tbuckley/cabot-search huggingface dataset:
Mechanisms of Transmural Heparin Transport in the Rat Abdominal Aorta After Local Vascular Delivery
Authors: Mark A. Lovich, Elazer R. Edelman
Journal: Circulation Research (1995)

Local vascular drug delivery systems provide elevated concentrations in target arterial tissues, while minimizing systemic side effects. Drug can now be released to isolated arterial segments from the endovascular or perivascular aspects of the blood vessel, yet the forces that determine drug distribution and deposition for these different modes of delivery have not been rigorously investigated. This study examines mechanisms of transmural transport of a model vasoactive drug, heparin, and compares estimates of the distribution after administration from either aspect of the artery. We showed that (1) heparin traversed the arterial wall rapidly; (2) diffusion far outweighed convection in the control of transmural heparin transport in the normal artery, but after endothelial injury, convective forces rose to one quarter the magnitude of diffusive forces; (3) the endothelium posed a minimal diffusive barrier to heparin; and (4) the diffusive barrier imposed by the adventitia depended on its thickness. These findings strongly suggest that vasoregulatory compounds can be administered to target tissue by either perivascular or endovascular means with equal efficacy, because the forces governing transport of heparin from either aspect of the blood vessel wall are not significantly different. Furthermore, the differences in arterial transport properties between heparin and other macromolecules suggest that distribution and the optimal aspect of delivery will depend just as much on the physicochemical properties of the drug as the state of the blood vessel wall.
Mental health diseases are an economic burden on patients, says report
Authors: A. Gonzalez Aguirre
Journal: BMJ (2003)

A survey by the mental health charity Mind shows that 64% of people in Britain had to pay for some form of care or treatment for a diagnosed mental problem, including for prescribed and non-prescribed drugs.

The report, which is published in conjunction with Health Which? magazine, is the result of a survey of everyone in two Mind networks: MindLink and Diverse Minds. The survey was sent out in January this year and focused on the economic impact of …
The role of the faculty of sports and exercise medicine for public health and elite athlete care
Authors: Timothy D Noakes
Journal: British Journal of Sports Medicine (2009)

It is a great time to be involved in British sports after the remarkable performances of Team GB in the recent Beijing Olympic Games. You do not need to be reminded, although the rest of world must be, that in the 1996 Atlanta Olympics, UK athletes—not yet Team GB—garnered just one medal. To progress in 12 years to the current situation, in which your Olympic athletes win more than 40 medals, is an achievement equalled perhaps only by Australia and East Germany in the recent past. Indeed, the evidence I have observed and the mood I encountered suggest that the world has yet to see the peak of this British Olympic success—Team GB has the capacity to improve yet further. In the years to come, it will become apparent that however remarkable your team's performance in the Beijing Olympics, it was relatively pedestrian compared to what lies ahead at the London Olympic Games and beyond.

I must add on a personal note that the success of Team GB is profoundly important for another reason—it makes sceptics like me, who were firmly convinced that success in many Olympic sports is drug-dependent, acknowledge that perhaps we are wrong. The nation that pioneered the special concept of fair play has shown that success in Olympic competition can be achieved without compromising those traditional British values.

We need also to understand the meaning of the ceremony we are enjoying this afternoon and how it relates to this revitalisation of British sports, for the Royal College of Surgeons is one of the world's greatest citadels of intellectual wisdom applied for the benefit of all the world's peoples. That the college should consider sports medicine and exercise sciences to be sufficiently important to enjoy its patronage is simply astonishing. Those who fought for this recognition for …
Serum levels of sex steroid hormones and matrix metalloproteinases after intra-articular glucocorticoid treatment in female patients with rheumatoid arthritis
Authors: T Weitoft, A Larsson, L Rönnblom
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> To study metalloproteinase activity and sex steroid hormone production in serum after intra-articular glucocorticoid treatment for knee synovitis. <h3>Methods:</h3> 18 female patients with rheumatoid arthritis and synovitis of the knee with need for intra-articular glucocorticoid treatment were included in this study. Serum samples of matrix metalloproteinases (MMP-1/TIMP complex and MMP-3), dehydroepiandrosterone sulphate, testosterone, oestradiol, steroid hormone binding globulin, follicle stimulating hormone and luteinising hormone were collected before injection with 20 mg triamcinolone hexacetonide, and 24 h, 48 h, 1 week and 2 weeks after injection, respectively. <h3>Results:</h3> Serum levels of MMP-3 were significantly decreased, but MMP-1/TIMP complex was unaffected. Dehydroepiandrosterone sulphate, testosterone and oestradiol levels all decreased and tended to return to baseline levels during the observation period. Steroid hormone binding globulin, follicle stimulating hormone and luteinising hormone levels were unchanged. <h3>Conclusions:</h3> Intra-articular glucocorticoid treatment causes a temporary, but considerable suppression of sex steroid hormone secretion. The reduction of MMP-3 indicates an inhibition of the inflammatory, but probably also the cartilage destructive processes within the treated joint.
Smoking and reproduction: gene damage to human gametes and embryos
Authors: M. T. Zenzes
Journal: Human Reproduction Update (2000)

