tbuckley/cabot-search huggingface dataset:
Danaparoid sodium lowers proteinuria in diabetic nephropathy.
Authors: J W van der Pijl, F J van der Woude, P H Geelhoed-Duijvestijn, M Frölich, F J van der Meer, H H Lemkes, L A van Es
Journal: Journal of the American Society of Nephrology (1997)

Diabetic nephropathy is a progressive renal disease with thickening of the glomerular basement membrane and mesangial expansion and proliferation as histological hallmarks. The presence of the glycosaminoglycan side chains of heparan sulfate proteoglycan, an important constituent of the glomerular basement membrane, is decreased in diabetic nephropathy proportionally to the degree of proteinuria. Danaparoid sodium is a mixture of sulfated glycosaminoglycans consisting mainly of heparan sulfate. The study presented here involved performing a randomized placebo-controlled crossover study with danaparoid sodium in diabetic patients with overt proteinuria. The aim of the study was to evaluate the effect on proteinuria and safety/tolerability. Nine patients completed the study, without major side effects; the crossover study consisted of two 6-wk periods of treatment with 750 anti-Xa units danaparoid sodium subcutaneously once-daily or placebo. Following danaparoid sodium, significant declines of both albuminuria and proteinuria were found. After danaparoid sodium, the albumin excretion ratio standardized for urinary creatinine reduced with 17% in comparison with an increase of 23% after placebo (95% confidence interval of the difference,-75.9-3.9%; P = 0.03). The percentage change of the urinary protein excretion corrected for urinary creatinine differed at 8 wk significantly between both treatment arms (P = 0.001). Additional parameters for safety as hematological, hemostasis, biochemical parameters, and fundusphotography did not show any clinically significant difference for both groups. Only two patients had minor skin hematomas at the injection site while using danaparoid sodium. In conclusion, the supplementation was found to be feasible and was not associated with side effects. A significant decline of proteinuria was found. More prospective dose-finding and long-term studies must be performed to see whether danaparoid sodium could not only induce a reduction of proteinuria but also halt the progression of renal disease.
<i>RET</i> Fusions Define a Unique Molecular and Clinicopathologic Subtype of Non–Small-Cell Lung Cancer
Authors: Rui Wang, Haichuan Hu, Yunjian Pan, Yuan Li, Ting Ye, Chenguang Li, Xiaoyang Luo, Lei Wang, Hang Li, Yang Zhang, Fei Li, Yongming Lu, Qiong Lu, Jie Xu, David Garfield, Lei Shen, Hongbin Ji, William Pao, Yihua Sun, Haiquan Chen
Journal: Journal of Clinical Oncology (2012)

The RET fusion gene has been recently described in a subset of non-small-cell lung cancers (NSCLCs). Because we have limited knowledge about these tumors, this study was aimed at determining the clinicopathologic characteristics of patients with NSCLC harboring the RET fusion gene.We examined the RET fusion gene in 936 patients with surgically resected NSCLC using a reverse transcriptase polymerase chain reaction (PCR) plus quantitative real-time PCR strategy, with validation using immunohistochemical and fluorescent in situ hybridization assays. A subset of 633 lung adenocarcinomas was also studied for EGFR, KRAS, HER2, and BRAF mutations, as well as ALK rearrangements. Patient characteristics, including age, sex, smoking history, stage, grade, International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of subtypes of lung adenocarcinoma, and relapse-free survival, were collected.Of 936 patients with NSCLC, the RET fusion gene was exclusively detected in 13 patients (11 of 633 patients with adenocarcinomas and two of 24 patients with adenosquamous cell carcinomas). Of the 13 patients, nine patients had KIF5B-RET, three patients had CCDC6-RET, and one patient had a novel NCOA4-RET fusion. Patients with lung adenocarcinomas with RET fusion gene had more poorly differentiated tumors (63.6%; P = .029 for RET v ALK, P = .007 for RET v EGFR), with a tendency to be younger (≤ 60 years; 72.7%) and never-smokers (81.8%) and to have solid subtype (63.6%) and a smaller tumor (≤ 3 cm) with N2 disease (54.4%). The median relapse-free survival was 20.9 months.RET fusion occurs in 1.4% of NSCLCs and 1.7% of lung adenocarcinomas and has identifiable clinicopathologic characteristics, warranting further clinical consideration and targeted therapy investigation.
T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow
Authors: Cécile Daussy, Fabrice Faure, Katia Mayol, Sébastien Viel, Georg Gasteiger, Emily Charrier, Jacques Bienvenu, Thomas Henry, Emilie Debien, Uzma A. Hasan, Jacqueline Marvel, Keigyou Yoh, Satoru Takahashi, Immo Prinz, Simon de Bernard, Laurent Buffat, Thierry Walzer
Journal: The Journal of Experimental Medicine (2014)

