tbuckley/cabot-search huggingface dataset:
Microvesicles and exosomes for intracardiac communication
Authors: Joost P.G. Sluijter, Vera Verhage, Janine C. Deddens, Frederieke van den Akker, Pieter A. Doevendans
Journal: Cardiovascular Research (2014)

The heart is an organ with a complex mixture of well-organized interactions of different cell types that facilitate proper myocardial contractility, sufficient perfusion, balanced myocardial extracellular stiffness, and controlled functioning of the immune system. Several cell types, including cardiomyocytes, endothelial cells, smooth muscle cells, fibroblasts, immune cells, and cardiac-derived stem cells, need a well-controlled communication system to use the complex orchestra of signalling molecules. The intercellular communication includes direct cell–cell contact, cell–matrix interaction, long-range signals, and electrical and extracellular chemical molecules. In addition to the extracellular molecules that cells can use to influence their environment, more and more attention is focused on the release of extracellular membrane vesicles by cells. These vesicles were always thought to be cell debris derivatives, but it appeared that these vesicles are used for horizontal transfer of information between cells, containing proteins, peptides, several classes of RNA molecules, and sometimes DNA. The main populations of released vesicles are classified on their (intra)cellular origin and include apoptotic bodies, microvesicles, and exosomes. Here, we provide an overview on the role of vesicles in cardiac communication and their use as potential therapeutics and biomarkers.
Supervised walking training improves maximum and pain-free walking distances in people with intermittent claudication
Authors: Sandeep Gupta, Mark R Elkins
Journal: British Journal of Sports Medicine (2013)

People with peripheral arterial disease may experience symptoms of limb ischaemia. When this occurs with walking and ceases upon rest, it is termed intermittent claudication. Symptoms of limb ischaemia can range from aches, cramps, numbness or, more commonly, pain. These symptoms can manifest anywhere in the lower limb, although the most common site is the calf muscle due to insufficient patency of the superficial femoral artery.1 ,2 In addition, these symptoms limit walking capacity (speed and distance) and in turn lower the quality of life.3 ,4 Whether symptomatic or not, peripheral arterial disease is also associated with an increased risk of cardiovascular and cerebrovascular events, death, as well as accelerated rates of bone loss and increased fracture risk.1 ,5

Several types of intervention (often in combination) are used to improve walking capacity, including medication, surgery and exercise training.1 Previous systematic reviews have established that supervised progressive exercise training can improve both maximum and pain-free walking distances, and that it is more effective in this regard than unsupervised exercise training6 and usual care or placebo.7 Although the effect of supervision is therefore clear, less is known about the influence of factors such as the duration of the training, whether the walking is done on a treadmill, and what pain threshold, if any, is used to determine when to stop walking.8 A systematic review of randomised trials comparing exercise regimens that differ by one of these factors is being undertaken.8 Until this is complete, a less direct estimate …
The Cytokine TWEAK Modulates Renal Tubulointerstitial Inflammation
Authors: Ana Belen Sanz, Pilar Justo, Maria Dolores Sanchez-Nin[Combining Tilde]o, Luis Miguel Blanco-Colio, Jeffrey A. Winkles, Matthias Kreztler, Aniela Jakubowski, Julia Blanco, Jesús Egido, Marta Ruiz-Ortega, Alberto Ortiz
Journal: Journal of the American Society of Nephrology (2008)

TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily of cytokines. In addition to binding and activating the fibroblast growth factor–inducible 14 receptor, TWEAK may regulate apoptosis, proliferation, and inflammation; however, the role of this system in kidney injury is unknown. In vitro, it was found that TWEAK induced the sustained activation of NF-κB in a murine tubular epithelial cell line (MCT). NF-κB activation was associated with degradation of IκB-α; translocation of RelA to the nucleus; and increased mRNA and protein expression of monocyte chemoattractant protein-1, RANTES, and IL-6. Similarly, in vivo, the systemic administration of TWEAK induced renal NF-κB activation, chemokine and IL-6 expression, and interstitial inflammation in mice. Parthenolide, which prevents IκB-α degradation, inhibited TWEAK-induced NF-κB activation and prevented the aforementioned changes in vitro and in vivo. After folic acid–induced acute kidney injury, fibroblast growth factor–inducible 14 expression increased in mouse tubular epithelium. Neutralization of TWEAK decreased the expression of chemokines in tubular cells and reduced interstitial inflammation. In conclusion, TWEAK has NF-κB–dependent proinflammatory effects on tubular epithelial cells in vitro and in vivo. Moreover, blockade of TWEAK reduces tubular chemokine expression and macrophage infiltration, suggesting that TWEAK modulates acute kidney injury by regulating the inflammatory response.
Phobic Anxiety Is Associated With Higher Serum Concentrations of Adipokines and Cytokines in Women With Diabetes
Authors: Aoife M. Brennan, Jessica L. Fargnoli, Catherine J. Williams, Tricia Li, Walter Willett, I. Kawachi, Lu Qi, Frank B. Hu, Christos S. Mantzoros
Journal: Diabetes Care (2009)

