tbuckley/cabot-search huggingface dataset:
Mechanically Driven Contour-Length Adjustment in Rat Cardiac Titin’s Unique N2B Sequence
Authors: M. Helmes, K. Trombitás, T. Centner, M. Kellermayer, S. Labeit, W. A. Linke, H. Granzier
Journal: Circulation Research (1999)

Abstract —The giant elastic protein titin is largely responsible for passive forces in cardiac myocytes. A number of different titin isoforms with distinctly different structural elements within their central I-band region are expressed in human myocardium. Their coexpression has so far prevented an understanding of the respective contributions of the isoforms to myocardial elasticity. Using isoform-specific antibodies, we find in the present study that rat myocardium expresses predominantly the small N2B titin isoform, which allows us to characterize the elastic behavior of this isoform. The extensibility and force response of N2B titin were studied by using immunoelectron microscopy and by measuring the passive force–sarcomere length (SL) relation of single rat cardiac myocytes under a variety of mechanical conditions. Experimental results were compared with the predictions of a mechanical model in which the elastic titin segment behaves as two wormlike chains, the tandem immunoglobulin (Ig) segments and the PEVK segment (rich in proline [P], glutamate [E], valine [V], and lysine [K] residues), connected in series. The overall contour length was predicted from the sequence of N2B cardiac titin. According to mechanical measurements, above ≈2.2 μm SL titin’s elastic segment extends beyond its predicted contour length. Immunoelectron microscopy indicates that a prominent source of this contour-length gain is the extension of the unique N2B sequence (located between proximal tandem Ig segment and PEVK), and that Ig domain unfolding is negligible. Thus, the elastic region of N2B cardiac titin consists of three mechanically distinct extensible segments connected in series: the tandem Ig segment, the PEVK segment, and the unique N2B sequence. Rate-dependent and repetitive stretch-release experiments indicate that both the contour-length gain and the recovery from it involve kinetic processes, probably unfolding and refolding within the N2B segment. As a result, the contour length of titin’s extensible segment depends on the rate and magnitude of the preceding mechanical perturbations. The rate of recovery from the length gain is slow, ensuring that the adjusted length is maintained through consecutive cardiac cycles and that hysteresis is minimal. Thus, as a result of the extensible properties of the unique N2B sequence, the I-band region of the N2B cardiac titin isoform functions as a molecular spring that is adjustable.
The Second-Meal Phenomenon in Type 2 Diabetes
Authors: Ana Jovanovic, Jean Gerrard, Roy Taylor
Journal: Diabetes Care (2009)

OBJECTIVE In health, the rise in glucose after lunch is less if breakfast is eaten. We evaluated the second-meal effect in type 2 diabetes. RESEARCH DESIGN AND METHODS Metabolic changes after lunch in eight obese type 2 diabetic subjects were compared on 3 days: breakfast eaten, no breakfast, and no breakfast but intravenous arginine 1 h before lunch. RESULTS Despite comparable insulin levels, the rise in plasma glucose after lunch was considerably less if breakfast had been eaten (0.68 ± 1.49 vs. 12.32 ± 1.73 vs. 7.88 ± 1.03 mmol · h−1 · l−1; P &amp;lt; 0.0001). Arginine administration almost halved the lunch rise in plasma glucose (12.32 ± 1.73 vs. 7.88 ± 1.03 mmol · h−1 · l−1). The plasma free fatty acid concentration at lunchtime directly related to plasma glucose rise after lunch (r = 0.67, P = 0.0005). CONCLUSIONS The second-meal effect is preserved in type 2 diabetes. Premeal administration of a nonglucose insulin secretagogue results in halving the postprandial glucose rise and has therapeutic potential.
Role of the Chinese Herbal Medicine Xianhuayin on the Reversal of Premalignant Mucosal Lesions in the Golden Hamster Buccal Pouch
Authors: Yan‐zhi Xu, Yong‐le Qiu, Zhi‐guang An, Feng‐ying Yang
Journal: International Journal of Oral Science (2010)

