tbuckley/cabot-search huggingface dataset:
The Epidemiology of Severe Acute Respiratory Syndrome in the 2003 Hong Kong Epidemic: An Analysis of All 1755 Patients
Authors: Gabriel M. Leung, Anthony J. Hedley, Lai-Ming Ho, Patsy Chau, Irene O.L. Wong, Thuan Q. Thach, Azra C. Ghani, Christl A. Donnelly, Christophe Fraser, Steven Riley, Neil M. Ferguson, Roy M. Anderson, Thomas Tsang, Pak-Yin Leung, Vivian Wong, Jane C.K. Chan, Eva Tsui, Su-Vui Lo, Tai-Hing Lam
Journal: Annals of Internal Medicine (2004)

As yet, no one has written a comprehensive epidemiologic account of a severe acute respiratory syndrome (SARS) outbreak from an affected country.
Tet3-Mediated Hydroxymethylation of Epigenetically Silenced Genes Contributes to Bone Morphogenic Protein 7-Induced Reversal of Kidney Fibrosis
Authors: Björn Tampe, Desiree Tampe, Claudia A. Müller, Hikaru Sugimoto, Valerie LeBleu, Xingbo Xu, Gerhard A. Müller, Elisabeth M. Zeisberg, Raghu Kalluri, Michael Zeisberg
Journal: Journal of the American Society of Nephrology (2014)

Methylation of CpG island promoters is an epigenetic event that can effectively silence transcription over multiple cell generations. Hypermethylation of the Rasal1 promoter contributes to activation of fibroblasts and progression of kidney fibrosis. Here, we explored whether such causative hypermethylation could be reversed through endogenous mechanisms and whether such reversal of hypermethylation is a constituent of the antifibrotic activity of bone morphogenic protein 7 (BMP7). We show that successful inhibition of experimental kidney fibrosis through administration of BMP7 associates with normalization of Rasal1 promoter hypermethylation. Furthermore, this reversal of pathologic hypermethylation was achieved specifically through Tet3-mediated hydroxymethylation. Collectively, our findings reveal a new mechanism that may be exploited to facilitate therapeutic DNA demethylation to reverse kidney fibrosis.
Linkage and Association of the Mitochondrial Aspartate/Glutamate Carrier SLC25A12 Gene With Autism
Authors: Nicolas Ramoz, Jennifer G Reichert, Christopher J Smith, Jeremy M Silverman, Irina N Bespalova, Kenneth L Davis, Joseph D Buxbaum
Journal: American Journal of Psychiatry (2004)

Autism/autistic disorder (MIM number 209850) is a complex, largely genetic psychiatric disorder. The authors recently mapped a susceptibility locus for autism to chromosome region 2q24-q33 (MIM number 606053). In the present study, genes across the 2q24-q33 interval were analyzed to identify an autism susceptibility gene in this region.Mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants in exons and flanking sequence within candidate genes and comparing the frequency of the variants between autistic and unrelated nonautistic subjects. Two single nucleotide polymorphisms (SNPs) that showed evidence for divergent distribution between autistic and nonautistic subjects were identified, both within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1). In the second stage, the two SNPs in SLC25A12 were further genotyped in 411 autistic families, and linkage and association tests were carried out in the 197 informative families.Linkage and association were observed between autistic disorder and the two SNPs, rs2056202 and rs2292813, found in SLC25A12. Using either a single affected subject per family or all affected subjects, evidence for excess transmission was found by the Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G haplotype. Similar results were observed using TRANSMIT for the analyses. Evidence for linkage was supported by linkage analysis with the two SNPs, with a maximal multipoint nonparametric linkage score of 1.57 and a maximal multipoint heterogeneity lod score of 2.11. Genotype relative risk could be estimated to be between 2.4 and 4.8 for persons homozygous at these loci.A strong association of autism with SNPs within the SLC25A12 gene was demonstrated. Further studies are needed to confirm this association and to decipher any potential etiological role of AGC1 in autism.
Biology of insulin-like factor 3 in human reproduction
Authors: R. Ivell, R. Anand-Ivell
Journal: Human Reproduction Update (2009)

