bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Different Growth Hormone Dosages on the Growth Velocity in Children Born Small for Gestational Age
Authors: Bozzola Elena , Lauriola Silvana , Messina Maria Francesca , Bona Gianni , Tinelli Carmine , Tatò Luciano
Published: December 2003

To assess whether short-term growth hormone (GH) treatment can improve the linear growth in children who were born small for gestational age (SGA), we started a randomized multicenter trial in 26 age- and sex-matched prepubertal children born SGA. During the 1st year of GH therapy, all children received GH 0.23 mg/kg/week, then during the 2nd year, 13 children received the same dose (group A), and in the other 13 children, the dose of GH was doubled, i.e., 0.46 mg/kg/week (group B). During the 1st year of therapy, the growth velocity significantly (p < 0.0001) increased in all patients. During the 2nd year, group A showed a significant decrease of the growth velocity (p < 0.015), whereas group B maintained the growth rate. The height in group A children significantly increased during the 1st and the 2nd year of GH therapy (p < 0.000002 and p < 0.000001, respectively), reaching the normal range in 8 out of 13 children at the end of 2 years of GH therapy. The height in group B children significantly increased during the 1st and the 2nd year of GH therapy (p < 0.000001 and p < 0.000001, respectively), reaching the normal range in all 11 children who completed the GH therapy. The height gain was similar in groups A and B treated with the same GH dosage during the 1st year of therapy. A greater increase in height gain was found in children of group B treated with the higher GH dosage during the 2nd year of therapy as compared with group A (p < 0.02). Significant increases in insulin-like growth factor I (p < 0.0001), acid-labile subunit (p < 0.0002), and bone/chronological age ratio (p < 0.0001) were found after the 1st year of GH therapy, but no significant changes were observed during the 2nd year, independently of the GH dose. In conclusion, the height velocity of children born SGA significantly increases during the 1st year of GH therapy, diminishes, but can decrease during the 2nd year, if the GH dosage is not raised.
Progression of Carotid Intima-Media Thickness and Plasma Antioxidants: The Los Angeles Atherosclerosis Study
Authors: Dwyer James H. , Paul-Labrador Maura J. , Fan Jing , Shircore Anne M. , Merz C. Noel Bairey , Dwyer Kathleen M.
Published: December 2003

Objective—

Recent epidemiologic and animal model data suggest that oxygenated carotenoids are protective against early atherosclerosis. We assessed the association between atherosclerotic progression, measured by carotid intima-media thickness (IMT), and plasma levels of oxygenated and hydrocarbon carotenoids, tocopherols, retinol, and ascorbic acid.

Methods and Results—

Participants were from an occupational cohort of 573 middle-aged women and men who were free of symptomatic cardiovascular disease at baseline. Ultrasound examination of the common carotid arteries, lipid level determination, and risk factor assessment were performed at baseline and 18-month follow-up. Plasma levels of antioxidants were determined at baseline only. Change in IMT was related to baseline plasma antioxidant levels in regression models controlling for covariates. In models adjusted for age, sex, and smoking status, 18-month change in IMT was significantly inversely related to the 3 measured oxygenated carotenoids (lutein, β-cryptoxanthin, zeaxanthin;
P
<0.02 for all) and one hydrocarbon carotenoid, α-carotene (
P
=0.003). After adjusting for additional cardiac risk factors and potential confounders, including high-sensitivity C-reactive protein, these associations remained significant (
P
<0.05).

Conclusions—

These findings suggest that higher levels of plasma oxygenated carotenoids (lutein, zeaxanthin, β-cryptoxanthin) and α-carotene may be protective against early atherosclerosis.
Vascular Endothelial Growth Factor Activates PI3K/Akt/Forkhead Signaling in Endothelial Cells
Authors: Abid Md. Ruhul , Guo Shaodong , Minami Takashi , Spokes Katherine C. , Ueki Kohjiro , Skurk Carsten , Walsh Kenneth , Aird William C.
Published: December 2003

Objective—

Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor that promotes endothelial cell (EC) survival, migration, and permeability. The forkhead transcription factors FKHR, FKHRL1, and AFX are mammalian orthologues of DAF-16, a forkhead protein that controls longevity in
Caenorhabditis elegans
. In this study, we examined whether VEGF is coupled to phosphatidyl inositol 3-kinase (PI3K)/Akt/forkhead in ECs.