Trail+DX5−Eomes− natural killer (NK) cells arise in the mouse fetal liver and persist in the adult liver. Their relationships with Trail−DX5+ NK cells remain controversial. We generated a novel Eomes-GFP reporter murine model to address this question. We found that Eomes− NK cells are not precursors of classical Eomes+ NK cells but rather constitute a distinct lineage of innate lymphoid cells. Eomes− NK cells are strictly dependent on both T-bet and IL-15, similarly to NKT cells. We observed that, in the liver, expression of T-bet in progenitors represses Eomes expression and the development of Eomes+ NK cells. Reciprocally, the bone marrow (BM) microenvironment restricts T-bet expression in developing NK cells. Ectopic expression of T-bet forces the development of Eomes− NK cells, demonstrating that repression of T-bet is essential for the development of Eomes+ NK cells. Gene profile analyses show that Eomes− NK cells share part of their transcriptional program with NKT cells, including genes involved in liver homing and NK cell receptors. Moreover, Eomes− NK cells produce a broad range of cytokines, including IL-2 and TNF in vitro and in vivo, during immune responses against vaccinia virus. Thus, mutually exclusive expression of T-bet and Eomes drives the development of different NK cell lineages with complementary functions.
Genetically Determined Resistance to Collagenase Action Augments Interstitial Collagen Accumulation in Atherosclerotic Plaques
Authors: Yoshihiro Fukumoto, Jun-o Deguchi, Peter Libby, Elena Rabkin-Aikawa, Yasuhiko Sakata, Michael T. Chin, Christopher C. Hill, Patrick R. Lawler, Nerea Varo, Frederick J. Schoen, Stephen M. Krane, Masanori Aikawa
Journal: Circulation (2004)

We hypothesized that collagenolytic activity produced by activated macrophages contributes to collagen loss and the subsequent instability of atheromatous lesions, a common trigger of acute coronary syndromes. However, no direct in vivo evidence links collagenases with the regulation of collagen content in atherosclerotic plaques.To test the hypothesis that collagenases influence the structure of atheromata, we examined collagen accumulation in atherosclerotic lesions of apolipoprotein E-deficient mice (apoE-/-) that express collagenase-resistant collagen-I (ColR/R/apoE-/-, n=12) or wild-type collagen-expressing mice (Col+/+/apoE-/-, n=12). Aortic atheromata of both groups had similar sizes and numbers of macrophages, a major source of collagenases. However, aortic intimas from ColR/R/apoE-/- mice contained fewer smooth muscle cells, a source of collagen, probably because of decreased migration or proliferation or increased cell death. Despite reduced numbers of smooth muscle cells, atheromata of ColR/R/apoE-/- mice contained significantly more intimal collagen than did those of Col+/+/apoE-/- mice.These results establish that collagenase action regulates plaque collagen turnover and smooth muscle cell accumulation.
Observation on serum anti-double stranded DNA antibodies of tripterine in systemic lupus erythematosus of (NZBxW)F1 mice
Authors: X Xu
Journal: Annals of the Rheumatic Diseases (2003)

Tripterine is one of the major active components isolated from the traditional Chinese herb Tripterygium wilfordii Hook. f. Previous studies have shown that tripterine inhibits not only humoral and cellular immune responses but also the inflammatory response.1

This study aimed at exploring the inhibitory effects of tripterine on lupus nephritis. We studied the effect of tripterine in (NZB×W)F1 mice, who spontaneously develop autoimmune disease characterised by the production of dsDNA antibodies and the development of a severe immune complex glomerulonephritis, like in human lupus nephritis.2,3 The dsDNA antibodies are thought to have a role in the pathogenesis of mouse lupus-like nephritis.4 Raised levels of circulating anti-dsDNA antibodies often precede the development of nephritis.5,6 …
Human Herpesvirus 6 (HHV-6) Causes Severe Thymocyte Depletion in SCID-hu Thy/Liv Mice
Authors: Alberto Gobbi, Cheryl A. Stoddart, Mauro S. Malnati, Giuseppe Locatelli, Fabio Santoro, Nancy W. Abbey, Christopher Bare, Valerie Linquist-Stepps, Mary Beth Moreno, Brian G. Herndier, Paolo Lusso, Joseph M. McCune
Journal: The Journal of Experimental Medicine (1999)

Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that may act as a cofactor in the progression of AIDS. Here, we describe the first small animal model of HHV-6 infection. HHV-6 subgroup A, strain GS, efficiently infected the human thymic tissue implanted in SCID-hu Thy/Liv mice, leading to the destruction of the graft. Viral DNA was detected in Thy/Liv implants by quantitative polymerase chain reaction (PCR) as early as 4 d after inoculation and peaked at day 14. The productive nature of the infection was confirmed by electron microscopy and immunohistochemical staining. Atypical thymocytes with prominent nuclear inclusions were detected by histopathology. HHV-6 replication was associated with severe, progressive thymocyte depletion involving all major cellular subsets. However, intrathymic T progenitor cells (ITTPs) appeared to be more severely depleted than the other subpopulations, and a preferred tropism of HHV-6 for ITTPs was demonstrated by quantitative PCR on purified thymocyte subsets. These findings suggest that thymocyte depletion by HHV-6 may be due to infection and destruction of these immature T cell precursors. Similar results were obtained with strain PL-1, a primary isolate belonging to subgroup B. The severity of the lesions observed in this animal model underscores the possibility that HHV-6 may indeed be immunosuppressive in humans.
MPs are to investigate GP commissioning and NHS spending
Authors: A. O'Dowd
Journal: BMJ (2010)

The new budget holding GP commissioning planned by the government is to be investigated by MPs on the recently formed parliamentary health select committee as one of its first inquiries.

The new committee, set up after the general election, is to carry out an inquiry into commissioning and public spending and is inviting written evidence from anyone interested.

One of the last reports by the previous health committee published in March, reviewed the progress of commissioning in the NHS in the past 20 years and concluded it had been a “costly failure”( BMJ 2010;340:c1792, doi:10.1136/bmj.c1792).

Its critical report said, “Weaknesses remain 20 years after the introduction of the purchaser-provider split. …
Calcitonin gene-related peptide relates to cough sensitivity in children with chronic cough
Authors: A. B. Chang, P. G. Gibson, J. Ardill, L. P. A. McGarvey
Journal: European Respiratory Journal (2007)

Airway neuropeptides, in particular calcitonin gene-related peptide (CGRP), are likely to be important in the pathogenesis of chronic cough. The present authors evaluated the following: 1) the relationship between cough sensitivity and bronchoalveolar lavage (BAL) neuropeptides; and 2) the effect of reflux oesophagitis (RO) on cough, cough sensitivity and BAL neuropeptides in children not selected for cough. It was hypothesised that CGRP would be increased in children with chronic cough and would relate to cough sensitivity. Capsaicin cough sensitivity was performed in children undergoing gastro-duodenal endoscopy. CGRP, substance P and neurokinin A were measured in BAL obtained nonbronchoscopically. Children were defined as “coughers” if chronic cough was present. Coughers (n = 21) had significantly reduced cough sensitivity but were just as likely as noncoughers (n = 19) to have RO. The median CGRP was significantly higher in coughers with oesophagitis than in noncoughers with oesophagitis. CGRP significantly negatively correlated to cough sensitivity in coughers but not in noncoughers. Elevated calcitonin gene-related peptide, but not substance P or neurokinin A, is only associated with chronic cough in children when oesophagitis coexists. Calcitonin gene-related peptide in bronchoalveolar lavage relates to cough sensitivity and is likely to be important in the pathophysiology of chronic cough.
Formula estimation of glomerular filtration rate: have we gone wrong?
Authors: Paul D Giles, David A Fitzmaurice
Journal: BMJ (2007)

<b>Paul D Giles</b> and <b>David A Fitzmaurice</b> argue that the introduction of estimated glomerular filtration rate to screen for chronic kidney disease in primary care will lead to pressure on specialist services and create patient anxiety without clear proof of benefit
Premature deaths attributable to blood pressure in China: a prospective cohort study
Authors: Jiang He, Dongfeng Gu, Jing Chen, Xigui Wu, Tanika N Kelly, Jian-feng Huang, Ji-chun Chen, Chung-Shiuan Chen, Lydia A Bazzano, Kristi Reynolds, Paul K Whelton, Michael J Klag
Journal: The Lancet (2009)
An analysis of in vitro T cell responsiveness in lepromatous leprosy.
Authors: G Kaplan, D E Weinstein, R M Steinman, W R Levis, U Elvers, M E Patarroyo, Z A Cohn
Journal: The Journal of Experimental Medicine (1985)

