tbuckley/cabot-search huggingface dataset:
Low Serum Testosterone Increases Mortality Risk among Male Dialysis Patients
Authors: Juan Jesu[Combining Acute Accent]s Carrero, Abdul Rashid Qureshi, Paolo Parini, Stefan Arver, Bengt Lindholm, Peter Ba[Combining Acute Accent]ra[Combining Acute Accent]ny, Olof Heimbu[Combining Diaeresis]rger, Peter Stenvinkel
Journal: Journal of the American Society of Nephrology (2009)

Men treated with hemodialysis (HD) have a very poor prognosis and an elevated risk of premature cardiovascular disease (CVD). In the general population, associations between low testosterone concentrations and cardiovascular risk have been suggested. We performed a prospective observational study involving a well characterized cohort of 126 men treated with HD to examine the relationship between testosterone concentration and subsequent mortality during a mean follow-up period of 41 mo. Independent of age, serum creatinine, and sexual hormone binding globulin (SHBG), testosterone levels inversely and strongly associated with the inflammatory markers IL-6 and CRP. Patients with a clinical history of CVD had significantly lower testosterone levels. During follow up, 65 deaths occurred, 58% of which were a result of CVD. Men with testosterone values in the lowest tertile had increased all-cause and CVD mortality (crude hazard ratios [HRs] 2.03 [95% CI 1.24 to 3.31] and 3.19 [1.49 to 6.83], respectively), which persisted after adjustment for age, SHBG, previous CVD, diabetes, ACEi/ARB treatment, albumin, and inflammatory markers, but was lost after adjustment for creatinine. In summary, among men treated with HD, testosterone concentrations inversely correlate with all-cause and CVD-related mortality, as well as with markers of inflammation. Hypogonadism may be an additional treatable risk factor for patients with chronic kidney disease.
Osteoarthritis as an outcome of paediatric sport: an epidemiological perspective
Authors: Dennis J Caine, Yvonne M Golightly
Journal: British Journal of Sports Medicine (2011)

Recent data suggest that the risk of paediatric sport injury is high and constitutes a significant public health burden. A concern regarding long-term consequences of youth sports injury is the risk of developing osteoarthritis (OA) at a young age. Based on the available evidence, a link between youth sports injuries, particularly acute injury of the knee and ankle, and OA, is likely. Early OA development and intense participation in high-impact, high-stress elite sports at an early age also may be associated, but follow-up of elite athletes into the early adult years is needed to examine this relationship. Given that some antecedents of early adult-onset OA may be traced to child and adolescent sports injury and related surgery, and perhaps intense training regimens, it follows that efforts to prevent sports-related joint injury should begin during the childhood years. Based on the results of recent research evidence, programmes addressing prevention of youth sports injuries may provide the rewarding results of OA prevention.
Primary Electrical Disorder or Primary Cardiomyopathy?
Authors: Zsófia Szentpáli, Tamas Szili-Torok, Kadir Caliskan
Journal: Circulation (2013)