To investigate the role of the Chinese herbal medicine Xianhuayin on the reversal of 7,12‐dimethylbenz[a]anthracene (DMBA)‐induced premalignant mucosal lesions in the oral buccal pouch of golden hamsters. The animals were randomly divided into a non‐diseased control group (n=5) and an experimental group including 50 animals in which the buccal mucosa had been painted with DMBA (0.5% in acetone) to generate an oral mucosa premalignant lesion. Animals in the experimental group were further divided into Xianhuayin‐treated group (n=30), untreated premalignant lesion group (n=10) and normal saline (NS)‐treated group (n=10). The cheek (buccal) pouch mucosa of the golden hamsters in each group was observed with light and electron microscopy eight weeks after intragastric administration with NS or Xianhuayin. In the non‐diseased control group, the buccal mucosa was keratinized and stratified squamous epithelium under a light microscope. In the untreated premalignant lesion group, variable degrees of epithelial dysplasia was observed. The irregular epithelial mucosa gradually became distinct in the Xianhuayin‐treated group. Scanning electronic microscopic (SEM) analysis showed that surface of the cells exhibited honeycomb structures in the hamster of untreated‐group. The cells were morphologically irregular, overlapped and loosened in the untreated premalignant lesion group. Most of the cell surface exhibited honeycomb structure in the Xianhuayin‐treated group. Transmission electronic microscopic (TEM) analysis showed that buccal mucosal epithelial cells were morphologically regular in the non‐diseased control group. Desmosomes and tonofibrils were reduced and the nucleus was morphologically irregular in the untreated premalignant lesion group. In the Xianhuayin‐treated group, the widening intercellular gap was gradually reduced, desmosomes and the cells becoming morphologically regular. No significant difference was observed between the hamsters in NS‐treated group and those in the untreated premalignant lesion group. Significant therapeutic efficacy was observed in the group receiving Xianhuayin. Xianhuayin is effective in the reversal of DMBA‐induced premalignant lesions in the buccal pouch of golden hamsters.
Calcineurin Pathway Is Required for Endothelin-1–Mediated Protection Against Oxidant Stress–Induced Apoptosis in Cardiac Myocytes
Authors: Tsuyoshi Kakita, Koji Hasegawa, Eri Iwai-Kanai, Souichi Adachi, Tatsuya Morimoto, Hiromichi Wada, Teruhisa Kawamura, Tetsuhiko Yanazume, Shigetake Sasayama
Journal: Circulation Research (2001)

Endothelin-1 (ET-1) acts not only as a growth-promoting peptide but also as a potent survival factor against myocardial cell apoptosis. However, the signaling pathways leading to myocardial cell protection by ET-1 are poorly understood. Using a culture system of primary cardiac myocytes derived from neonatal rats, we show in the present study that ET-1 almost completely blocked the hydrogen peroxide-induced increase in the percentage of TdT-mediated dUTP-biotin nick-end labeling-positive myocytes. Apoptosis inhibition by ET-1 was confirmed by cytofluorometric analysis as well as by examination of the ladder formation, morphological features, and caspase-3 cleavage. We have found that ET-1 converts the nuclear factor of activated T lymphocytes (NFATc) in cardiac myocytes into high-mobility forms and translocates cytoplasmic NFATc to the nuclei. In addition, ET-1 stimulates the interaction between NFATc and the cardiac-restricted zinc-finger protein GATA4 in these cells. The immunosuppressants cyclosporin A and FK506, which antagonize calcineurin, negated the inhibitory effect of ET-1 on apoptosis. Calcineurin activation de novo was sufficient to inhibit hydrogen peroxide-induced apoptosis. ET-1 induced the expression of an antiapoptotic protein bcl-2 in cardiac myocytes in a cyclosporin A-dependent manner, but it did not alter the expression of bax. Cyclosporin A also attenuated the ET-1-stimulated transcription of the bcl-2 gene in these cells. These findings demonstrate that the calcineurin pathway is required for the inhibitory effect of ET-1 on oxidant stress-induced apoptosis in cardiac myocytes.
American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer
Authors: Antonio C. Wolff, M. Elizabeth H. Hammond, Jared N. Schwartz, Karen L. Hagerty, D. Craig Allred, Richard J. Cote, Mitchell Dowsett, Patrick L. Fitzgibbons, Wedad M. Hanna, Amy Langer, Lisa M. McShane, Soonmyung Paik, Mark D. Pegram, Edith A. Perez, Michael F. Press, Anthony Rhodes, Catharine Sturgeon, Sheila E. Taube, Raymond Tubbs, Gail H. Vance, Marc van de Vijver, Thomas M. Wheeler, Daniel F. Hayes
Journal: Journal of Clinical Oncology (2006)

