tbuckley/cabot-search huggingface dataset:
Age-Related Loss of Brain Volume and T2 Relaxation Time in Youth With Type 1 Diabetes
Authors: Gaby S. Pell, Ashleigh Lin, R. Mark Wellard, George A. Werther, Fergus J. Cameron, Sue J. Finch, Jennifer Papoutsis, Elisabeth A. Northam
Journal: Diabetes Care (2012)

OBJECTIVE—2 Childhood-onset type 1 diabetes is associated with neurocognitive deficits, but there is limited evidence to date regarding associated neuroanatomical brain changes and their relationship to illness variables such as age at disease onset. This report examines age-related changes in volume and T2 relaxation time (a fundamental parameter of magnetic resonance imaging that reflects tissue health) across the whole brain. RESEARCH DESIGN AND METHODS— Type 1 diabetes, N = 79 (mean age 20.32 ± 4.24 years), and healthy control participants, N = 50 (mean age 20.53 ± 3.60 years). There were no substantial group differences on socioeconomic status, sex ratio, or intelligence quotient. RESULTS— Regression analyses revealed a negative correlation between age and brain changes, with decreasing gray matter volume and T2 relaxation time with age in multiple brain regions in the type 1 diabetes group. In comparison, the age-related decline in the control group was small. Examination of the interaction of group and age confirmed a group difference (type 1 diabetes vs. control) in the relationship between age and brain volume/T2 relaxation time. CONCLUSIONS— We demonstrated an interaction between age and group in predicting brain volumes and T2 relaxation time such that there was a decline in these outcomes in type 1 diabetic participants that was much less evident in control subjects. Findings suggest the neurodevelopmental pathways of youth with type 1 diabetes have diverged from those of their healthy peers by late adolescence and early adulthood but the explanation for this phenomenon remains to be clarified.
A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis
Authors: Yohei Takahashi, Ikuyo Kou, Atsushi Takahashi, Todd A Johnson, Katsuki Kono, Noriaki Kawakami, Koki Uno, Manabu Ito, Shohei Minami, Haruhisa Yanagida, Hiroshi Taneichi, Taichi Tsuji, Teppei Suzuki, Hideki Sudo, Toshiaki Kotani, Kota Watanabe, Kazuhiro Chiba, Naoya Hosono, Naoyuki Kamatani, Tatsuhiko Tsunoda, Yoshiaki Toyama, Michiaki Kubo, Morio Matsumoto, Shiro Ikegawa
Journal: Nature Genetics (2011)
Hypoxia Enhances Platelet-derived Growth Factor Signaling in the Pulmonary Vasculature by Down-Regulation of Protein Tyrosine Phosphatases
Authors: Henrik ten Freyhaus, Markus Dagnell, Maike Leuchs, Marius Vantler, Eva M Berghausen, Evren Caglayan, Norbert Weissmann, Bhola K Dahal, Ralph T Schermuly, Arne Ostman, Kai Kappert, Stephan Rosenkranz
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Platelet-derived growth factor (PDGF) plays a pivotal role in the pathobiology of pulmonary hypertension (PH) because it promotes pulmonary vascular remodeling. PH is frequently associated with pulmonary hypoxia.Objectives: To investigate whether hypoxia alters PDGF β receptor (βPDGFR) signaling in the pulmonary vasculature.Methods: The impact of chronic hypoxia on signal transduction by the βPDGFR was measured in human pulmonary arterial smooth muscle cells (hPASMC) in vitro, and in mice with hypoxia-induced PH in vivo.Measurements and Main Results: Chronic hypoxia significantly enhanced PDGF-BB–dependent proliferation and chemotaxis of hPASMC. Pharmacologic inhibition of PI3 kinase (PI3K) and PLCγ abrogated these events under both normoxia and hypoxia. Although hypoxia did not affect βPDGFR expression, it increased the ligand-induced tyrosine phosphorylation of the receptor, particularly at binding sites for PI3K (Y751) and PLCγ (Y1021). The activated βPDGFR is dephosphorylated by protein tyrosine phosphatases (PTPs). Interestingly, hypoxia decreased expression of numerous PTPs (T cell PTP, density-enhanced phosphatase-1, PTP1B, and SH2 domain-containing phosphatase-2), resulting in reduced PTP activity. Hypoxia-inducible factor (HIF)-1α is involved in this regulation of gene expression, because hypoxia-induced βPDGFR hyperphosphorylation and PTP down-regulation were abolished by HIF-1α siRNA and by the HIF-1α inhibitor 2-methoxyestradiol. βPDGFR hyperphosphorylation and PTP down-regulation were also present in vivo in mice with chronic hypoxia-induced PH.Conclusions: Hypoxia reduces expression and activity of βPDGFR-antagonizing PTPs in a HIF-1α–dependent manner, thereby enhancing receptor activation and proliferation and chemotaxis of hPASMC. Because hyperphosphorylation of the βPDGFR and down-regulation of PTPs occur in vivo, this mechanism likely has significant impact on the development and progression of PH and other hypoxia-associated diseases.
Phase I safety, pharmacokinetic and pharmacodynamic trial of BMS-599626 (AC480), an oral pan-HER receptor tyrosine kinase inhibitor, in patients with advanced solid tumors
Authors: J.-C. Soria, J. Cortes, C. Massard, J.-P. Armand, D. De Andreis, S. Ropert, E. Lopez, A. Catteau, J. James, J.-F. Marier, M. Beliveau, R.E. Martell, J. Baselga
Journal: Annals of Oncology (2011)
Manganese Superoxide Dismutase Attenuates Cisplatin-Induced Renal Injury
Authors: Christopher A. Davis, Harry S. Nick, Anupam Agarwal
Journal: Journal of the American Society of Nephrology (2001)

