tbuckley/cabot-search huggingface dataset:
Platelet activation induced by porcine factor VIII (HYATE:C)
Authors: H. Chang, M. Mody, A.H. Lazarus, F. Ofosu, M.B. Garvey, V. Blanchette, J. Teitel, J. Freedman
Journal: American Journal of Hematology (1998)

We studied the effects of porcine factor VIII (P-FVIII; Hyate:C) and other coagulation products employed in the management of patients with hemophilia A, on platelet activation in vitro. Exposure of normal resting platelets to P-FVIII resulted in platelet activation, as manifested by increased expression of the platelet surface activation markers CD62, CD63, and activated-GPIIbIIIa, and by activation-induced modulation of expression of normal platelet membrane glycoproteins CD41, CD42, and CD36. In contrast, platelet activation was not observed after exposure of the platelets to human FVIII, FEIBA, recombinant FVIIa, or cryosupernatant plasma. As with thrombin, exposure of platelets to P-FVIII resulted in the generation of platelet microparticles, an effect not seen not with the other products. In contrast to the characteristic reduction in expression in the number of CD42 molecules detected on thrombin-activated platelets, P-FVIII-stimulated platelets showed a small increase in CD42 expression. In contrast to thrombin, P-FVIII did not cause platelet dense granule release. The results indicate that therapeutic P-FVIII activates platelets, likely in ways that are different from the platelet activation seen with thrombin. The observed platelet activation and microparticle generation may provide a "hypercoagulable" mechanism for hemostasis with P-FVIII therapy separate from, and additional to, that due to increased circulating FVIII levels. Am. J. Hematol. 57:200–205, 1998. © 1998 Wiley-Liss, Inc.
Re: Association of a Common Variant of the CASP8 Gene With Reduced Risk of Breast Cancer
Authors: Bernd Frank, Justo Lorenzo Bermejo, Kari Hemminki, Rüdiger Klaes, Peter Bugert, Barbara Wappenschmidt, Rita K. Schmutzler, Barbara Burwinkel
Journal: JNCI Journal of the National Cancer Institute (2005)
Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease
Authors: Kenneth Rosenfield, Michael R. Jaff, Christopher J. White, Krishna Rocha-Singh, Carlos Mena-Hurtado, D. Christopher Metzger, Marianne Brodmann, Ernst Pilger, Thomas Zeller, Prakash Krishnan, Roger Gammon, Stefan Müller-Hülsbeck, Mark R. Nehler, James F. Benenati, Dierk Scheinert
Journal: New England Journal of Medicine (2015)

The treatment of peripheral artery disease with percutaneous transluminal angioplasty is limited by the occurrence of vessel recoil and restenosis. Drug-coated angioplasty balloons deliver antiproliferative agents directly to the artery, potentially improving vessel patency by reducing restenosis.In this single-blind, randomized trial conducted at 54 sites, we assigned, in a 2:1 ratio, 476 patients with symptomatic intermittent claudication or ischemic pain while at rest and angiographically significant atherosclerotic lesions to angioplasty with a paclitaxel-coated balloon or to standard angioplasty. The primary efficacy end point was primary patency of the target lesion at 12 months (defined as freedom from binary restenosis or from the need for target-lesion revascularization). The primary safety end point was a composite of freedom from perioperative death from any cause and freedom at 12 months from limb-related death (i.e., death from a medical complication related to a limb), amputation, and reintervention.The two groups were well matched at baseline; 42.9% of the patients had diabetes, and 34.7% were current smokers. At 12 months, the rate of primary patency among patients who had undergone angioplasty with the drug-coated balloon was superior to that among patients who had undergone conventional angioplasty (65.2% vs. 52.6%, P=0.02). The proportion of patients free from primary safety events was 83.9% with the drug-coated balloon and 79.0% with standard angioplasty (P=0.005 for noninferiority). There were no significant between-group differences in functional outcomes or in the rates of death, amputation, thrombosis, or reintervention.Among patients with symptomatic femoropopliteal peripheral artery disease, percutaneous transluminal angioplasty with a paclitaxel-coated balloon resulted in a rate of primary patency at 12 months that was higher than the rate with angioplasty with a standard balloon. The drug-coated balloon was noninferior to the standard balloon with respect to safety. (Funded by Lutonix-Bard; LEVANT 2 ClinicalTrials.gov number, NCT01412541.).
Responsibility for the Disadvantaged
Authors: D. A. Brewerton
Journal: BMJ (1974)