To develop a guideline to improve the accuracy of human epidermal growth factor receptor 2 (HER2) testing in invasive breast cancer and its utility as a predictive marker.
Mdm2 Promotes Systemic Lupus Erythematosus and Lupus Nephritis
Authors: Ramanjaneyulu Allam, Sufyan G. Sayyed, Onkar P. Kulkarni, Julia Lichtnekert, Hans-Joachim Anders
Journal: Journal of the American Society of Nephrology (2011)

Systemic lupus erythematosus (SLE) is a polyclonal autoimmune syndrome directed against multiple nuclear autoantigens. Although RNA and DNA seem to have identical immunostimulatory effects on systemic and intrarenal inflammation, each seems to differ with regard to the propensity to induce mitogenic effects such as lymphoproliferation. To identify potential mechanisms by which DNA specifically contributes to the pathogenesis of lupus nephritis, we stimulated cells with immunostimulatory DNA or RNA in vitro and used microarray to compare the transcriptomes of RNA- and DNA-induced genes. Immunostimulatory DNA, but not RNA, induced Mdm2, which is a negative regulator of p53. In vivo, we observed greater expression and activation of Mdm2 in the spleen and kidneys in a mouse model of lupus (MRL-Faslpr mice) than healthy controls. Treatment of MRL-Faslpr mice with the Mdm2 inhibitor nutlin-3a prevented nephritis and lung disease and significantly prolonged survival. Inhibition of Mdm2 reduced systemic inflammation and abrogated immune complex disease by suppressing plasma cells and the production of lupus autoantibodies. In addition, nutlin-3a suppressed the abnormal expansion of all T cell subsets, including CD3+CD4−CD8− T cells, which associated with attenuated systemic inflammation. However, inhibiting Mdm2 did not cause myelosuppression or affect splenic regulatory T cells, neutrophils, dendritic cells, or monocytes. Taken together, these data suggest that the induction of Mdm2 promotes the expansion of plasma cells and CD3+CD4−CD8− T cells, which cause autoantibody production and immune complex disease in MRL-Faslpr mice. Antagonizing Mdm2 may have therapeutic potential in lupus nephritis.
Extracorporeal lung assist: more than kicking a dead horse?
Authors: M. M. Hoeper, T. Welte
Journal: European Respiratory Journal (2008)

p to now, the history of extracorporeal lung support has been a tale of great expectations and even greater disappointments.In 1972, HILL et al. [1] published the first case report on the use of extracorporeal membrane oxygenation (ECMO) in a young patient who suffered from acute respiratory distress syndrome (ARDS) after trauma.At that time, mortality rates from ARDS were extremely high and thus this report was embraced with great enthusiasm.However, only 2 yrs later reality caught up when the results of a randomised controlled trial using ECMO in ARDS were published showing mortality rates of .90% in both treatment arms [2].
Dissection of the lymphokine-activated killer phenomenon. Relative contribution of peripheral blood natural killer cells and T lymphocytes to cytolysis.
Authors: J H Phillips, L L Lanier
Journal: The Journal of Experimental Medicine (1986)

