tbuckley/cabot-search huggingface dataset:
β-Blocker Dialyzability and Mortality in Older Patients Receiving Hemodialysis
Authors: Matthew A. Weir, Stephanie N. Dixon, Jamie L. Fleet, Matthew A. Roberts, Daniel G. Hackam, Matthew J. Oliver, Rita S. Suri, Robert R. Quinn, Sundus Ozair, Michael M. Beyea, Abhijat Kitchlu, Amit X. Garg
Journal: Journal of the American Society of Nephrology (2014)

Some β-blockers are efficiently removed from the circulation by hemodialysis (“high dialyzability”) whereas others are not (“low dialyzability”). This characteristic may influence the effectiveness of the β-blockers among patients receiving long-term hemodialysis. To determine whether new use of a high-dialyzability β-blocker compared with a low-dialyzability β-blocker associates with a higher rate of mortality in patients older than age 66 years receiving long-term hemodialysis, we conducted a propensity-matched population-based retrospective cohort study using the linked healthcare databases of Ontario, Canada. The high-dialyzability group (n=3294) included patients initiating atenolol, acebutolol, or metoprolol. The low-dialyzability group (n=3294) included patients initiating bisoprolol or propranolol. Initiation of a high- versus low-dialyzability β-blocker was associated with a higher risk of death in the following 180 days (relative risk, 1.4; 95% confidence interval, 1.1 to 1.8; P<0.01). Supporting this finding, we repeated the primary analysis in a cohort of patients not receiving hemodialysis and found no significant association between dialyzability and the risk of death (relative risk, 1.0; 95% confidence interval, 0.9 to 1.3; P=0.71). β-Blocker exposure was not randomly allocated in this study, so a causal relationship between dialyzability and mortality cannot be determined. However, our findings should raise awareness of this potentially important drug characteristic and prompt further study.
THE MECHANISM OF ANTIGENIC STIMULATION OF PRIMARY AND SECONDARY CLONAL PRECURSOR CELLS
Authors: Norman R. Klinman
Journal: The Journal of Experimental Medicine (1972)

Cell transfers to carrier-immunized irradiated mice have permitted an analysis of the in vitro stimulation of clonal precursors of anti-2,4-dinitrophenyl (DNP) antibody-producing cells derived from both immune and nonimmune mice. The results indicate that: (a) carrier-specific enhancement is obligatory for stimulation of primary precursor cells and increases both the size and number of detectable foci derived from secondary precursors. (b) This carrier-specific enhancement is most apparent in the stimulation of precursors of high-affinity antibody producer cells. (c) The antibody produced by primary foci, like that of secondary foci, appears homogeneous. (d) The frequency of clonal precursors in normal spleens is 38% that in spleens from mice 4–8 months after immunization, and the number of such precursors in normal spleens can be reduced fivefold by specific suppression of donor mice with soluble antigen. (e) The average of association constants of primary monofocal antibodies, like that of primary serum antibody produced in carrier-primed mice, is less than 10-fold lower than that of secondary clonal or serum antibody. (f) The affinity of primary monofocal antibodies shows a slight dependence on stimulating antigen concentration; however, a minimum threshold affinity consonant with stimulation is apparent. (g) Free hapten inhibits antigenic stimulation of primary precursor cells at a much lower concentration than is required for the inhibition of secondary precursors. These results are interpreted as indicating that (a) primary stimulation, like secondary stimulation, results from the selective stimulation by antigen of a population of cells differing from one another in their potential antibody product but each having only a single such product; (b) the antigen receptors of primary cells interact with antigen as if they are monovalent while receptors of secondary cells evidence multivalence; (c) antigenic stimulation appears to require both a relatively high affinity of receptors for bound antigen and an interlinking of receptors through such antigen; stimulation is thus seen as resulting from a stabilization of receptors within antigen-receptor aggregates to the cell surface; (d) T-cells appear to serve both in cross-linking antigens and in amplifying the size of stimulated clones.
Effectiveness of injury prevention programs in female youth soccer: a systematic review
Authors: C Lerch, M Cordes, J Baumeister
Journal: British Journal of Sports Medicine (2011)