OBJECTIVE Phobic anxiety has been associated with increased risk of cardiovascular disease (CVD), but the underlying mechanisms are poorly understood. We aimed to determine whether associations of phobic anxiety with several known markers of CVD might be contributors. RESEARCH DESIGN AND METHODS We used a 16-point validated index (Crown-Crisp) measured in 1988 to categorize 984 women with type 2 diabetes from the Nurses' Health Study as having low, moderate, or high phobic anxiety. Groups were then compared for differences in adipokines (adiponectin and leptin), inflammatory markers (C-reactive protein and tumor necrosis factor [TNF]-α receptor II), and markers of endothelial function (sE-selectin, soluble intercellular adhesion molecule [sICAM]-1) measured on blood samples provided between 1989 and 1990. RESULTS Higher levels of phobic anxiety were associated with higher BMI and lower education. Higher levels of phobic anxiety were also associated with higher leptin and soluble TNF-α receptor II in both crude analyses and after adjustment for potential confounders. sICAM and sE-selectin were higher in the highest tertile compared with the middle tertile, but there was no significant trend across tertiles. We found no association between phobic anxiety and adiponectin. CONCLUSIONS High levels of phobic anxiety are associated with increased levels of leptin and inflammatory markers, which may in part explain the previously observed relationship between anxiety and other psychosocial disorders with CVD.
S129 Neutrophil function and advancing age: the effects of Simvastatin in health and during pneumonia
Authors: E. Sapey, H. Greenwood, J. Hazeldine, G. Walton, D. Thickett, J. M. Lord, R. A. Stockley
Journal: Thorax (2011)

<h3>Background</h3> Age is associated with a decline in immunity, including neutrophil function. This may partially explain the worsening clinical outcomes seen following pneumonia in the elderly. Statins may improve outcomes from pneumonia although it is unknown whether they influence neutrophil function at conventional therapeutic concentrations. This is crucial, as statins may be beneficial adjuvants during infections. <h3>Methods</h3> We studied the effect of 5 ng/ml Simvastatin (equivalent to 80 mg orally) on key neutrophil functions: speed and accuracy of migration using time-lapse imaging (μm/min), Neutrophil Extracellular Trap formation using cell-impermeable DNA-binding dye (in AFU) and generation of reactive oxygen species (ROS, in RLU). <h3>Results</h3> We studied 70 healthy subjects (aged 20–90 years, 10 in each decennial) and 6 young (&lt;35 years) and 6 older (&gt;65 years) patients during an admission with pneumonia. All studied neutrophil functions declined with age (eg, neutrophil chemotaxis, r =−0.7, p&lt;0.001). Specifically, average neutrophil chemotaxis for subjects &gt;65 yrs was 0.72 μm/min (SD ± 0.28, p&lt;0.001) slower than subjects &lt;35. These neutrophils produced less NETS (average difference =−1725AFU±283, p=0.007) and peak ROS (average difference −117RLU±31; p=0.04). Neutrophils from young patients with pneumonia displayed an up-regulation of function that was not seen in older pneumonia patients. There were no age-associated differences in the surface expression of chemo-attractant receptors, but there appears to be differential intracellular signalling with reduced expression of adhesion molecules. Incubating neutrophils from older subjects with Simvastatin improved all functions back to that seen in young subjects (chemotactic speed + 0.92 μm/min ±0.27, p=0.001: NET + 1386AFU±273, p=0.04: ROS +223RLU±39, p=0.005). Similar improvements were seen with neutrophils from older subjects with pneumonia. This was a dose-dependent phenomenon; not seen at higher concentrations of Simvastatin. <h3>Conclusion</h3> With age, there is a global deterioration in neutrophil function and no up-regulation when pneumonia is present, which may partially explain the age-associated mortality. Simvastatin up-regulates neutrophil function in the elderly, even during pneumonia. This up-regulation may explain the beneficial effects seen clinically. In vivo studies are warranted, to determine if simvastatin should be utilised during episodes of acute infection.
Adiponectin Promotes Monocyte-to-Fibroblast Transition in Renal Fibrosis
Authors: Jun Yang, Song-Chang Lin, Gang Chen, Liqun He, Zhaoyong Hu, Lawrence Chan, JoAnn Trial, Mark L. Entman, Yanlin Wang
Journal: Journal of the American Society of Nephrology (2013)

