tbuckley/cabot-search huggingface dataset:
Familial Risk Analyses of Attention Deficit Hyperactivity Disorder and Substance Use Disorders
Authors: Joseph Biederman, Carter R Petty, Timothy E Wilens, Maria G Fraire, Caitlin A Purcell, Eric Mick, Michael C Monuteaux, Stephen V Faraone
Journal: American Journal of Psychiatry (2007)

Objective: A robust and bidirectional comorbidity between attention deficit hyperactivity disorder (ADHD) and psychoactive substance use disorder (alcohol or drug abuse or dependence) has been consistently reported in the extant literature. Method: First-degree relatives from a large group of pediatrically and psychiatrically referred boys with (112 probands, 385 relatives) and without (105 probands, 358 relatives) ADHD were comprehensively assessed by blind raters with structured diagnostic interviews. Familial risk analysis examined the risks in first-degree relatives for ADHD, psychoactive substance use disorder, alcohol dependence, and drug dependence after stratifying probands by the presence and absence of these disorders. Results: ADHD in the proband was consistently associated with a significant risk for ADHD in relatives. Drug dependence in probands increased the risk for drug dependence in relatives irrespective of ADHD status, whereas alcohol dependence in relatives was predicted only by ADHD probands with comorbid alcohol dependence. In addition, ADHD in the proband predicted drug dependence in relatives, and drug dependence in comparison probands increased the risk for ADHD in relatives. Both alcohol dependence and drug dependence bred true in families without evidence for a common risk between these disorders. Conclusions: Patterns of familial risk analysis suggest that the association between ADHD and drug dependence is most consistent with the hypothesis of variable expressivity of a common risk between these disorders, whereas the association between ADHD and alcohol dependence is most consistent with the hypothesis of independent transmission of these disorders. Findings also suggest specificity for the transmission of alcohol and drug dependence.
Effects of Epinephrine on Lipid Partition and Metabolism in the Rabbit
Authors: ABRAHAM DURY
Journal: Circulation Research (1957)

Epinephrine overdosage in intact rabbits caused significant modifications in plasma lipid distribution and transport, and phospholipid metabolism of plasma, liver and aorta. Aortic phospholipid synthesis was accelerated shortly after epinephrine injection and persisted for 24 hours, but plasma and liver turnover rates were maximally elevated after 48 hours. Changes in plasma neutral fat concentration were paralleled by alterations in the levels of S f 12-400 lipoproteins and a relationship between S f 0-12 and plasma cholesterol levels is suggested by the data.
The Urine Anion Gap: The Critical Clue to Resolve a Diagnostic Dilemma in a Patient with Ketoacidosis
Authors: Jack G Hilton, Arthur C Vandenbroucke, Robert G Josse, Gloria C Buckley, Mitchell L Halperin
Journal: Diabetes Care (1984)

Usually, ketoacidosis presents few if any diagnostic or therapeutic problems; in this article, we report a case where ketoacidosis was clinically occult and biochemically obscure. The patient presented with acute pancreatitis associated with a modest antecedent alcohol intake. Metabolic acidosis with a normal anion gap (10 meq/L) was observed together with moderate hyperglycemia and a 2 + (but not 4 +) test for serum ketones. None of the usual causes of metabolic acidosis with a normal anion gap was identified nor was there an obvious explanation for a reduction in unmeasured anion gap (e.g., hypoalbuminemia, dysproteinemia, or the presence of abnormal halides). Despite the initial normal anion gap, ketoacidosis was suspected clinically and this was confirmed by the elevated serum B-hydroxybutyrate of 8 mmol/L. We deduced that the serum unmeasured anions, which should have been increased by at least 8 meq/L, were being underestimated because of the effect of hypertriglyceridemia on the serum chloride determination. When the serum chloride was reestimated by a method not influenced by hyperlipidemia, the value was 102 mmol/L not 112 mmol/L and, when reevaluated, the anion gap was indeed appropriately elevated. In addition, the urine anion gap (Na + K − Cl) was 103 meq/L in the absence of renal disease. This indicated that the expected large quantity of urinary ammonium must have been masked by an even greater quantity of unmeasured anion; in this case proven by direct measurement to be B-hydroxybutyrate. Finally, metabolism of the alcohol ingested, which yields hepatic NADH, could explain, in part, the modest hyperglycemia and the absence of a 4 + test for serum ketones. With this information, appropriate treatment for ketoacidosis was instituted and within 36− 48 h the bicarbonate (23 mmol/L) and the anion gap (11 meq/L) returned to normal. Thus, knowledge of how the determination of the serum chloride can be influenced by hypertriglyceridemia and, at the same time, our utilization of the urine anion gap permitted us to make the diagnosis and effect the treatment of an obscure case of metabolic acidosis due to ketoacidosis.
DNA-Repair Gene Polymorphisms Predict Favorable Clinical Outcome Among Patients With Advanced Squamous Cell Carcinoma of the Head and Neck Treated With Cisplatin-Based Induction Chemotherapy
Authors: Miguel Quintela-Fandino, Ricardo Hitt, Pedro P. Medina, Soledad Gamarra, Luis Manso, Hernan Cortes-Funes, Montserrat Sanchez-Cespedes
Journal: Journal of Clinical Oncology (2006)