Methods and Results—

We demonstrate that human ECs express members of the forkhead family (FKHR, FKHRL1, and AFX) and that VEGF modulates the phosphorylation, subcellular localization, and transcriptional activity of one or more of these isoforms by a PI3K/Akt signaling pathway. VEGF inhibited EC apoptosis, promoted DNA synthesis and the G
1
-to-S transition, and reduced expression of the cyclin-dependent kinase inhibitor p27
kip1
. Each of these effects was blocked by the PI3K inhibitor LY294002 or by a phosphorylation-resistant mutant of FKHRL1, but not by wild-type FKHRL1.

Conclusions—

These results suggest that VEGF signaling in ECs is coupled to forkhead transcription factors through a PI3K/Akt-dependent pathway.
Role of Leukotriene B4Receptors in the Development of Atherosclerosis: Potential Mechanisms
Authors: Subbarao Krishnaprasad , Jala Venkatakrishna R. , Mathis Steven , Suttles Jill , Zacharias Wolfgang , Ahamed Jasimuddin , Ali Hydar , Tseng Michael T. , Haribabu Bodduluri
Published: December 2003

Objective—Leukotriene B4(LTB4), a potent leukocyte chemoattractant, is known to promote several inflammatory diseases, including atherosclerosis. We sought to determine mechanisms through which LTB4modulates atherosclerosis in cell lines expressing LTB4receptors, BLT-1, and in mice deficient in BLT-1 as well as macrophage cell lines derived from BLT-1+/+and BLT-1−/−mice.

Methods and Results—Analysis of global changes in gene expression induced by LTB4in rat basophilic leukemia cells (RBL-2H3) expressing the human BLT-1 showed highest-fold increase in expression of fatty acid translocase/CD36 and the chemokine MCP1/JE/CCL2 , which are critical in atherogenesis. To determine the importance of BLT-1 in atherogenesis, we crossed BLT-1-null mice with apolipoprotein (apo)-E-deficient mice, which develop severe atherosclerosis. Deletion of BLT-1 significantly reduced the lesion formation in apo-E−/−mice only during initiating stages (4 and 8 weeks) but had no effect on the lesion size in mice fed atherogenic diet for 19 weeks. Macrophage cell lines from BLT-1-deficient mice expressed the low-affinity LTB4receptor, BLT-2, and exhibited chemotaxis to LTB4.

Conclusions—The effects of LTB4in atherosclerosis are likely mediated through the high-affinity BLT-1 and the low-affinity BLT-2 receptors. LTB4promotes atherosclerosis by chemo-attracting monocytes, by providing an amplification loop of monocyte chemotaxis via CCL2 production, and by converting monocytes to foam cells by enhanced expression of CD36 and fatty acid accumulation.
Randomized Comparison Between Stenting and Off-Pump Bypass Surgery in Patients Referred for Angioplasty
Authors: Eefting Frank , Nathoe Hendrik , van Dijk Diederik , Jansen Erik , Lahpor Jaap , Stella Pieter , Suyker Willem , Diephuis Jan , Suryapranata Harry , Ernst Sjef , Borst Cornelius , Buskens Erik , Grobbee Diederick , de Jaegere Peter
Published: December 2003

Background—

Stenting improves cardiac outcome in comparison with balloon angioplasty. Compared with conventional surgery, off-pump bypass surgery on the beating heart without cardiopulmonary bypass may reduce morbidity, hospital stay, and costs. The purpose, therefore, was to compare cardiac outcome, quality of life, and cost-effectiveness 1 year after stenting and after off-pump surgery.