N oncompaction cardiomyopathy (NCCM) is a rare pri- mary cardiomyopathy caused by an arrest in myocardial morphogenesis. 1 The clinical manifestations are highly variable from asymptomatic to severe heart failure, arrhythmias, sudden cardiac death, or systemic thrombo-embolic events.Association of NCCM and electric disorders has been reported as rare case reports with WPW syndrome and Brugada syndrome, 2 But to the best of our knowledge, an association with catecholaminergic polymorphic ventricular tachycardia (CPVT) and NCCM has never been reported.The aim of the case report is to present unique features of both NCCM and gene mutation-proven CPVT in 1 patient, raising new questions.
Preclinical Testing of PI3K/AKT/mTOR Signaling Inhibitors in a Mouse Model of Ovarian Endometrioid Adenocarcinoma
Authors: Rong Wu, Tom C. Hu, Alnawaz Rehemtulla, Eric R. Fearon, Kathleen R. Cho
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Genetically engineered mouse (GEM) models of ovarian cancer that closely recapitulate their human tumor counterparts may be invaluable tools for preclinical testing of novel therapeutics. We studied murine ovarian endometrioid adenocarcinomas (OEA) arising from conditional dysregulation of canonical WNT and PI3K/AKT/mTOR pathway signaling to investigate their response to conventional chemotherapeutic drugs and mTOR or AKT inhibitors. Experimental Design: OEAs were induced by injection of adenovirus expressing Cre recombinase (AdCre) into the ovarian bursae of Apcflox/flox; Ptenflox/flox mice. Tumor-bearing mice or murine OEA-derived cell lines were treated with cisplatin and paclitaxel, mTOR inhibitor rapamycin, or AKT inhibitors API-2 or perifosine. Treatment effects were monitored in vivo by tumor volume and bioluminescence imaging, in vitro by WST-1 proliferation assays, and in OEA tissues and cells by immunoblotting and immunostaining for levels and phosphorylation status of PI3K/AKT/mTOR signaling pathway components. Results: Murine OEAs developed within 3 weeks of AdCre injection and were not preceded by endometriosis. OEAs responded to cisplatin + paclitaxel, rapamycin, and AKT inhibitors in vivo. In vitro studies showed that response to mTOR and AKT inhibitors, but not conventional cytotoxic drugs, was dependent on the status of PI3K/AKT/mTOR signaling. AKT inhibition in APC−/Pten− tumor cells resulted in compensatory upregulation of ERK signaling. Conclusions: The studies show the utility of this GEM model of ovarian cancer for preclinical testing of novel PI3K/AKT/mTOR signaling inhibitors and provide evidence for compensatory signaling, suggesting that multiple rather than single agent targeted therapy will be more efficacious for treating ovarian cancers with activated PI3K/AKT/mTOR signaling. Clin Cancer Res; 17(23); 7359–72. ©2011 AACR.
A maturase-encoding group III twintron is conserved in deeply rooted euglenoid species: are group III introns the chicken or the egg?
Authors: N. A. Doetsch, M. D. Thompson, R. B. Hallick
Journal: Molecular Biology and Evolution (1998)

The fourth intron of the Euglena gracilis chloroplast photosystem II gene, psbCi4, is a 1,605-bp twintron composed of two group III introns and a coding locus for a 458-aa polypeptide, mat1, located in the internal intron. psbCi4 homologs have been identified in seven euglenoids, including E. myxocylindracea, E. viridis, E. deses, E. pisciformis, Cryptoglena pigra, Eutreptia sp., and Lepocinclis beutschlii. All of the species examined contain both the group III twintron and the mat1 locus, revealing a more widespread occurrence of group III introns than previously known. The L. beutschlii mat1 locus is interrupted by two novel mini-group II introns of 224 and 258 nt, the smallest group II introns yet identified. Reverse transcriptase polymerase chain reaction analysis confirmed the splicing boundaries of the external and internal E. myxocylindracea, E. viridis, and E. deses introns as well as the novel L. beutschlii mat1 introns. As determined by comparative phylogenetic analysis, group III introns contain a structural homolog of group II intron domain VI. The mat1 loci encode peptide motifs characteristic of group II intron maturases. A group III intron-encoded protein whose predicted sequence is similar to group II intron-encoded maturases and a bona fide domain VI within group III introns are compelling evidence for a common ancestor of group II and group III introns.
Dietary L-Lysine Prevents Arterial Calcification in Adenine-Induced Uremic Rats
Authors: Akihiro Shimomura, Isao Matsui, Takayuki Hamano, Takuya Ishimoto, Yumiko Katou, Kenji Takehana, Kazunori Inoue, Yasuo Kusunoki, Daisuke Mori, Chikako Nakano, Yoshitsugu Obi, Naohiko Fujii, Yoshitsugu Takabatake, Takayoshi Nakano, Yoshiharu Tsubakihara, Yoshitaka Isaka, Hiromi Rakugi
Journal: Journal of the American Society of Nephrology (2014)