In lepromatous leprosy, there is extensive replication of Mycobacterium leprae (M. leprae) within dermal macrophages. This lack of microbial resistance has been attributed to a defective cell-mediated immune response to M. leprae antigens. We have examined the in vitro response of T cells to M. leprae to determine if hyporesponsiveness could be reversed. The study included 40 unselected patients from New York and from Colombia, most with the severe lepromatous form of the disease. We first noted that lepromatous leprosy patients were of two types: those unable to respond, as assessed by T cell proliferation and immune (gamma) interferon (IFN-gamma) release, and a second group, exhibiting low but detectable responses relative to tuberculoid controls. When the effect of exogenous recombinant interleukin-2 (IL-2) on the response to M. leprae antigens was compared in the two groups, many of the low responders, but not the nonresponders, showed enhanced proliferation and IFN-gamma release. To evaluate a possible suppressive effect of monocytes, these cells were eliminated with a cell-specific monoclonal antibody and complement. Depletion of monocytes often expanded preexisting weak responses but did not reverse the anergy of the M. leprae nonresponders. The enhancement was not M. leprae-specific, since it was also observed when bacillus Calmette-Guerin was the antigenic stimulus for proliferation and IFN-gamma production. Removal of the suppressor T cell subset, with OKT8 antibody and complement, also did not restore responses in nonresponder patients. We conclude that a sizable number of lepromatous leprosy patients exhibit a low degree of responsiveness to M. leprae and that the responses can be enhanced in vitro with IL-2 or with monocyte depletion. Nonresponsiveness, however, cannot be reversed. Since currently available assays measure the function of previously sensitized T cells, suppressor mechanisms may yet contribute to defective cell-mediated immunity by impairing the initial sensitization to M. leprae antigens.
Habitual Caffeine Intake and the Risk of Hypertension in Women
Authors: Wolfgang C Winkelmayer, Meir J Stampfer, Walter C Willett, Gary C Curhan
Journal: JAMA (2005)

Caffeine acutely increases blood pressure, but the association between habitual consumption of caffeinated beverages and incident hypertension is uncertain.To examine the association between caffeine intake and incident hypertension in women.Prospective cohort study conducted in the Nurses' Health Studies (NHSs) I and II of 155,594 US women free from physician-diagnosed hypertension followed up over 12 years (1990-1991 to 2002-2003 questionnaires). Caffeine intake and possible confounders were ascertained from regularly administered questionnaires. We also tested the associations with types of caffeinated beverages.Incident physician-diagnosed hypertension.During follow-up, 19,541 incident cases of physician-diagnosed hypertension were reported in NHS I and 13,536 in NHS II. In both cohorts, no linear association between caffeine consumption and risk of incident hypertension was observed after multivariate adjustment (NHS I, P for trend = .29; NHS II, P for trend = .53). Using categorical analysis, an inverse U-shaped association between caffeine consumption and incident hypertension was found. Compared with participants in the lowest quintile of caffeine consumption, those in the third quintile had a 13% and 12% increased risk of hypertension, respectively (95% confidence interval in NHS I, 8%-18%; in NHS II, 6%-18%). When studying individual classes of caffeinated beverages, habitual coffee consumption was not associated with increased risk of hypertension. By contrast, consumption of cola beverages was associated with an increased risk of hypertension, independent of whether it was sugared or diet cola (P for trend <.001).No linear association between caffeine consumption and incident hypertension was found. Even though habitual coffee consumption was not associated with an increased risk of hypertension, consumption of sugared or diet cola was associated with it. Further research to elucidate the role of cola beverages in hypertension is warranted.
Interactions between the Hypothalamic-Pituitary-Adrenal Axis and the Female Reproductive System: Clinical Implications
Authors: George P. Chrousos
Journal: Annals of Internal Medicine (1998)