Insulin-like factor 3 (INSL3) is a neohormone that has evolved to address specific mammalian traits, in particular, the first phase of testicular descent towards the scrotum during mid-gestation. A thorough literature search was made in PubMed using the terms INSL3, as well as the older synonyms RLF and Ley-IL. INSL3 is a major secretory product of the testicular Leydig cells in the fetus and in adult men, and in rodent models, reduction in fetal INSL3 expression is an early marker of the testicular dysgenesis syndrome. In women, it is produced in lower amounts by ovarian theca and luteal cells, and circulating levels are increased in women with polycystic ovarian syndrome. During pregnancy, there is evidence for an interaction regulating the feto-placental unit. The presence of INSL3 in amniocentesis samples taken at 12–14 weeks gestation is absolutely specific for male gender, and levels are predictive of subsequent pre-eclampsia and/or birthweight. INSL3 is also involved in adult traits, such as spermatogenesis and bone metabolism. In adult men, INSL3 is constitutively expressed and secreted into the bloodstream at a constant level, reflecting the number and/or functional capacity of the Leydig cells. In complete contrast, testosterone is highly variable within individuals, is acutely responsive to fluctuations in the hypothalamic–pituitary–gonadal axis and appears to have marginal diagnostic value. INSL3 declines consistently with age in adult men. INSL3 promises to become an important new diagnostic tool to characterize those men with late-onset hypogonadism and to add clinical diagnostic value at amniocentesis.
Mouse plasmacytoma growth in vivo: enhancement by interleukin 6 (IL-6) and inhibition by antibodies directed against IL-6 or its receptor.
Authors: A Vink, P Coulie, G Warnier, J C Renauld, M Stevens, D Donckers, J Van Snick
Journal: The Journal of Experimental Medicine (1990)

Murine plasmacytomas show a striking dependence on interleukin 6 (IL-6) for their growth in vitro. Here, we present evidence suggesting that IL-6 also plays an essential role in the in vivo development of these tumors. This conclusion is based on the finding that the tumorigenicity of an IL-6-dependent plasmacytoma cell line was increased approximately 100-fold on transfection with an IL-6 expression vector, whereas it was inhibited in animals treated with monoclonal antibodies capable of blocking the binding of IL-6 to its receptor. Injection of these antibodies 1 d before tumor challenge protected greater than 50% of the mice and retarded tumor growth in all animals. Tumors arising in antibody-treated mice retained their IL-6 dependence in vitro, suggesting that the level of protection could be improved if stronger IL-6 antagonists were available.
Concomitance of Diabetic Retinopathy and Proteinuria Accelerates the Rate of Decline of Kidney Function in Type 2 Diabetic Patients
Authors: Roberto Trevisan, Monica Vedovato, Cinzia Mazzon, Anna Coracina, Elisabetta Iori, Antonio Tiengo, Stefano Del Prato
Journal: Diabetes Care (2002)

OBJECTIVE—To evaluate the rate of progression of renal disease in proteinuric type 2 diabetic patients with and without retinopathy. RESEARCH DESIGN AND METHODS—Thirty-eight proteinuric type 2 diabetic patients with diabetic retinopathy and 27 without were enrolled in an observational study for the evaluation of rate of glomerular filtration rate (GFR) decline and followed up for a median period of 6 years. GFR was determined at least once per year, and blood pressure, glycated hemoglobin, and proteinuria were determined every 4 months. RESULTS—Although the two groups had comparable GFR, albuminuria, blood pressure, and HbA1c at entry of the study, the rate of decline of GFR was higher in type 2 diabetic patients with retinopathy (−6.5 ± 4.4 ml/year) than in those without (−1.8 ± 4.8 ml/year; P &amp;lt; 0.0001). Protein and albumin excretion rate increased significantly in patients with retinopathy, while they did not change in those without. Mean blood pressure between the two groups of patients were similar both at entry and during the follow-up, although the proportion of patients treated with at least two antihypertensive drugs was higher in patients with retinopathy. On a multiple regression analysis, only mean blood pressure and proteinuria were significant determinants of progression of renal disease in type 2 diabetic patients with retinopathy. CONCLUSIONS—The rate of progression of renal disease in proteinuric type 2 diabetic patients with retinopathy is faster than that observed in those without retinopathy. The screening for retinopathy identifies patients at high risk for rapid deterioration of kidney function.
Insufficient Production and Tissue Delivery of CD4<b>+</b>Memory T Cells in Rapidly Progressive Simian Immunodeficiency Virus Infection
Authors: Louis J. Picker, Shoko I. Hagen, Richard Lum, Edward F. Reed-Inderbitzin, Lyn M. Daly, Andrew W. Sylwester, Joshua M. Walker, Don C. Siess, Michael Piatak, Chenxi Wang, David B. Allison, Vernon C. Maino, Jeffrey D. Lifson, Toshiaki Kodama, Michael K. Axthelm
Journal: The Journal of Experimental Medicine (2004)