Purpose Cisplatin kills tumor cells through DNA cross linking. Alterations in the function of DNA repair genes may affect DNA repair proficiency and influence cancer patients' response to cisplatin. We studied whether single nucleotide polymorphisms (SNPs) of DNA repair genes predict the response to cisplatin or prognosis in patients with squamous cell carcinoma of the head and neck (SCCHN). Methods A polymerase chain reaction–restriction fragment length polymorphism (RFLP) approach was used to determine the frequency of the SNPs: XPD-Asp312Asn, XPD-Lys751Gln, ERCC1-C8092A, and XRCC1-Arg399Gln in DNA from peripheral lymphocytes of 103 stage IV SCCHN patients. Results The frequencies of the distinct genotypes were, respectively, for the homozygous common allele, heterozygous and homozygous polymorphic variant: 53%, 40%, and 7% for ERCC1; 50%, 42%, and 8% for XPD-312; 35%, 57%, and 8% for XPD751; and 35%, 51%, and 13% for XRCC1. Patients with only common alleles at all the SNPs tested had a median overall survival of 5.1 months (range, 4.3 to 6.0 months) as compared with not reached for patients with at least one polymorphic variant (P &lt; .001). Estimates from Cox's multivariate analysis suggest that the accumulation of each polymorphic variant decreases the probability of dying by a factor of 2.1 (P &lt; .001; the presence of seven polymorphic variants confers a 175-fold protection). The accumulation of polymorphic variants increases by 2.94-fold the probability of achieving a complete response to treatment (P = .041). Conclusion Using a multivariate model, the presence of polymorphic variants in DNA-repair genes are powerful prognosis factors and response to cisplatin predictors among SCCHN patients.
Response of Retinoblastoma With Vitreous Tumor Seeding to Adenovirus-Mediated Delivery of Thymidine Kinase Followed by Ganciclovir
Authors: Patricia Chévez-Barrios, Murali Chintagumpala, William Mieler, Evelyn Paysse, Milton Boniuk, Claudia Kozinetz, Mary Y. Hurwitz, Richard L. Hurwitz
Journal: Journal of Clinical Oncology (2005)