Methods and Results—

Patients referred for angioplasty (n=280) were randomly assigned to stenting (n=138) or off-pump bypass surgery. At 1 year, survival free from stroke, myocardial infarction, and repeat revascularization was 85.5% after stenting and 91.5% after off-pump surgery (relative risk, 0.93; 95% CI, 0.86 to 1.02). Freedom from angina was 78.3% after stenting and 87.0% after off-pump surgery (
P
=0.06). Quality-adjusted lifetime was 0.82 year after stenting and 0.79 year after off-pump surgery (
P
=0.09). Hospital stay after the initial procedure was 1.43 and 5.77 days, respectively (
P
<0.01). Stenting reduced overall costs by $2933 (26.2%) per patient ($8276 versus $11 209;
P
<0.01). Stenting was more cost-effective in 95% of the bootstrap estimates.

Conclusions—

At 1 year, stenting was more cost-effective than off-pump surgery while maintaining comparable cardiac outcome and quality of life. Stenting rather than off-pump surgery, therefore, can be recommended as a first-choice revascularization strategy in selected patients.
No-Reflow Phenomenon Persists Long-Term After Ischemia/Reperfusion in the Rat and Predicts Infarct Expansion
Authors: Reffelmann Thorsten , Hale Sharon L. , Dow Joan S. , Kloner Robert A.
Published: December 2003

Background—

No-reflow after reperfusion therapy for myocardial infarction is a strong predictor of clinical outcome. But its fate on a long-term basis and potential significance for infarct healing are not yet known.

Methods and Results—

Twenty-nine female Fisher rats were subjected to 60 minutes of coronary occlusion followed by reperfusion. At 4 weeks, 15 survivors were euthanized after measurement of regional myocardial blood flow (radioactive microspheres) and in vivo staining of perfused tissue (0.5 mL 50% Uniperse blue IV). Infarct size (34.3±3.4%), scar thickness (1.19±0.10 mm), and infarct expansion index (0.51±0.04) were assessed from histological sections (2 additional exclusions because of failed occlusion). Regional myocardial blood flow in the reperfused infarct was reduced significantly compared with noninfarcted tissue (1.98±0.47 versus 4.55±0.86 mL · min
−1
· g
−1
,
P
<0.003, apical slice, and 1.77±0.44 versus 5.34±0.38 mL · min
−1
· g
−1
,
P
<0.0001, second slice), accompanied by a striking reduction of perfused capillaries within the infarct (n=23±4 versus 163±8 in the noninfarcted tissue,
P
<0.0001, microscopically assessed as capillaries containing blue particles per high-power field). Macroscopically, no-reflow areas were visible in 9 of 13 hearts. The number of perfused capillaries within the infarct correlated significantly with infarct expansion index (
r
=−0.76,
P
<0.003), infarct thickness (
r
=0.60,
P
<0.03), and the ratio of infarct to septum thickness (
r
=0.74,
P
<0.004).

Conclusions—

The no-reflow phenomenon persists for 1 month after reperfusion and predicts worse scar thinning and infarct expansion. Thus, one might shift the “open-artery” hypothesis downstream to an “open-microvessel” hypothesis, relating infarct healing, infarct expansion, and outcome to the completeness of microvascular reperfusion above and beyond epicardial artery patency.
Toll-Like Receptor-2 Modulates Ventricular Remodeling After Myocardial Infarction
Authors: Shishido Tetsuro , Nozaki Naoki , Yamaguchi Seiji , Shibata Yoko , Nitobe Joji , Miyamoto Takuya , Takahashi Hiroki , Arimoto Takanori , Maeda Kunihiko , Yamakawa Mitsunori , Takeuchi Osamu , Akira Shizuo , Takeishi Yasuchika , Kubota Isao
Published: December 2003

Background—

Toll-like receptors (TLRs) are members of the interleukin-1 receptor family and transduce similar signals as interleukin-1 receptor in response to exogenous pathogens. Recent studies have demonstrated that TLRs are activated by endogenous signals, such as heat shock proteins and oxidative stress, that may contribute to ventricular remodeling after myocardial infarction. In this study, we determined whether TLR-2 was involved in cardiac remodeling after myocardial infarction.