Assisted conception is a useful methodology for detecting disturbances in clinical outcome, meiotic maturation, and genetic integrity of human gametes. Germinal cells are vulnerable to genetic damage from smoking, but can repair damage during meiosis. In ejaculated spermatozoa, repair capacity declines drastically. Smoking alters the meiotic spindle of oocytes and spermatozoa, leading to chromosome errors which affect reproductive outcomes. Smoking is associated with reduced numbers of retrieved oocytes, leading to early age of menopause. Oocyte elimination occurs preferentially during meiosis I, a period sensitive to genetic damage. Smoking inhibits embryo fragmentation; inhibition may confer survival advantage to embryos genetically altered. Smoking is associated with low sperm quality, but clinical effects are not recognized. Cadmium (a heavy metal), nicotine (a toxic alkaloid), and its metabolite cotinine, are detectable in gonadal tissues and fluids in association with smoking. Cotinine incorporates into ovarian granulosa–lutein cells, compromising the developmental potential of follicles. Benzo[a]pyrene is a carcinogenic polycyclic aromatic hydrocarbon resulting from cigarette combustion. Its reactive metabolite binds covalently to DNA, forming adducts. Smoking-related adducts were detectable in ovarian granulosa–lutein cells, oocytes, spermatozoa and preimplantation embryos. Transmission of altered DNA from smoking by spermatozoa was demonstrated in preimplantation embryos and in association with increased risk of childhood cancer.
Clinical Implications of the Osteoprotegerin/RANKL/RANK System for Bone and Vascular Diseases
Authors: Lorenz C. Hofbauer
Journal: JAMA (2004)

Bone resorption by osteoclasts is coupled with bone formation by osteoblasts, and this balanced process continuously remodels and adapts the skeleton. The receptor activator of nuclear factor kappaB ligand (RANKL) has been identified as an essential cytokine for the formation and activation of osteoclasts. The effects of RANKL are physiologically counterbalanced by the decoy receptor osteoprotegerin (OPG). Estrogen deficiency, glucocorticoid exposure, T-cell activation (eg, rheumatoid arthritis), and skeletal malignancies (eg, myeloma, metastases) enhance the ratio of RANKL to OPG and, thus, promote osteoclastogenesis, accelerate bone resorption, and induce bone loss. Moreover, alterations of the OPG/RANKL/RANK system have been implicated in vascular diseases. RANKL blockade (using OPG or RANK fusion proteins or RANKL antibodies) has prevented bone loss caused by osteoporosis, chronic inflammatory disorders, and malignant tumors in animal models and may emerge as a therapy in humans based on studies in postmenopausal osteoporosis, myeloma bone disease, and osteolytic metastases. This review summarizes the clinical implications of the OPG/RANKL/RANK system for bone and vascular diseases.
An HIV Vaccine — Evolving Concepts
Authors: Margaret I. Johnston, Anthony S. Fauci
Journal: New England Journal of Medicine (2007)