The hypothalamic-pituitary-adrenal axis exerts profound, multilevel inhibitory effects on the female reproductive system. Corticotropin-releasing hormone (CRH) and CRH-induced proopiomelanocortin peptides inhibit hypothalamic gonadotropin-releasing hormone secretion, whereas glucocorticoids suppress pituitary luteinizing hormone and ovarian estrogen and progesterone secretion and render target tissues resistant to estradiol. The hypothalamic-pituitary-adrenal axis is thus responsible for the "hypothalamic" amenorrhea of stress, which is also seen in melancholic depression, malnutrition, eating disorders, chronic active alcoholism, chronic excessive exercise, and the hypogonadism of the Cushing syndrome. Conversely, estrogen directly stimulates the CRH gene promoter and the central noradrenergic system, which may explain adult women's slight hypercortisolism; preponderance of affective, anxiety, and eating disorders; and mood cycles and vulnerability to autoimmune and inflammatory disease, both of which follow estradiol fluctuations. Several components of the hypothalamic-pituitary-adrenal axis and their receptors are present in reproductive tissues as autacoid regulators. These include ovarian and endometrial CRH, which may participate in the inflammatory processes of the ovary (ovulation and luteolysis) and endometrium (blastocyst implantation and menstruation), and placental CRH, which may participate in the physiology of pregnancy and the timing of labor and delivery. The hypercortisolism of the latter half of pregnancy can be explained by high levels of placental CRH in plasma. This hypercortisolism causes a transient postpartum adrenal suppression that, together with estrogen withdrawal, may partly explain the depression and autoimmune phenomena of the postpartum period.
Use of Sildenafil (Viagra) in Patients With Cardiovascular Disease
Authors: Melvin D. Cheitlin, Adolph M. Hutter, Ralph G. Brindis, Peter Ganz, Sanjay Kaul, Richard O. Russell, Randall M. Zusman, James S. Forrester, Pamela S. Douglas, David P. Faxon, John D. Fisher, Raymond J. Gibbons, Jonathan L. Halperin, Adolph M. Hutter, Judith S. Hochman, Sanjiv Kaul, William S. Weintraub, William L. Winters, Michael J. Wolk
Journal: Circulation (1999)

A. Use of Viagra clearly contraindicated 1. Concurrent use of nitrates (see Appendix A) B. Cardiovascular effects of Viagra may be potentially hazardous (use dependent on individual clinical assessment) 1. Patients with active coronary ischemia who are not taking nitrates (eg, positive exercise test for ischemia) 2. Patients with congestive heart failure and borderline low blood pressure and borderline low volume status 3. Patients on a complicated, multidrug, antihypertensive program 4. Patients taking drugs that can prolong the half-life of Viagra (see Appendix B)
Influence of chemical penetration enhancers on skin permeability of ellagic acid-loaded niosomes
Authors: Varaporn Buraphacheep Junyaprasert, Pratyawadee Singhsa, Anchalee Jintapattanakit
Journal: Asian Journal of Pharmaceutical Sciences (2013)

This study aimed to develop niosomes of ellagic acid (EA), a potent antioxidant phytochemical substance, for dermal delivery and to investigate the influence of chemical penetration enhancers on the physicochemical properties of EA-loaded niosomes. The EA niosomes were prepared by reverse phase evaporation method using Span 60, Tween 60 and cholesterol as vesicle forming agents and Solulan C24 as a steric stabilizer. Polyethylene glycol 400 (PEG) was used as a solubilizer while dimethylsulfoxide (DMSO) or N-methyl-2-pyrrolidone (NMP) was used as a skin penetration enhancer. It was found that the mean particle sizes of EA-loaded niosomes were in the range of 312–402 nm with PI values of lower than 0.4. The niosomes were determined to be spherical multilamellar vesicles as observed by transmission electron microscope and optical microscopy. All niosomes were stable after 4 months storage at 4 °C. In vitro skin permeation through human epidermis revealed that the skin enhancers affected the penetration of EA from the niosomes at 24 h. The DMSO niosomes showed the highest EA amount in epidermis; whereas the NMP niosomes had the highest EA amount in the acceptor medium. Concomitantly, the skin distribution by confocal laser scanning microscopy showed the high fluorescence intensity of the DMSO niosomes and NMP niosomes at a penetration depth of between 30–90 μm (the epidermis layer) and 90–120 μm (the dermis layer) under the skin, respectively. From the results, it can be concluded that the DMSO niosomes are suitable for epidermis delivery of EA while the NMP niosomes can be used for dermis delivery of EA.