tbuckley/cabot-search huggingface dataset:
Neuropsychological functions and quality of life in survived patients with intracranial germ cell tumors after treatment
Authors: S.-Y. Liang, T.-F. Yang, Y.-W. Chen, M.-L. Liang, H.-H. Chen, K.-P. Chang, I.-K. Shan, Y.-S. Chen, T.-T. Wong
Journal: Neuro-Oncology (2013)

The notable survival chances of intracranial germ cell tumors (icGCTs) lead to a rising concern over long-term neurocognitive outcome. Yet, prior evidence related to this issue fails to provide a comprehensive examination of the effects of tumor location and radiotherapy. We attempt to explore their impacts on the neuropsychological functions and life quality in children with icGCT after multimodality treatments. A retrospective review of 56 patients diagnosed with icGCTs at age <20 and treated at the Taipei Veterans General Hospital was provided. Intelligence, memory, visual organization, attention, and executive function were assessed by neurocognitive tests; adaptation to life, emotional and behavioral changes, interpersonal relationships, and impact on the family were evaluated by parent-report instruments. Effects of tumor locations (germinomas and nongerminomatous malignant germ cell tumors in the pineal, suprasellar, and basal ganglia) and irradiation on these measurements were examined. Patients with tumors in the basal ganglia region had lower full-scale IQs than those with tumors in the pineal or suprasellar regions. Subscores of intelligence scale and short-term retention of verbal and visual stimuli showed evident group differences, as did the quality of life and adaptive skills, particularly in psychosocial domains. Patients treated with whole-ventricular irradiation had better outcomes. Extensive irradiation field and high irradiation dosage influenced intellectual functions, concept crystallization, executive function, and memory. Tumor location and irradiation field/dosage appear to be the crucial factors related to certain neuropsychological, emotional, and behavioral dysfunctions that in turn alter the quality of life in children with icGCTs who survive after treatment.
Outcomes of Transplanting Deceased-Donor Kidneys between Elderly Donors and Recipients
Authors: Markus Giessing, T. Florian Fuller, Frank Friedersdorff, Serdar Deger, Andreas Wille, Hans-Hellmut Neumayer, Danilo Schmidt, Klemens Budde, Lutz Liefeldt
Journal: Journal of the American Society of Nephrology (2008)

Rate of acceptance of deceased-donor kidneys decreases with donor age despite the growing number of aged transplant candidates on the waiting list. In the Eurotransplant Senior Program, HLA-unmatched kidneys from deceased donors aged ≥65 yr are transplanted regionally into recipients aged ≥65 yr. Because we have become more willing to accept kidneys from donors aged ≥75 yr than previous years, we performed a retrospective analysis of this subgroup. Kidneys were accepted from donors aged ≥75 yr provided a normal creatinine on admission to the hospital, a Cockcroft-Gault creatinine clearance >80 ml/min, and an absence of comorbidities. We compared outcomes of kidneys from donors aged ≥75 yr with both younger-donor kidneys transplanted in the Eurotransplant Senior Program and with younger-donor HLA-matched kidneys transplanted into recipients ≥60 yr. There were no differences in 5-yr graft and patient survival or rate of delayed graft function between groups. Graft function, measured by creatinine and creatinine clearance, differed without pattern at only three of 12 time points during 5 yr of follow-up. In conclusion, our data suggest that kidneys from deceased donors aged ≥75 yr can be transplanted safely into recipients aged ≥65 yr if similar donor criteria and local allocation practices are used.
Cell-Selective Inhibition of NF-κB Signaling Improves Therapeutic Index in a Melanoma Chemotherapy Model
Authors: Thomas Enzler, Yasuyo Sano, Min-Kyung Choo, Howard B. Cottam, Michael Karin, Hensin Tsao, Jin Mo Park
Journal: Cancer Discovery (2011)

