tbuckley/cabot-search huggingface dataset:
IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease
Authors: Marianna Sadagurski, Zhiyong Cheng, Aldo Rozzo, Isabella Palazzolo, Gregory R. Kelley, Xiaocheng Dong, Dimitri Krainc, Morris F. White
Journal: Journal of Clinical Investigation (2011)

Aging is a major risk factor for the progression of neurodegenerative diseases, including Huntington disease (HD). Reduced neuronal IGF1 or Irs2 signaling have been shown to extend life span in mice. To determine whether Irs2 signaling modulates neurodegeneration in HD, we genetically modulated Irs2 concentrations in the R6/2 mouse model of HD. Increasing Irs2 levels in the brains of R6/2 mice significantly reduced life span and increased neuronal oxidative stress and mitochondrial dysfunction. In contrast, reducing Irs2 levels throughout the body (except in β cells, where Irs2 expression is needed to prevent diabetes onset; R6/2•Irs2+/-•Irs2βtg mice) improved motor performance and extended life span. The slower progression of HD-like symptoms was associated with increased nuclear localization of the transcription factor FoxO1 and increased expression of FoxO1-dependent genes that promote autophagy, mitochondrial function, and resistance to oxidative stress. Mitochondrial function improved and the number of autophagosomes increased in R6/2•Irs2+/-•Irs2βtg mice, whereas aggregate formation and oxidative stress decreased. Thus, our study suggests that Irs2 signaling can modulate HD progression. Since we found the expression of Irs2 to be normal in grade II HD patients, our results suggest that decreasing IRS2 signaling could be part of a therapeutic approach to slow the progression of HD.
Membranoproliferative Glomerulonephritis Following Gemcitabine and Vinorelbine Chemotherapy for Peritoneal Mesothelioma
Authors: P. M. Fracasso, B. R. Tan, M. Grieff, J. Stephenson, H. Liapis, N. L. Umbeck, D. D. Von Hoff, E. K. Rowinsky
Journal: JNCI Journal of the National Cancer Institute (1999)
Prenatal immune challenge alters the hypothalamic-pituitary-adrenocortical axis in adult rats.
Authors: J M Reul, I Stec, G J Wiegers, M S Labeur, A C Linthorst, E Arzt, F Holsboer
Journal: Journal of Clinical Investigation (1994)

We investigated whether non-abortive maternal infections would compromise fetal brain development and alter hypothalamic-pituitary-adrenocortical (HPA) axis functioning when adult. To study putative teratogenic effects of a T cell-mediated immune response versus an endotoxic challenge, 10-d-pregnant rats received a single intraperitoneal injection of 5 x 10(8) human red blood cells (HRBC) or gram-negative bacterial endotoxin (Escherichia coli LPS: 30 micrograms/kg). The adult male progeny (3 mo old) of both experimental groups showed increased basal plasma corticosterone levels. In addition, after novelty stress the HRBC group, but not the LPS group, showed increased ACTH and corticosterone levels. Both groups showed substantial decreases in mineralocorticoid (MR) and glucocorticoid receptor (GR) levels in the hippocampus, a limbic brain structure critical for HPA axis regulation, whereas GR concentrations in the hypothalamus were unchanged and in anterior pituitary were slightly increased. HRBC and LPS indeed stimulated the maternal immune system as revealed by specific anti-HRBC antibody production and enhanced IL-1 beta mRNA expression in splenocytes, respectively. This study demonstrates that a T cell-mediated immune response as well as an endotoxic challenge during pregnancy can induce anomalies in HPA axis function in adulthood. Clinically, it may be postulated that disturbed fetal brain development due to prenatal immune challenge increases the vulnerability to develop mental illness involving inadequate responses to stress.
<scp>l</scp>-Methylfolate as Adjunctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized, Double-Blind, Parallel-Sequential Trials
Authors: George I. Papakostas, Richard C. Shelton, John M. Zajecka, Bijan Etemad, Karl Rickels, Alisabet Clain, Lee Baer, Elizabeth D. Dalton, Garret R. Sacco, David Schoenfeld, Michael Pencina, Allison Meisner, Teodoro Bottiglieri, Erik Nelson, David Mischoulon, Jonathan E. Alpert, James G. Barbee, Sidney Zisook, Maurizio Fava
Journal: American Journal of Psychiatry (2012)

