immune cells in several locations. In the fetal compartment of the placenta, cytotrophoblast stem cells lie adjacent to macrophages (Hofbauer cells) that reside within the chorionic villus stroma. At sites of placental attachment to the mother, invasive cytotrophoblasts encounter specialized maternal natural killer (NK) cells (CD56bright), macrophages, and T cells that accumulate within the uterine wall during pregnancy. Here we tested the hypothesis that fetal cytotrophoblasts can direct the migration of these maternal immune cells. First, we assayed the chemotactic activity of cytotrophoblast conditioned medium samples, using human peripheral blood mononuclear cells as targets. The placental samples preferentially attracted NK cells (both CD56dim and CD56bright), monocytes, and T cells, suggesting that our hypothesis was correct. A screen to identify chemokine activity through the induction of a Ca2+ flux in cells transfected with individual chemokine receptors suggested that cytotrophoblasts secreted monocyte inflammatory protein (MIP)-1α. This was confirmed by localizing the corresponding mRNA and protein, both in vitro and in vivo. MIP-1α protein in conditioned medium was further characterized by immunoblotting and enzyme-linked immunosorbent assay. Immunodepletion of MIP-1α from cytotrophoblast conditioned medium showed that this chemokine was responsible for a significant portion of the induced monocyte and CD56bright NK cell chemotax-is. These data suggest the specific conclusion that cytotrophoblasts can attract monocytes and CD56bright NK cells by producing MIP-1α and the more general hypothesis that these cells may organize and act on leukocytes at the maternal–fetal interface.
Role of poly(ADP-ribose) synthetase in inflammation and ischaemia–reperfusion
Authors: C. Szabó, V.L. Dawson
Journal: Trends in Pharmacological Sciences (1998)

Oxidative and nitrosative stress can trigger DNA strand breakage, which then activates the nuclear enzyme poly(ADP-ribose) synthetase (PARS). This enzyme has also been termed poly(ADP-ribose) polymerase (PARP) or poly(ADP-ribose) transferase (pADPRT). Rapid activation of the enzyme depletes the intracellular concentration of its substrate, nicotinamide adenine dinucleotide, thus slowing the rate of glycolysis, electron transport and subsequently ATP formation. This process can result in cell dysfunction and cell death. In this article, Csaba Szabó and Valina Dawson overview the impact of pharmacological inhibition or genetic inactivation of PARS on the course of oxidant-induced cell death in vitro, and in inflammation and reperfusion injury in vivo. A major trigger for DNA damage in pathophysiological conditions is peroxynitrite, a cytotoxic oxidant formed by the reaction between the free radicals nitric oxide and superoxide. The pharmacological inhibition of poly(ADP-ribose) synthetase is a novel approach for the experimental therapy of various forms of inflammation and shock, stroke, myocardial and intestinal ischaemia-reperfusion, and diabetes mellitus.
Are interactive specialization and massive redeployment compatible?
Authors: Michael L. Anderson
Journal: Behavioral and Brain Sciences (2008)

Abstract I offer a simple method for further investigating the Interactive Specialization framework, and some data that may or may not be compatible with the approach, depending on the precise meaning of “specialization.” Findings from my lab indicate that, while networks of brain areas cooperate in specialized ways to support cognitive functions, individual brain areas participate in many such networks, in different cognitive domains.
Activation of AKT by O-Linked N-Acetylglucosamine Induces Vascular Calcification in Diabetes Mellitus
Authors: Jack M. Heath, Yong Sun, Kaiyu Yuan, Wayne E. Bradley, Silvio Litovsky, Louis J. Dell’Italia, John C. Chatham, Hui Wu, Yabing Chen
Journal: Circulation Research (2014)