Abstract The transcription factor NF-κB promotes the survival of cancer cells exposed to doxorubicin and other chemotherapeutic agents. IκB kinase is essential for chemotherapy-induced NF-κB activation and considered a prime target for anticancer treatment. An IκB kinase inhibitor sensitized human melanoma xenografts in mice to killing by doxorubicin yet also exacerbated treatment toxicity in the host animals. By using mouse models that simulate cell-selective targeting, we found that impaired NF-κB activation in melanoma and host myeloid cells accounts for therapeutic and adverse effects, respectively. Ablation of tumor-intrinsic NF-κB activity resulted in apoptosis-driven tumor regression after treatment with doxorubicin. By contrast, chemotherapy in mice with myeloid-specific loss of NF-κB activation led to a massive intratumoral recruitment of interleukin-1β–producing neutrophils and necrotic tumor lesions, a condition associated with increased host mortality but not accompanied by tumor regression. Therefore, a molecular target-based therapy may be steered toward different clinical outcomes depending on the drug's cell-specific effects. Significance: Our findings show that the IκB kinase–NF-κB signaling pathway is important for both promoting treatment resistance and preventing host toxicity in cancer chemotherapy; however, the two functions are exerted by distinct cell type–specific mechanisms and can therefore be selectively targeted to achieve an improved therapeutic outcome. Cancer Discovery; 1(6); 496–507. ©2011 AACR. Read the Commentary on this article by Aggarwal and Sung, p. 469 This article is highlighted in the In This Issue feature, p. 457
Treatment of Invasive Retinoblastoma in a Murine Model Using an Oncolytic Picornavirus
Authors: Lalita Wadhwa, Mary Y. Hurwitz, Patricia Chévez-Barrios, Richard L. Hurwitz
Journal: Cancer Research (2007)

Abstract Retinoblastoma, the most common intraocular malignancy of childhood, metastasizes by initial invasion of the choroid and the optic nerve. There is no effective treatment for metastatic retinoblastoma, especially when the central nervous system (CNS) is involved, and prevention of this complication is a treatment priority. Seneca Valley Virus (SVV-001) is a conditionally replication-competent picornavirus that is not pathogenic to normal human cells but can kill human retinoblastoma cells in vitro with an IC50 of &amp;lt;1 viral particle (vp) per cell. A xenograft murine model of metastatic retinoblastoma was used to examine the therapeutic potential of SVV-001. Histopathologic analysis of ocular and brain tissues after a single tail vein injection of SVV-001 (1 × 1013 vp/kg) showed effective treatment of choroid and ocular nerve tumor invasion (1 of 20 animals with invasive disease in the treated group versus 7 of 20 animals with invasive disease in the control group; P = 0.017) and prevention of CNS metastasis (0 of 20 animals with CNS metastatic disease in the treated group versus 4 of 20 animals with CNS disease in the control group; P = 0.036). There were no observed adverse events due to the virus in any of the treated animals. SVV-001 may be effective as a treatment of locally invasive and metastatic retinoblastoma. [Cancer Res 2007;67(22):10653–6]
Breaking self-tolerance in nonobese diabetic mice.
Authors: W M Ridgway, M Fassò, A Lanctot, C Garvey, C G Fathman
Journal: The Journal of Experimental Medicine (1996)

Unresponsiveness to self is maintained through two mechanisms of immune regulation: thymic-negative selection and peripheral tolerance. Although thymic-negative selection is a major mechanism to eliminate self-reactive T cells, normal mice have readily detectable populations of T cells reactive to self-proteins but do not exhibit autoimmune responses. It has been postulated that autoimmune disease results from breakdown or loss of peripheral tolerance. We present data that demonstrate that peripheral tolerance or unresponsiveness to self can be broken in nonobese diabetic (NOD) mice. Immunization of NOD mice (but not of conventional mice) with self-peptides caused an immune response to self-peptide with resultant autoproliferation of peripheral lymphocytes. Autoproliferation of self-reactive T cells in NOD mice resulted from the recognition and proliferation of the activated T cells to endogenously processed and presented self-antigens. This loss of self-tolerance demonstrated in vitro may well be the basis of NOD autoimmune disease in vivo.
Low-Grade Chronic Inflammation in the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) Population
Authors: Susanne R. de Rooij, Giel Nijpels, Peter M. Nilsson, John J. Nolan, Rafael Gabriel, Elisabetta Bobbioni-Harsch, Geltrude Mingrone, Jacqueline M. Dekker
Journal: Diabetes Care (2009)