Patients with major depression who have an insufficient response to selective serotonin reuptake inhibitors (SSRIs) may benefit from the addition of 15 mg/day of l-methylfolate, the only form of folate that crosses the blood-brain barrier. Adding 7.5 mg/day was no more effective than adding placebo, but 15.0 mg/day plus ongoing SSRI treatment produced a 32% response rate, compared to 15% for augmentation with placebo. Side effects in the two groups were comparable in type and frequency.
Serum 25-OH vitamin D after photochemotherapy
Authors: SAM SHUSTER, LAWRENCE CHADWICK, CELIA MOSS, JANET MARKS
Journal: British Journal of Dermatology (1981)

SUMMARY Patients receiving photochemotherapy (PUVA) for psoriasis were shown to have an increase in scrum 25-OH vitamin D. The effect was not seen with UV-A alone or 8-MOP alone.
Is dietary erucic acid hepatotoxic in pregnancy? an experimental study in rats and hamsters
Authors: Humberto Reyes, José Ribalta, Ismael Hernández, Marco Arrese, Nelly Pak, Michael Wells, Ralph E. Kirsch
Journal: Hepatology (1995)

The hypothesis that dietary erucic acid may contribute to the pathogenesis of intrahepatic cholestasis of pregnancy has been examined in pregnant rats and hamsters after prolonged feeding of diets containing 25% rapeseed oil rich in erucic acid (40% of fatty acids) or corn oil, without erucic acid. Both dietary oils were well tolerated, although weight gain was 17% to 20% less in animals receiving rapeseed oil. Rats and hamsters were studied on the last day of pregnancy and compared with age- and diet-matched nonpregnant animals. Histological examination showed no major morphologic abnormalities in liver, heart, kidneys, and adrenals. Similar microscopic deposits of fat were found in the livers and hearts of pregnant hamsters of both dietary groups. Chromatographic analysis of fatty acids in liver, heart, and kidney homogenates of hamsters and in isolated rat liver cells reflected the fatty acid composition of the dietary oils: oleic (18:1) and linoleic (18:2) acids were among the predominant fatty acids. Erucic acid was found in a higher proportion in the heart (14% by weight of total fatty acids) than in the liver (3%) and kidneys (3%) of animals fed rapeseed oil. Bile flow and biliary lipid composition was similar in rats and hamsters fed rapeseed or corn oil. Bile flow tended to be less in pregnant than in nonpregnant animals. Pregnant hamsters fed rapeseed oil tended to have the lowest bile flow. The lithogenic index of bile was slightly decreased in pregnant rats and increased in pregnant hamsters, although these proportional changes were similar for both diets. In all circumstances the lithogenic index remained below a value of 1.(ABSTRACT TRUNCATED AT 250 WORDS)
Five year prognosis in patients with angina identified in primary care: incident cohort study
Authors: B. S Buckley, C. R Simpson, D. J McLernon, A. W Murphy, P. C Hannaford
Journal: BMJ (2009)

<b>Objective</b> To ascertain the risk of acute myocardial infarction, invasive cardiac procedures, and mortality among patients with newly diagnosed angina over five years. <b>Design</b> Incident cohort study of patients with primary care data linked to secondary care and mortality data. <b>Setting</b> 40 primary care practices in Scotland. <b>Participants</b> 1785 patients with a diagnosis of angina as their first manifestation of ischaemic heart disease, 1 January 1998 to 31 December 2001. <b>Main outcome measures</b> Adjusted hazard ratios for acute myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, death from ischaemic heart disease, and all cause mortality, adjusted for demographics, lifestyle risk factors, and comorbidity at cohort entry. <b>Results</b> Mean age was 62.3 (SD 11.3). Male sex was associated with an increased risk of acute myocardial infarction (hazard ratio 2.01, 95% confidence interval 1.35 to 2.97), death from ischaemic heart disease (2.80, 1.73 to 4.53), and all cause mortality (1.82, 1.33 to 2.49). Increasing age was associated with acute myocardial infarction (1.04, 1.02 to 1.06, per year of age increase), death from ischaemic heart disease (1.09, 1.06 to 1.11, per year of age increase), and all cause mortality (1.09, 1.07 to 1.11, per year of age increase). Smoking was associated with subsequent acute myocardial infarction (1.94, 1.31 to 2.89), death from ischaemic heart disease (2.12, 1.32 to 3.39), and all cause mortality (2.11, 1.52 to 2.95). Obesity was associated with death from ischaemic heart disease (2.01, 1.17 to 3.45) and all cause mortality (2.20, 1.52 to 3.19). Previous stroke was associated with all cause mortality (1.78, 1.13 to 2.80) and chronic kidney disease with death from ischaemic heart disease (5.72, 1.74 to 18.79). Men were more likely than women to have coronary artery bypass grafting or percutaneous transluminal coronary angioplasty after a diagnosis of angina; older people were less likely to receive percutaneous transluminal coronary angioplasty. Acute myocardial infarction after a diagnosis of angina was associated with an increased risk of death from ischaemic heart disease and all cause mortality (8.84 (5.31 to 14.71) and 4.23 (2.78 to 6.43), respectively). Neither of the invasive cardiac procedures significantly reduced the subsequent risk of all cause mortality. <b>Conclusions</b> In this sample of people with incident angina from primary care, there were sex differences in survival and age and sex differences in the provision of revascularisation after a diagnosis. Acute myocardial infarction after a diagnosis of angina was strongly predictive of mortality. To minimise adverse outcomes, optimal preventive treatments should be used in patients with angina.
Empirical assessment of colour symmetries
Authors: Lewis D. Griffin
Journal: Behavioral and Brain Sciences (1999)

