tbuckley/cabot-search huggingface dataset:
The Nutritional Significance of Lipid Rafts
Authors: Parveen Yaqoob
Journal: Annual Review of Nutrition (2009)

The structure, size, stability, and functionality of lipid rafts are still in debate, but recent techniques allowing direct visualization have characterized them in a wide range of cell types. Lipid rafts are potentially modifiable by diet, particularly (but not exclusively) by dietary fatty acids. However, it is not clear whether dietary polyunsaturated fatty acids (PUFAs) are incorporated into raft lipids or whether their low affinity to cholesterol disallows this and causes phase separation from rafts and displacement of raft proteins. This review examines the potential for dietary modification of raft structure and function in the immune system, brain and retinal tissue, the gut, and in cancer cells. Although there is increasing evidence to suggest that membrane microdomains, and their modulation, have an impact in health and disease, it is too early to judge whether modulation of lipid rafts is responsible for the immunomodulatory effects of n-3 PUFA. In addition to dietary fatty acids, gangliosides and cholesterol may also modulate microdomains in a number of tissues, and recent work has highlighted sphingolipids in membrane microdomains as potential targets for inhibition of tumor growth by n-3 PUFA. The roles of fatty acids and gangliosides in cognitive development, age-related cognitive decline, psychiatric disorders, and Alzheimer's disease are poorly understood and require clarification, particularly with respect to the contribution of lipid rafts. The roles of lipid rafts in cancer, in microbial pathogenesis, and in insulin resistance are only just emerging, but compelling evidence indicates the growing importance of membrane microdomains in health and disease.
Risk Factors for Development of Decreased Kidney Function in a Southeast Asian Population
Authors: Somnuek Domrongkitchaiporn, Piyamitr Sritara, Chagriya Kitiyakara, Wasana Stitchantrakul, Vorasakdi Krittaphol, Porntip Lolekha, Sayan Cheepudomwit, Tada Yipintsoi
Journal: Journal of the American Society of Nephrology (2005)

End-stage kidney disease has become an increasing burden in all regions of the world. However, limited epidemiologic data on chronic kidney disease in Southeast Asian populations are available. Therefore, a cohort study over a period of 12 yr (1985 to 1997) in 3499 employees of the Electric Generation Authority of Thailand, aged 35 to 55 yr, was conducted to determine the prevalence of decreased kidney function and risk factors associated with future development of decreased kidney function. The prevalence of decreased kidney function (GFR &lt;60 ml/min) increased from 1.7% (95% confidence interval [CI], 1.3 to 2.1) in 1985 to 6.8% (95% CI, 5.7 to 7.9) in 1997, and the prevalence of elevated serum creatinine was 6.1% (95% CI, 5.3 to 6.9) and 16.9% (95% CI, 15.3 to 18.5) in 1985 and 1997 surveys, respectively. The adjusted odds ratio for future development of decreased kidney function was 2.57 (1.0 to 6.81) for systolic hypertension (&gt;159 mmHg), 1.82 (1.12 to 2.98) for hyperuricemia (&gt;6.29 mg/dl), 1.68 (1.02 to 2.77) for elevated body mass index (&gt;24.9 kg/m<sup>2</sup>) compared with subjects with systolic BP &lt;140 mmHg, serum uric acid &lt;4.5 mg/dl, and body mass index 20.8 to 22.8 kg/m<sup>2</sup>. The rising prevalence of decreased kidney function in this population resulted mainly from the increasing prevalence of the risk factors in the population. Screening to detect decreased kidney function and early intervention to modify the associated risk factors should be considered in otherwise healthy individuals. Future studies are also necessary to determine whether implementation of these measures results in a reduction of ESRD incidence in the population.
Comparison of Fulvestrant Versus Tamoxifen for the Treatment of Advanced Breast Cancer in Postmenopausal Women Previously Untreated With Endocrine Therapy: A Multinational, Double-Blind, Randomized Trial
Authors: Anthony Howell, John F.R. Robertson, Paul Abram, Mikhail R. Lichinitser, Richard Elledge, Emilio Bajetta, Toru Watanabe, Charles Morris, Alan Webster, Isaiah Dimery, C. Kent Osborne
Journal: Journal of Clinical Oncology (2004)