ABSTRACT. Cisplatin is a potent chemotherapeutic agent that is used to treat many human malignancies. Unfortunately, in addition to side effects such as ototoxicity, anaphylaxis, and bone marrow suppression, a significant percentage of patients receiving cisplatin develop severe nephrotoxicity. Mitochondrial dysfunction that is mediated via the generation of reactive oxygen species has been implicated in the pathogenesis of cisplatin-induced renal injury. To address the mechanism, it was hypothesized that overexpression of antioxidant enzymes, such as mitochondria-localized manganese superoxide dismutase (MnSOD) or mitochondria-targeted catalase (mito-Cat), would be cytoprotective in cisplatin-induced cell injury. To this end, human MnSOD or a mito-Cat vector were stably transfected into human embryonic kidney 293 cells. Cells that overexpressed MnSOD exhibited significantly less cell rounding and detachment compared with both mito-Cat and vector controls after exposure to 20 μM cisplatin. Cell injury as assessed by DNA fragmentation and annexin V binding assays was significantly decreased in the cells that overexpressed MnSOD compared with vector alone and mito-Cat. In addition, elevated levels of MnSOD were strongly associated with increased clonogenic potential after cisplatin challenge. Thus, overexpression of MnSOD, and not catalase, protects against cisplatin-induced renal epithelial cell injury. These results demonstrate the importance of reactive oxygen species in the mechanism that underlies cisplatin-induced renal injury and specifically implicate the superoxide radical, and not hydrogen peroxide, as the mediator.
Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study
Authors: David A Hafler, Alastair Compston, Stephen Sawcer, Eric S Lander, Mark J Daly, Philip L De Jager, Paul I W de Bakker, Stacey B Gabriel, Daniel B Mirel, Adrian J Ivinson, Margaret A Pericak-Vance, Simon G Gregory, John D Rioux, Jacob L McCauley, Jonathan L Haines, Lisa F Barcellos, Bruce Cree, Jorge R Oksenberg, Stephen L Hauser
Journal: New England Journal of Medicine (2007)

Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis.We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis.A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1x10(-4)); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10(-8)), as were a nonsynonymous SNP in the interleukin-7 receptor alpha gene (IL7RA) (P=2.94x10(-7)) and multiple SNPs in the HLA-DRA locus (P=8.94x10(-81)).Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis.
Evolution of Animal and Plant Dicers: Early Parallel Duplications and Recurrent Adaptation of Antiviral RNA Binding in Plants
Authors: Krishanu Mukherjee, Henry Campos, Bryan Kolaczkowski
Journal: Molecular Biology and Evolution (2012)

RNA interference (RNAi) is a eukaryotic molecular system that serves two primary functions: 1) gene regulation and 2) protection against selfish elements such as viruses and transposable DNA. Although the biochemistry of RNAi has been detailed in model organisms, very little is known about the broad-scale patterns and forces that have shaped RNAi evolution. Here, we provide a comprehensive evolutionary analysis of the Dicer protein family, which carries out the initial RNA recognition and processing steps in the RNAi pathway. We show that Dicer genes duplicated and diversified independently in early animal and plant evolution, coincident with the origins of multicellularity. We identify a strong signature of long-term protein-coding adaptation that has continually reshaped the RNA-binding pocket of the plant Dicer responsible for antiviral immunity, suggesting an evolutionary arms race with viral factors. We also identify key changes in Dicer domain architecture and sequence leading to specialization in either gene-regulatory or protective functions in animal and plant paralogs. As a whole, these results reveal a dynamic picture in which the evolution of Dicer function has driven elaboration of parallel RNAi functional pathways in animals and plants.
St. Thomas's Hospital
Authors: R. H. Goolden
Journal: BMJ (1863)

