tbuckley/cabot-search huggingface dataset:
Localization and Functional Characterization of Glycosaminoglycan Domains in the Normal Human Kidney as Revealed by Phage Display-Derived Single Chain Antibodies
Authors: Joost F.M. Lensen, Angelique L.W.M.M. Rops, Tessa J.M. Wijnhoven, Theo Hafmans, Wouter F.J. Feitz, Egbert Oosterwijk, Bernhard Banas, René J.M. Bindels, Lambert P.W.J. van den Heuvel, Johan van der Vlag, Jo H.M. Berden, Toin H. van Kuppevelt
Journal: Journal of the American Society of Nephrology (2005)

Glycosaminoglycans (GAG) play an important role in renal homeostasis. They are strongly negatively charged polysaccharides that bind and modulate a myriad of proteins, including growth factors, cytokines, and enzymes. With the aid of specific phage display-derived antibodies, the distribution of heparan sulfate (HS) and chondroitin sulfate (CS) domains in the normal human kidney was studied. HS domains were specifically located in basement membranes and/or surfaces of renal cells and displayed a characteristic distribution over the nephron. A characteristic location in specific parts of the tubular system was also observed. CS showed mainly an interstitial location. Immunoelectron microscopy indicated specific ultrastructural location of domains. Only partial overlap with any of seven different proteoglycan core proteins was observed. Two HS domains, one highly sulfated (defined by antibody HS4C3) and one low sulfated (defined by antibody RB4Ea12), were studied for their cell biologic relevance with respect to the proliferative effect of FGF-2 on human mesangial cells in vitro. Fibroblast growth factor 2 (FGF-2) binding was HS dependent. Addition of purified HS4C3 antibody but not of the RB4Ea12 antibody counteracted the binding and the proliferative effect of FGF-2, indicating that the HS4C3 domain is involved in FGF-2 handling by mesangial cells. In conclusion, specific GAG domains are differentially distributed in the normal human kidney and are likely involved in binding of effector molecules such as FGF-2. The availability of tools to identify and study relevant GAG structures allows the development of glycomimetica to halt, for instance, mesangial proliferation and matrix production as seen in diabetic nephropathy.
PI3Kα is essential for the recovery from Cre/tamoxifen cardiotoxicity and in myocardial insulin signalling but is not required for normal myocardial contractility in the adult heart
Authors: Brent A. McLean, Pavel Zhabyeyev, Vaibhav B. Patel, Ratnadeep Basu, Nirmal Parajuli, Jessica DesAulniers, Allan G. Murray, Zamaneh Kassiri, Bart Vanhaesebroeck, Gavin Y. Oudit
Journal: Cardiovascular Research (2015)

AimsGenetic mouse models have yielded conflicting conclusions about the role of PI3Kα in heart physiology: specifically, the question of whether PI3Kα has a direct role in regulating myocardial contractility. This has led to concerns that PI3K inhibitors currently in clinical trials for cancer may potentiate cardiotoxicity. Here we seek to clarify the role of PI3Kα in normal heart physiology and investigate changes in related signalling pathways.
Lymphangitis carcinomatosa complicating primary malignant peritoneal mesothelioma.
Authors: P. S. Craft, M. S. Reading, S. Jain, R. A. O'Neil
Journal: Thorax (1996)

A patient with malignant peritoneal mesothelioma and a diffuse pulmonary infiltrate is described. Computed tomographic scanning suggested lymphangitis carcinomatosa. This was confirmed on transbronchial biopsy to be due to metastatic mesothelioma.
The metabolic regulator PGC-1α links hepatitis C virus infection to hepatic insulin resistance
Authors: Amir Shlomai, Maya Mouler Rechtman, Ela Olga Burdelova, Alona Zilberberg, Sarit Hoffman, Irit Solar, Sigal Fishman, Zamir Halpern, Ella H. Sklan
Journal: Journal of Hepatology (2012)
Ethnicity and Attitudes Toward Patient Autonomy
Authors: Leslie J. Blackhall
Journal: JAMA (1995)