To evaluate the efficacy and tolerability of fulvestrant (Faslodex; AstraZeneca Pharmaceuticals LP, Wilmington, DE), a new estrogen receptor (ER) antagonist that downregulates ER and has no agonist effects, versus tamoxifen, an antiestrogen with agonist and antagonist effects, for the treatment of advanced breast cancer in postmenopausal women.In this multicenter, double-blind, randomized trial, patients with metastatic/locally advanced breast cancer previously untreated for advanced disease were randomly assigned to receive either fulvestrant (250 mg, via intramuscular injection, once monthly; n = 313) or tamoxifen (20 mg, orally, once daily; n = 274). Patients' tumors were positive for ER (ER+) and/or progesterone receptor (PgR+), or had an unknown receptor status.At a median follow-up of 14.5 months, there was no significant difference between fulvestrant and tamoxifen for the primary end point of time to progression (TTP; median TTP, 6.8 months and 8.3 months, respectively; hazard ratio, 1.18; 95% CI, 0.98 to 1.44; P =.088). In a prospectively planned subset analysis of patients with known ER+ and/or PgR+ tumors ( approximately 78%), median TTP was 8.2 months for fulvestrant and 8.3 months for tamoxifen (hazard ratio, 1.10; 95% CI, 0.89 to 1.36; P =.39). The objective response rate for the overall population was 31.6% with fulvestrant and 33.9% with tamoxifen, and 33.2% and 31.1%, respectively, in the known hormone receptor-positive subgroup. Both treatments were well tolerated.In the overall population, between-group differences in efficacy end points favored tamoxifen, and statistical noninferiority of fulvestrant could not be demonstrated. However, in patients with hormone receptor-positive tumors, fulvestrant had similar efficacy to tamoxifen and was well tolerated.
A Model to Determine Workforce Needs for Endocrinologists in the United States Until 2020
Authors: Robert A. Rizza, Robert A. Vigersky, Helena W. Rodbard, Paul W. Ladenson, William F. Young, Martin I. Surks, Richard Kahn, Paul F. Hogan
Journal: Diabetes Care (2003)

The objective of this study was to define the workforce needs for the specialty of Endocrinology, Diabetes, and Metabolism in the United States between 1999 and 2020. An interactive model of factors likely to influence the balance between the supply and demand of endocrinologists during the next 20 years was constructed. The model used data from a wide range of sources and was developed under the guidance of a panel of experts derived from sponsoring organizations of endocrinologists. We determined current and projected numbers and demographics of endocrinologists in the U.S. workforce and the anticipated balance between supply and demand from 1999 to 2020. There were 3,623 adult endocrinologists in the workforce in 1999, of which 2,389 (66%) were in office-based practice. Their median age was 49 years. Both total office visits and services performed by endocrinologists (particularly for diabetes) increased substantially during the 1990s. Waiting time for an initial appointment is presently longer for endocrinologists than for other physicians. Compared with a balanced, largely closed-staff health maintenance organization, the current national supply of endocrinologists is estimated to be 12% lower than demand. The number of endocrinologists entering the market has continuously fallen over the previous 5 years, from 200 in 1995 to 171 in 1999. Even if this downward trend were abruptly stopped, the model predicts that demand will exceed supply from now until 2020. While this gap narrows from 2000 to 2008 due to projected growth of managed care, it widens thereafter due to the aging of both the population and the endocrine workforce. Inclusion of other factors such as projected real income growth and increased prevalence of age-related endocrine disorders (e.g., diabetes and osteoporosis) further accentuates the deficit. If the number of endocrinologists entering the workforce remains at 1999 levels, demand will continue to exceed supply from now through 2020 for adult endocrinologists, and the gap will widen progressively from 2010 onward. The present analysis indicates that the number of endocrinologists entering the workforce will not be sufficient to meet future demand. These data suggest that steps should be taken to stop the ongoing decline in the number of endocrinologists in training and consideration should be given to actions designed to increase the number of endocrinologists in practice in the years ahead.
What is the evidence for chronic concussion-related changes in retired athletes: behavioural, pathological and clinical outcomes?
Authors: Paul McCrory, Willem H Meeuwisse, Jeffrey S Kutcher, Barry D Jordan, Andrew Gardner
Journal: British Journal of Sports Medicine (2013)