Introduction There is growing evidence on the higher vulnerability of the knee in young female soccer players. In adult female soccer populations injury prevention programs had demonstrated positive effects on injury incidence. Beside this functional component it is not only common sense but neuroscientific knowledge from motor learning studies that exercises which include a playful and joyful character are more suitable for young people and may support an enduring effect of prevention. Purpose The aim of the study was (1) to assess the effectiveness of injury prevention programs in female youth soccer and on the other hand to see (2) if prevention programs have been adapted to this specific adolescent population. Methods A systematic literature search was performed in relevant databases (PubMed, PEDro, BioMedLib) to identify injury prevention programs. Randomised controlled trials comparing the effects in female youth soccer players (&lt;18) on the incidence of injuries were screened by two independent reviewers. Results Five studies were included, reporting investigations of injury prevention programs in female youth soccer. Four studies demonstrated an effect on the incidence of different injuries. All programs consist of multi-component exercises categorised by the authors as related to strength, flexibility, plyometrics, agility and balance. In four studies a functional adult prevention program was applied to the young soccer players whereas one study adopted the program to adolescents in terms of the higher variability of exercises to avoid boredom. Conclusion On the basis of the results of five high-quality studies, this review help to demonstrate the effectiveness of injury prevention programs in female youth soccer players. However, the number of studies investigating such intervention programs should be increased. To strengthen the enduring effect of injury prevention the development of joyful and playful programs especially for female youth soccer players may be an option to construct successful intervention programs. This project was supported by the Youth Soccer Foundation ( http://www.stiftung-jugendfussball.de ).
The Drug Development Crisis: Efficiency and Safety
Authors: C. Thomas Caskey
Journal: Annual Review of Medicine (2006)

Despite advancements in genetics, chemistry, and protein engineering, recent years have seen fewer approvals of new drugs, increases in development costs, and high-profile drug withdrawals. This article focuses on technologic methods for improving drug development efficiency. These technologies include high-content cell screening, expression profiling, mass spectroscopy, mouse models of disease, and a post-launch screening program that enables investigations of adverse drug effects. Implementation of these new technologies promises to improve performance in drug development and safety.
Long-term survival of skin allografts induced by donor splenocytes and anti-CD154 antibody in thymectomized mice requires CD4(+) T cells, interferon-gamma, and CTLA4.
Authors: T G Markees, N E Phillips, E J Gordon, R J Noelle, L D Shultz, J P Mordes, D L Greiner, A A Rossini
Journal: Journal of Clinical Investigation (1998)

Treatment of C57BL/6 mice with one transfusion of BALB/c spleen cells and anti-CD154 (anti-CD40-ligand) antibody permits BALB/c islet grafts to survive indefinitely and BALB/c skin grafts to survive for approximately 50 d without further intervention. The protocol induces long-term allograft survival, but the mechanism is unknown. We now report: (a) addition of thymectomy to the protocol permitted skin allografts to survive for > 100 d, suggesting that graft rejection in euthymic mice results from thymic export of alloreactive T cells. (b) Clonal deletion is not the mechanism of underlying long-term graft survival, as recipient thymectomized mice were immunocompetent and harbor alloreactive T cells. (c) Induction of skin allograft acceptance initially depended on the presence of IFN-gamma, CTLA4, and CD4(+) T cells. Addition of anti-CTLA4 or anti-IFN-gamma mAb to the protocol was associated with prompt graft rejection, whereas anti-IL-4 mAb had no effect. The role of IFN-gamma was confirmed using knockout mice. (d) Graft survival was associated with the absence of IFN-gamma in the graft. (e) Long-term graft maintenance required the continued presence of CD4(+) T cells. The results suggest that, with modification, our short-term protocol may yield a procedure for the induction of long-term graft survival without prolonged immunosuppression.
Risk of Endometrial Cancer Following Estrogen Replacement With and Without Progestins
Authors: E. Weiderpass, H.-O. Adami, J. A. Baron, C. Magnusson, R. Bergstrom, A. Lindgren, N. Correia, I. Persson
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: Unopposed estrogen replacement therapy (i.e., estrogen without progestins) increases the risk of endometrial cancer. In this study, we examined the endometrial cancer risk associated with combined estrogen-progestin regimens currently in use, since the safety profiles of these regimens have not been clearly defined. METHODS: We conducted a nationwide population-based, case-control study in Sweden of postmenopausal women aged 50-74 years. We collected information on use of hormone replacement from 709 case patients with incident endometrial cancer and from 3368 control subjects. We used unconditional logistic regression to calculate odds ratios (ORs) as estimates of relative risks. All individual comparisons were made with women who never used the respective hormone replacement regimens. RESULTS: Treatment with estrogens alone was associated with a marked duration- and dose-dependent increase in the relative risk of endometrial cancer. Five or more years of treatment had an OR of 6.2 for estradiol (95% confidence interval [CI] = 3.1-12.6) and of 6.6 for conjugated estrogens (95% CI = 3.6-12.0). Following combined estrogen-progestin use, the association was considerably weaker than that for estrogen alone; the OR was 1.6 (95% CI = 1.1-2.4) after 5 or more years of use. This increase in risk was confined to women with cyclic use of progestins, i.e., fewer than 16 days per cycle (most commonly 10 days per cycle [OR = 2.9; 95% CI = 1.8-4.6 for 5 or more years of use]), whereas continuous progestin use along with estrogens was associated with a reduced risk (OR = 0.2; 95% CI = 0.1-0.8 for 5 or more years of use). CONCLUSION: The risk of developing endometrial cancer is increased after long-term use of estrogens without progestins and with cyclically added progestins. Continuously added progestins may be needed to minimize the endometrial cancer risk associated with estrogen replacement therapy.
Antibodies against major histocompatibility complex class II antigens directly inhibit the growth of T cells infected with Theileria parva without affecting their state of activation.
Authors: M Eichhorn, T D Prospero, V T Heussler, D A Dobbelaere
Journal: The Journal of Experimental Medicine (1993)