Much psychiatric illness in adolescence is regarded as a transient phase of turmoil or crisis related to maturation, essentially a normal or even valuable experience.This book gives a trans-Atlantic perspective.Throughout, sociological factors are accorded a major role.Many of the authors are at pains to explain or defend, and some identify themselves with, the adolescent's counter-culture.An extreme example is the judgement that "the truly brilliant psychotics and criminals occupy high offices in govern- ment, in industry, and in the military," while most of those so-named are the victims of poverty, oppressive laws, and hypocritical values.A more moderate view
Basigin Mediates Pulmonary Hypertension by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation
Authors: Kimio Satoh, Taijyu Satoh, Nobuhiro Kikuchi, Junichi Omura, Ryo Kurosawa, Kota Suzuki, Koichiro Sugimura, Tatsuo Aoki, Kotaro Nochioka, Shunsuke Tatebe, Saori Miyamichi-Yamamoto, Masanobu Miura, Toru Shimizu, Shohei Ikeda, Nobuhiro Yaoita, Yoshihiro Fukumoto, Tatsuro Minami, Satoshi Miyata, Kazufumi Nakamura, Hiroshi Ito, Kenji Kadomatsu, Hiroaki Shimokawa
Journal: Circulation Research (2014)

Cyclophilin A (CyPA) is secreted from vascular smooth muscle cells (VSMCs) by oxidative stress and promotes VSMC proliferation. However, the role of extracellular CyPA and its receptor Basigin (Bsg, encoded by Bsg) in the pathogenesis of pulmonary hypertension (PH) remains to be elucidated.To determine the role of CyPA/Bsg signaling in the development of PH.In the pulmonary arteries of patients with PH, immunostaining revealed strong expression of CyPA and Bsg. The pulmonary arteries of CyPA(±) and Bsg(±) mice exposed to normoxia did not differ in morphology compared with their littermate controls. In contrast, CyPA(±) and Bsg(±) mice exposed to hypoxia for 4 weeks revealed significantly reduced right ventricular systolic pressure, pulmonary artery remodeling, and right ventricular hypertrophy compared with their littermate controls. These features were unaltered by bone marrow reconstitution. To further evaluate the role of vascular Bsg, we harvested pulmonary VSMCs from Bsg(+/+) and Bsg(±) mice. Proliferation was significantly reduced in Bsg(±) compared with Bsg(+/+) VSMCs. Mechanistic studies demonstrated that Bsg(±) VSMCs revealed reduced extracellular signal-regulated kinase 1/2 activation and less secretion of cytokines/chemokines and growth factors (eg, platelet-derived growth factor-BB). Finally, in the clinical study, plasma CyPA levels in patients with PH were increased in accordance with the severity of pulmonary vascular resistance. Furthermore, event-free curve revealed that high plasma CyPA levels predicted poor outcome in patients with PH.These results indicate the crucial role of extracellular CyPA and vascular Bsg in the pathogenesis of PH.
Preoperative CTLA-4 Blockade: Tolerability and Immune Monitoring in the Setting of a Presurgical Clinical Trial
Authors: Bradley C. Carthon, Jedd D. Wolchok, Jianda Yuan, Ashish Kamat, Derek S. Ng Tang, Jingjing Sun, Geoffrey Ku, Patricia Troncoso, Christopher J. Logothetis, James P. Allison, Padmanee Sharma
Journal: Clinical Cancer Research (2010)

Cytotoxic T lymphocyte associated antigen (CTLA-4) blockade is being explored in numerous clinical trials as an immune-based therapy for different malignancies. Our group conducted the first preoperative clinical trial with the anti-CTLA-4 antibody ipilimumab in 12 patients with localized urothelial carcinoma of the bladder.Six patients were treated with 3 mg/kg/dose of anti-CTLA-4 and six patients were treated with 10 mg/kg/dose of antibody. Primary end points of the study were safety and immune monitoring.Most drug-related adverse events consisted of grade 1/2 toxicities. All patients had measurable immunologic pharmacodynamic effects, consisting of an increased frequency of CD4+ICOShi T cells in tumor tissues and the systemic circulation. To determine if CD4+ICOShi T cells could be a correlative marker for clinical outcome after treatment with anti-CTLA-4, a cohort of metastatic melanoma patients was studied retrospectively for frequency of CD4+ICOShi T cells and survival. Data from this small cohort of patients indicated that an increased frequency of CD4+ICOShi T cells, sustained over a period of 12 weeks of therapy, correlates with increased likelihood of clinical benefit consisting of overall survival.Our trial shows that anti-CTLA-4 therapy has a tolerable safety profile in the presurgical setting and that a preoperative model can be used to obtain biological data on human immune responses, which can efficiently guide the monitoring of patients treated in the metastatic disease setting.
Whipple's disease diagnosed at hip arthroplasty.
Authors: M Farr, C A Hollywell, C J Morris, G R Struthers, P A Bacon, K W Walton
Journal: Annals of the Rheumatic Diseases (1984)