Methods and Results—

Myocardial infarction was induced by surgical left anterior descending coronary artery ligation on wild-type (WT) mice and TLR-2–knockout (KO) mice. The survival rate was significantly higher in KO mice than in WT mice 4 weeks after myocardial infarction (65% versus 43%,
P
<0.03). Infarct size and degree of inflammatory cell infiltration in infarct area were similar between WT and KO mice. However, myocardial fibrosis in the noninfarct area of KO mice was much less than in WT mice (
P
<0.01) and was accompanied by reduced transforming growth factor-β
1
and collagen type 1 mRNA expressions (
P
<0.01 and
P
<0.05, respectively). Left ventricular dimensions at end diastole were smaller in KO mice than in WT mice at 1 week (
P
<0.05) and 4 weeks (
P
<0.01) after surgery. Furthermore, fractional shortening was higher (27.7±2.5% versus 21.2±2.6%,
P
<0.05, at 1 week, and 24.3±2.0% versus 16.6±2.5%,
P
<0.01, at 4 weeks) in KO mice compared with WT mice.

Conclusions—

These data suggest that TLR-2 plays an important role in ventricular remodeling after myocardial infarction.
Pharmacological Modulation of Cardiac Gap Junctions to Enhance Cardiac Conduction
Authors: Eloff Benjamin C. , Gilat Eran , Wan Xiaoping , Rosenbaum David S.
Published: December 2003

Background—

Disease-induced alterations of cardiac gap junctions lead to intercellular uncoupling, which is an important mechanism of arrhythmogenesis. Therefore, drugs that selectively open gap junctions potentially offer a novel strategy for antiarrhythmic therapy. Because the peptide ZP123 was found to increase conductance between paired myocytes, we hypothesized that ZP123 would suppress acidosis-induced gap junction closure in the intact heart.

Methods and Results—

High-resolution optical mapping was used to measure conduction velocity (CV) and action potential duration from ventricular epicardium of Langendorff-perfused guinea pig hearts at baseline (pH 7.4) and during 45 minutes of perfusion with acidotic (pH 6.0) Tyrode’s solution with (n=8) and without (control, n=7) ZP123 (80 nmol/L). Acidosis produced conduction slowing transverse (29.1±0.1 to 16.8±0.2 cm/s,
P
<0.0001) and longitudinal (47.2±2.4 to 33.2±4.8 cm/s,
P
<0.0001) to cardiac fibers. Importantly, ZP123 inhibited conduction slowing during acidosis by approximately 60%. The peak effect of ZP123 was achieved after 16 minutes of acidosis, consistent with inhibition of uncoupling. ZP123 did not affect Na
+
current in isolated myocytes, additionally affirming that preservation of CV was attributable to the compound’s action on gap junctions. ZP123 had no effect on CV in the absence of acidosis, suggesting that drug activity targets gap junctions under metabolic stress. Action potential duration heterogeneity was significantly reduced by ZP123 (6.7±0.8 ms) compared with controls (9.7±3.1 ms,
P
<0.05), presumably by enhancing cell-to-cell coupling.

Conclusions—

These data suggest that ZP123 significantly attenuates gap junction closure during acidosis. Preservation of intercellular coupling diminished CV slowing and heterogeneous repolarization, eliminating arrhythmogenic substrates.
Cardiac-Specific Overexpression of Fibroblast Growth Factor-2 Protects Against Myocardial Dysfunction and Infarction in a Murine Model of Low-Flow Ischemia
Authors: House Stacey L. , Bolte Craig , Zhou Ming , Doetschman Thomas , Klevitsky Raisa , Newman Gilbert , Schultz Jo El J.
Published: December 2003

Background—

Preconditioning the heart before an ischemic insult has been shown to protect against contractile dysfunction, arrhythmias, and infarction. Pharmacological studies have suggested that fibroblast growth factor-2 (FGF2) is involved in cardioprotection. However, because of the number of FGFs expressed in the heart and the promiscuity of FGF ligand-receptor interactions, the specific role of FGF2 during ischemia-reperfusion injury remains unclear.