To evaluate the feasibility and safety of adenovirus-mediated gene therapy as a treatment for tumor seeds in the vitreous of children with retinoblastoma.An Institutional Biosafety Committee-, Institutional Review Board-, Recombinant DNA Advisory Committee-, and US Food and Drug Administration-approved phase I study used intrapatient dose escalation of adenoviral vector containing a herpes simplex thymidine kinase gene (AdV-TK) followed by systemic administration of ganciclovir to treat bilateral retinoblastoma with vitreous tumor seeding refractory to standard therapies. Vitreous tumor seeds were treated by intravitreous injection of AdV-TK adjacent to disease sites. Each injection was followed by ganciclovir delivered intravenously every 12 hours for 7 days.Eight patients with vitreous tumor seeds were enrolled. One patient who was treated with 10(8) viral particles (vp) had resolution of the tumor seeds around the injection site. The seven patients who were treated with doses > or = 10(10) vp had resolution of their vitreous tumor seeds documented by fundoscopy. Toxicity included mild inflammation at 10(10) vp and moderate inflammation, corneal edema, and increased intraocular pressure at 10(11) vp. One patient was free of active vitreous tumor seeds 38 months after therapy. There has been no evidence of extraocular spread of tumor along the needle tract in any patient.AdV-TK followed by ganciclovir can be administered safely to children with retinoblastoma. Suicide gene therapy may contribute to the treatment of children with retinoblastoma tumor seeds in the vitreous, a resistant complication of retinoblastoma.
Antibodies against native collagen and citrullinated proteins precede the development of rheumatoid arthritis with a consecutive pattern
Authors: Mikael Brink, Johan Rönnelid, Monika Hansson, Linda Mathsson, Guy Serre, Per-Johan Jakobsson, Rikard Holmdahl, Lars Klareskog, Solbritt Rantapää Dahlqvist
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background and objective</h3> Presence of antibodies against cyclic citrullinated peptides (anti-CCP2) has been demonstrated to precede the development of rheumatoid arthritis (RA) by several years. The RR for developing subsequent RA was increased by the combination of HLA- shared epitopes (SE) and also presence of PTPN22 T variant. The underlying process of why RA-patients develop antibodies against certain citrullinated peptides is largely unknown and here the authors have investigated antibody concentration against thirteen citrullinated proteins, besides anti-CCP2, to elucidate their predictive value in the prepatient phase of RA together with information about HLA-SE, and cigarette smoking. <h3>Material and methods</h3> This study comprised 406 individuals, with 717 samples, who were identified before onset of symptoms of RA (median 7.4 years IQR 3.3–12.6 years), as donors to the Medical Biobank of Northern Sweden. 204 of them were also sampled at the time of diagnose, and have been analysed together with 1305 population controls from the Medical Biobank for concentrations of antibodies towards thirteen different citrullinated peptides in plasma; fibrinogen 36–50, fibrinogen 72, fibrinogen 74, fibrinogen α 36–50, fibrinogen α 621–635, fibrinogen β 60–74, fibrinogen 573, fibrinogen 591, α-enolase 1, collagen Type II C1 arginine and citrulline and U1, CCP-1, vimentin 2–17, vimentin 60–75 using the microarray based ImmunoCAP ISAC system (Phadia Diagnostics, Uppsala, Sweden). All samples were also analysed for anti-CCP2 antibodies with ELISA (Euro-Diagnostics). Cutoff levels were set with 98% specificity. <h3>Results</h3> The three antibodies with highest sensitivity for predicting RA was anti-CCP2 (33.8%), fibrinogen 36–52 (24.3%) and α enolase 1 (24.1%) counting ever being positive in all prepatient samples. On individual and group level, the concentrations of the citrullinated antibodies increased significantly the closer to onset of symptoms the samples were collected. The number of positive samples also increased the closer to disease onset. The predating time for the antibodies to appear (with concentrations above cut-off) varied significantly between them. <h3>Conclusion</h3> Citrullinated antibodies and antibodies against native collagen appeared many years before onset of symptoms and at different time points. The concentrations increased gradually with few exceptions until onset of symptoms and there was an epitope spreading. Citrullination was an important preceding process for disease development maybe initiated by an earlier non-citrullinated antibody stimulation.
Receptor for AGE (RAGE) Mediates Neointimal Formation in Response to Arterial Injury
Authors: Zhongmin Zhou, Kai Wang, Marc S. Penn, Steven P. Marso, Michael A. Lauer, Farhad Forudi, Xiaorong Zhou, Wu Qu, Yan Lu, David M. Stern, Ann Marie Schmidt, A. Michael Lincoff, Eric J. Topol
Journal: Circulation (2003)

Receptor for advanced-glycation end products (RAGE) and its ligands AGEs and S100/calgranulins have been implicated in a range of disorders. However, the role of RAGE/ligand interaction in neointimal hyperplasia after vascular injury remains unclear.We examined the expression of RAGE and its ligands after balloon injury of the carotid artery in both Zucker diabetic and nondiabetic rats. Using a soluble portion of the extracellular domain of RAGE, we determined the effects of suppressing RAGE/ligand interaction on vascular smooth muscle cell (VSMC) proliferation and neointimal formation after arterial injury. We demonstrate a significantly increased accumulation of AGE and immunoreactivities of RAGE and S100/calgranulins in response to balloon injury in diabetic compared with nondiabetic rats. Blockade of RAGE/ligand interaction significantly decreased S100-stimulated VSMC proliferation in vitro and bromodeoxyuridine (BrdU)-labeled proliferating VSMC in vivo, and suppressed neointimal formation and increased luminal area in both Zucker diabetic and nondiabetic rats.These findings indicate that RAGE/ligand interaction plays a key role in neointimal formation after vascular injury irrespective of diabetes status and suggest a novel target to minimize neointimal hyperplasia.
Cardiovascular Risk Reduction in High-Risk Pediatric Patients
Authors: Rae-Ellen W. Kavey, Vivek Allada, Stephen R. Daniels, Laura L. Hayman, Brian W. McCrindle, Jane W. Newburger, Rulan S. Parekh, Julia Steinberger
Journal: Circulation (2006)