To study differences in the attitudes of elderly subjects from different ethnic groups toward disclosure of the diagnosis and prognosis of a terminal illness and toward end-of-life decision making.Survey.Thirty-one senior citizen centers within Los Angeles County, California.A stratified quota sample of 200 subjects aged 65 years and older self-identified as being from each of four ethnic groups: European American, African American, Korean American, or Mexican American (N = 800).Korean Americans (47%) and Mexican Americans (65%) were significantly less likely than European Americans (87%) and African Americans (88%) to believe that a patient should be told the diagnosis of metastatic cancer. Korean Americans (35%) and Mexican Americans (48%) were less likely than African Americans (63%) and European Americans (69%) to believe that a patient should be told of a terminal prognosis and less likely to believe that the patient should make decisions about the use of life-supporting technology (28% and 41% vs 60% and 65%). Instead, Korean Americans and Mexican Americans tended to believe that the family should make decisions about the use of life support. On stepwise multiple logistic regression, ethnicity was the primary factor related to attitudes toward truth telling and patient decision making.Korean-American and Mexican-American subjects were more likely to hold a family-centered model of medical decision making rather than the patient autonomy model favored by most of the African-American and European-American subjects. This finding suggests that physicians should ask their patients if they wish to receive information and make decisions or if they prefer that their families handle such matters.
Analgesia for Forceps Delivery
Authors: J. F. O'Sullivan
Journal: BMJ (1962)

Following a conversation with Professor Marples in 1961 it was realized that this fungus was the same as the one she had isolated from two patients and seven hedge- hogs (Erinaceus europaeus) in New Zealand.It was then discovered that eight of our patients had had close contact with hedgehogs prior to the onset of their erup- tions, and four had dogs which frequently caught hedgehogs; one patient could not be traced.The fungus was isolated from one hedgehog with which two patients had been in contact, from another caught by a dog belonging to a patient who had been infected two years previously, and from a third found by a family which had also been infected two years before.In four patients the eruption had a well-defined edge, typical of a ringworm infection, but in the other nine it was clinically indistinguishable from eczema.In four of the latter patients pustules were present.-Thefinger-nails were infected in two patients.It would seem likely that this dermatophyte is wide- spread in hedgehogs in this country and that hedgehogs introduced into New Zealand in 1885 were infected with it.
Clinical trials: how to cope with medical needs, ethics and timelines
Authors: Andrea Rubbert-Roth, Gerd-Rüdiger Burmester
Journal: Annals of the Rheumatic Diseases (2009)

Current strategies for the management of rheumatoid arthritis (RA) include control of rheumatoid inflammation as soon and as efficiently as possible, slowing progression of structural damage and restoring patients’ functionality while assuring short- and long-term safety.1 2

Despite the approval of tumour necrosis factor (TNF) inhibitors within the past decade and the development of biological agents with a different mode of action, new drugs are currently being developed with the goal to improve efficacy, reduce side effects or to allow a more convenient application considering the patient’s needs. There is also a clear need for efficacious drugs at lower costs than current biological treatment.

Up to now, randomised and placebo-controlled trials have formed the cornerstone of new drug development. In RA, a typical trial enrols patients for whom methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs) had previously failed, even though a precise definition of therapeutic failure is missing. Typically, patients undergo a washout period of concomitant DMARD treatment, which almost inevitably leads to a high mean baseline Disease Activity Score (DAS), that would otherwise be considered inadequate with regard to standards of care. Regulatory agencies have often required a duration of the placebo-controlled treatment phase of 24 weeks; however, more recently, trials have allowed escape rules for patients not achieving early improvement at week 16.

In this issue of the Annals of the Rheumatic Diseases , Maarten Boers concludes from his meta-analysis of trials using biological agents in RA that the time for 6-month placebo trials has now passed ( see article on page 186 ).3 His analysis is based on 20 trials including 15 placebo and 18 active control cohorts comprising more than 10 000 patients. For placebo controlled trials, he elegantly demonstrates that ACR20 and ACR50 levels clearly differ already after 3 months and the mean difference …
Risk of Suicide Among US Military Service Members Following Operation Enduring Freedom or Operation Iraqi Freedom Deployment and Separation From the US Military
Authors: Mark A. Reger, Derek J. Smolenski, Nancy A. Skopp, Melinda J. Metzger-Abamukang, Han K. Kang, Tim A. Bullman, Sondra Perdue, Gregory A. Gahm
Journal: JAMA Psychiatry (2015)