He had been ill five months, from his own account.He complained of great and increasing debility, so that he was obliged to give up work, becoming very much emaciated, and having intense thirst.The skin was dry and harsh.He passed large quantities of urine.He had good ap.petite; no cough.The chest was well developed and healthy.Pulse 84, feeble.The tongue was coated with dirty mucus, brown in the centre, and very red at the apex and edges.He had no headache; no recollection of a blow on the head or accident; nor had he suffered from other illness.The emaciation and debility were excessive, so that he appeared to take little notice of what was passing about him; and roused himself with difficulty to answer ques- tions.The specific gravity of the urine was 1041 ; the quantity as yet was not determined.On admission, he had a warm bath; and his hair was cut close.He was ordered five grains of calomel and five grains of Dover's powder Et night, and a senna draught in the morning; a drachm of sulphate of mag- nesia in peppermint-water three times a day.The urine, being measured, was found to be thirteen pints.Feb. 201st.The quantity of urine was fifteen pints; specific gravity, 1043.He left off his medicine, and was ordered a Turkish bath on alternate days.Feb. 25th.The amount of urine was ten pints; spe- cific gravity, 1041.The diet of this patient was deter- ,mined at this date as follows:-Mixed diet-Twelve ounces of bread, and thr ee-fourths of an ounce of butter; one pint of tea with milk (no sugar) for breakfast; and the same for tea; milk, with rice-or bread-pudding.Alternately for dinner-Half-pints of milk; four ounces of roast meat when dressed, witliout bone.Extras- Oreens; half a pound of beefsteak; a pint of porter; two -eggs; and an unlimited supply of water, lemonade, and other hospital drinks.Marchl 4th.Urine of specific gravity, 1040; quantity under ten pints.March 11th.Urine of specific gravity, 1037; quan- tityunder ten pints.He was very much more alive and cheerful, and-increasing in strength.March 14th.Urine of specific gravity, 1030; quantity under ten pints.March 21st.Urine of specific gravity, 1037; quantity under nine pints.April 1st.Urine of specific gravity, 1027; quantity under eight pints.April 4th.Urine of specific gravity, 1030; quantitv under seven pints.The specific gravity was less after coming from the bath.0 April 8th.Urine of specific gravity, 1031; quantity under seven pints and a half.April 18th.Urine-specific gravity of two portions, taken at different times in the day, 1041 and 1030; total quantity, under seven pints and a half.He had been takini, some sweetm-neats, which accounted for the higher specific gravity.
The importance of a lipopolysaccharide-initiated, cytokine-mediated host defense mechanism in mice against extraintestinally invasive Escherichia coli.
Authors: A Cross, L Asher, M Seguin, L Yuan, N Kelly, C Hammack, J Sadoff, P Gemski
Journal: Journal of Clinical Investigation (1995)

Extraintestinally invasive Escherichia coli (EC) that possess both a complete LPS and K1 capsule evade both complement-mediated bacteriolysis and neutrophil-mediated killing. Since C3H/HeJ mice that are hyporesponsive to LPS were uniquely susceptible to lethal infection with EC of this phenotype, we speculated there was an LPS-initiated host defense mechanism against this pathogenic phenotype. The LPS-normoresponsive C3H/HeN as well as the C3H/HeJ mice cleared these EC from the circulation within 4 h of intravenous administration. Whereas electron micrographs of the liver demonstrated these EC undergoing degeneration within the phagolysosomes of of both macrophages and Kupffer cells of C3H/HeN mice, these EC replicated within these cells of the C3H/HeJ mice. Restoration of anti-EC activity of C3H/HeJ mice occurred with activation of Kupffer cells and peritoneal macrophages in vivo with BCG and in vitro with IFN-gamma, but not with LPS. Pretreatment of C3H/HeJ mice with a combination of recombinant murine IL-1 and TNF-alpha also restored the killing of K1(+)-EC but did not enhance the killing of a K1(-)-EC mutant. These data are consistent with the hypothesis that (a) there is no intrinsic inability of C3H/HeJ phagocytes to kill EC, but (b) an LPS-initiated, cytokine-mediated host defense mechanism is required for such killing. These studies emphasize the importance of bacterial surface characteristics in the interaction with specific host defenses.
Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials
Authors: M. Schurks, R. J. Glynn, P. M. Rist, C. Tzourio, T. Kurth
Journal: BMJ (2010)