The quality of potential symmetries of the similarity structure of the Basic Colour Terms has been assessed. The assessment was made on the basis of a database of similarity judgements, made by subjects in response to linguistically expressed questions. All potential symmetries can be statistically rejected, although the well-known and some novel interpretable symmetries are shown to be approximately correct.
Replication-Associated Mutational Asymmetry in the Human Genome
Authors: Chun-Long Chen, Lauranne Duquenne, Benjamin Audit, Guillaume Guilbaud, Aurélien Rappailles, Antoine Baker, Maxime Huvet, Yves d'Aubenton-Carafa, Olivier Hyrien, Alain Arneodo, Claude Thermes
Journal: Molecular Biology and Evolution (2011)

During evolution, mutations occur at rates that can differ between the two DNA strands. In the human genome, nucleotide substitutions occur at different rates on the transcribed and non-transcribed strands that may result from transcription-coupled repair. These mutational asymmetries generate transcription-associated compositional skews. To date, the existence of such asymmetries associated with replication has not yet been established. Here, we compute the nucleotide substitution matrices around replication initiation zones identified as sharp peaks in replication timing profiles and associated with abrupt jumps in the compositional skew profile. We show that the substitution matrices computed in these regions fully explain the jumps in the compositional skew profile when crossing initiation zones. In intergenic regions, we observe mutational asymmetries measured as differences between complementary substitution rates; their sign changes when crossing initiation zones. These mutational asymmetries are unlikely to result from cryptic transcription but can be explained by a model based on replication errors and strand-biased repair. In transcribed regions, mutational asymmetries associated with replication superimpose on the previously described mutational asymmetries associated with transcription. We separate the substitution asymmetries associated with both mechanisms, which allows us to determine for the first time in eukaryotes, the mutational asymmetries associated with replication and to reevaluate those associated with transcription. Replication-associated mutational asymmetry may result from unequal rates of complementary base misincorporation by the DNA polymerases coupled with DNA mismatch repair (MMR) acting with different efficiencies on the leading and lagging strands. Replication, acting in germ line cells during long evolutionary times, contributed equally with transcription to produce the present abrupt jumps in the compositional skew. These results demonstrate that DNA replication is one of the major processes that shape human genome composition.
Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study
Authors: H A Poirel, M S Cairo, N A Heerema, J Swansbury, A Aupérin, E Launay, W G Sanger, P Talley, S L Perkins, M Raphaël, K McCarthy, R Sposto, M Gerrard, A Bernheim, C Patte
Journal: Leukemia (2008)
Mitochondrial uncoupling downregulates calsequestrin expression and reduces SR Ca2+ stores in cardiomyocytes
Authors: S. L. Hanninen, J. J. Ronkainen, H. Leskinen, P. Tavi
Journal: Cardiovascular Research (2010)