A pressing question in military suicide prevention research is whether deployment in support of Operation Enduring Freedom or Operation Iraqi Freedom relates to suicide risk. Prior smaller studies report differing results and often have not included suicides that occurred after separation from military service.To examine the association between deployment and suicide among all 3.9 million US military personnel who served during Operation Enduring Freedom or Operation Iraqi Freedom, including suicides that occurred after separation.This retrospective cohort design used administrative data to identify dates of deployment for all service members (October 7, 2001, to December 31, 2007) and suicide data (October 7, 2001, to December 31, 2009) to estimate rates of suicide-specific mortality. Hazard ratios were estimated from time-dependent Cox proportional hazards regression models to compare deployed service members with those who did not deploy.Suicide mortality from the Department of Defense Medical Mortality Registry and the National Death Index.Deployment was not associated with the rate of suicide (hazard ratio, 0.96; 99% CI, 0.87-1.05). There was an increased rate of suicide associated with separation from military service (hazard ratio, 1.63; 99% CI, 1.50-1.77), regardless of whether service members had deployed or not. Rates of suicide were also elevated for service members who separated with less than 4 years of military service or who did not separate with an honorable discharge.Findings do not support an association between deployment and suicide mortality in this cohort. Early military separation (<4 years) and discharge that is not honorable were suicide risk factors.
Discriminants of Prevalent Fractures in Chronic Kidney Disease
Authors: Thomas L. Nickolas, Serge Cremers, Amy Zhang, Valeri Thomas, Emily Stein, Adi Cohen, Ryan Chauncey, Lucas Nikkel, Michael T. Yin, Xiaowei S. Liu, Stephanie Boutroy, Ronald B. Staron, Mary B. Leonard, Donald J. McMahon, Elzbieta Dworakowski, Elizabeth Shane
Journal: Journal of the American Society of Nephrology (2011)

Patients with chronic kidney disease (CKD) have higher rates of fracture than the general population. Increased bone remodeling, leading to microarchitectural deterioration and increased fragility, may accompany declining kidney function, but there are no reliable methods to identify patients at increased risk for fracture. In this cross-sectional study of 82 patients with predialysis CKD, high-resolution imaging revealed that the 23 patients with current fractures had significantly lower areal density at the femoral neck; total, cortical, and trabecular volumetric bone density; cortical area and thickness; and trabecular thickness. Compared with levels in the lowest tertile, higher levels of osteocalcin, procollagen type-1 N-terminal propeptide, and tartrate-resistant acid phosphatase 5b were associated with higher odds of fracture, even after adjustment for femoral neck T-score. Discrimination of fracture prevalence was best with a femoral neck T-score of -2.0 or less and a value in the upper two tertiles for osteocalcin, procollagen type-1 N-terminal propeptide, or tartrate-resistant acid phosphatase 5b; these values corresponded to the upper half of the normal premenopausal reference range. In summary, these cross-sectional data suggest that measurement of bone turnover markers may increase the diagnostic accuracy of densitometry to identify patients with CKD at high risk for fracture.
Effect of Stream Velocity on Bacterial Deposition and Growth
Authors: S. Rodbard, C. Yamamoto
Journal: Cardiovascular Research (1969)

Interrelations between channel and stream were analysed by using bacteria as indicator cells. At sites of laminar flow, bacteria were not deposited on the wall. At sites of turbulence, many bacteria were deposited and growth was facilitated. However, high stream velocities inhibited growth.
Working in swine-confinement buildings causes an accelerated decline in FEV1: a 7-yr follow-up of Danish farmers
Authors: M. Iversen, R. Dahl
Journal: European Respiratory Journal (2000)

Work in swine confinement units causes exposure to high levels of organic dust and is associated with a high prevalence of work-related respiratory symptoms and probably with accelerated decline in forced expiratory volume in one second (FEV1). A 7-yr follow-up on FEV1, forced vital capacity (FVC), bronchial reactivity, and respiratory symptoms was performed on 181 Danish farmers. The participation rate was 76.3% and nonparticipants had more symptoms, were more likely to be current-smokers and had lower lung function in the first survey than participants in both surveys. Farmers who worked exclusively with pigs in the follow-up had an accelerated decline in FEV1 but not in FVC compared with dairy farmers, where the observed decline in FEV1 was close to the expected. For a nonsmoking pig farmer compared to a nonsmoking dairy farmer the mean additional decline in FEV1 was 17 mL x yr(-1) (53.0 mL x yr(-1) versus 36.1 mL x yr(-1)). The authors conclude that working in swine confinement units causes an accelerated decline in forced expiratory volume in one second but not in forced vital capacity. The mean decline is approximately 0.5 L during a working life and some farmers will develop clinically significant airway obstruction due to work in swine confinement units.
<i>N</i>‐acetylcysteine is unlikely to reduce hospitalisation for chronic obstructive pulmonary disease
Authors: P. Ernst, S. Suissa
Journal: European Respiratory Journal (2003)