<b>Objective</b> To evaluate the effect of vitamin E supplementation on incident total, ischaemic, and haemorrhagic stroke. <b>Design</b> Systematic review and meta-analysis of randomised, placebo controlled trials published until January 2010. <b>Data sources</b> Electronic databases (Medline, Embase, Cochrane Central Register of Controlled Trials) and reference lists of trial reports. <b>Selection criteria</b> Randomised, placebo controlled trials with ≥1 year of follow-up investigating the effect of vitamin E on stroke. <b>Review methods and data extraction</b> Two investigators independently assessed eligibility of identified trials. Disagreements were resolved by consensus. Two different investigators independently extracted data. Risk ratios (and 95% confidence intervals) were calculated for each trial based on the number of cases and non-cases randomised to vitamin E or placebo. Pooled effect estimates were then calculated. <b>Results</b> Nine trials investigating the effect of vitamin E on incident stroke were included, totalling 118 765 participants (59 357 randomised to vitamin E and 59 408 to placebo). Among those, seven trials reported data for total stroke and five trials each for haemorrhagic and ischaemic stroke. Vitamin E had no effect on the risk for total stroke (pooled relative risk 0.98 (95% confidence interval 0.91 to 1.05), P=0.53). In contrast, the risk for haemorrhagic stroke was increased (pooled relative risk 1.22 (1.00 to 1.48), P=0.045), while the risk of ischaemic stroke was reduced (pooled relative risk 0.90 (0.82 to 0.99), P=0.02). There was little evidence for heterogeneity among studies. Meta-regression did not identify blinding strategy, vitamin E dose, or morbidity status of participants as sources of heterogeneity. In terms of absolute risk, this translates into one additional haemorrhagic stroke for every 1250 individuals taking vitamin E, in contrast to one ischaemic stroke prevented per 476 individuals taking vitamin E. <b>Conclusion</b> In this meta-analysis, vitamin E increased the risk for haemorrhagic stroke by 22% and reduced the risk of ischaemic stroke by 10%. This differential risk pattern is obscured when looking at total stroke. Given the relatively small risk reduction of ischaemic stroke and the generally more severe outcome of haemorrhagic stroke, indiscriminate widespread use of vitamin E should be cautioned against.
It is preferable for surgical patients to use e-cigarettes rather than smoke cigarettes
Authors: K. Farsalinos, V. Voudris
Journal: BMJ (2014)

The title of Holmes and Southern’s letter led us to expect descriptions of case reports on the detrimental effects of e-cigarettes and an attempt to associate such effects with the use of e-cigarettes.1 Instead, the letter just mentions the theoretical adverse effects of e-cigarettes on surgical outcomes and is not backed by …
Construction of a Minimal HIV-1 Variant that Selectively Replicates in Leukemic Derived T-Cell Lines: Towards a New Virotherapy Approach
Authors: Rienk E. Jeeninga, Barbara Jan, Birgit van der Linden, Henk van den Berg, Ben Berkhout
Journal: Cancer Research (2005)

Abstract T-cell acute lymphoblastic leukemia is a high-risk type of blood-cell cancer. We analyzed the possibility of developing virotherapy for T-cell acute lymphoblastic leukemia. Virotherapy is based on the exclusive replication of a virus in leukemic cells, leading to the selective removal of these malignant cells. We constructed a minimized derivative of HIV-1, a complex lentivirus encoding multiple accessory functions that are essential for virus replication in untransformed cells, but dispensable in leukemic T cells. This mini-HIV virus has five deletions (vif, vpR, vpU, nef, and U3) and replicated in the SupT1 cell line, but did not replicate in normal peripheral blood mononuclear cells. The stripped down mini-HIV variant was also able to efficiently remove leukemic cells from a mixed culture with untransformed control cells. In contrast to wild-type HIV-1, we did not observe bystander killing in mixed culture experiments with the mini-HIV variant. Furthermore, viral escape was not detected in long-term cultures. The mini-HIV variant that uses CD4 and CXCR4 for cell entry could potentially be used against CXCR4-expressing malignancies such as T-lymphoblastic leukemia/lymphoma, natural killer leukemia, and some myeloid leukemias.
Diabetes in Non-Hispanic White Youth
Authors: Ronny A. Bell, Elizabeth J. Mayer-Davis, Jennifer W. Beyer, Ralph B. D'Agostino, Jean M. Lawrence, Barbara Linder, Lenna L. Liu, Santica M. Marcovina, Beatriz L. Rodriguez, Desmond Williams, Dana Dabelea
Journal: Diabetes Care (2009)