The unique features of the human immunodeficiency virus (HIV) envelope protein have thwarted efforts to identify a protective vaccine. However, a vaccine that does not prevent infection but reduces HIV levels and preserves memory CD4+ T cells could benefit both the recipient and the community at risk. Several vaccines that induce T-cell responses are now in early clinical trials. This review summarizes the science and strategies in the search for an effective vaccine to control HIV infection.
Impaired Fibrillin-1 Function Promotes Features of Plaque Instability in Apolipoprotein E–Deficient Mice
Authors: Jozef L. Van Herck, Guido R.Y. De Meyer, Wim Martinet, Cor E. Van Hove, Kenn Foubert, Mart H. Theunis, Sandra Apers, Hidde Bult, Christiaan J. Vrints, Arnold G. Herman
Journal: Circulation (2009)

Background— Arterial stiffness has been associated with an increased cardiovascular risk. The aim of this study was to investigate the interaction between arterial stiffness and atherosclerosis. Methods and Results— Mice with a mutation (C1039G +/− ) in the fibrillin-1 gene leading to fragmentation of the elastic fibers were crossbred with apolipoprotein E–deficient (ApoE −/− ) mice. Subsequently, ApoE −/− and ApoE −/− C1039G +/− mice were fed a Western-type diet for 10 or 20 weeks. Our results show that the interaction between arterial stiffness and atherosclerosis is bidirectional. On the one hand, arterial stiffness in ApoE −/− C1039G +/− mice increased more rapidly in the presence of atherosclerotic plaques. On the other hand, arterial stiffness promoted the development of larger and more unstable plaques in ApoE −/− C1039G +/− mice. The plaque area at the aortic root was increased 1.5- and 2.1-fold in ApoE −/− C1039G +/− mice after 10 and 20 weeks of Western-type diet, respectively. After 10 weeks of Western-type diet, plaques of ApoE −/− C1039G +/− mice showed increased apoptosis of smooth muscle cells, which was associated with a decrease in collagen content, an enlargement of the necrotic core, and an increase in macrophages. After 20 weeks of Western-type diet, the number of buried fibrous caps was increased in atherosclerotic lesions of ApoE −/− C1039G +/− mice, not only at the level of the aortic valves but also in the brachiocephalic artery and in the upper, middle, and lower thoracic aorta. Furthermore, acute plaque rupture was observed. Conclusion— These results indicate that fragmentation of the elastic fibers leads to increased vascular stiffness, which promotes features of multifocal plaque instability.
Formation of Extracellular Matrix-Digesting Invadopodia by Primary Aortic Smooth Muscle Cells
Authors: Emilia Furmaniak-Kazmierczak, Scott W. Crawley, Rhonda L. Carter, Donald H. Maurice, Graham P. Côté
Journal: Circulation Research (2007)

Invasion of the subendothelial space by vascular smooth muscle cells (VSMCs) contributes to the development and progression of diverse cardiovascular diseases. In this report we show that the expression of activated versions of Src, Cdc42 and Rac1, or a kinase-dead but open form of the p21-activated kinase (PAK1), induces primary rat aorta VSMCs to form extracellular matrix-degrading actin-rich protrusions that are morphologically similar to the invadopodia formed by highly invasive tumor cells. The matrix-degrading structures are enriched in known markers for invadopodia, including cortactin and tyrosine-phosphorylated cortactin and contain the matrix metalloproteinases MMP-9 and MT1-MMP and the urokinase plasminogen activator receptor (uPAR). In contrast to other cell types, invadopodia formation in VSMCs is only weakly supported by the phorbol ester PBDu. Invadopodia formation by Src was dependent on Cdc42, Rac, and ERK, but not on p38 MAPK. Invadopodia formation induced by kinase-dead PAK1 required Src and ERK activity and a direct interaction with the exchange factor PIX. VSMCs embedded in a three-dimensional collagen matrix formed actin- and cortactin-rich extensions that penetrated through holes in the matrix, suggesting that invadopodia-like structures are formed in a three-dimensional environment.
Prognostic significance and therapeutic implications of centromere protein F expression in human nasopharyngeal carcinoma
Authors: Jing Yan Cao, Li Liu, Shu Peng Chen, Xing Zhang, Yan Jun Mi, Zhi Gang Liu, Man Zhi Li, Hua Zhang, Chao Nan Qian, Jian Yong Shao, Li Wu Fu, Yun Fei Xia, Mu Sheng Zeng
Journal: Molecular Cancer (2010)