The mechanisms linking human immunodeficiency virus replication to the progressive immunodeficiency of acquired immune deficiency syndrome are controversial, particularly the relative contribution of CD4+ T cell destruction. Here, we used the simian immunodeficiency virus (SIV) model to investigate the relationship between systemic CD4+ T cell dynamics and rapid disease progression. Of 18 rhesus macaques (RMs) infected with CCR5-tropic SIVmac239 (n = 14) or CXCR4-tropic SIVmac155T3 (n = 4), 4 of the former group manifested end-stage SIV disease by 200 d after infection. In SIVmac155T3 infections, naive CD4+ T cells were dramatically depleted, but this population was spared by SIVmac239, even in rapid progressors. In contrast, all SIVmac239-infected RMs demonstrated substantial systemic depletion of CD4+ memory T cells by day 28 after infection. Surprisingly, the extent of CD4+ memory T cell depletion was not, by itself, a strong predictor of rapid progression. However, in all RMs destined for stable infection, this depletion was countered by a striking increase in production of short-lived CD4+ memory T cells, many of which rapidly migrated to tissue. In all rapid progressors (P &amp;lt; 0.0001), production of these cells initiated but failed by day 42 of infection, and tissue delivery of new CD4+ memory T cells ceased. Thus, although profound depletion of tissue CD4+ memory T cells appeared to be a prerequisite for early pathogenesis, it was the inability to respond to this depletion with sustained production of tissue-homing CD4+ memory T cells that best distinguished rapid progressors, suggesting that mechanisms of the CD4+ memory T cell generation play a crucial role in maintaining immune homeostasis in stable SIV infection.
Inhibition of Tumor Growth and Metastasis in Non–Small Cell Lung Cancer by LY2801653, an Inhibitor of Several Oncokinases, Including MET
Authors: Wenjuan Wu, Chen Bi, Kelly M. Credille, Jason R. Manro, Victoria L. Peek, Gregory P. Donoho, Lei Yan, John A. Wijsman, S. Betty Yan, Richard A. Walgren
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Lung cancer is the leading cause of cancer-related death worldwide. Sustained activation, overexpression, or mutation of the MET pathway is associated with a poor prognosis in a variety of tumors, including non–small cell lung cancer (NSCLC), implicating the MET pathway as a potential therapeutic target for lung cancer. Previously, we reported on the development of LY2801653: a novel, orally bioavailable oncokinase inhibitor with MET as one of its targets. Here, we discuss the evaluation of LY2801653 in both preclinical in vitro and in vivo NSCLC models. Experimental Design/Results: Treatment with LY2801653 showed tumor growth inhibition in tumor cell lines and patient-derived tumor xenograft models as a single agent (37.4%–90.0% inhibition) or when used in combination with cisplatin, gemcitabine, or erlotinib (66.5%–86.3% inhibition). Mechanistic studies showed that treatment with LY2801653 inhibited the constitutive activation of MET pathway signaling and resulted in inhibition of NCI-H441 cell proliferation, anchorage-independent growth, migration, and invasion. These in vitro findings were confirmed in the H441 orthotopic model where LY2801653 treatment significantly inhibited both primary tumor growth (87.9% inhibition) and metastasis (64.5% inhibition of lymph node and 67.7% inhibition of chest wall). Tumor-bearing animals treated with LY2801653 had a significantly greater survival time (87% increase compared with the vehicle-treated mice). In the MET-independent NCI-H1299 orthotopic model, treatment with LY2801653 showed a significant inhibition of primary tumor growth but not metastasis. Conclusions: Collectively, these results support clinical evaluation of LY2801653 in NSCLCs and suggest that differences in the MET activation of tumors may be predictive of response. Clin Cancer Res; 19(20); 5699–710. ©2013 AACR.
Use of piretanide, a new loop diuretic, in cirrhosis with ascites: relationship between the diuretic response and the plasma aldosterone level.
Authors: V Arroyo, J Bosch, R Casamitjana, J Cabrera, F Rivera, J Rodes
Journal: Gut (1980)