Vascular calcification (VC) is a life-threatening complication of CKD. Severe protein restriction causes a shortage of essential amino acids, and exacerbates VC in rats. Therefore, we investigated the effects of dietary L-lysine, the first-limiting amino acid of cereal grains, on VC. Male Sprague-Dawley rats at age 13 weeks were divided randomly into four groups: low-protein (LP) diet (group LP), LP diet+adenine (group Ade), LP diet+adenine+glycine (group Gly) as a control amino acid group, and LP diet+adenine+L-lysine·HCl (group Lys). At age 18 weeks, group LP had no VC, whereas groups Ade and Gly had comparable levels of severe VC. L-Lysine supplementation almost completely ameliorated VC. Physical parameters and serum creatinine, urea nitrogen, and phosphate did not differ among groups Ade, Gly, and Lys. Notably, serum calcium in group Lys was slightly but significantly higher than in groups Ade and Gly. Dietary L-lysine strongly suppressed plasma intact parathyroid hormone in adenine rats and supported a proper bone-vascular axis. The conserved orientation of the femoral apatite in group Lys also evidenced the bone-protective effects of L-lysine. Dietary L-lysine elevated plasma alanine, proline, arginine, and homoarginine but not lysine. Analyses in vitro demonstrated that alanine and proline inhibit apoptosis of cultured vascular smooth muscle cells, and that arginine and homoarginine attenuate mineral precipitations in a supersaturated calcium/phosphate solution. In conclusion, dietary supplementation of L-lysine ameliorated VC by modifying key pathways that exacerbate VC.
Predicting Residual Disease and Local Recurrence in Patients With Ductal Carcinoma In Situ
Authors: M. J. Silverstein
Journal: JNCI Journal of the National Cancer Institute (1997)

phenotype and p53 gene mutation in lymphomas of mucosa-associated lymphoid tissue. Am J Pathol 1996;148:643–8. (23) de Jong D, Boot H, van Heerde P, Hart GA, Taal BG. Histological grading in gastric lymphoma: pretreatment criteria and clinical relevance. Gastroenterology 1997;112:1466–74. (24) Coiffier B, Salles G. Does surgery belong to medical history for gastric lymphomas? Ann Oncol 1997;8:419–21.
Determination of the Pulmonary Capillary Blood Flow in Man
Authors: MARIO RIGATTO, GERARD M. RIGATTO, ALFRED P. FISHMAN
Journal: Circulation Research (1961)

A method is described for the measurement of the pulmonary capillary blood flow in human subjects with normal lungs. The method depends on the performance of a vital capacity maneuver using nitrous oxide as the test gas. It attempts to circumvent the deficiencies of previous respiratory methods by using an infrared analyzer for the continuous measurement of the concentration of N 2 O in expired air, by ensuring that the respiratory maneuver is completed before recirculation occurs, and by determining simultaneously the values involved in the formula used for the calculation of the flow. As a basis for the method, the pulmonary recirculation time and the rate of N 2 O absorption by the lungs were measured separately. The values for the pul monary capillary blood flow obtained by the N 2 O method correlate well with those obtained by the direct Fick method: in 12 subjects, the average value by the N 2 O method was 5.65 L./min. in comparison with 5.55 L./min. by the direct Pick method; the mean Percentile deviation between the values obtained by the two methods in each subject was 11 per cent. The results obtained by the N 2 O method were also shown to be reproducible : In 14 subjects, successive measurements on the same occasion showed a mean percentile deviation of 6 per cent.
Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA
Authors: Alasdair Leslie, Daniel Kavanagh, Isobella Honeyborne, Katja Pfafferott, Charles Edwards, Tilly Pillay, Louise Hilton, Christina Thobakgale, Danni Ramduth, Rika Draenert, Sylvie Le Gall, Graz Luzzi, Anne Edwards, Christian Brander, Andrew K. Sewell, Sarah Moore, James Mullins, Corey Moore, Simon Mallal, Nina Bhardwaj, Karina Yusim, Rodney Phillips, Paul Klenerman, Bette Korber, Photini Kiepiela, Bruce Walker, Philip Goulder
Journal: The Journal of Experimental Medicine (2005)

Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two examples of “negatively associated” or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.
Monotonicity of Nerve Tests in Diabetes
Authors: Peter J. Dyck, Peter C. O’Brien, William J. Litchy, C. Michel Harper, Christopher J. Klein, P. James B. Dyck
Journal: Diabetes Care (2005)