Mitochondrial cardiomyopathy is associated with deleterious remodelling of cardiomyocyte Ca(2+) signalling that is partly due to the suppressed expression of the sarcoplasmic reticulum (SR) Ca(2+) buffer calsequestrin (CASQ2). This study was aimed at determining whether CASQ2 downregulation is directly caused by impaired mitochondrial function.Mitochondrial stress was induced in cultured neonatal rat cardiomyocytes by means of the mitochondrial uncoupler carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP). Ca(2+) transients and reactive oxygen species (ROS) were measured by confocal microscopy using the indicators fluo-4 and MitoSOX red, respectively. Mitochondrial stress led to concentration-dependent downregulation of calsequestrin (CASQ2) and changes in the Ca(2+) signals of the cardiomyocytes that were accompanied by reduction in SR Ca(2+) content and amplitude and duration of Ca(2+) sparks. Caspase 3, p38, and p53 inhibitors had no effect on FCCP-induced CASQ2 downregulation; however, it was attenuated by the ROS scavenger N-acetylcysteine (NAC). Importantly, NAC not only decreased FCCP-induced ROS production, but it also restored the Ca(2+) signals, SR Ca(2+) content, and Ca(2+) spark properties to control levels.Mitochondrial uncoupling results in fast transcriptional changes in CASQ2 expression that manifest as compromised Ca(2+) signalling, and these changes can be prevented by ROS scavengers. As impaired mitochondrial function has been implicated in several cardiac pathologies as well as in normal ageing, the mechanisms described here might be involved in a wide spectrum of cardiac conditions.
Does CPAP delay the development of cardiovascular disease in patients with obstructive sleep apnoea hypopnoea?
Authors: N T Ayas, G B J Mancini, J Fleetham
Journal: Thorax (2006)

Large, long term, randomised clinical trials are needed to establish whether CPAP treatment of patients with OSAH has a cardiovascular benefit

Obstructive sleep apnoea hypopnoea (OSAH) is a common under-recognised disorder characterised by recurrent upper airway collapse during sleep.1 These recurrent episodes of upper airway collapse lead to sleep fragmentation, oxyhaemoglobin desaturation, and excessive daytime sleepiness. OSAH also causes sustained activation of the sympathetic nervous system, systemic inflammation with increased levels of C-reactive protein (CRP) and interleukin 6,2 glucose intolerance, and endothelial dysfunction.3 Many of these physiological/biochemical abnormalities are implicated in the pathogenesis of cardiovascular disease (CVD). Indeed, there are compelling epidemiologic data implicating OSAH in the development of systemic hypertension, myocardial infarction, and cerebrovascular events.

OSAH is an independent risk factor for CVD. In a recent study from the Sleep Heart Health Cohort the prevalence of CVD (including myocardial infarction, angina, coronary revascularization, heart failure, stroke) was 1.42 times greater in patients with OSAH (apnoea hypopnoea index (AHI) >11 events/hour) than in those without OSAH (AHI 0–1.3 events/hour) after controlling for potential confounders.4 Furthermore, in a community based study, patients with moderate to severe OSAH were 2.89 times more likely to develop systemic hypertension over a 5 year period than patients without OSAH.5 Similarly, Mooe et al 6 followed 408 subjects with coronary disease diagnosed by cardiac catheterisation. Patients with OSAH had a much higher risk of the composite outcome (death, stroke, transient ischaemic attack, myocardial infarction) than patients without OSAH (26.3% v 16.2%) when followed for an average of 5.1 years.