Twenty patients with cirrhosis and ascites but no renal failure were given piretanide, a new loop diuretic, in order to investigate its efficacy and to relate the diuretic response with the pretreatment plasma aldosterone concentration. Eleven patients responded to piretanide 12 mg/day (equivalent in potency to 80 mg furosemide); there was no response in nine patients. Both groups were similar with regard to liver function, plasma urea, serum creatinine, plasma electrolytes, urine volume, and urine potassium concentration. The basal urinary sodium excretion was significantly higher in those patients who responded (23.6 +/- 5.7 mmol/day vs. 4.3 +/- 1.42 mmol/day; P &lt; 0.01) (M +/- SE). Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were normal or only slightly increased in patients who responded to piretanide (PRA = 1.22 +/- 0.20 ng/ml/h; PAC = 12.25 +/- 2.20 ng/100 ml) and very high in patients who did not respond (PRA = 8.71 +/- 1.18 ng/ml/h; PAC = 84.6 +/- 16.2 ng/100 ml) (P &lt; 0.001). Patients unresponsive to piretanide 12 mg/day also failed to respond when the dose was increased to 24 mg/day. However, the addition of spironolactone, 150 mg/day, to piretanide was followed in these patients by a marked increase in diuresis and natriuresis. These results strongly suggest that the pre-treatment level of aldosterone is an important factor influencing the response to loop diuretics in patients with non-azotaemic cirrhosis and ascites.
Molecular Pathways: Environmental Estrogens Activate Nongenomic Signaling to Developmentally Reprogram the Epigenome
Authors: Rebecca Lee Yean Wong, Cheryl Lyn Walker
Journal: Clinical Cancer Research (2013)

Abstract Exposure to environmental xenoestrogens is a major health concern because of the ability of these compounds to perturb estrogen receptor (ER) signaling and act as endocrine disrupting compounds (EDC). Inappropriate exposure to EDCs during development, even at low doses, can predispose individuals to an increased lifetime risk of disease, including cancer. Recent data indicate that perinatal exposure to EDCs increases cancer risk by (re)programming the epigenome via alterations in DNA and histone methylation. We and others have begun to dissect the mechanisms by which xenoestrogens disrupt the epigenetic machinery to reprogram the epigenome and induce developmental reprogramming. Our studies revealed that xenoestrogens induce nongenomic ER signaling to activate PI3K/AKT, resulting in AKT phosphorylation and inactivation of the histone methyltransferase EZH2, thus providing a direct link to disruption of the epigenome. Other epigenetic “readers, writers, and erasers” may also be targeted by nongenomic signaling, suggesting this is a central mechanism by which xenoestrogens and other EDCs disrupt the epigenome to induce developmental reprogramming. Elucidating mechanisms of developmental reprogramming of the epigenome is important for understanding how environmental exposures increase cancer risk, and provides a rationale for developing epigenetic interventions that can reverse the effects of environmental exposures to reduce cancer risk. Clin Cancer Res; 19(14); 3732–7. ©2013 AACR.
Molecular and Cellular Mechanisms of Learning Disabilities: A Focus on NF1
Authors: C. Shilyansky, Y.S. Lee, A.J. Silva
Journal: Annual Review of Neuroscience (2010)

Neurofibromatosis Type I (NF1) is a single-gene disorder characterized by a high incidence of complex cognitive symptoms, including learning disabilities, attention deficit disorder, executive function deficits, and motor coordination problems. Because the underlying genetic cause of this disorder is known, study of NF1 from a molecular, cellular, and systems perspective has provided mechanistic insights into the etiology of higher-order cognitive symptoms associated with the disease. In particular, studies of animal models of NF1 indicated that disruption of Ras regulation of inhibitory networks is critical to the etiology of cognitive deficits associated with NF1. Animal models of Nf1 identified mechanisms and pathways that are required for cognition, and represent an important complement to the complex neuropsychological literature on learning disabilities associated with this condition. Here, we review findings from NF1 animal models and human populations affected by NF1, highlighting areas of potential translation and discussing the implications and limitations of generalizing findings from this single-gene disease to idiopathic learning disabilities.
Non-coeliac flat jejunal mucosa.
Authors: M Batt
Journal: Gut (1989)

Case historyA housewife aged 42 years, was admitted to hospital after suffering diarrhoea and weight loss over a period of six months.The symptoms were of relatively sudden onset but were not associated with recent travel, dietary changes, or treatment with antibiotics.It was her first such illness and at times she would have her bowels open up to 12 times each day passing pale stools which contained no obvious blood nor mucus.She had lost 9 kg weight and had vomited intermittently for 10 days before admission.Six months previously she had had epigastric symptoms and a subsequent barium meal showed a gastric ulcer and hiatal herniation.The digestive symptoms settled on treatment with cimetidine.On admission the patient looked unwell, was dehydrated but apyrexial.Examination was normal except for signs of dehydration and a tachycardia.Sigmoidoscopy revealed pale liquid stool with no evidence of colitis.The histology of a rectal biopsy appeared normal.Routine blood tests showed haemoglobin 12 g/100 ml with normal indices, leucocytosis of
A 3-Level Prognostic Classification in Septic Shock Based on Cortisol Levels and Cortisol Response to Corticotropin
Authors: Djillali Annane
Journal: JAMA (2000)