Although for most children the process of atherosclerosis is subclinical, dramatically accelerated atherosclerosis occurs in some pediatric disease states, with clinical coronary events occurring in childhood and very early adult life. As with most scientific statements about children and the future risk for cardiovascular disease, there are no randomized trials documenting the effects of risk reduction on hard clinical outcomes. A growing body of literature, however, identifies the importance of premature cardiovascular disease in the course of certain pediatric diagnoses and addresses the response to risk factor reduction. For this scientific statement, a panel of experts reviewed what is known about very premature cardiovascular disease in 8 high-risk pediatric diagnoses and, from the science base, developed practical recommendations for management of cardiovascular risk.
Impact of Degree of Obesity on Surrogate Estimates of Insulin Resistance
Authors: Sun H. Kim, Fahim Abbasi, Gerald M. Reaven
Journal: Diabetes Care (2004)

OBJECTIVE—To evaluate the role of adiposity in the relationship between specific and surrogate estimates of insulin-mediated glucose uptake (IMGU) in a large nondiabetic population. RESEARCH DESIGN AND METHODS—Healthy volunteers were classified by BMI into normal weight (&amp;lt;25.0 kg/m2, n = 208), overweight (25.0–29.9 kg/m2, n = 168), and obese (≥30.0 kg/m2, n = 109) groups. We then assessed how differences in BMI affect the correlation between steady-state plasma glucose (SSPG) concentration at the end of a 180-min infusion of octreotide, glucose, and insulin (a specific measure of IMGU) and five surrogate estimates: fasting plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and area under the curve for insulin in response to oral glucose (I-AUC). RESULTS—Correlation coefficients (r values) between SSPG and surrogate measures of IMGU were all significant (P &amp;lt; 0.05), but the magnitude varied between BMI groups: normal weight: fasting plasma glucose 0.20, fasting plasma insulin 0.33, HOMA-IR 0.36, QUICKI −0.33, and I-AUC 0.69; overweight: fasting plasma glucose 0.19, fasting plasma insulin 0.55, HOMA-IR 0.55, QUICKI −0.54, and I-AUC 0.72; and obese: fasting plasma glucose 0.40, fasting plasma insulin 0.56, HOMA-IR 0.60, QUICKI −0.61, and I-AUC 0.69. CONCLUSIONS—The relationship between direct and surrogate estimates of IMGU varies with BMI, with the weakest correlations seen in the normal-weight group and the strongest in the obese group. In general, I-AUC is the most useful surrogate estimate of IMGU in all weight groups. Fasting plasma insulin, HOMA-IR, and QUICKI provide comparable information about IMGU. Surrogate estimates of IMGU based on fasting insulin and glucose account for no more than 13% of the variability in insulin action in the normal-weight group, 30% in the overweight group, and 37% in the obese group.
Nuclear miRNA Regulates the Mitochondrial Genome in the Heart
Authors: Samarjit Das, Marcella Ferlito, Oliver A. Kent, Karen Fox-Talbot, Richard Wang, Delong Liu, Nalini Raghavachari, Yanqin Yang, Sarah J. Wheelan, Elizabeth Murphy, Charles Steenbergen
Journal: Circulation Research (2012)

Rationale: Mitochondria are semiautonomous cellular organelles with their own genome, which not only supply energy but also participate in cell death pathways. MicroRNAs (miRNAs) are usually 19 to 25 nt long, noncoding RNAs, involved in posttranscriptional gene regulation by binding to the 3′-untranslated regions of target mRNA, which impact on diverse cellular processes. Objective: To determine if nuclear miRNAs translocate into the mitochondria and regulate mitochondrial function with possible pathophysiological implications in cardiac myocytes. Methods and Results: We find that miR-181c is encoded in the nucleus, assembled in the cytoplasm, and finally translocated into the mitochondria of cardiac myocytes. Immunoprecipitation of Argonaute 2 from the mitochondrial fraction indicates binding of cytochrome c oxidase subunit 1 (mt-COX1) mRNA from the mitochondrial genome with miR-181c. Also, a luciferase reporter construct shows that mi-181c binds to the 3′UTR of mt-COX1. To study whether miR-181c regulates mt-COX1, we overexpressed precursor miR-181c (or a scrambled sequence) in primary cultures of neonatal rat ventricular myocytes. Overexpression of miR-181c did not change mt-COX1 mRNA but significantly decreased mt-COX1 protein, suggesting that miR-181c is primarily a translational regulator of mt-COX1. In addition to altering mt-COX1, overexpression of miR-181c results in increased mt-COX2 mRNA and protein content, with an increase in both mitochondrial respiration and reactive oxygen species generation in neonatal rat ventricular myocytes. Thus, our data show for the first time that miR-181c can enter and target the mitochondrial genome, ultimately causing electron transport chain complex IV remodeling and mitochondrial dysfunction. Conclusions: Nuclear miR-181c translocates into the mitochondria and regulates mitochondrial genome expression. This unique observation may open a new dimension to our understanding of mitochondrial dynamics and the role of miRNA in mitochondrial dysfunction.
Proteolytic Processing Converts the Repelling Signal Sema3E into an Inducer of Invasive Growth and Lung Metastasis
Authors: Claus Christensen, Noona Ambartsumian, Giorgio Gilestro, Birthe Thomsen, Paolo Comoglio, Luca Tamagnone, Per Guldberg, Eugene Lukanidin
Journal: Cancer Research (2005)