We have analyzed the effect of antibodies (Abs) directed against major histocompatibility complex (MHC) class II Abs on the proliferation of Theileria parva-infected (Tpi) T cells. Anti-MHC class II Abs exert a direct effect on Tpi T cells causing an acute block in their proliferation. The inhibition does not involve apoptosis and is also entirely reversible. The rapid arrest of DNA synthesis caused by anti-MHC class II Abs is not due to interference with the state of activation of the T cells since the transcriptional activator NF-kappa B remains activated in arrested cells. In addition, interleukin 2 (IL-2), IL-2R, and c-myc gene expression are also unaffected. By analyzing the cell-cycle phase distribution of inhibited cells, it could be shown that cells in all phases of the cell cycle are inhibited. The signal transduction pathway that results in inhibition was shown to be independent of protein kinase C and extracellular Ca2+. Tyrosine kinase inhibitors, however, partly reduced the level of inhibition and, conversely, phosphatase inhibitors enhanced it. The possible relevance of this phenomenon in other systems is discussed.
An unusual cause of pyrexia
Authors: D C Howlett
Journal: Gut (2005)

A 58 year old male patient presented with a 24 hour history of nausea, vomiting, and right shoulder tip pain with associated rigors. On examination he was tachycardic, 100 beats per minute, and pyrexial (38°C) but clinical examination was otherwise unremarkable. He was taking no medications and the only …
Lethal Skeletal Dysplasia in Mice and Humans Lacking the Golgin GMAP-210
Authors: Patrick Smits, Andrew D. Bolton, Vincent Funari, Minh Hong, Eric D. Boyden, Lei Lu, Danielle K. Manning, Noelle D. Dwyer, Jennifer L. Moran, Mary Prysak, Barry Merriman, Stanley F. Nelson, Luisa Bonafé, Andrea Superti-Furga, Shiro Ikegawa, Deborah Krakow, Daniel H. Cohn, Tom Kirchhausen, Matthew L. Warman, David R. Beier
Journal: New England Journal of Medicine (2010)

Establishing the genetic basis of phenotypes such as skeletal dysplasia in model organisms can provide insights into biologic processes and their role in human disease.We screened mutagenized mice and observed a neonatal lethal skeletal dysplasia with an autosomal recessive pattern of inheritance. Through genetic mapping and positional cloning, we identified the causative mutation.Affected mice had a nonsense mutation in the thyroid hormone receptor interactor 11 gene (Trip11), which encodes the Golgi microtubule-associated protein 210 (GMAP-210); the affected mice lacked this protein. Golgi architecture was disturbed in multiple tissues, including cartilage. Skeletal development was severely impaired, with chondrocytes showing swelling and stress in the endoplasmic reticulum, abnormal cellular differentiation, and increased cell death. Golgi-mediated glycosylation events were altered in fibroblasts and chondrocytes lacking GMAP-210, and these chondrocytes had intracellular accumulation of perlecan, an extracellular matrix protein, but not of type II collagen or aggrecan, two other extracellular matrix proteins. The similarities between the skeletal and cellular phenotypes in these mice and those in patients with achondrogenesis type 1A, a neonatal lethal form of skeletal dysplasia in humans, suggested that achondrogenesis type 1A may be caused by GMAP-210 deficiency. Sequence analysis revealed loss-of-function mutations in the 10 unrelated patients with achondrogenesis type 1A whom we studied.GMAP-210 is required for the efficient glycosylation and cellular transport of multiple proteins. The identification of a mutation affecting GMAP-210 in mice, and then in humans, as the cause of a lethal skeletal dysplasia underscores the value of screening for abnormal phenotypes in model organisms and identifying the causative mutations.
Radical prostatectomy v radiation: only a randomised trial can provide the answer
Authors: M. Roach
Journal: BMJ (2014)