A patient is reported with a six-year history of seronegative inflammatory arthritis, lymphadenopathy, and a rash. Many investigations, including repeat jejunal and synovial needle biopsies, failed to establish the diagnosis. Eventually right hip destruction led to arthroplasty. Synovial membrane obtained at operation was examined by electron microscopy and organisms were found with the morphological characteristics of those in patients where the diagnosis was firmly established as Whipple's disease. We propose that Whipple's disease should be seriously considered as a rare but distinct and treatable possibility in the differential diagnosis of seronegative inflammatory arthritis.
Affirmation of a developmental systems approach to genetics
Authors: Carolyn Tucker Halpern
Journal: Behavioral and Brain Sciences (2012)

Abstract More than 40 years ago, Gilbert Gottlieb and like-minded scholars argued for the philosophical necessity of approaching genetic contributions to development through a multilevel, bidirectional systems perspective. Charney's target article builds on this heritage in significant ways, offering more recent examples of the interactions of biology and context, as well as the diversity of developmental mechanisms, and reaffirming a way forward for genetic research.
Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation
Authors: Fumiyo Ikeda, Riko Nishimura, Takuma Matsubara, Sakae Tanaka, Jun-ichiro Inoue, Sakamuri V. Reddy, Kenji Hata, Kenji Yamashita, Toru Hiraga, Toshiyuki Watanabe, Toshio Kukita, Katsuji Yoshioka, Anjana Rao, Toshiyuki Yoneda
Journal: Journal of Clinical Investigation (2004)

Receptor activator of NF-kappaB ligand (RANKL) plays an essential role in osteoclast formation and bone resorption. Although genetic and biochemical studies indicate that RANKL regulates osteoclast differentiation by activating receptor activator of NF-kappaB and associated signaling molecules, the molecular mechanisms of RANKL-regulated osteoclast differentiation have not yet been fully established. We investigated the role of the transcription factor c-Jun, which is activated by RANKL, in osteoclastogenesis using transgenic mice expressing dominant-negative c-Jun specifically in the osteoclast lineage. We found that the transgenic mice manifested severe osteopetrosis due to impaired osteoclastogenesis. Blockade of c-Jun signaling also markedly inhibited soluble RANKL-induced osteoclast differentiation in vitro. Overexpression of nuclear factor of activated T cells 1 (NFAT1) (NFATc2/NFATp) or NFAT2 (NFATc1/NFATc) promoted differentiation of osteoclast precursor cells into tartrate-resistant acid phosphatase-positive (TRAP-positive) multinucleated osteoclast-like cells even in the absence of RANKL. Overexpression of NFAT1 also markedly transactivated the TRAP gene promoter. These osteoclastogenic activities of NFAT were abrogated by overexpression of dominant-negative c-Jun. Importantly, osteoclast differentiation and induction of NFAT2 expression by NFAT1 overexpression or soluble RANKL treatment were profoundly diminished in spleen cells of the transgenic mice. Collectively, these results indicate that c-Jun signaling in cooperation with NFAT is crucial for RANKL-regulated osteoclast differentiation.
Glucose Control and the Renal and Retinal Complications of Insulin-dependent Diabetes
Authors: H. Peter Chase
Journal: JAMA (1989)

Two hundred thirty subjects with insulin-dependent diabetes were followed up longitudinally by measuring glycohemoglobin values to relate glucose control with renal and retinal complications. Subjects with long-term poor control (glycohemoglobin values greater than 1.5 times the upper limit of normal) had 3.6 times the prevalence of microalbuminuria and 2.5 times the prevalence of level 3 to 6 retinopathy than that found in subjects with long-term good control (glycohemoglobin values within 1.33 times the upper limit of normal). Variables related to kidney damage were glucose control and, to a lesser degree, duration of diabetes. Variables related to eye disease were, in descending order of significance, duration of diabetes, glucose control, and age. No subject whose mean glycohemoglobin value was consistently within 1.1 times the upper limit of normal had retinopathy or microalbuminuria. In contrast, when the mean glycohemoglobin value was more than 1.5 times the upper limit of normal, 24 (29%) of 82 subjects had microalbuminuria and 30 (37%) of 82 had level 3 to 6 retinopathy.
Referral of patients with primary biliary cirrhosis for liver transplantation.
Authors: J M Neuberger, B K Gunson, J A Buckels, E Elias, P McMaster
Journal: Gut (1990)