Vascular calcification is a serious cardiovascular complication that contributes to the increased morbidity and mortality of patients with diabetes mellitus. Hyperglycemia, a hallmark of diabetes mellitus, is associated with increased vascular calcification and increased modification of proteins by O-linked N-acetylglucosamine (O-GlcNAcylation).We sought to determine the role of protein O-GlcNAcylation in regulating vascular calcification and the underlying mechanisms.Low-dose streptozotocin-induced diabetic mice exhibited increased aortic O-GlcNAcylation and vascular calcification, which was also associated with impaired aortic compliance in mice. Elevation of O-GlcNAcylation by administration of Thiamet-G, a potent inhibitor for O-GlcNAcase that removes O-GlcNAcylation, further accelerated vascular calcification and worsened aortic compliance of diabetic mice in vivo. Increased O-GlcNAcylation, either by Thiamet-G or O-GlcNAcase knockdown, promoted calcification of primary mouse vascular smooth muscle cells. Increased O-GlcNAcylation in diabetic arteries or in the O-GlcNAcase knockdown vascular smooth muscle cell upregulated expression of the osteogenic transcription factor Runx2 and enhanced activation of AKT. O-GlcNAcylation of AKT at two new sites, T430 and T479, promoted AKT phosphorylation, which in turn enhanced vascular smooth muscle cell calcification. Site-directed mutation of AKT at T430 and T479 decreased O-GlcNAcylation, inhibited phosphorylation of AKT at S473 and binding of mammalian target of rapamycin complex 2 to AKT, and subsequently blocked Runx2 transactivity and vascular smooth muscle cell calcification.O-GlcNAcylation of AKT at 2 new sites enhanced AKT phosphorylation and activation, thus promoting vascular calcification. Our studies have identified a novel causative effect of O-GlcNAcylation in regulating vascular calcification in diabetes mellitus and uncovered a key molecular mechanism underlying O-GlcNAcylation-mediated activation of AKT.
Phrenic Evulsion as an Aid in the Treatment of Pulmonary Tuberculosis and Bronchiectasis
Authors: H. M. Davies
Journal: BMJ (1926)

The orthopaedic aspects of the condition concern us very acutely, especially silnce industrial inisurance alnd workmen''s compensation cases have become so iiumerous.79The thera- peutic indications are the same as in other types of the condition: attention to general health anid free eliminia- tion, physiotherapy, protection of the affected portion of the spine by a Thomas collar, a spinal brace or jacket, and an attempt to neutralize or correct the faulty spinal curves and bring about a normal weight-bearing alignmenit.Con- ceivably a spinal fusion operationi miglht bo a rational pro- cedure in an occasionial case.Relief from less radical meiasures is ordinarily easy to obtain, and for this, in the commonly met cases exhibiting low back pain and sciatica, the low short back brace with an abdominal supportinig pad devised by Goldthwait has been a sheet anichor which has held.If rest of the affected part, diminution of intra- articular friction, and free elimin-ation can be provided, we may expect symptomatic relief.SUTMMARY.1. Rheumatoid arthritis is a disease in n-Ihich nio specifio organism has been found which cani be held conistantly responsible for its causation.Probably many different t-pes of organisms and maniy other factors play etiologic larts in its onset and course.2. In the early stages of rheumatoid arthritis, if these Drganisms and if the other factors can be overcome, complete recovery is possible.In the later stages, if the -factors inimical to normal vitality can be eliminated and the essentials for normal body mechanics can be satisfied, arrest of the disease anid great fuinctional betterment may be expected.In this stage thle simple eradication of a possible surgical focus of infection will rarely be successful in controlling the progress of the disease.3. Osteo-arthritis is a disease in wlich nio specific organism has been conclusively proved to be responsible for its causation.On the basis of the present evidence, its manifestations may occur unassociated with any demon- strable remote or local focus of ilnfection.4. In the early stages of osteo-arthritis, if a faulty body chemistry and a faulty body mechanics caln be corrected and intra-articular friction can be lessened, almost complete relief of the subjective symptoms is possible.In the later stages, if intelligent physiotherapy, protective appliances, and well conceived surgery be added to these measures, relief of discomfort and greatly improved function may be expected.
No harm from five year ingestion of oats in coeliac disease
Authors: E. K. Janatuinen, T. A. Kemppainen, R. J. K. Julkunen, V.-M. Kosma, M. Mäki, M. Heikkinen, M. I. J. Uusitupa
Journal: Gut (2002)