In vitro culture of human peripheral blood lymphocytes in IL-2 results in the generation of cytotoxic cells that can lyse fresh and cultured solid tumor cells, as well as hematopoietic tumor cell lines, without deliberate immunization or MHC restriction. This has been referred to as the lymphokine activated killer (LAK) phenomenon. Here, we show that the majority of this activity is mediated by NK cells that express the Leu-19 (NKH-1) antigen, but do not express CD3. The precursor of this effector population also expressed the phenotype CD3-, Leu-19+. Peripheral blood CD3+ T lymphocytes contributed little to the LAK phenomenon, although low levels of non-MHC restricted cytotoxicity against hematopoietic tumor cell targets were mediated by a subset of CD3+ T lymphocytes that coexpressed the Leu-19 antigen. These studies clearly indicated that the LAK phenomenon is not mediated by a unique LAK cell, but is mediated mainly by IL-2-activated peripheral blood NK cells.
Amide proton transfer imaging of adult diffuse gliomas: correlation with histopathological grades
Authors: O. Togao, T. Yoshiura, J. Keupp, A. Hiwatashi, K. Yamashita, K. Kikuchi, Y. Suzuki, S. O. Suzuki, T. Iwaki, N. Hata, M. Mizoguchi, K. Yoshimoto, K. Sagiyama, M. Takahashi, H. Honda
Journal: Neuro-Oncology (2013)

Amide proton transfer (APT) imaging is a novel molecular MRI technique to detect endogenous mobile proteins and peptides through chemical exchange saturation transfer. We prospectively assessed the usefulness of APT imaging in predicting the histological grade of adult diffuse gliomas.Thirty-six consecutive patients with histopathologically proven diffuse glioma (48.1 ± 14.7 y old, 16 males and 20 females) were included in the study. APT MRI was conducted on a 3T clinical scanner and was obtained with 2 s saturation at 25 saturation frequency offsets ω = -6 to +6 ppm (step 0.5 ppm). δB0 maps were acquired separately for a point-by-point δB0 correction. APT signal intensity (SI) was defined as magnetization transfer asymmetry at 3.5 ppm: magnetization transfer ratio (MTR)asym = (S[-3.5 ppm] - S[+3.5 ppm])/S0. Regions of interest were carefully placed by 2 neuroradiologists in solid parts within brain tumors. The APT SI was compared with World Health Organization grade, Ki-67 labeling index (LI), and cell density.The mean APT SI values were 2.1 ± 0.4% in grade II gliomas (n = 8), 3.2 ± 0.9% in grade III gliomas (n = 10), and 4.1 ± 1.0% in grade IV gliomas (n = 18). Significant differences in APT intensity were observed between grades II and III (P < .05) and grades III and IV (P < .05), as well as between grades II and IV (P < .001). There were positive correlations between APT SI and Ki-67 LI (P = .01, R = 0.43) and between APT SI and cell density (P < .05, R = 0.38). The gliomas with microscopic necrosis showed higher APT SI than those without necrosis (P < .001).APT imaging can predict the histopathological grades of adult diffuse gliomas.
Cognitive Outcomes Following Contemporary Treatment Without Cranial Irradiation for Childhood Acute Lymphoblastic Leukemia
Authors: H. M. Conklin, K. R. Krull, W. E. Reddick, D. Pei, C. Cheng, C. H. Pui
Journal: JNCI Journal of the National Cancer Institute (2012)