N-acetylcysteine is unlikely to reduce hospitalisation for chronic obstructive pulmonary diseaseTo the Editor:We read with interest the recent paper by GERRITS et al.[1] reporting on the effectiveness of N-acetylcysteine in reducing re-hospitalisations for chronic obstructive pulmonary disease (COPD).We are concerned, however, that the apparent benefit is actually the result of bias in study design and analysis.The paper mentions that patients were considered users if they received N-acetylcysteine "immediately" after discharge.However, we are not given the definition of "immediately" nor are we provided with the average and range of the length of time from hospital discharge to dispensing of the first prescription for N-acetylcysteine.Since follow-up time starts at discharge from hospital for all subjects, irrespective of whether they will or will not be dispensed N-acetylcysteine, there is a strong possibility of immortal time bias [2].Indeed, the time period from discharge to the first dispensing is "immortal" by definition since re-admissions could not occur during this period; if they did occur before the first prescription, the subject would have been classified as "unexposed".Moreover, this immortal time period is in fact unexposed, since the subject has not yet received the drug, but is misclassified as exposed by this approach to data analysis.Consequently, such misclassified immortal time will cause the rate of re-admission in the "unexposed" to be artificially inflated resulting in an impression of a protective rate ratio for exposure.This bias will also accentuate the apparent dose/ response effect, since the daily dose calculation uses the immortal unexposed time and also considers it as exposed.It would be useful to redo these analyses, after properly classifying exposures.
Large body size and sedentary lifestyle during childhood and early adulthood and esophageal squamous cell carcinoma in a high-risk population
Authors: A. Etemadi, A. Golozar, F. Kamangar, N.D. Freedman, R. Shakeri, C. Matthews, F. Islami, P. Boffetta, P. Brennan, C.C. Abnet, R. Malekzadeh, S.M. Dawsey
Journal: Annals of Oncology (2011)
Regulation of Interleukin-12 by Complement Receptor 3 Signaling
Authors: Thomas Marth, Brian L. Kelsall
Journal: The Journal of Experimental Medicine (1997)

Complement receptor type 3 (CR3, CD11b/CD18) serves as a receptor for a number of endogenous ligands and infectious organisms, and is involved in adhesion and host defense functions. Here, we report that signaling via CR3 plays an important role in regulating production of interleukin-12 (IL-12), a key mediator of cell-mediated immunity (CMI). We demonstrate with a variety of stimuli a dose-dependent, specific downregulation of IL-12 secretion by human monocytes in vitro after exposure to antibodies to CR3 (anti-CD11b and anti-CD18), as well as to the natural CR3 ligands, iC3b, and Histoplasma capsulatum. CR3 antibodies also suppressed interferon-γ (IFN-γ) production in cultures of human peripheral blood mononuclear cells (PBMC). We determined that one mechanism by which CR3 antibodies may suppress IL-12 production is by the inhibition of IFN-γ–induced tyrosine phosphorylation. Finally, in a murine model of IL-12–dependent septic shock, we provide evidence that administration of CR3 antibodies leads to suppression of IL-12 and IFN-γ in vivo. Our studies thus define a novel role for CR3 in regulating CMI functions via IL-12.
Iodine-131—Metaiodobenzylguanidine Double Infusion With Autologous Stem-Cell Rescue for Neuroblastoma: A New Approaches to Neuroblastoma Therapy Phase I Study
Authors: Katherine K. Matthay, Alekist Quach, John Huberty, Benjamin L. Franc, Randall A. Hawkins, Hollie Jackson, Susan Groshen, Suzanne Shusterman, Gregory Yanik, Janet Veatch, Patricia Brophy, Judith G. Villablanca, John M. Maris
Journal: Journal of Clinical Oncology (2009)