OBJECTIVE Low-grade chronic inflammation has been hypothesized to underlie the constellation of cardiometabolic risk factors, possibly by inducing insulin resistance. In the present study, we investigated associations between inflammation markers, insulin sensitivity (expressed as the ratio of the M value to the mean plasma insulin concentrations measured during the final 40 min of the clamp [M/I]), and a range of cardiometabolic risk factors in a large, healthy population. RESEARCH DESIGN AND METHODS The Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort includes 1,326 nondiabetic European men and women, aged between 30 and 60 years. We measured cardiometabolic risk factors and performed a hyperinsulinemic-euglycemic clamp. We determined total white blood cell count (WBC) and erythrocyte sedimentation rate (ESR) as markers of chronic inflammation. RESULTS WBC and ESR were both strongly associated with M/I. WBC and ESR were further associated with a range of cardiometabolic risk factors. Associations between WBC and HDL cholesterol, triglycerides, heart rate, fasting C-peptide, and insulin and 2-h insulin in men and women and between WBC and 2-h glucose in women remained significant after adjustment for both M/I and waist circumference. Associations between ESR and HDL cholesterol, heart rate, fasting, and 2-h insulin in men and women and between ESR and fat mass in women remained significant after adjustment for M/I and waist circumference. CONCLUSIONS This study showed that low-grade chronic inflammation is associated with the cardiometabolic risk profile of a healthy population. Insulin resistance, although strongly associated with inflammation, does not seem to play a large intermediary role.
Mitochondrial DNA Mutations in Focal Segmental Glomerulosclerosis Lesions
Authors: Kunihiro Yamagata, Kaori Muro, Jouichi Usui, Masahiro Hagiwara, Hirayasu Kai, Yoh Arakawa, Yoshio Shimizu, Chie Tomida, Kouichi Hirayama, Masaki Kobayashi, Akio Koyama
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Glomerular epithelial cells are primary pathogenic sites in focal segmental glomerulosclerosis (FGS) lesions. Glomerular epithelial cells are regarded as terminally differentiated cells that do not proliferate. These characteristics are also noted for neurons and muscular cells, which are major sites of mitochondrial DNA (mtDNA) mutation accumulation. Screening for mtDNA mutations was performed with renal biopsy specimens from patients with primary FGS and patients with IgA nephropathy (as subjects with secondary FGS and as control subjects). mtDNA extracted from kidney biopsy specimens was amplified with appropriate primer pairs for study of the mtDNA point mutations 3243A→G, 3271T→C, 8344A→G, and 8993T→G/C, as well as the common deletion (a 4977-bp deletion spanning mtDNA nucleotide pairs 8469 to 13447). In situ amplification of both total mtDNA and the common deletion was also performed. Two patients with FGS demonstrated the 3243A→G point mutation; 12 patients with FGS and seven patients with IgA nephropathy accompanied by glomerulosclerotic lesions exhibited the common deletion in their kidney tissue. No patient demonstrated the mtDNA mutations 3271T→C, 8344A→G, or 8993T→G/C. The degree of heteroplasmy for the 3243A→G point mutation was >85%; however, the heteroplasmy for the common deletion was <1%. As determined with in situ PCR, normal mtDNA was mainly distributed in the tubular epithelium and mtDNA with the common deletion was mainly distributed among glomerular epithelial cells. In conclusion, it is suggested that mtDNA mutations are distributed in glomerular epithelial cells among some patients with primary FGS or secondary FGS with IgA nephropathy. These mutations may be related to glomerular epithelial cell damage.
Teratogenic mechanisms of medical drugs
Authors: M. M. H. J. van Gelder, I. A. L. M. van Rooij, R. K. Miller, G. A. Zielhuis, L. T. W. de Jong-van den Berg, N. Roeleveld
Journal: Human Reproduction Update (2010)

Although prescription drug use is common during pregnancy, the human teratogenic risks are undetermined for more than 90% of drug treatments approved in the USA during the past decades. A particular birth defect may have its origins through multiple mechanisms and possible exposures, including medications. A specific pathogenic process may result in different outcomes depending upon factors such as embryonic age at which a drug is administered, duration and dose of exposure and genetic susceptibility. This review focuses on the teratogenic mechanisms associated with a number of medications. We used three methods to identify the teratogenic mechanisms of medications: the MEDLINE and EMBASE databases, two recent books on teratogenic agents and a list of drugs classified as U.S. Food and Drug Administration class D or X. Mechanisms were included only if they are associated with major structural birth defects and medications that are used relatively frequently by women of reproductive age. We identified six teratogenic mechanisms associated with medication use: folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption and specific receptor- or enzyme-mediated teratogenesis. Many medications classified as class X are associated with at least one of these mechanisms. Identifying teratogenic mechanisms may not only be relevant for etiologic and post-marketing research, but may also have implications for drug development and prescribing behavior for women of reproductive age, especially since combinations of seemingly unrelated prescription and over the counter medications may utilize similar teratogenic mechanisms with a resultant increased risk of birth defects.
An optimization framework for unsupervised identification of rare copy number variation from SNP array data
Authors: Gökhan Yavaş, Mehmet Koyutürk, Meral Özsoyoğlu, Meetha P Gould, Thomas LaFramboise
Journal: Genome biology (2009)