The hypothalamic-pituitary-adrenal axis is a major determinant of the host response to stress. The relationship between its activation and patient outcome is not known.To evaluate the prognostic value of cortisol levels and a short corticotropin stimulation test in patients with septic shock.Prospective inception cohort study conducted between October 1991 and September 1995 in 2 teaching hospital adult intensive care units in France.A total of 189 consecutive patients who met clinical criteria for septic shock.A short corticotropin stimulation test was performed in all patients by intravenously injecting 0.25 mg of tetracosactrin; blood samples were taken immediately before the test (T0) and 30 (T30) and 60 (T60) minutes afterward.Twenty-eight-day mortality as a function of variables collected at the onset of septic shock, including cortisol levels before the corticotropin test and the cortisol response to corticotropin (delta max, defined as the difference between T0 and the highest value between T30 and T60).The 28-day mortality was 58% (95% confidence interval [CI], 51%-65%) and median time to death was 17 days (95% CI, 14-27 days). In multivariate analysis, independent predictors of death (P < or = .001 for all) were McCabe score greater than 0, organ system failure score greater than 2, arterial lactate level greater than 2.8 mmol/L, ratio of PaO2 to fraction of inspired oxygen no more than 160 mm Hg, cortisol level at T0 greater than 34 microg/dL and delta max no more than 9 microg/dL. Three groups of patient prognoses were identified: good (cortisol level at T0 < or = 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 26%), intermediate (cortisol level at T0 34 microg/dL and delta max < or = 9 microg/dL or cortisol level at T0 > 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 67%), and poor (cortisol level at T0 > 34 microg/dL and delta max < or = 9 microg/dL; 28-day mortality rate, 82%).Our data suggest that a short corticotropin test has a good prognostic value and could be helpful in identifying patients with septic shock at high risk for death.
The minor histocompatibility antigen HA-3 arises from differential proteasome–mediated cleavage of the lymphoid blast crisis (Lbc) oncoprotein
Authors: Eric Spierings, Anthony G. Brickner, Jennifer A. Caldwell, Suzanne Zegveld, Nia Tatsis, Els Blokland, Jos Pool, Richard A. Pierce, Sahana Mollah, Jeffrey Shabanowitz, Laurence C. Eisenlohr, Peter Van Veelen, Ferry Ossendorp, Donald F. Hunt, Els Goulmy, Victor H. Engelhard
Journal: Blood (2003)
Does a negative screening colonoscopy ever need to be repeated?
Authors: H Brenner
Journal: Gut (2005)

<b>Background and aims:</b> Screening colonoscopy is thought to be a powerful and cost-effective tool to reduce colorectal cancer incidence and mortality. Whether and when colonoscopy with negative findings has to be repeated is not well defined. The aim of this study was to assess the long term risk of clinically manifest colorectal cancer among subjects with negative findings at colonoscopy. <b>Patients:</b> 380 cases and 485 controls participating in a population based case-control study in Germany. <b>Methods:</b> Detailed history and results of previous colonoscopies were obtained by interview and from medical records. Adjusted relative risks of colorectal cancer among subjects with a previous negative colonoscopy compared with those without previous colonoscopy were estimated according to time since colonoscopy. <b>Results:</b> Subjects with previous negative colonoscopy had a 74% lower risk of colorectal cancer than those without previous colonoscopy (adjusted odds ratio (aOR) = 0.26 (95% confidence interval, 0.16 to 0.40)). This low risk was seen even if the colonoscopy had been done up to 20 or more years previously. Particularly low risks were seen for sigma cancer (aOR = 0.13 (0.04 to 0.43)) and for rectal cancer (aOR = 0.19 (0.09 to 0.39)), and after a negative screening colonoscopy at ages 55 to 64 (aOR = 0.17 (0.08 to 0.39)) and older (aOR = 0.21 (0.10 to 0.41)). <b>Conclusions:</b> Subjects with negative findings at colonoscopy are at very low risk of colorectal cancer and might not need to undergo repeat colonoscopy for 20 years or more, if at all. The possibility of extending screening intervals to 20 years or more might reduce complications and increase the feasibility and cost-effectiveness of colonoscopy based screening programmes.