To investigate the incidence, prevalence, and clinical characteristics of diabetes among U.S. non-Hispanic white (NHW) youth.Data from the SEARCH for Diabetes in Youth Study (SEARCH study), a multicenter study of diabetes among youth aged 0-19 years, were examined. Incidence rates were calculated per 100,000 person-years across 4 incident years (2002-2005), and prevalence in 2001 was calculated per 1,000 youths. Information obtained by questionnaire, physical examination, and blood and urine collection was analyzed to describe the characteristics of youth who completed an in-person visit.The prevalence of type 1 diabetes (at ages 0-19 years) was 2.00/1,000, which was similar for male (2.02/1,000) and female (1.97/1,000) subjects. The incidence of type 1 diabetes was 23.6/100,000, slightly higher for male compared with female subjects (24.5 vs. 22.7 per 100,000, respectively, P = 0.04). Incidence rates of type 1 diabetes among youth aged 0-14 years in the SEARCH study are higher than all previously reported U.S. studies and many European studies. Few cases of type 2 diabetes in youth aged <10 years were found. The prevalence of type 2 diabetes (at ages 10-19 years) was 0.18/1,000, which is significantly higher for female compared with male subjects (0.22 vs. 0.15 per 1,000, P = 0.01). Incidence of type 2 diabetes was 3.7/100,000, with similar rates for female and male subjects (3.9 vs. 3.4 per 1,000, respectively, P = 0.3). High levels of abnormal cardiometabolic and behavioral risk factor profiles were common among youth with both type 1 and type 2 diabetes. For example, within each of four age-groups for youth with type 1 diabetes and two age-groups for youth with type 2 diabetes, >40% had elevated LDL cholesterol, and <3% of youth aged >10 years met current recommendations for intake of saturated fat. Among youth aged >or=15 years, 18% with type 1 and 26% with type 2 diabetes were current smokers.The SEARCH study is one of the most comprehensive studies of diabetes in NHW youth. The incidence of type 1 diabetes in NHW youth in the U.S. is one of the highest in the world. While type 2 diabetes is still relatively rare, rates are several-fold higher than those reported by European countries. We believe efforts directed at improving the cardiometabolic and behavioral risk factor profiles in this population are warranted.
Pretransplant Risk Score for New-Onset Diabetes After Kidney Transplantation
Authors: Harini A. Chakkera, E. Jennifer Weil, Christine M. Swanson, Amylou C. Dueck, Raymond L. Heilman, Kunam S. Reddy, Khaled Hamawi, Hasan Khamash, Adyr A. Moss, David C. Mulligan, Nitin Katariya, William C. Knowler
Journal: Diabetes Care (2011)

OBJECTIVE New-onset diabetes after kidney transplantation (NODAT) has adverse clinical and economic implications. A risk score for NODAT could help identify research subjects for intervention studies. RESEARCH DESIGN AND METHODS We conducted a single-center retrospective cohort study using pretransplant clinical and laboratory measurements to construct a risk score for NODAT. NODAT was defined by hemoglobin A1c (HbA1c) ≥6.5%, fasting serum glucose ≥126 mg/dL, or prescribed therapy for diabetes within 1 year posttransplant. Three multivariate logistic regression models were constructed: 1) standard model, with both continuous and discrete variables; 2) dichotomous model, with continuous variables dichotomized at clinically relevant cut points; and 3) summary score defined as the sum of the points accrued using the terms from the dichotomous model. RESULTS A total of 316 subjects had seven pretransplant variables with P &amp;lt; 0.10 in univariate logistic regression analyses (age, planned corticosteroid therapy posttransplant, prescription for gout medicine, BMI, fasting glucose and triglycerides, and family history of type 2 diabetes) that were selected for multivariate models. Areas under receiver operating curves for all three models were similar (0.72, 0.71, and 0.70). A simple risk score calculated as the sum of points from the seven variables performed as well as the other two models in identifying risk of NODAT. CONCLUSIONS A risk score computed from seven simple pretransplant variables can identify risk of NODAT.