OBJECTIVE—The objective of this study was to test whether monotone worsening of nerve function, attributable to diabetes, can be demonstrated before criteria for diabetic sensorimotor polyneuropathy (DSPN) have been met. Which nerve tests are best? RESEARCH DESIGN AND METHODS—From a prevalence cohort of 504 individuals in the Rochester Diabetic Neuropathy study (RDNS), we identified 238 individuals (group 1) who at first examination were without polyneuropathy (DSPN) by a sum score of the normal deviates (from percentiles) of five attributes of nerve conduction of the legs (i.e., their five nerve conduction normal deviate values were &amp;lt;97.5th percentile) and were followed longitudinally two or more times. Of these 238, 90 (group 2) were followed six or more times at yearly or biyearly intervals. We compared different nerve tests for the ones most sensitive and reliable in showing latent nerve dysfunction and monotone (the extent to which a variable measured repeatedly over time reveals a significant trend of worsening or improvement). RESULTS—In group 1 patients, the mean sum score of five attributes of nerve conduction (Σ 5 NC nds) at baseline was 1.08 and at the last examination (only patients with Σ 5 NC nds &amp;lt;97.5th percentile) was 3.63, markedly higher than that in healthy subjects (only of individuals with Σ 5 NC nds &amp;lt;97.5th percentile) (−0.12), indicating a subtle latent shift of nerve conduction tests toward abnormality. Serial evaluations of many individual and especially sum scores of nerve conduction tests in group 2 patients showed statistically significant worsening with time, even when nerve conduction tests were still well within normal limits. Neurologic signs also worsened but barely to significant levels; however, symptoms and quantitative sensation tests did not. Considering the composite score Σ 5 NC nds, 42 (of 90 group 2 patients) showed significant worsening, 22 were still without DSPN by nerve conduction test criteria, and some were even below the 50th percentile at the last evaluation. CONCLUSIONS—Subtle and latent functional worsening of nerve conduction can be demonstrated even before nerve conduction test criteria for DSPN have been met. For demonstrating monotone worsening, the order (from best to worst) of tests was: some composite scores of nerve conduction and individual attributes of nerve conduction. We did not show monotone worsening of symptoms or of quantitative sensation test results. In multivariate analysis of risk factors and their association with worsening Σ 5 NC nds, 24-h microalbuminuria (a marker of microvessel disease) was found to be a significant covariate, an indication that the asymptomatic alterations of nerve conduction are meaningful.
Insulin Receptor Substrate-2 Mediated Insulin-like Growth Factor-I Receptor Overexpression in Pancreatic Adenocarcinoma through Protein Kinase Cδ
Authors: Junhye Kwon, Susann Stephan, Ananya Mukhopadhyay, Michael H. Muders, Shamit K. Dutta, Julie S. Lau, Debabrata Mukhopadhyay
Journal: Cancer Research (2009)

Pancreatic adenocarcinoma (PCA) is an almost invariably fatal disease. Recently, it has been shown by several groups as well as ours that insulin-like growth factor-I receptor (IGF-IR) overexpression is related to higher proliferation, survival, angiogenesis, and highly invasive pancreatic tumors. Several studies have been carried out to understand the pathways that lead to growth factor-mediated signaling, but the molecular mechanism of receptor overexpression remains mostly unknown. Treatment with neutralizing antibodies or a specific kinase inhibitor against IGF-IR could block the receptor expression in PCA cells. Furthermore, we also showed that insulin receptor substrate (IRS)-2, but not IRS-1, is involved in regulation of IGF-IR expression, which is most likely not transcriptional control. By blocking mammalian target of rapamycin (mTOR) pathway with rapamycin as well as other biochemical analysis, we defined a unique regulation of IGF-IR expression mediated by protein kinase Cdelta (PKCdelta) and mTOR pathway. Moreover, we showed that the down-regulation of IGF-IR expression due to IRS-2 small interfering RNA can be compensated by overexpression of dominant-active mutant of PKCdelta, suggesting that PKCdelta is downstream of IGF-IR/IRS-2 axis. Overall, these findings suggest a novel regulatory role of IRS-2 on the expression of IGF-IR through PKCdelta and mTOR in pancreatic cancer cells.
Comparison of two yttrium-90 regimens in inflammatory and osteoarthropathies.
Authors: R Will, B Laing, J Edelman, F Lovegrove, I Surveyor
Journal: Annals of the Rheumatic Diseases (1992)