All patients with primary biliary cirrhosis referred to this unit for consideration for transplantation between April 1981 and January 1989 were analysed retrospectively to assess whether disease stage at referral affects the outcome after grafting and whether greater awareness of the benefits of the procedure means that patients are now being referred at an earlier stage. Seventy of the 107 patients have been grafted, with an overall one year actuarial survival of 62%. A better prognosis at the time of referral, as assessed by both serum bilirubin concentration and a mathematically derived prognostic index, was associated with a greater probability of survival after grafting. Patients in the tertile with the best prognosis (median serum bilirubin concentration at referral 84 mumol/l and estimated survival in the absence of transplantation of more than nine months) had a 78% one year actuarial survival after transplantation, whereas those in the tertile with the worst prognosis (median serum bilirubin concentration 467 mumol/l and estimated survival of less than four months) had a one year actuarial survival of only 50%. No trend towards earlier referral of patients, however, was shown using either of these two markers. This retrospective analysis suggests that many patients are being referred too late for an optimal outcome. We recommend that patients with primary biliary cirrhosis who are potential candidates for liver grafting should be referred to a transplant centre before the serum bilirubin concentration approaches 150 mumol/l.
Lack of response to exogenous interferon-α in the liver of chimpanzees chronically infected with hepatitis C virus
Authors: Robert E. Lanford, Bernadette Guerra, Catherine B. Bigger, Helen Lee, Deborah Chavez, Kathleen M. Brasky
Journal: Hepatology (2007)

Abstract The mechanism of the interferon-alpha (IFNα)–induced antiviral response is not completely understood. We recently examined the transcriptional response to IFNα in uninfected chimpanzees. The transcriptional response to IFNα in the liver and peripheral blood mononuclear cells (PBMCs) was rapidly induced but was also rapidly down-regulated, with most interferon-alpha–stimulated genes (ISGs) returning to the baseline within 24 hours. We have extended these observations to include chimpanzees chronically infected with hepatitis C virus (HCV). Remarkably, using total genome microarray analysis, we observed almost no induction of ISG transcripts in the livers of chronically infected animals following IFNα dosing, whereas the response in PBMCs was similar to that in uninfected animals. In agreement with this finding, no decrease in the viral load occurred with up to 12 weeks of pegylated IFNα therapy. The block in the response to exogenous IFNα appeared to be HCV-specific because the response in a hepatitis B virus–infected animal was similar to that of uninfected animals. The lack of a response to exogenous IFNα may be due to an already maximally induced ISG response because chronically HCV-infected chimpanzees already have a highly up-regulated hepatic ISG response. Alternatively, negative regulation may block the response to exogenous IFNα, yet it does not prevent the continued response to endogenous ISG stimuli. The IFNα response in chronically HCV-infected chimpanzees may be mechanistically similar to the null response in the human population. Conclusion: In chimpanzees infected with HCV, the highly elevated hepatic ISG expression may prevent the further induction of ISGs and antiviral efficacy following an IFNα treatment. (HEPATOLOGY 2007.)
Urinary concentrating defect in experimental hemochromatosis.
Authors: X J Zhou, N D Vaziri, D Pandian, Z Q Wang, M Mazowiecki, S Y Liao, F Oveisi
Journal: Journal of the American Society of Nephrology (1996)

We studied the urinary concentrating capacity in experimental hemochromatosis. Sprague-Dawley rats were randomized into iron (Fe)-loaded (injected sc with 1.2 g elemental iron/kg body weight as iron dextran) and pair-fed control groups. The urinary concentrating ability was studied after 10 months of iron loading. At basal condition, urine osmolality (Uosm) was significantly lower (P < 0.05) in the Fe-loaded rats compared with the control animals despite comparable urinary arginine-vasopressin (AVP) excretion in the two groups. Although 48-h water deprivation resulted in comparable rises in plasma concentration and urinary excretion of AVP in the two groups, maximal Uosm in the Fe-loaded animals was significantly lower than that seen in the control group (P < 0.01). Moreover, the observed urinary concentrating defect could not be corrected by pharmacological doses of exogenous AVP. There was no significant difference in renal chloride, sodium, calcium, or magnesium handling at either basal or sodium depleted states. Histologic studies showed marked iron deposition in the cortex and outer medulla accompanied by mild tubular atrophy particularly in the distal convoluted tubules. Thus, chronic experimental iron overload leads to nephrogenic diabetes insipidus marked by AVP-resistant urinary concentrating defect.
Hormonal Control of Gene Expression in the Ovary
Authors: JOANNE S. RICHARDS
Journal: Endocrine Reviews (1994)