Sooriakumaran and colleagues’ study is one of several that conclude survival is better after prostatectomy than radiotherapy.1 2 These studies have many features in common. They assume a cause and effect association between survival and treatment. They claim that they corrected for confounders. They acknowledge suboptimal radiotherapy (dose and use of androgen deprivation therapy).3 They …
US group lobbies UN to outlaw male circumcision
Authors: Janice Hopkins Tanne
Journal: BMJ (2005)

A US lobby group is urging the United Nations to classify male circumcision as a violation of human rights violation.

The group wants the UN to outlaw the practice and wants a 1996 US federal law banning female genital mutilation to be amended to include circumcision of men and boys under the age of 18. Matthew Hess, president of MGMbill.org (MGM bill stands for the male genital mutilation bill), said that his group was working “to end male genital mutilation.” He said that male circumcision violated the UN's Declaration of Human Rights, the Convention on the Rights of the Child, and the International Covenant of Civil and Political Rights.

The organisation wants UNAIDS, the joint UN programme on HIV and AIDS, …
Overview of Steroidogenic Enzymes in the Pathway from Cholesterol to Active Steroid Hormones
Authors: Anita H. Payne, Dale B. Hales
Journal: Endocrine Reviews (2004)

Significant advances have taken place in our knowledge of the enzymes involved in steroid hormone biosynthesis since the last comprehensive review in 1988. Major developments include the cloning, identification, and characterization of multiple isoforms of 3β-hydroxysteroid dehydrogenase, which play a critical role in the biosynthesis of all steroid hormones and 17β-hydroxysteroid dehydrogenase where specific isoforms are essential for the final step in active steroid hormone biosynthesis. Advances have taken place in our understanding of the unique manner that determines tissue-specific expression of P450aromatase through the utilization of alternative promoters. In recent years, evidence has been obtained for the expression of steroidogenic enzymes in the nervous system and in cardiac tissue, indicating that these tissues may be involved in the biosynthesis of steroid hormones acting in an autocrine or paracrine manner. This review presents a detailed description of the enzymes involved in the biosynthesis of active steroid hormones, with emphasis on the human and mouse enzymes and their expression in gonads, adrenal glands, and placenta.
Cutaneous paraneoplastic granulomatous eruptions secondary to metastatic carcinoid tumour
Authors: J.M. Cohen, V.E. Nambudiri, M.H. Kulke, D.J. Todd, G.F. Murphy, N.R. LeBoeuf
Journal: British Journal of Dermatology (2014)

J.M.C. and V.E.N. contributed equally to this work. Funding sources: none. Conflicts of interest: none declared. Dear Editor, Cutaneous granulomatous eruptions comprise a rare subset of paraneoplastic dermatitides most commonly associated with haematological malignancies. The pathogenesis of these eruptions remains poorly understood. Carcinoid tumours are uncommon neuroendocrine neoplasms that most often arise in the gastrointestinal tract and produce excess serotonin leading to diarrhoea and flushing. Metastases can result in elevated systemic neuroendocrine mediator levels, causing carcinoid syndrome, with cutaneous manifestations including flushing, rosacea, pellagra and, rarely, sclerodermatous changes.1 A 48‐year‐old woman with an 8‐year history of metastatic carcinoid and a 4‐year history of intermittent corticosteroid‐responsive inflammatory polyarthritis and annular facial papules and plaques presented for dermatological evaluation of new bilateral thigh red–orange plaques with yellow papules. The patient's metastatic carcinoid tumour was stable following diagnosis, but progressed 4 years prior to dermatological evaluation, requiring bowel resections, octreotide, diphenoxylate with atropine and deodorized tincture of opium.
Effect of oral digoxin in high‐risk heart failure patients: a pre‐specified subgroup analysis of the DIG trial
Authors: Mihai Gheorghiade, Kanan Patel, Gerasimos Filippatos, Stefan D. Anker, Dirk J. van Veldhuisen, John G.F. Cleland, Marco Metra, Inmaculada B. Aban, Stephen J. Greene, Kirkwood F. Adams, John J.V. McMurray, Ali Ahmed
Journal: European Journal of Heart Failure (2013)
A simple method for short-term (6-hour) transport of the dog heart prior to orthotopic transplantation
Authors: E. Proctor, G. Matthews
Journal: Thorax (1970)