Abstract Background Our recent cDNA microarray data showed that centromere protein F (CENP-F) is significantly upregulated in primary cultured nasopharyngeal carcinoma (NPC) tumor cells compared with normal nasopharyngeal epithelial cells. The goal of this study was to further investigate the levels of CENP-F expression in NPC cell lines and tissues to clarify the clinical significance of CENP-F expression in NPC as well as the potential therapeutic implications of CENP-F expression. Methods Real-time RT-PCR and western blotting were used to examine CENP-F expression levels in normal primary nasopharyngeal epithelial cells (NPEC), immortalized nasopharyngeal epithelial cells and NPC cell lines. Levels of CENP-F mRNA were determined by real-time RT-PCR in 23 freshly frozen nasopharyngeal biopsy tissues, and CENP-F protein levels were detected by immunohistochemistry in paraffin sections of 202 archival NPC tissues. Statistical analyses were applied to test for prognostic associations. The cytotoxicities of CENP-F potential target chemicals, zoledronic acid (ZOL) and FTI-277 alone, or in combination with cisplatin, in NPC cells were determined by the MTT assay. Results The levels of CENP-F mRNA and protein were higher in NPC cell lines than in normal and immortalized NPECs. CENP-F mRNA level was upregulated in nasopharyngeal carcinoma biopsy tissues compared with noncancerous tissues. By immunohistochemical analysis, CENP-F was highly expressed in 98 (48.5%) of 202 NPC tissues. Statistical analysis showed that high expression of CENP-F was positively correlated with T classification ( P &lt; 0.001), clinical stage ( P &lt; 0.001), skull-base invasion ( P &lt; 0.001) and distant metastasis ( P = 0.012) inversely correlated with the overall survival time in NPC patients. Multivariate analysis showed that CENP-F expression was an independent prognostic indicator for the survival of the patient. Moreover, we found that ZOL or FTI-277 could significantly enhance the chemotherapeutic sensitivity of NPC cell lines (HONE1 and 6-10B) with high CENP-F expression to cisplatin, although ZOL or FTI-277 alone only exhibited a minor inhibitory effect to NPC cells. Conclusion Our data suggest that CENP-F protein is a valuable marker of NPC progression, and CENP-F expression is associated with poor overall survival of patients. In addition, our data indicate a potential benefit of combining ZOL or FTI-277 with cisplatin in NPC suggesting that CENP-F expression may have therapeutic implications.
Chemokines and Their Receptors: Drug Targets in Immunity and Inflammation
Authors: Antonella Viola, Andrew D. Luster
Journal: The Annual Review of Pharmacology and Toxicology (2007)

The chemokine system coordinates leukocyte migration in immunity and inflammation and is implicated in the pathogenesis of many human diseases. Although several successful strategies have been identified to develop drugs targeting chemokines and their receptors, this has not yet resulted in many new therapeutics. This is likely due to a complexity of the chemokine system, which was not initially appreciated, that is characterized by redundancy, pleiotropy, and differences among species. Nevertheless, our understanding of chemokine biology is continuing to grow and several promising drugs are currently being tested in late-stage clinical trials. In this review, we examine the role of chemokines in health and diseases and discuss strategies to target the chemokine system.
Nerve growth factor receptor immunostaining suggests an extrinsic origin for hypertrophic nerves in Hirschsprung's disease.
Authors: H Kobayashi, D S O'Briain, P Puri
Journal: Gut (1994)

The expression of nerve growth factor receptor in colon from 20 patients with Hirshsprung9s disease and 10 controls was studied immunohistochemically. The myenteric and submucous plexuses in the ganglionic bowel and hypertrophic nerve trunks in the aganglionic bowel displayed strong expression of nerve growth factor receptor. The most important finding was the identical localisation of nerve growth factor receptor immunoreactivity on the perineurium of both hypertrophic nerve trunks in Hirshsprung9s diseases, and of normal extrinsic nerves, seen as a thick ring surrounding the nerve trunks. This suggests that the hypertrophic nerve trunks are of extrinsic origin and that nerve growth factor receptor plays a role in their development and maintenance.
GM-CSF expands dendritic cells and their progenitors in mouse liver
Authors: Venu G. Pillarisetty, George Miller, Alaap B. Shah, Ronald P. DeMatteo
Journal: Hepatology (2003)