The maturation of ovarian follicles involves several sequential stages: initiation, growth, selection, ovulation, and luteinization (Fig. 1). Although the factor(s) that initiates the growth of “resting” primordial follicles remain elusive, the key endocrine events controlling follicular growth in mammals have been known for many years. For example, once follicles have begun to grow, basal concentrations of the gonadotropins, FSH and LH, maintain growth up until the small antral stage. Small antral follicles are selected to continue growth by subtle increases in basal concentrations of gonadotropins, such as those that occur at menses in primates (1) or at the end of pregnancy in rodents (2). Once selected, the growing dominant follicle(s) acquires specific functional characteristics that permit it to differentiate to the preovulatory stage and synthesize estradiol. Increased serum estradiol triggers the surge of gonadotropins that, in turn, stimulates the preovulatory follicle(s) to ovulate and luteinize (form the corpus luteum).
Our Shifting Understanding of Factors Influencing Prostate-Specific Antigen
Authors: E. A. Singer, R. S. DiPaola
Journal: JNCI Journal of the National Cancer Institute (2013)

Prostate cancer continues to be a substantial burden on men's health with 238 590 new cases and 29 720 deaths expected in 2013, making it the most commonly diagnosed noncutaneous malignancy and the second leading cause of cancer mortality in men (1).Nonmodifiable risk factors such as age, race, and family history are known to contribute to a man's risk of developing prostate cancer.In this issue of the Journal, Flynn-Evans and colleagues examine the potential role of shiftwork as an additional prostate cancer risk factor (2).Flynn-Evans and colleagues combined the results from three separate National Health and Nutrition Examination Surveys (NHANESs) to determine the impact of work schedule on the serum prostate-specific antigen (PSA) values (total and percentage free) of men aged 40 to 65 years (2).Although an imperfect biomarker, increased total PSA and low percentage free PSA are associated with a higher risk of prostate cancer.Because disruptions in circadian rhythms have been implicated in carcinogenesis, the authors sought to investigate the differences between the serum PSA values of men performing shiftwork (defined by the authors as regular night shifts or a rotating schedule) vs all other schedules (3).NHANES, which provides a representative sample of adult, noninstitutionalized American men, is a unique vehicle with which to perform this study.From the combined results of the 2005 to 2006, 2007 to 2008, and 2009 to 2010 surveys, a total of 2017 men had both occupational and PSA information available for analysis.The authors conclude that current shiftworkers aged 40 to 65 years had a statistically significant positive association with elevated PSA of 4.0 ng/mL or greater compared with nonshiftworkers (2).Flynn-Evans and colleagues (2) provide supportive data for the hypothesis that shiftwork may affect serum PSA values, although with some limitations.Although the NHANES dataset is designed to represent the United States as a whole through extrapolation, the sample size of 2017 is small, and the work described by Flynn-Evans and colleagues required corrective measures to properly weight each of the three NHANESs used.For example, only 3% of men in this study had a total PSA value greater than or equal to 4.0 ng/mL, which was their a priori definition of elevated PSA.Although their multivariable model adjusted for age, body mass index, race/ethnicity, health insurance, average hours of sleep per night, and months on the current job, it did not consider other potential covariables, some of which are available through NHANES.For example, NHANES has been used to show an association between altered PSA levels and some medications, diet, and physical activity (4-7).It is possible to hypothesize that nonmedical determinants of health, such as opportunities to exercise, personal dietary preferences, and the availability of healthy eating choices, could vary based on whether a man is a day worker vs. shiftworker.
Induction of Apoptosis by Celecoxib in Cell Culture: An Uncertain Role for Cyclooxygenase-2
Authors: Michael A. Kern, Peter Schirmacher, Tobias Schilling, Martina Müller
Journal: Cancer Research (2007)

In Response: 

We appreciate the letter by Schonthal stating some interesting aspects of the role of prostaglandin pathways in the liver. The data obtained by Schonthal basically confirms our experimental findings ( [1][1]). In his letter, Schonthal, however, disagrees with one of our conclusions