Objective The purpose of this paper was to review the current state of evidence for chronic traumatic encephalopathy (CTE) in retired athletes and to consider the potential differential diagnoses that require consideration when retired athletes present with cognitive and psychiatric problems. Data sources MEDLINE, CINAHL, EMBASE, Mosby's Index, PsycEXTRA, PsycINFO and Scopus. Key words included CTE, dementia pugilistica, punch drunk syndrome, traumatic encephalopathy, CTE, repetitive head injury, sports concussion, multiple concussions, chronic concussions, subconcussive blow and sports-related traumatic brain injury. Results At present, there are no published epidemiological, cross-sectional or prospective studies relating to modern CTE. Owing to the nature of the published studies, being case reports or pathological case series, it is not possible to determine the causality or risk factors with any certainty. As such, the speculation that repeated concussion or subconcussive impacts cause CTE remains unproven. The extent to which age-related changes, psychiatric or mental health illness, alcohol/drug use or coexisting dementing illnesses contribute to this process is largely unaccounted for in the published literature. Conclusions At present, the interpretation of causation in the modern CTE case studies should proceed cautiously. The causal assumptions require further prospective or longitudinal studies on the topic.
Bleomycin-Induced Flagellate Hyperpigmentation
Authors: Omar A Ibrahimi, R Rox Anderson
Journal: New England Journal of Medicine (2010)

A 39-year-old woman with a long-standing vascular malformation of the posterior tongue underwent intralesional sclerotherapy with a single dose of bleomycin. Within 1 week after treatment, painless, nonpruritic, flagellate hyperpigmentation developed on her trunk. She had no alopecia and no changes in the appearance of nails or mucosa. She reported having no dyspnea or pulmonary symptoms. Bleomycin is a glycopeptide antibiotic commonly used for chemical pleurodesis, the treatment of cutaneous warts, and the treatment of a variety of cancers. The rate of flagellate hyperpigmentation in patients who are treated with bleomycin may be as high as 20%. Most tissues contain . . .
JAK/STAT Signaling Is Associated With Cardiac Dysfunction During Ischemia and Reperfusion
Authors: Eduardo Mascareno, Mohammed El-Shafei, Nilanjana Maulik, M. Sato, Yueling Guo, Dipak K. Das, M.A.Q. Siddiqui
Journal: Circulation (2001)

Background Activation of the heart renin-angiotensin system (RAS) under pathophysiological conditions has been correlated with the development of ischemic injury. The binding of angiotensin II to its receptors triggers induction of several, perhaps multifunctional, intracellular signaling pathways, notable among them the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. In this study, we investigated whether the JAK/STAT signaling is involved in the ischemia/reperfusion injury in adult rat myocardium. Methods and Results We report here that 2 components of the JAK/STAT signaling pathway, namely STAT 5A and STAT 6, are selectively activated in the rat heart subjected to ischemia/reperfusion. The activated STATs bind to a conserved nucleotide sequence (St domain) in the promoter of the angiotensinogen (ANG) gene and consequently upregulate the level of ANG mRNA. Treatment of the hearts with losartan (4.5 μmol/L), an AT 1 blocker, or with tyrphostin AG490 (5 μmol/L), an inhibitor of JAK 2 phosphorylation, results in loss of the STAT/ANG promoter binding activity and an upregulated level of ANG mRNA. Hearts treated with the JAK 2 inhibitor tyrphostin AG490 showed a reduction in myocardial infarct size and in number of cardiomyocytes undergoing apoptosis. The treated hearts also showed a recovery in functional hemodynamics of the myocardium. Conclusions These findings suggest that activation of the JAK/STAT signaling pathway is a significant contributing factor to the pathogenesis of myocardial ischemia and that interference in activation of the pathway potentiates recovery in cardiac function.
Long-lasting complete remission in patients with hairy cell leukemia treated with 2-CdA: a 5-year survey
Authors: F Lauria, D Rondelli, PL Zinzani, M Bocchia, G Marotta, M Salvucci, D Raspadori, MA Ventura, S Birtolo, F Forconi, S Tura
Journal: Leukemia (1997)
Transgenic Mice Expressing the p75 CCAAT-Displacement Protein/Cut Homeobox Isoform Develop a Myeloproliferative Disease–Like Myeloid Leukemia
Authors: Chantal Cadieux, Sylvie Fournier, Alan C. Peterson, Christian Bédard, Barry J. Bedell, Alain Nepveu
Journal: Cancer Research (2006)