Dendritic cells (DCs) are rare but ubiquitous antigen–presenting cells situated in lymphoid and nonlymphoid organs throughout the body. The study of DCs located in the liver has been restricted by their relative scarcity and the difficulty of their isolation. Because granulocyte–macrophage colony-stimulating factor (GM–CSF) is a critical growth factor for DCs in vitro , we postulated that it would expand hepatic DCs in vivo . We found that adenoviral–mediated GM–CSF overexpression in normal mice increased the number of liver DCs 400–fold to more than 100 million cells. GM–CSF-recruited DCs were CD11c + DEC205 - and had high expression of major histocompatibility complex (MHC) class II, CD54, and CD80 but low CD40 and CD86 staining. Further maturation occurred after overnight culture. In addition to CD11c + DEC205 - DCs, a population of CD11c - DEC205 low/- cells resembling DC progenitors described previously in normal mice was expanded as serum GM–CSF levels increased. GM–CSF-recruited CD11c + DEC205 - DCs and CD11c - DEC205 low/- cells had different functional capabilities. CD11c + DEC205 - DCs captured far more protein antigen in vivo , produced higher amounts of interleukin (IL)–6 and tumor necrosis factor (TNF)–α, and induced greater allogeneic and antigen–specific T–cell stimulation. A proportion of CD11c - DEC205 low/- cells differentiated into CD11c + cells and gained T–cell stimulatory ability when cultured in the presence of GM–CSF. In conclusion, our findings show that GM–CSF can profoundly influence recruitment and development of DCs in murine liver.
Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders
Authors: Alexander J. Gill, Colleen E. Kovacsics, Stephanie A. Cross, Patricia J. Vance, Lorraine L. Kolson, Kelly L. Jordan-Sciutto, Benjamin B. Gelman, Dennis L. Kolson
Journal: Journal of Clinical Investigation (2014)

Heme oxygenase-1 (HO-1) is an inducible, detoxifying enzyme that is critical for limiting oxidative stress, inflammation, and cellular injury within the CNS and other tissues. Here, we demonstrate a deficiency of HO-1 expression in the brains of HIV-infected individuals. This HO-1 deficiency correlated with cognitive dysfunction, HIV replication in the CNS, and neuroimmune activation. In vitro analysis of HO-1 expression in HIV-infected macrophages, a primary CNS HIV reservoir along with microglia, demonstrated a decrease in HO-1 as HIV replication increased. HO-1 deficiency correlated with increased culture supernatant glutamate and neurotoxicity, suggesting a link among HIV infection, macrophage HO-1 deficiency, and neurodegeneration. HO-1 siRNA knockdown and HO enzymatic inhibition in HIV-infected macrophages increased supernatant glutamate and neurotoxicity. In contrast, increasing HO-1 expression through siRNA derepression or with nonselective pharmacologic inducers, including the CNS-penetrating drug dimethyl fumarate (DMF), decreased supernatant glutamate and neurotoxicity. Furthermore, IFN-γ, which is increased in CNS HIV infection, reduced HO-1 expression in cultured human astrocytes and macrophages. These findings indicate that HO-1 is a protective host factor against HIV-mediated neurodegeneration and suggest that HO-1 deficiency contributes to this degeneration. Furthermore, these results suggest that HO-1 induction in the CNS of HIV-infected patients on antiretroviral therapy could potentially protect against neurodegeneration and associated cognitive dysfunction.
Wolff-Parkinson-White syndrome. The problem, evaluation, and surgical correction.
Authors: J J Gallagher, M Gilbert, R H Svenson, W C Sealy, J Kasell, A G Wallace
Journal: Circulation (1975)

Physiological studies of the type we have described, when performed in patients with the WPW syndrome, can yield diagnostic information regarding the mechanism of arrhythmia, demonstrate functional properties of therapeutic import, facilitate therapeutic decision-making about drug regimens and presumptively localize the site of pre-excitation as a basis for possible surgical intervention. Based on our experience, we feel that in selected patients, surgical correction of the WPW syndrome is entirely feasible, and can be accomplished in the majority of patients in whom free wall A-V connections are present. The continuing challenge of identification and correction of septal accessory pathways directs our present work with the WPW syndrome.