Two yttrium-90 (90Y) radiosynovectomy procedures were compared. One procedure, performed at the Royal Perth Rehabilitation Hospital (RPRH) required a shorter immobilisation time than that performed at the Sir Charles Gardiner Hospital (SCGH). There were no significant differences in outcome between the two procedures for the groups with inflammatory and osteoarthropathy. Thirty two patients (45 joints) with inflammatory arthropathy were treated (25 with rheumatoid arthritis, three with psoriatic arthritis, two with ankylosing spondylitis, and two with unspecified inflammatory arthropathy) and 40 patients (58 joints) with osteoarthropathy. A separate assessment of local lymph node spread in patients treated by the RPRH showed a minor spread of 90Y in one of 37 joints assessed. A marked improvement in the patient evaluation scores in the inflammatory arthropathy group at three months persisted at 12 months. Good lasting responses were more common in patients with inflammatory arthropathy with a normal joint or early radiological disease. A marked improvement in the pain and evaluation scores occurred at three months in the group with osteoarthropathy but had disappeared by six months after treatment.
Evidence for Variable Selective Pressures at a Large Secondary Structure of the Human Mitochondrial DNA Control Region
Authors: F. Pereira, P. Soares, J. Carneiro, L. Pereira, M. B. Richards, D. C. Samuels, A. Amorim
Journal: Molecular Biology and Evolution (2008)

A combined effect of functional constraints and random mutational events is responsible for the sequence evolution of the human mitochondrial DNA (mtDNA) control region. Most studies targeting this noncoding segment usually focus on its primary sequence information disregarding other informative levels such as secondary or tertiary DNA conformations. In this work, we combined the most recent developments in DNA folding calculations with a phylogenetic comparative approach in order to investigate the formation of intrastrand secondary structures in the human mtDNA control region. Our most striking results are those regarding a new cloverleaf-like secondary structure predicted for a 93-bp stretch of the control region 5′-peripheral domain. Randomized sequences indicated that this structure has a more negative folding energy than the average of random sequences with the same nucleotide composition. In addition, a sliding window scan across the complete mitochondrial genome revealed that it stands out as having one of the highest folding potential. Moreover, we detected several lines of evidence of both negative and positive selection on this structure with high levels of conservation at the structure-relevant stem regions and the occurrence of compensatory base changes in the primate lineage. In the light of previous data, we discuss the possible involvement of this structure in mtDNA replication and/or transcription. We conclude that maintenance of this structure is responsible for the observed heterogeneity in the rate of substitution among sites in part of the human hypervariable region I and that it is a hot spot for the 3′ end of human mtDNA deletions.
Articular cartilage superficial zone collagen birefringence reduced and cartilage thickness increased before surface fibrillation in experimental osteoarthritis
Authors: H. E Panula, M. M Hyttinen, J. P A Arokoski, T. K Langsjo, A. Pelttari, I. Kiviranta, H. J Helminen
Journal: Annals of the Rheumatic Diseases (1998)

To investigate articular cartilage collagen network, thickness of birefringent cartilage zones, and glycosaminoglycan concentration in macroscopically normal looking knee joint cartilage of young beagles subjected to experimental slowly progressive osteoarthritis (OA).OA was induced by a tibial 30 degree valgus osteotomy in 15 female beagles at the age of 3 months. Fifteen sisters were controls. Cartilage specimens were collected seven (Group 1) and 18 months (Group 2) postoperatively. Collagen induced optical path difference and cartilage zone thickness measurements were determined from histological sections of articular cartilage with smooth and intact surface by computer assisted quantitative polarised light microscopy. Volume density of cartilage collagen fibrils was determined by image analysis from transmission electron micrographs and content of glycosaminoglycans by quantitative digital densitometry from histological sections.In the superficial zone of the lateral tibial and femoral cartilage, the collagen induced optical path difference (birefringence) decreased by 19 to 71% (p < 0.05) seven months postoperatively. This suggests that severe superficial collagen fibril network deterioration took place, as 18 months postoperatively, macroscopic and microscopic OA was present in many cartilage areas. Thickness of the uncalcified cartilage increased while the superficial zone became thinner in the same sites. In operated dogs, glycosaminoglycan content first increased (Group 1) in the lateral tibial condyle and then decreased (Group 2) (p < 0.05).In this OA model, derangement of the superficial zone collagen network was the probable reason for birefringence reduction. This change occurred well before macroscopic OA.