Bone marrow–derived fibroblasts may contribute substantially to the pathogenesis of renal fibrosis through the excessive production and deposition of extracellular matrix. However, the mechanisms underlying the accumulation and activation of these fibroblasts are not understood. Here, we used a mouse model of tubulointerstitial fibrosis to determine whether adiponectin, which is elevated in CKD and is associated with disease progression, regulates monocyte-to-fibroblast transition and fibroblast activation in injured kidneys. In wild-type mice, the expression of adiponectin and the number of bone marrow–derived fibroblasts in the kidney increased after renal obstruction. In contrast, the obstructed kidneys of adiponectin-knockout mice had fewer bone marrow–derived fibroblasts. Adiponectin deficiency also led to a reduction in the number of myofibroblasts, the expression of profibrotic chemokines and cytokines, and the number of procollagen-expressing M2 macrophages in injured kidneys. Consistent with these findings, adiponectin-deficiency reduced the expression of collagen I and fibronectin. Similar results were observed in wild-type and adiponectin-knockout mice after ischemia-reperfusion injury. In cultured bone marrow–derived monocytes, adiponectin stimulated the expression of α-smooth muscle actin (SMA) and extracellular matrix proteins and activated AMP-activated protein kinase (AMPK) in a time- and dose-dependent manner. Furthermore, specific activation of AMPK increased the expression of α-SMA and extracellular matrix proteins, while inhibition of AMPK attenuated these responses. Taken together, these findings identify adiponectin as a critical regulator of monocyte-to-fibroblast transition and renal fibrosis, suggesting that inhibition of adiponectin/AMPK signaling may represent a novel therapeutic target for fibrotic kidney disease.
A society without an obvious future: can elitism help? Presidential address before the 71st annual meeting of the American Society for Clinical Investigation, Washington, D.C., 5 May 1979.
Authors: K L Melmon
Journal: Journal of Clinical Investigation (1979)

Addressing an alert group of scientists is a privilege, even if the topic of discussion will only be about science rather than investigation per se.Although I was eager to pursue this challenge, I wondered if any topic that was not centered on stimulating clinical investigation, cell biology, receptors, molecular biol- ogy, or recombinant DNA would be met with in- difference by a group such as ours.My answer was no, it would not.Our interests are catholic and varied.Still, we consistently ask others to protect us.Although we pride ourselves on application of philosophical logic to develop new knowledge, we rarely use it to defend any but the most direct or the most obtuse threats to the provision of the wherewithal to perform science.When a few of us reach out beyond the laboratory to apply the scientific method to literary, sociologic, or ecologic concerns, we frequently scorn the postulates or dismiss the efforts and premises of such outliers.Much as we might want to isolate ourselves from the real world, it continually intrudes upon our precious privacy.The plight of the medical scientist at Stanford University working without an academi- cally oriented administration was recently depicted in Science (1).The research enterprise is now being described by some as an obviously "bankrupt or- ganization."We are all aware that the number and
Natural History of Rising Serum Prostate-Specific Antigen in Men With Castrate Nonmetastatic Prostate Cancer
Authors: Matthew R. Smith, Fairooz Kabbinavar, Fred Saad, Arif Hussain, Marc C. Gittelman, David L. Bilhartz, Chris Wynne, Robin Murray, Norman R. Zinner, Claude Schulman, Ronald Linnartz, Ming Zheng, Carsten Goessl, Yong-Jiang Hei, Eric J. Small, Richard Cook, Celestia S. Higano
Journal: Journal of Clinical Oncology (2005)