Continuous positive airway pressure (CPAP) is the primary treatment for OSAH.7 It is very effective in eliminating upper airway collapse during sleep, improving sleep fragmentation, and decreasing daytime sleepiness.8 There are accumulating data that CPAP may reduce risks of CVD …
Interim Comparison of a Continuous Infusion Versus a Short Daily Infusion of Cytarabine Given in Combination With Cladribine for Pediatric Acute Myeloid Leukemia
Authors: Kristine R. Crews, Varsha Gandhi, Deo Kumar Srivastava, Bassem I. Razzouk, Xin Tong, Fred G. Behm, William Plunkett, Susana C. Raimondi, Ching-Hon Pui, Jeffrey E. Rubnitz, Clinton F. Stewart, Raul C. Ribeiro
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To identify the optimal schedule for infusion of cytarabine (ara-C) given with cladribine (2-CdA) to pediatric patients with acute myeloid leukemia (AML), and to compare the effects of the two schedules on the pharmacokinetics of ara-C triphosphate (ara-CTP) in leukemic cells. PATIENTS AND METHODS: Forty-nine pediatric patients with newly diagnosed primary AML received a 5-day course of ara-C 500 mg/m 2 /d and 2-CdA 9 mg/m 2 /d. They were randomly assigned to receive ara-C as either a 2-hour daily infusion (arm A) or a continuous infusion (arm B). Cellular pharmacokinetics were studied on days 1 and 2. All patients then received two courses of remission induction chemotherapy with daunorubicin, ara-C, and etoposide (DAV). RESULTS: Thirty-two percent of patients (seven of 22) in arm A and 63% (17 of 27) in arm B entered complete remission (P = .045) after ara-C and 2-CdA therapy. Coadministration of 2-CdA increased the intracellular concentration of ara-CTP in 20 of 36 patients, although we found no statistically significant difference between the treatment arms in this effect (P = .63). The incidence of toxicity did not differ significantly between the two treatment arms (P = .53). After two courses of DAV, the rate of complete remission was 91% in arm A and 96% in arm B (P = .58). CONCLUSION: Intracellular accumulation of ara-CTP is increased when 2-CdA is given with ara-C, but no schedule-dependent differences in this effect were seen. The combination of 2-CdA and ara-C seems to be effective therapy for pediatric AML.
Inhibition of proliferation of normal and transformed neural cells by blood group-related oligosaccharides.
Authors: F F Santos-Benito, A Fernández-Mayoralas, M Martín-Lomas, M Nieto-Sampedro
Journal: The Journal of Experimental Medicine (1992)

A synthetic tetrasaccharide structurally related to blood groups and selectin ligands inhibited division of astrocytes, gliomas, and neuroblastomas at micromolar concentrations. The compound was cytostatic for primary astrocytes in culture, but cytotoxic for fast proliferating cell lines.
Using socio-demographic and early clinical features in general practice to identify people with lung cancer earlier
Authors: Barbara Iyen-Omofoman, Laila J Tata, David R Baldwin, Chris JP Smith, Richard B Hubbard
Journal: Thorax (2013)

<h3>Introduction</h3> In the UK, most people with lung cancer are diagnosed at a late stage when curative treatment is not possible. To aid earlier detection, the socio-demographic and early clinical features predictive of lung cancer need to be identified. <h3>Methods</h3> We studied 12 074 cases of lung cancer and 120 731 controls in a large general practice database. Logistic regression analyses were used to identify the socio-demographic and clinical features associated with cancer up to 2 years before diagnosis. A risk prediction model was developed using variables that were independently associated with lung cancer up to 4 months before diagnosis. The model performance was assessed in an independent dataset of 1 826 293 patients from the same database. Discrimination was assessed by means of a receiver operating characteristic (ROC) curve. <h3>Results</h3> Clinical and socio-demographic features that were independently associated with lung cancer were patients' age, sex, socioeconomic status and smoking history. From 4 to 12 months before diagnosis, the frequency of consultations and symptom records of cough, haemoptysis, dyspnoea, weight loss, lower respiratory tract infections, non-specific chest infections, chest pain, hoarseness, upper respiratory tract infections and chronic obstructive pulmonary disease were also independently predictive of lung cancer. On validation, the model performed well with an area under the ROC curve of 0.88. <h3>Conclusions</h3> This new model performed substantially better than the current National Institute for Health and Clinical Excellence referral guidelines and all comparable models. It has the potential to predict lung cancer cases sufficiently early to make detection at a curable stage more likely by allowing general practitioners to better risk stratify their patients. A clinical trial is needed to quantify the absolute benefits to patients and the cost effectiveness of this model in practice.
Antigen Presentation in the Autoimmune Diabetes of the NOD Mouse
Authors: Emil R. Unanue
Journal: Annual Review of Immunology (2014)

This paper reviews the presentation of peptides by major histocompatibility complex (MHC) class II molecules in the autoimmune diabetes of the nonobese diabetic (NOD) mouse. Islets of Langerhans contain antigen-presenting cells that capture the proteins and peptides of the beta cells' secretory granules. Peptides bound to I-A(g7), the unique MHC class II molecule of NOD mice, are presented in islets and in pancreatic lymph nodes. The various beta cell-derived peptides interact with selected CD4 T cells to cause inflammation and beta cell demise. Many autoreactive T cells are found in NOD mice, but not all have a major role in the initiation of the autoimmune process. I emphasize here the evidence pointing to insulin autoreactivity as a seminal component in the diabetogenic process.