Background: Six to 12 months of ingestion of moderate amounts of oats does not have a harmful effect in adult patients with coeliac disease. As the safety of long term intake of oats in coeliac patients is not known, we continued our previous 6–12 month study for five years. Aim: To assess the safety of long term ingestion of oats in the diet of coeliac patients. Patients: In our previous study, the effects of a gluten free diet and a gluten free diet including oats were compared in a randomised trial involving 92 adult patients with coeliac disease (45 in the oats group, 47 in the control group). After the initial phase of 6–12 months, patients in the oats group were allowed to eat oats freely in conjunction with an otherwise gluten free diet. After five years, 35 patients in the original oats group (23 still on an oats diet) and 28 in the control group on a conventional gluten free diet were examined. Methods: Clinical and nutritional assessment, duodenal biopsies for conventional histopathology and histomorphometry, and measurement of antiendomysial, antireticulin, and antigliadin antibodies. Results: There were no significant differences between controls and those patients consuming oats with respect to duodenal villous architecture, inflammatory cell infiltration of the duodenal mucosa, or antibody titres after five years of follow up. In both groups histological and histomorphometric indexes improved equally with time. Conclusions: This study provides the first evidence of the long term safety of oats as part of a coeliac diet in adult patients with coeliac disease. It also appears that the majority of coeliac patients prefer oats in their diet.
Effect of Phloretin on Water and Solute Movement in the Toad Bladder
Authors: Sherman Levine, Nicholas Franki, Richard M. Hays
Journal: Journal of Clinical Investigation (1973)

It is generally believed that urea crosses the cell membrane through aqueous channels, and that its movement across the membrane is accelerated in the direction of net water flow (solvent drag effect). The present report presents evidence for a vasopressin-sensitive pathway for the movement of urea, other amides, and certain non-amides, which is independent of water flow. Phloretin, when present at 10(-4) M concentration in the medium bathing the luminal surface of the toad bladder, strongly inhibits the movement of urea, acetamide, and propionamide across the toad bladder, both in the absence and presence of vasopressin. The vasopressin-stimulated movement of formaldehyde and thiourea is also reduced. Osmotic water flow, on the other hand, is not affected; nor is the movement of ethanol and ethylene glycol, or the net transport of sodium. On the basis of these studies we would conclude that the movement of many, if not all, solutes across the cell membrane is independent of water flow, and that a vasopressin-sensitive carrier may be involved in the transport of certain solutes across the cell membrane.
An exceptional high concentration of serum CA 19.9 in a patient with alcoholic liver disease
Authors: E D. GOEDE, S H YAP
Journal: Gut (1997)

Editor,—Since the discovery by Koprowski and co-workers in 1979, raised serum concentrations of carbohydrate antigenic determinant, CA 19.9, has been used as an additional diagnostic test for adenocarcinoma of the upper gastrointestinal tract.1-3 According to Benamouzig et al ,3 at the usual 37 U/ml cut off value, CA 19.9 had a sensitivity of 90% and a specificity of 45% for malignant biliary obstruction due to pancreatic or biliary neoplasm. For a more increased cut off value of 200 U/ml, its sensitivity was 65% and specificity was 91%. If higher cut off values are used, specificity rises so that at levels greater than 1000 U/ml, …
Color Doppler assessment of mitral regurgitation with orthogonal planes.
Authors: F Helmcke, N C Nanda, M C Hsiung, B Soto, C K Adey, R G Goyal, R P Gatewood
Journal: Circulation (1987)