Abstract The p75 CCAAT-displacement protein/Cut homeobox (CDP/Cux) isoform was previously reported to be overexpressed in human breast cancers. To investigate its oncogenic potential, we engineered two transgenic mouse lines expressing p75 CDP/Cux under the control of the mouse mammary tumor virus-long terminal repeat. The FVB strain of mouse is generally used in the generation of mouse models for breast cancer. The transgene was introduced into the hprt locus of 129/Ola embryonic stem cells and, following germ line passage, was backcrossed onto the FVB and C57BL/6 mouse strains. Here, we describe the phenotype of p75 CDP/Cux transgenic virgin female mice of the first backcross generations. We report that after a long latency period, ∼33% of mice from two independent transgenic lines and from backcrosses into either the FVB or the C57BL/6 strains succumbed to a similar disease characterized by splenomegaly, hepatomegaly, and frequent infiltration of leukocytes into nonhematopoietic organs like the kidneys and lungs. Although an excess of B or T cells was observed in three diseased mice, in 17 other cases, histologic and flow cytometry analyses revealed the expansion of a population of neutrophils in the blood, spleen, and bone marrow. The increase in neutrophils correlated with signs of anemia and thrombocytopenia, whereas there was no indication of a reactive process. Therefore, p75 CDP/Cux transgenic mice displayed heightened susceptibility to a disease defined as a myeloproliferative disease–like myeloid leukemia. These results indicate that the overexpression of p75 CDP/Cux could alter homeostasis in the hematopoietic compartment. (Cancer Res 2006; 66(19): 9492-501)
Henoch-Schönlein Purpura Nephritis
Authors: ANUP RAI, CYNTHIA NAST, SHARON ADLER
Journal: Journal of the American Society of Nephrology (1999)

Henoch-Schonlein purpura (HSP) is a systemic vasculitic disorder first reported by Heberden in 1806. The association of purpura and joint pain was described by Schonlein in 1837, who termed it “peliosis rheumatica.” Henoch added a description of four children with skin lesions associated with
Production of transforming growth factor beta 1 during repair of arterial injury.
Authors: M W Majesky, V Lindner, D R Twardzik, S M Schwartz, M A Reidy
Journal: Journal of Clinical Investigation (1991)

Repair of arterial injury produced by balloon angioplasty leads to the formation of a neointima and a narrowing of the vascular lumen. In this study, we examined the possibility that smooth muscle cells (SMC) in injured rat carotid arteries are stimulated to produce type-1 transforming growth factor-beta (TGF-beta 1) during neointima formation in vivo. Levels of TGF-beta 1 transcripts (2.4 kb) were significantly increased within 6 h after carotid injury and reached a maximum (five to sevenfold) by 24 h. Regenerating left carotids had sustained increases in TGF-beta 1 mRNA levels (about fivefold) over the next 2 wk, during which time a substantial neointimal thickening was formed. No changes in basal TGF-beta 1 mRNA levels were found in contralateral uninjured carotids at any of the times examined. Immunohistochemical studies showed that a large majority of neointimal SMC were stained for TGF-beta 1 protein in an intracellular pattern, consistent with active TGF-beta 1 synthesis in this tissue. Neointima formation and TGF-beta 1 immunoreactivity were correlated with increases in fibronectin, collagen alpha 2(I), and collagen alpha 1(III) gene expression. Infusion of purified, recombinant TGF-beta 1 into rats with a preexisting neointima produced a significant stimulation of carotid neointimal SMC DNA synthesis. These results suggest that TGF-beta 1 plays an important role as an endogenous growth regulatory factor produced by neointimal SMC themselves during progressive neointimal thickening after balloon angioplasty.
Poor Survival for Infants With <i>MYCN</i>-Amplified Metastatic Neuroblastoma Despite Intensified Treatment: The International Society of Paediatric Oncology European Neuroblastoma Experience
Authors: Adela Canete, Mary Gerrard, Hervé Rubie, Victoria Castel, Andrea Di Cataldo, Caroline Munzer, Ruth Ladenstein, Bénédicte Brichard, José D. Bermúdez, Jerôme Couturier, Bruno de Bernardi, Andrew J. Pearson, Jean Michon
Journal: Journal of Clinical Oncology (2009)