A method of transporting the isolated dog heart for periods of up to 6 hours is described. It consists essentially of flush-cooling the heart with a suitable water-based solution at 4-6° C. followed by storage in a specially designed portable container which maintains the temperature of the heart at 4-6° C. The viability of the hearts was tested by orthotopic transplantation. Of nine hearts so stored (six for 6 hours), all supported the recipient circulation immediately after transplantation, with a mean systemic arterial pressure of 70 to 100 mm. Hg and a mean max. dp/dt of the left ventricular pressure of 1,050 mm. Hg/second without catecholamine stimulation. A comparable group of hearts flush-cooled in the same way but stored in ice after the manner of the method used for kidney transport was markedly inferior in performance to those stored at 4-6° C. Some of the limitations of non-perfusion methods of storing the heart are discussed.
Genetic Risk and Carcinogen Exposure: a Common Inherited Defect of the Carcinogen-Metabolism Gene Glutathione S-Transferase M1 (GSTM1) That Increases Susceptibility to Bladder Cancer
Authors: D. A. Bell, J. A. Taylor, D. F. Paulson, C. N. Robertson, J. L. Mohler, G. W. Lucier
Journal: JNCI Journal of the National Cancer Institute (1993)

Background : Numerous studies have associated bladder cancer with exposure to carcinogens present in tobacco smoke and other environmental or occupational exposures. Approximately 50% of all humans inherit two deleted copies of the GSTM1 gene which encodes for the carcinogendetoxification enzyme glutathione S -transferase M1. Recent findings suggest that the GSTM1 gene may modulate the internal dose of environmental carcinogens and thereby affect the risk of developing bladder cancer. Purpose : We investigated whether the absence of the GSTM1 gene affects bladder cancer risk and whether there are racial differences in GSTM1 genotype frequency. Methods : Using a polymerase chain reaction (PCR)-based method, we examined the frequency of the homozygous deleted genotype (GSTM1 0/0) in 229 patients with transitional cell carcinoma of the bladder and 211 control subjects who were enrolled from the Urology Clinics at Duke University Medical Center and the University of North Carolina Hospitals. Control subjects were urology clinic patients who primarily presented with benign prostatic hypertrophy or impotence, who had no history of any cancer other than nonmelanoma skin cancer, and who were frequency matched to case patients on race, sex, and age (10-year age intervals). In order to explore racial differences in GSTM1 gene frequency, genotype was also determined in a community-based sample of 466 paid, healthy, unrelated volunteers from Durham and Chapel Hill, N.C. The presence or absence of the GSTM1 gene locus was determined by using a differential PCR, a semiquantitative technique in which multiple genes are coamplified. Results : Overall, the GSTM1 0/0 genotype conferred a 70% increased risk of bladder cancer (odds ratio [OR] = 1.7; 95% confidence interval [CI] = 1.2−2.5; P = .004). Absence of the GSTM1 gene encoding the glutathione S -transferase M1enzyme significantly increased risk to persons with exposure to the carcinogens in tobacco smoke (OR = 1.8; 95% CI = 1.2−3.0; P = .01) but poses little increased risk to persons without such exposure. Persons with smoking exposure of more than 50 pack-years who had the GSTM1 0/0 genotype had a sixfold greater risk relative to persons in the lowest risk group (i.e., nonsmokers who were GSTM1 +/+ or +/0). In the pooled clinic control and community sample groups (677 individuals), the GSTM1 0/0 genotype occurred less frequently among Blacks (35%) than among Whites (49%, P<.001). Conclusions : These findings support a protective role for the GSTM1 gene in bladder cancer. From these findings, it is estimated that 25% of all bladder cancer may be attributable to the at-risk GSTM1 0/0 genotype. [J Natl Cancer Inst 85: 1159–1164, 1993]