Treatment of acute lymphoblastic leukemia (ALL) has included the use of prophylactic cranial irradiation in up to 20% of children with high-risk disease despite known cognitive risks of this treatment modality.Patients enrolled on the St Jude ALL Total Therapy Study XV, which omitted prophylactic cranial irradiation in all patients, were assessed 120 weeks after completion of consolidation therapy (n = 243) using a comprehensive cognitive battery. χ(2) analysis was used to compare the percentage of below-average performers among the entire ALL patient group to the expected rate based on the normative sample. Univariate logistic regression was used to estimate the effect of intensity of chemotherapy (treatment arm), age at diagnosis, and sex on the probability of below-average performance. All statistical tests were two-sided.Overall, the ALL group had a statistically significantly higher risk for below-average performance on a measure of sustained attention (67.31% more than 1 SD below the normative mean for omission errors, P < .001) but not on measures of intellectual functioning, academic skills, or memory. Patients given higher intensity chemotherapy were at greater risk for below-average performance compared with those given lower intensity therapy on measures of processing speed (27.14% vs 6.25%, P = .009) and academic abilities (Math Reasoning: 18.60% vs 3.90%, P = .008; Word Reading: 20.00% vs 2.60%, P = .007; Spelling: 27.91% vs 3.90%, P = .001) and had higher parent-reported hyperactivity (23.00% vs 9.84%, P = .018) and learning problems (35.00% vs 16.39%, P = .005). Neither age at diagnosis nor sex was associated with risk for below-average cognitive performance.Omitting cranial irradiation may help preserve global cognitive abilities, but treatment with chemotherapy alone is not without risks. Caregiver education and development of interventions should address both early attention deficits and cognitive late effects.
Recommendations for Management of Diabetes During Ramadan
Authors: Monira Al-Arouj, Radhia Bouguerra, John Buse, Sherif Hafez, Mohamed Hassanein, Mahmoud Ashraf Ibrahim, Faramarz Ismail-Beigi, Imad El-Kebbi, Oussama Khatib, Suhail Kishawi, Abdulrazzaq Al-Madani, Aly A. Mishal, Masoud Al-Maskari, Abdalla Ben Nakhi, Khaled Al-Rubean
Journal: Diabetes Care (2005)

It is estimated that there are 1.1–1.5 billion Muslims worldwide, comprising 18–25% of the world population (1,2). Fasting during Ramadan, a holy month of Islam, is an obligatory duty for all healthy adult Muslims. An ∼4.6% prevalence of diabetes worldwide (3) coupled with the results of the population-based Epidemiology of Diabetes and Ramadan 1422/2001 (EPIDIAR) study, which showed (in 12,243 people with diabetes from 13 Islamic countries) that ∼43% of patients with type 1 diabetes and ∼79% of patients with type 2 diabetes fast during Ramadan (4), lead to the estimation that some 40–50 million people with diabetes worldwide fast during Ramadan.

Ramadan is a lunar-based month, and its duration varies between 29 and 30 days. Its timing changes with respect to seasons. Depending on the geographical location and season, the duration of the daily fast may range from a few to more than 20 h. Muslims who fast during Ramadan must abstain from eating, drinking, use of oral medications, and smoking from predawn to after sunset; however, there are no restrictions on food or fluid intake between sunset and dawn. Most people consume two meals per day during this month, one after sunset, referred to in Arabic as Iftar (breaking of the fast meal), and the other before dawn, referred to as Suhur (predawn). Fasting is not meant to create excessive hardship on the Muslim individual. The Koran specifically exempts the sick from the duty of fasting (Holy Koran, Al-Bakarah, 183–185), especially if fasting might lead to harmful consequences for the individual. Patients with diabetes fall under this category because their chronic metabolic disorder may place them at high risk for various complications if the pattern and amount of their meal and fluid intake is markedly altered. This exemption represents more than a simple permission not to …
Dramatic impact of using protective equipment on the level of hurling-related head injuries: an ultimately successful 27-year programme
Authors: Patrick J Crowley, Michael J Crowley
Journal: British Journal of Sports Medicine (2013)