Abstract Copy number variants (CNVs) have roles in human disease, and DNA microarrays are important tools for identifying them. In this paper, we frame CNV identification as an objective function optimization problem. We apply our method to data from hundreds of samples, and demonstrate its ability to detect CNVs at a high level of sensitivity without sacrificing specificity. Its performance compares favorably with currently available methods and it reveals previously unreported gains and losses.
Developing the Clinical Application of Genetic Diagnosis: The Role of NIDDK
Authors: Judith E. Fradkin
Journal: JAMA (1994)

<h3>To the Editor.</h3> —The article by Drs Wilfond and Nolan<sup>1</sup>is inaccurate with respect to the role of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in cystic fibrosis (CF) carrier screening. Having supported CF gene identification, the NIDDK felt an obligation to ensure responsible use of the information. In response to concerns about screening the population prematurely, the NIDDK convened a distinguished panel 6 months after the gene identification to discuss the principles and preconditions for carrier screening. The recommendations of this group are widely accepted and have been reiterated in subsequent position papers by the American Society of Human Genetics (ASHG). The NIDDK response was timely and appropriate. The statement by Wilfond and Nolan, "Thus, almost by default, ASHG was placed in the position of responding to... and organizing an NIH [National Institutes of Health] workshop to develop policy guidelines," is incorrect. The NIH
A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit
Authors: Simon Finfer, Rinaldo Bellomo, Neil Boyce, Julie French, John Myburgh, Robyn Norton
Journal: New England Journal of Medicine (2004)

It remains uncertain whether the choice of resuscitation fluid for patients in intensive care units (ICUs) affects survival. We conducted a multicenter, randomized, double-blind trial to compare the effect of fluid resuscitation with albumin or saline on mortality in a heterogeneous population of patients in the ICU.We randomly assigned patients who had been admitted to the ICU to receive either 4 percent albumin or normal saline for intravascular-fluid resuscitation during the next 28 days. The primary outcome measure was death from any cause during the 28-day period after randomization.Of the 6997 patients who underwent randomization, 3497 were assigned to receive albumin and 3500 to receive saline; the two groups had similar baseline characteristics. There were 726 deaths in the albumin group, as compared with 729 deaths in the saline group (relative risk of death, 0.99; 95 percent confidence interval, 0.91 to 1.09; P=0.87). The proportion of patients with new single-organ and multiple-organ failure was similar in the two groups (P=0.85). There were no significant differences between the groups in the mean (+/-SD) numbers of days spent in the ICU (6.5+/-6.6 in the albumin group and 6.2+/-6.2 in the saline group, P=0.44), days spent in the hospital (15.3+/-9.6 and 15.6+/-9.6, respectively; P=0.30), days of mechanical ventilation (4.5+/-6.1 and 4.3+/-5.7, respectively; P=0.74), or days of renal-replacement therapy (0.5+/-2.3 and 0.4+/-2.0, respectively; P=0.41).In patients in the ICU, use of either 4 percent albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days.
Tight glycaemic control in acute exacerbations of COPD
Authors: S J Finney
Journal: Thorax (2006)