Methods and Results—

FGF2-deficient (
Fgf2
knockout) mice and mice with a cardiac-specific overexpression of all 4 isoforms of human
FGF2
(
FGF2
transgenic [Tg]) were compared with wild-type mice to test whether endogenous FGF2 elicits cardioprotection. An ex vivo work-performing heart model of ischemia was developed in which murine hearts were subjected to 60 minutes of low-flow ischemia and 120 minutes of reperfusion. Preischemic contractile function was similar among the 3 groups. After ischemia-reperfusion, contractile function of
Fgf2
knockout hearts recovered to 27% of its baseline value compared with a 63% recovery in wild-type hearts (
P
<0.05). In
FGF2
Tg hearts, an 88% recovery of postischemic function occurred (
P
<0.05). Myocardial infarct size was also reduced in
FGF2
Tg hearts compared with wild-type hearts (13% versus 30%,
P
<0.05). There was a 2-fold increase in FGF2 release from Tg hearts compared with wild-type hearts (
P
<0.05). No significant alterations in coronary flow or capillary density were detected in any of the groups, implying that the protective effect of FGF2 is not mediated by coronary perfusion changes.

Conclusions—

These results provide evidence that endogenous FGF2 plays a significant role in the cardioprotective effect against ischemia-reperfusion injury.
Decrease in Mitochondrial Complex I Activity in Ischemic/Reperfused Rat Heart
Authors: Paradies Giuseppe , Petrosillo Giuseppe , Pistolese Marilva , Di Venosa Nicola , Federici Antonio , Ruggiero Francesca Maria
Published: December 2003

Reactive oxygen species (ROS) are considered an important factor in ischemia/reperfusion injury to cardiac myocytes. Mitochondrial respiration is an important source of ROS production and hence a potential contributor to cardiac reperfusion injury. In this study, we have examined the effect of ischemia and ischemia followed by reperfusion of rat hearts on various parameters related to mitochondrial function, such as complex I activity, oxygen consumption, ROS production, and cardiolipin content. The activity of complex I was reduced by 25% and 48% in mitochondria isolated from ischemic and reperfused rat heart, respectively, compared with the controls. These changes in complex I activity were associated with parallel changes in state 3 respiration. The capacity of mitochondria to produce H
2
O
2
increased on reperfusion. The mitochondrial content of cardiolipin, which is required for optimal activity of complex I, decreased by 28% and 50% as function of ischemia and reperfusion, respectively. The lower complex I activity in mitochondria from reperfused rat heart could be completely restored to the level of normal heart by exogenous added cardiolipin. This effect of cardiolipin could not be replaced by other phospholipids nor by peroxidized cardiolipin. It is proposed that the defect in complex I activity in ischemic/reperfused rat heart could be ascribed to a ROS-induced cardiolipin damage. These findings may provide an explanation for some of the factors responsible for myocardial reperfusion injury.
Comments on Marcus Kreuzer's Article
Authors: Sperber Jonathan
Published: December 2003

Marcus Kreuzer's vigorously-argued essay on the progress of parliamentarization in Imperial Germany is an innovative intervention into a long-running scholarly debate about a central assertion of the Sonderweg thesis, namely the power or powerlessness of the democratically elected Reichstag of Imperial Germany. Plausibly dividing historians who have studied the topic into three groups: “optimists,” who perceive a steady increase in parliamentary power and a move toward democratic and parliamentary government, particularly in the Wilhelmian Era; “pessimists,” who deny the power of the Reichstag vis-à-vis the executive increased at any point in the history of the empire; and “skeptics” who point toward an increase in the power of the Reichstag, once again primarily in the Wilhelmian era, but deny that such an increase in power was leading toward democratic or parliamentary government. Kreuzer points out that underlying all three arguments is an implicit assumption of what a powerful parliament should be. Blinded by the “Westminster model” of British parliamentary government, he suggests, pessimists and skeptics have condemned the imperial Reichstag for not resembling the House of Commons. Yet the British governmental system represented just one possible form of parliamentarization. By systematically comparing the powers of the Reichstag with those of today's West European and North American legislatures, Kreuzer ascertains that the Reichstag was a politically influential parliament, thus demonstrating that the optimists have had the better of the argument about parliamentarization.
Identifying Underserved End-User Groups in the Provision of Climate Information
Authors: Archer Emma R.M.
Published: December 2003