Purpose To report the results of a prospective, nonrandomized European study on infants with neuroblastoma and MYCN gene amplification. Patients and Methods Infants with neuroblastoma (stage 2, 3, 4, and 4s) and MYCN gene amplification who were diagnosed between 1999 and 2004 were eligible for enrollment onto the study. After diagnosis, staging, and mandatory biologic studies, induction chemotherapy (IC) with conventional drugs was administered, followed by delayed surgery, megatherapy (busulfan-melphalan as a conditioning regimen), and local radiotherapy. Results Of the 46 infants enrolled onto the study, 35 infants were eligible; of these 35 infants, 97% had metastatic spread (24 infants had stage 4, and 10 infants had stage 4s). Two-year overall survival (OS) was 30% (SE, 0.08), with median survival time of 12 months, and 23 deaths due to disease. Two-year, event-free survival (EFS) was 29% (SE, 0.07). The treatment was well tolerated with no deaths as a result of toxicity or severe toxicity. Despite protocol adherence, 30% of the patients who were assessable for response to IC experienced disease progression or did not respond. Stage and high lactate dehydrogenase reached significance in the univariate analysis (P = .028 and .039, respectively for OS; and P = .05 and .031 respectively, for EFS). Ten of 16 patients who received megatherapy are still alive. Conclusion Although treatment was well tolerated, survival was poor and our IC failed to achieve a satisfactory response in 30% of our patients. New therapeutic approaches and more intense world-wide collaboration are needed to achieve a cure in this population.
Chronic Lobular Hepatitis: A Clinicopathological and Prognostic Study
Authors: Yun-Fan Liaw, Chia-Ming Chu, Tong-Jong Chen, Deng-Yn Lin, Chi-Sin Chang-Chien, Cheng-Shyong Wu
Journal: Hepatology (1982)

A series of 80 patients with chronic lobular hepatitis (CLH) was reviewed clinically and histologically to demonstrate etiology, clinical presentation, course, and prognosis of this disorder. Data from our study indicate that CLH in Taiwan is a disease of viral origin, mostly hepatitis B (67.5%) and some non–A, non–B. It occurs predominantly in young males (81.3%); frequently commences as acute viral hepatitis (57.5%); and has clinical and laboratory features similar to convalescent viral hepatitis or even indistinguishable from full–blown acute viral hepatitis. Clinical and histological follow–up study indicate that CLH may extend for several years with remissions and relapses. No evidence of progression to cirrhosis was observed at least in a 4½–year period of follow–up. It is concluded that CLH is a persistent but nonprogressive disease although the number of non–A, non–B CLH is too small to ascertain its nonprogressive course. The prognosis is generally good, and no specific therapy is required.
A platelet and granulocyte membrane defect in paroxysmal nocturnal hemoglobinuria: usefulness for the detection of platelet antibodies
Authors: Richard H. Aster, Sara E. Enright
Journal: Journal of Clinical Investigation (1969)

The tendency of platelets and leukocytes to lyse after their interaction with antibody and complement was studied by measuring the release of 51Cr from cells labeled with this isotope. Platelets from six patients with paroxysmal nocturnal hemoglobinuria (PNH) were 15-230 times more sensitive to antibodies and 10-32 times more sensitive to complement than normal platelets or platelets from patients with other types of thrombocytopenic or hemolytic disorders. Mixed white blood cell (WBC) preparations from patients with PNH were 3-20 times more sensitive to anti-WBC antibodies and 5-10 times more sensitive to C′ than were WBC preparations from normal subjects, but PNH lymphocytes showed normal immunologic reactivity. PNH platelets, like PNH erythrocytes, lysed more readily than normal platelets in acidified serum and in media of reduced ionic strength, but these characteristics were not demonstrable with PNH WBC's under the conditions of study. In PNH, platelets appear to comprise a single population with respect to their sensitivity to immune lysis, yet their survival time as measured with 51Cr falls within normal limits. PNH granulocytes likewise appear to consist of a single, uniformly sensitive population.
A checkpoint for autoreactivity in human IgM+ memory B cell development
Authors: Makoto Tsuiji, Sergey Yurasov, Klara Velinzon, Saskia Thomas, Michel C. Nussenzweig, Hedda Wardemann
Journal: The Journal of Experimental Medicine (2006)

Autoantibodies are removed from the repertoire at two checkpoints during B cell development in the bone marrow and the periphery. Despite these checkpoints, up to 20% of the antibodies expressed by mature naive B cells in healthy humans show low levels of self-reactivity. To determine whether self-reactive antibodies are also part of the antigen-experienced memory B cell compartment, we analyzed recombinant antibodies cloned from single circulating human IgM+ memory B cells. Cells expressing antibodies specific for individual bacterial polysaccharides were expanded in the IgM+ memory compartment. In contrast, B cells expressing self-reactive and broadly bacterially reactive antibodies were removed from the repertoire in the transition from naive to IgM+ memory B cell. Selection against self-reactive antibodies was implemented before the onset of somatic hypermutation. We conclude that a third checkpoint selects against self-reactivity during IgM+ memory B cell development in humans.