A new standard of care?I t is now clear that hyperglycaemia of even short duration can be associated with adverse outcome in the acutely ill.2][3][4][5] In this issue of Thorax Baker and colleagues extend this list, having performed a retrospective analysis of outcome in patients admitted to hospital with an acute exacerbation of chronic obstructive pulmonary disease (COPD). 6ultivariate analysis revealed that hyperglycaemia held more adverse prognostic significance even than spirometry.Not surprisingly, the authors propound the hypothesis that rigorous glycaemic control should improve mortality and/or reduce the length of hospital stay in this patient population which is so commonly encountered during the acute general medical take.To this end, they propose that a randomised trial of insulin therapy should be undertaken.How robust are the data presented in this potentially important study?Although the authors are commendably open about the limitations of their study, these may be significant.Firstly, their (retrospective) identification of patients relied entirely on clinical coding, audits of which have suggested levels of accuracy as low as 60%. 7It is therefore unlikely that the study population was both complete and homogeneous.Indeed, the microbiological data presented suggest that a degree of overlap with patients suffering from community acquired pneumonia is possible, in whom hyperglycaemia is known to be associated with a poor outcome. 5Secondly, some measure- ments of blood glucose levels were made after hospital admission, during which the potentially significant confounding effects of therapeutic corticosteroids on glycaemic control were not quantified.Thirdly, single measurements of maximal blood glucose values were used in the analysis, which do not reflect the
In Vivo Evidence for the Contribution of Human Histocompatibility Leukocyte Antigen (Hla)-Dq Molecules to the Development of Diabetes
Authors: Li Wen, F. Susan Wong, Jie Tang, Ning-Yuan Chen, Martha Altieri, Chella David, Richard Flavell, Robert Sherwin
Journal: The Journal of Experimental Medicine (2000)

Although DQA1*0301/DQB1*0302 is the human histocompatibility leukocyte antigen (HLA) class II gene most commonly associated with human type 1 diabetes, direct in vivo experimental evidence for its diabetogenic role is lacking. Therefore, we generated C57BL/6 transgenic mice that bear this molecule and do not express mouse major histocompatibility complex (MHC) class II molecules (DQ8+/mII−). They did not develop insulitis or spontaneous diabetes. However, when DQ8+/mII− mice were bred with C57BL/6 mice expressing costimulatory molecule B7-1 on β cells (which normally do not develop diabetes), 81% of the DQ8+/mII−/B7-1+ mice developed spontaneous diabetes. The diabetes was accompanied by severe insulitis composed of both T cells (CD4+ and CD8+) and B cells. T cells from the diabetic mice secreted large amounts of interferon γ, but not interleukin 4, in response to DQ8+ islets and the putative islet autoantigens, insulin and glutamic acid decarboxylase (GAD). Diabetes could also be adoptively transferred to irradiated nondiabetic DQ8+/mII−/B7-1+ mice. In striking contrast, none of the transgenic mice in which the diabetes protective allele (DQA1*0103/DQB1*0601, DQ6 for short) was substituted for mouse MHC class II molecules but remained for the expression of B7-1 on pancreatic β cells (DQ6+/mII−/B7-1+) developed diabetes. Only 7% of DQ−/mII−/B7-1+ mice developed diabetes at an older age, and none of the DQ−/mII+/B7-1+ mice or DQ8+/mII+/B7-1+ mice developed diabetes. In conclusion, substitution of HLA-DQA1*0301/DQB1*0302, but not HLA-DQA1*0103/DQB1*0601, for murine MHC class II provokes autoimmune diabetes in non–diabetes-prone rat insulin promoter (RIP).B7-1 C57BL/6 mice. Our data provide direct in vivo evidence for the diabetogenic effect of this human MHC class II molecule and a unique “humanized” animal model of spontaneous diabetes.
Determinants of Insulin Resistance in Infants at Age 1 Year
Authors: Carla A. Borgoño, Jill K. Hamilton, Chang Ye, Anthony J. Hanley, Philip W. Connelly, Mathew Sermer, Bernard Zinman, Ravi Retnakaran
Journal: Diabetes Care (2012)

The offspring of women with gestational diabetes mellitus (GDM) display a propensity for the early accrual of cardiometabolic risk factors, including insulin resistance, in childhood and adolescence. Thus, we sought to identify early life determinants of insulin resistance in infants of women with and without GDM.In total, 104 full-term, singleton infants born to women with (n = 36) and without (n = 68) GDM were evaluated at age 1 year, with insulin resistance assessed by homeostasis model (HOMA-IR).HOMA-IR at 1 year did not differ between infants born to mothers with and without GDM (P = 0.74). The sole independent predictor of infant HOMA-IR in the non-GDM group was birth weight (t = 3.33, P = 0.002). In contrast, weight gain in the 1st year was the only independent predictor of HOMA-IR in infants of women with GDM (t = 2.19, P = 0.039).In the 1st year of life, weight gain in infants born to women with GDM is associated with insulin resistance, unlike in their peers.