Purpose Iodine-131—metaiodobenzylguanidine ( 131 I-MIBG) provides targeted radiotherapy with more than 30% response rate in refractory neuroblastoma, but activity infused is limited by radiation safety and hematologic toxicity. The goal was to determine the maximum-tolerated dose of 131 I-MIBG in two consecutive infusions at a 2-week interval, supported by autologous stem-cell rescue (ASCR) 2 weeks after the second dose. Patients and Methods The 131 I-MIBG dose was escalated using a 3 + 3 phase I trial design, with levels calculated by cumulative red marrow radiation index (RMI) from both infusions. Using dosimetry, the second infusion was adjusted to achieve the target RMI, except at level 4, where the second infusion was capped at 21 mCi/kg. Results Twenty-one patients were enrolled onto the study at levels 1 to 4, with 18 patients assessable for toxicity and 20 patients assessable for response. Cumulative 131 I-MIBG given to achieve the target RMI ranged from 22 to 50 mCi/kg, with cumulative RMI of 3.2 to 8.92 Gy. No patient had a dose-limiting toxicity. Reversible grade 3 nonhematologic toxicity occurred in six patients at level 4, establishing the recommended cumulative dose as 36 mCi/kg. The median time to absolute neutrophil count more than 500/μL after ASCR was 13 days (4 to 27 days) and to platelet independence was 17 days (6 to 47 days). Responses included two partial responses, eight mixed responses, three stable disease, and seven progressive disease. Responses by semiquantitative MIBG score occurred in eight patients, soft tissue responses occurred in five of 11 patients, but bone marrow responses occurred in only two of 13 patients. Conclusion The lack of toxicity with this approach allowed dramatic dose intensification of 131 I-MIBG, with minimal toxicity and promising activity.
Prehypertension and Cardiovascular Disease Risk in the Women’s Health Initiative
Authors: Judith Hsia, Karen L. Margolis, Charles B. Eaton, Nanette K. Wenger, Matthew Allison, LieLing Wu, Andrea Z. LaCroix, Henry R. Black
Journal: Circulation (2007)

Background— Prehypertension is common and is associated with increased vascular mortality. The extent to which it increases risk of nonfatal myocardial infarction, stroke, and congestive heart failure is less clear. Methods and Results— We determined the prevalence of prehypertension, its association with other coronary risk factors, and the risk for incident cardiovascular disease events in 60 785 postmenopausal women during 7.7 years of follow-up using Cox regression models that included covariates as time-dependent variables. Prehypertension was present at baseline in 39.5%, 32.1%, 42.6%, 38.7%, and 40.3% of white, black, Hispanic, American Indian, and Asian women, respectively ( P &lt;0.0001 across ethnic groups). Age, body mass index, and prevalence of diabetes mellitus and hypercholesterolemia increased across blood pressure categories, whereas smoking decreased (all P &lt;0.0001). Compared with normotensive women (referent), adjusted hazard ratios for women with prehypertension were 1.58 (95% confidence interval [CI], 1.12 to 2.21) for cardiovascular death, 1.76 (95% CI, 1.40 to 2.22) for myocardial infarction, 1.93 (95% CI, 1.49 to 2.50) for stroke, 1.36 (95% CI, 1.05 to 1.77) for hospitalized heart failure, and 1.66 (95% CI, 1.44 to 1.92) for any cardiovascular event. Hazard ratios for the composite outcome with prehypertension did not differ between ethnic groups ( P =0.71 for interaction), although the numbers of events among Hispanic and Asian women were small. Conclusions— Prehypertension is common and was associated with increased risk of myocardial infarction, stroke, heart failure, and cardiovascular death in white and nonwhite postmenopausal women. Risk factor clustering was conspicuous, emphasizing the need for trials evaluating the efficacy of global cardiovascular risk reduction through primordial prevention.
Mechanisms underlying dysphagia in eosinophilic oesophagitis
Authors: S. E. Attwood
Journal: Gut (2009)

Eosinophilic oesophagitis (EO) is essentially a new disease not generally recognised in the UK or many other western European countries until early this decade. It is characterised by dysphagia, usually intermittent with a wide range of symptom severity and disruption to quality of life. The mechanism underlying the symptom of dysphagia is often not clear in EO because the changes seen at endoscopy are very variable. In this issue of Gut ( see page 1056 ), Mittal’s group from San Diego address the pathophysiology of dysphagia using endoscopic ultrasound, and their results are intriguing.1

Korsapati et al propose that the mechanism of dysphagia is through a discoordination of longitudinal muscle of the oesophagus.1 Standard manometry fails to show an abnormality of peristalsis in most patients with EO,2 and this is confirmed by Korsapati et al . They then use endoscopic ultrasound to measure the thickness (as a marker of muscle contraction) of the circular and longitudinal muscle of the oesophagus and observe its reaction to an edrophonium stress test. The combined thickness of the muscle and submucosal layers is significantly greater at rest in patients with EO compared with controls. During contractions, however, the thickness of the muscle in patients has a lower peak than in controls, indicating dysfunctional contraction. In patients with symptomatic EO suffering dysphagia, they observed that the longitudinal muscle fails to react normally, with both a weaker contraction and a time delay (asynchrony) during the edrophonium stress, whereas the circular muscle seems to be unaffected …