Purpose To describe the natural history of nonmetastatic prostate cancer and rising prostate-specific antigen (PSA) despite androgen deprivation therapy. Patients and Methods: The 201 patients in this report were the placebo control group from an aborted randomized controlled trial to evaluate the effects of zoledronic acid on time to first bone metastasis in men with prostate cancer, no bone metastases, and rising PSA despite androgen deprivation therapy. Relationships between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were baseline PSA, Gleason sum, history of bilateral orchiectomies, regional lymph node metastases at diagnosis, prior prostatectomy, time from androgen deprivation therapy to random assignment, time from diagnosis to random assignment, and PSA velocity. Results At 2 years, 33% of patients had developed bone metastases. Median bone metastasis–free survival was 30 months. Median time to first bone metastases and overall survival were not reached. Baseline PSA level greater than 10 ng/mL (relative risk, 3.18; 95% CI, 1.74 to 5.80; P &lt; .001) and PSA velocity (4.34 for each 0.01 increase in PSA velocity; 95% CI, 2.30 to 8.21; P &lt; .001) independently predicted shorter time to first bone metastasis. Baseline PSA and PSA velocity also independently predicted overall survival and metastasis-free survival. Other covariates did not consistently predict clinical outcomes. Conclusion Men with nonmetastatic prostate cancer and rising PSA despite androgen deprivation therapy have a relatively indolent natural history. Baseline PSA and PSA velocity independently predict time to first bone metastasis and survival.
The Influence of Bacille Calmette-Guérin Vaccine Strain on the Immune Response against Tuberculosis
Authors: Nicole Ritz, Binita Dutta, Susan Donath, Dan Casalaz, Tom G. Connell, Marc Tebruegge, Roy Robins-Browne, Willem A. Hanekom, Warwick J. Britton, Nigel Curtis
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Approximately 100 million doses of bacille Calmette-Guérin (BCG) vaccine are given each year to protect against tuberculosis (TB). More than 20 genetically distinct BCG vaccine strains are in use worldwide. Previous studies suggest that BCG vaccine strain influences the immune response and protection against TB. Current data on which BCG vaccine strain induces the optimal immune response in humans are insufficient.To compare the immune response to three different BCG vaccine strains given to infants at birth.Newborn infants in a tertiary women's hospital were immunized at birth with one of three BCG vaccine strains. A stratified randomization according to the mother's region of birth was used.The presence of mycobacterial-specific polyfunctional CD4 T cells measured by flow cytometry 10 weeks after immunization. Of the 209 infants immunized, data from 164 infants were included in the final analysis (BCG-Denmark, n = 54; BCG-Japan, n = 54; BCG-Russia, n = 57). The proportion of polyfunctional CD4 T cells was significantly higher in infants immunized with BCG-Denmark (0.013%) or BCG-Japan (0.016%) than with BCG-Russia (0.007%) (P = 0.018 and P = 0.003, respectively). Infants immunized with BCG-Japan had higher concentrations of secreted Th1 cytokines; infants immunized with BCG-Denmark had higher proportions of CD107-expressing cytotoxic CD4 T cells.There are significant differences in the immune response induced by different BCG vaccine strains in newborn infants. Immunization with BCG-Denmark or BCG-Japan induced higher frequencies of mycobacterial-specific polyfunctional and cytotoxic T cells and higher concentrations of Th1 cytokines. These findings have potentially important implications for global antituberculosis immunization policies and future tuberculosis vaccine trials.
Degradation of the epidermal-dermal junction by proteolytic enzymes from human skin and human polymorphonuclear leukocytes.
Authors: R A Briggaman, N M Schechter, J Fraki, G S Lazarus
Journal: The Journal of Experimental Medicine (1984)