We evaluated 147 patients with adequate color Doppler and angiographic studies for mitral regurgitation. Sixty-five patients had no mitral regurgitation by both color Doppler and angiography and 82 patients had mitral regurgitation by both techniques. Thus the sensitivity and specificity of color Doppler for the detection of mitral regurgitation was 100%. Three two-dimensional echocardiographic planes (parasternal long and short axis, apical four-chamber view) were used to analyze variables of the mitral regurgitant jet signals in the left atrium. The best correlation with angiography was obtained when the regurgitant jet area (RJA) (maximum or average from three planes) expressed as a percentage of the left atrial area (LAA) obtained in the same plane as the maximum regurgitant area was considered. The maximum RJA/LAA was under 20% in 34 of 36 patients with angiographic grade I mitral regurgitation, between 20% and 40% in 17 of 18 patients with grade II mitral regurgitation, and over 40% in 26 of 28 patients with severe mitral regurgitation. Maximum RJA/LAA also correlated with angiographic regurgitant fractions (r = .78) obtained in 21 of 40 patients in normal sinus rhythm and with no evidence of associated aortic regurgitation. Other variables of the regurgitant jet such as maximal linear and transverse dimensions, maximal area, or maximal area expressed as a percentage of the LAA in one or two planes correlated less well with angiography. Color Doppler is a useful noninvasive technique that is not only highly sensitive and specific in the identification of mitral regurgitation but also provides accurate estimation of its severity.
<i>ETV6</i> mutations in early immature human T cell leukemias
Authors: Pieter Van Vlierberghe, Alberto Ambesi-Impiombato, Arianne Perez-Garcia, J. Erika Haydu, Isaura Rigo, Michael Hadler, Valeria Tosello, Giusy Della Gatta, Elisabeth Paietta, Janis Racevskis, Peter H. Wiernik, Selina M. Luger, Jacob M. Rowe, Montserrat Rue, Adolfo A. Ferrando
Journal: The Journal of Experimental Medicine (2011)

Early immature T cell acute lymphoblastic leukemias (T-ALLs) account for ∼5–10% of pediatric T-ALLs and are associated with poor prognosis. However, the genetic defects that drive the biology of these tumors remain largely unknown. In this study, analysis of microarray gene expression signatures in adult T-ALL demonstrated a high prevalence of early immature leukemias and revealed a close relationship between these tumors and myeloid leukemias. Many adult immature T-ALLs harbored mutations in myeloid-specific oncogenes and tumor suppressors including IDH1, IDH2, DNMT3A, FLT3, and NRAS. Moreover, we identified ETV6 mutations as a novel genetic lesion uniquely present in immature adult T-ALL. Our results demonstrate that early immature adult T-ALL represents a heterogeneous category of leukemias characterized by the presence of overlapping myeloid and T-ALL characteristics, and highlight the potential role of ETV6 mutations in these tumors.
SMURF1 silencing diminishes a CD44-high cancer stem cell-like population in head and neck squamous cell carcinoma
Authors: Ali Khammanivong, Raj Gopalakrishnan, Erin B Dickerson
Journal: Molecular Cancer (2014)

Bone morphogenetic protein (BMP) signaling is thought to play key roles in regulating the survival and maintenance of cancer stem cells (CSCs), which contribute to disease recurrences and treatment failures in many malignances, including head and neck squamous cell carcinoma (HNSCC). Intracellular BMP signaling is regulated by SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) during cellular development. However, little is known about the role or regulation of BMP signaling in HNSCC CSCs. Two CSC-like populations, CD44high/BMI1high and CD44high/ALDHhigh, were enriched from HNSCC cell lines and evaluated for the expression of SMURF1 by qRT-PCR, flow cytometry, and immunoblotting. The activation status of BMP signaling in these populations was determined by using immunoblotting to detect phosphorylated SMAD1/5/8 (pSMAD1/5/8) levels. Knockdown of SMURF1 transcripts by RNA interference was used to assess the role of SMURF1 in BMP signaling and CSC maintenance. Loss of CSC-like phenotypes following SMURF1 knockdown was determined by changes in CD44high levels, cellular differentiation, and reduction in colony formation. Populations of enriched CSC-like cells displayed decreased levels of pSMAD1/5/8 and BMP signaling target gene ID1 while SMURF1, CD44, and BMI1 were highly expressed when compared to non-CSC populations. Stable knockdown of SMURF1 expression in CSC-like cells increased pSMAD1/5/8 protein levels, indicating the reactivation of BMP signaling pathways. Decreased expression of SMURF1 also promoted adipogenic differentiation and reduced colony formation in a three-dimensional culture assay, indicating loss of tumorigenic capacity. The role of SMURF1 and inhibition of BMP signaling in maintaining a CSC-like population was confirmed by the loss of a CD44high expressing subpopulation in SMURF1 knockdown cells. Our findings suggest that inhibition of BMP signaling potentiates the long-term survival of HNSCC CSCs, and that this inhibition is mediated by SMURF1. Targeting SMURF1 and restoring BMP signaling may offer a new therapeutic approach to promote differentiation and reduction of CSC populations leading to reduced drug resistance and disease recurrence.