Major head injuries are not uncommon in the Irish national game of hurling. Historically, helmets were not worn.We report a multistage campaign to facilitate and encourage the use of appropriate headgear among the estimated 100 000 hurling players in Ireland. This campaign lasted for 27 years between 1985 and 2012, and involved a number of different stages including: (1) facilitating the establishment of a business dedicated to developing head protection equipment suitable for hurling, (2) placing a particular emphasis on continual product enhancement to the highest industrial standards, (3) engaging continually with the game's controlling body, the Gaelic Athletic Association (GAA), with the ultimate objective of securing a mandatory usage policy for protective helmets and faceguards, (4) longitudinal research to monitor hurling injury, equipment usage and players' attitudes and (5) widely communicating key research findings to GAA leaders and members, as well as to 1000 clubs and schools.One of our three relevant studies included 798 patients and identified a dramatic association between the type of head protection used by a player, if any, and the site of the injury requiring treatment. While 51% of the injured players without head protection suffered head trauma, this rate was only 35% among the players wearing helmets and 5% among players who were wearing full head protection (both a helmet and faceguard).The GAA responded in three stages to the accumulating evidence: (1) they introduced a mandatory regulation for those aged less than 18 years in 2005; (2) this ruling was extended to all players under 21 years in 2007 and (3) finally extended to all players irrespective of age, gender or grade from January 2010. The latter ruling applied to both games and organised training sessions.
Plasma adiponectin and leptin levels in Japanese patients with psoriasis
Authors: H. Takahashi, H. Tsuji, I. Takahashi, Y. Hashimoto, A. Ishida-Yamamoto, H. Iizuka
Journal: British Journal of Dermatology (2008)

Journal Article Plasma adiponectin and leptin levels in Japanese patients with psoriasis Get access H. Takahashi, H. Takahashi Department of Dermatology, Asahikawa Medical College, 2‐1‐1‐1 Midorigaokahigashi, Asahikawa 078‐8510, Japan E‐mail: ht@asahikawa‐med.ac.jp Search for other works by this author on: Oxford Academic Google Scholar H. Tsuji, H. Tsuji Department of Dermatology, Asahikawa Medical College, 2‐1‐1‐1 Midorigaokahigashi, Asahikawa 078‐8510, Japan E‐mail: ht@asahikawa‐med.ac.jp Search for other works by this author on: Oxford Academic Google Scholar I. Takahashi, I. Takahashi Department of Dermatology, Asahikawa Medical College, 2‐1‐1‐1 Midorigaokahigashi, Asahikawa 078‐8510, Japan E‐mail: ht@asahikawa‐med.ac.jp Search for other works by this author on: Oxford Academic Google Scholar Y. Hashimoto, Y. Hashimoto Department of Dermatology, Asahikawa Medical College, 2‐1‐1‐1 Midorigaokahigashi, Asahikawa 078‐8510, Japan E‐mail: ht@asahikawa‐med.ac.jp Search for other works by this author on: Oxford Academic Google Scholar A. Ishida‐Yamamoto, A. Ishida‐Yamamoto Department of Dermatology, Asahikawa Medical College, 2‐1‐1‐1 Midorigaokahigashi, Asahikawa 078‐8510, Japan E‐mail: ht@asahikawa‐med.ac.jp Search for other works by this author on: Oxford Academic Google Scholar H. Iizuka H. Iizuka Department of Dermatology, Asahikawa Medical College, 2‐1‐1‐1 Midorigaokahigashi, Asahikawa 078‐8510, Japan E‐mail: ht@asahikawa‐med.ac.jp Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 159, Issue 5, 1 November 2008, Pages 1207–1208, https://doi.org/10.1111/j.1365-2133.2008.08823.x Published: 01 November 2008
Hodgkin's disease in 92 patients with HIV infection: The Italian experience
Authors: U. Tirelli, D. Errante, E. Vaccher, L. Repetto, G. Rizzardini, M. Spina, R. Gastaldi, G. Bertola, D. Serraino, A. Carbone, S. Monfardini
Journal: Annals of Oncology (1992)