The degradation of normal human skin by the human polymorphonuclear leukocyte proteinases cathepsin G and elastase, and by a human skin chymotrypsin-like proteinase that appears to be a mast cell constituent, was examined. Enzymes were incubated with fresh, split-thickness skin for up to 8 h; the tissue was examined ultrastructurally and immunohistochemically using antibodies to known basement membrane constituents. In all cases, the primary damage observed was at the epidermal-dermal junction. Elastase degraded the lamina densa leaving scattered and disorganized anchoring fibrils, dermal microfibril bundles, and normal-appearing collagen fibers. Immunohistochemically, type IV collagen, laminin, KF1 antigen, and EBA antigen were absent. The bullous pemphigoid antigen was present and localized on the basal cells. Epidermal-dermal separation produced by the chymotrypsin-like proteinases, cathepsin G, and the human skin proteinase, was confined to the lamina lucida. The lamina densa and sub-lamina densa fibrillar network remained intact. The human skin chymotrypsin-like proteinase produced extensive epidermal-dermal separation, while cathepsin G, at comparable concentrations, produced only focal separations. Immunohistochemically, all antigens were present after incubation with enzyme. The bullous pemphigoid antigen, however, was found on the epidermal side of the split, while laminin was found on the dermal side. These results show that the epidermal-dermal junction is highly susceptible to neutral serine proteinases located in mast cells and polymorphonuclear leukocytes. Although all the proteinases produce epidermal-dermal separation, the patterns and extent of degradation are different. The distinctive patterns of degradation may provide a clue to the involvement of these proteinases in skin diseases.
Chemokine Receptor Polymorphism and Risk of Acute Rejection in Human Renal Transplantation
Authors: Reza Abdi, Tran Thi Bich Huong, Alfredo Sahagun-Ruiz, Philip M. Murphy, Barry M. Brenner, Edgar L. Milford, David H. McDermott
Journal: Journal of the American Society of Nephrology (2002)

Chemokines regulate the trafficking of leukocytes in immunity and inflammation and have been implicated in mouse models in acute cardiac and renal allograft rejection; however, their significance to human transplantation is not yet defined. The association of human chemokine receptor genetic variants, CCR5-Delta32, CCR5-59029-A/G, CCR2-V64I, CX3CR1-V249I, and CX3CR1-T280M, with outcome in 163 renal transplant recipients was examined here. Significant reductions were found in risk of acute renal transplant rejection in recipients who possessed the CCR2-64I allele (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.12 to 0.78; P = 0.014) or who were homozygous for the 59029-A allele (OR, 0.37; 95% CI, 0.16 to 0.85; P = 0.016). There were no significant differences in the incidence of rejection among patients stratified as with or without CCR5-Delta32 or by the CX3CR1-V249I or CX3CR1-T280M genotypes. Adjustment for known risk factors for transplant rejection confirmed the univariate findings for possession of the CCR2-64I allele (OR, 0.20; P = 0.032) and homozygosity for the 59029-A allele (OR, 0.26; P = 0.027). It was concluded that the risk of acute rejection in renal transplantation is associated with genetic variation in the chemokine receptors CCR2 and CCR5.
"Why don't you sue?"
Authors: Y Lindsay
Journal: BMJ (1994)

Our daughter was born with spina bifida. She has a large lumbosacral myelomeningocele with an associated neuropathic bladder, patulous anus, and neurological deficits of her legs. Fortunately the lesion is closed with excellent skin cover and Emily shows no signs, as yet, of developing hydrocephalus.

We were not expecting our first child to be born in anything other than perfect health. I had done all the right things, including taking folic acid supplements as had just been recommended by the Department of Health when we were planning the pregnancy. We have no family history of neural tube defects and I had had an uncomplicated antenatal period. My husband, who was working in France at the time, returned home to be at my side when I went for my routine 20 week ultrasound scan, our discussed intention being that he could be with me for a termination of pregnancy if the worst happened.

The worst did not happen then. Normal vertebrae, normal kidneys, we were told, so off we went happily to await the …
Initial Treatment of Immune Thrombocytopenic Purpura with High-Dose Dexamethasone
Authors: Yunfeng Cheng, Raymond S.M. Wong, Yannie O.Y. Soo, Chung Hin Chui, Fung Yi Lau, Natalie P.H. Chan, Wai Shan Wong, Gregory Cheng
Journal: New England Journal of Medicine (2003)

The role of high-dose dexamethasone in the treatment of immune thrombocytopenic purpura in adults is controversial. We assessed the effectiveness of high-dose dexamethasone as initial treatment in a series of consecutive adults with immune thrombocytopenic purpura.