We have previously shown that the expression of a semaphorin, known as a repelling cue in axon guidance, Sema3E, correlates with the ability to form lung metastasis in murine adenocarcinoma cell models. Now, besides providing evidence for the relevance of SEMA3E to human disease by showing that SEMA3E is frequently expressed in human cancer cell lines and solid tumors from breast cancer patients, we show biological activities of Sema3E, which support the implication of Sema3E in tumor progression and metastasis. In vivo, expression of Sema3E in mammary adenocarcinoma cells induces the ability to form experimental lung metastasis, and in vitro, the Sema3E protein exhibits both migration and growth promoting activity on endothelial cells and pheochromocytoma cells. This represents the first evidence of a metastasis-promoting function of a class 3 semaphorin, as this class of genes has hitherto been implicated in tumor biology only as tumor suppressors and negative regulators of growth. Moreover, we show that the full-size Sema3E protein is converted into a p61-Sema3E isoform due to furin-dependent processing, and by analyzing processing-deficient and truncated forms, we show that the generation of p61-Sema3E is required and sufficient for the function of Sema3E in lung metastasis, cell migration, invasive growth, and extracellular signal-regulated kinase 1/2 activation of endothelial cells. These findings suggest that certain breast cancer cells may increase their lung-colonizing ability by converting the growth repellent, Sema3E, into a growth attractant and point to a type of semaphorin signaling different from the conventional signaling induced by full-size dimeric class 3 semaphorins.
Genetically modified "obligate" anaerobic Salmonella typhimurium as a therapeutic strategy for neuroblastoma
Authors: Zhu-Ling Guo, Bin Yu, Bo-Tao Ning, Shing Chan, Qiu-Bin Lin, James Chun-Bong Li, Jian-Dong Huang, Godfrey Chi-Fung Chan
Journal: Journal of Hematology & Oncology (2015)

Neuroblastoma currently has poor prognosis, therefore we proposed a new strategy by targeting neuroblastoma with genetically engineered anaerobic Salmonella (Sal-YB1).Nude and nonobese diabetic-severe combined immunodeficiency (NOD-SCID) orthotopic mouse models were used, and Sal-YB1 was administered via tail vein. The therapeutic effectiveness, bio-safety, and mechanisms were studied.No mice died of therapy-related complications. Tumor size reduction was 70 and 30% in nude and NOD-SCID mice, respectively. No Salmonella was detected in the urine; 75% mice had positive stool culture if diaminopimelic acid was added, but all turned negative subsequently. Tumor tissues had more Sal-YB1 infiltration, necrosis, and shrinkage in Sal-YB1-treated mice. Significantly higher expression of TLR4, TNF-stimulated gene 6 protein (TSG6), and cleaved caspase 1, 3, 8, and 9 was found in the tumor masses of the Sal-YB1-treated group with a decrease of interleukin 1 receptor-associated kinase (IRAK) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα). There was a high release of TNFα both in human macrophages and mouse tumor tissues with Sal-YB1 treatment. The antitumor effect of the supernatant derived from macrophages treated with Sal-YB1 could be reversed with TNFα and pan-caspase inhibitors.This new approach in targeting neuroblastoma by bio-engineered Salmonella with the assistance of macrophages indirectly may have a clinical therapeutic impact in the future.
The burden of illness and economic evaluation for COPD
Authors: S.D. Ramsey, S.D. Sullivan
Journal: European Respiratory Journal (2003)

In today's cost-conscious environment, understanding the economic implications associated with disease processes and their treatments is as important as understanding their clinical impact. Medical expenditures for treating chronic obstructive pulmonary disease (COPD) and the indirect costs of morbidity can represent a substantial economic and social burden. Very little economic information concerning COPD is available, however, particularly outside of a few very well-developed Western nations. This article will provide an approach for conducting high-quality studies aimed at estimating the economic burden of chronic obstructive pulmonary disease and for making economic evaluations of healthcare interventions aimed at preventing and treating this disease.