Despite improvements in the science of climate forecasting, the application of forecasts faces key challenges. Prominent among such challenges is the fact that certain subgroupings of end users of climate information remain excluded from its potential benefits, or underserved. This paper suggests that such an omission may occur in part due to a lack of sophistication in the way the end user is viewed in the field of forecast applications research. End-user studies working both at generic and finer scales are cited, identifying reasons why certain user groups may be excluded from potential benefits of the forecast system. A case study in the Limpopo Province, South Africa, shows more specifically how one characteristic, namely gender, may determine such exclusion. The paper concludes by considering recommendations to improve inclusivity of climate information systems.
Defective B-cell-negative selection and terminal differentiation in the ICF syndrome
Authors: Blanco-Betancourt Carla E. , Moncla Anne , Milili Michèle , Jiang Yun Liang , Viegas-Péquignot Evani M. , Roquelaure Bertrand , Thuret Isabelle , Schiff Claudine
Published: December 2003

Immunodeficiency, centromeric region instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disease. Mutations in the DNA methyltransferase 3B (DNMT3B) gene are responsible for most ICF cases reported. We investigated the B-cell defects associated with agammaglobulinemia in this syndrome by analyzing primary B cells from 4 ICF patients. ICF peripheral blood (PB) contains only naive B cells; memory and gut plasma cells are absent. Naive ICF B cells bear potentially autoreactive long heavy chain variable regions complementarity determining region 3's (VHCDR3's) enriched with positively charged residues, in contrast to normal PB transitional and mature B cells, indicating that negative selection is impaired in patients. Like anergic B cells in transgenic models, newly generated and immature B cells accumulate in PB. Moreover, these cells secrete immunoglobulins and exhibit increased apoptosis following in vitro activation. However, they are able to up-regulate CD86, indicating that mechanisms other than anergy participate in silencing of ICF B cells. One patient without DNMT3B mutations shows differences in immunoglobulin E (IgE) switch induction, suggesting that immunodeficiency could vary with the genetic origin of the syndrome. In this study, we determined that negative selection breakdown and peripheral B-cell maturation blockage contribute to agammaglobulinemia in the ICF syndrome. (Blood. 2004;103:2683-2690)
Mast cell–mediated inflammatory responses require the α2β1 integrin
Authors: Edelson Brian T. , Li Zhengzhi , Pappan Loretta K. , Zutter Mary M.
Published: December 2003

Although the α2β1 integrin is widely expressed and has been extensively studied, it has not been previously implicated in mast cell biology. We observed that α2 integrin subunit-deficient mice exhibited markedly diminished neutrophil and interleukin-6 responses during Listeria monocytogenes– and zymosan-induced peritonitis. Since exudative neutrophils of wild-type mice expressed little α2β1 integrin, it seemed unlikely that this integrin mediated neutrophil migration directly. Here, we demonstrate constitutive α2β1 integrin expression on peritoneal mast cells. Although α2-null mice contain normal numbers of peritoneal mast cells, these α2-null cells do not support in vivo mast cell–dependent inflammatory responses. We conclude that α2β1 integrin provides a costimulatory function required for mast cell activation and cytokine production in response to infection.
Diazepam Inhibits Organophosphate‐induced Central Respiratory Depression
Authors: Dickson Eric W. , Bird Steven B. , Gaspari Romolo J. , Boyer Edward W. , Ferris Craig F.
Published: December 2003

Objectives: Current evidence suggests that mortality from acute organophosphate (OP) poisoning is partially mediated through central nervous system (CNS) respiratory center depression (CRD). However, the exact mechanism of OP‐induced CRD is unknown. In these studies, the authors investigated the hypothesis that OP‐induced CRD is the result of overstimulation of CNS respiratory centers. Methods: Wistar rats received prophylaxis with either normal saline (controls), atropine, the peripherally acting anticholinergics glycopyrrolate (GLYC), ipratropium bromide (IB), or the CNS respiratory center attenuator diazepam. To determine if a dual CNS/peripheral cholinergic mechanism is responsible for animal death, two additional groups received combination treatment with diazepam plus either IB or GLYC. All treatments were completed 5 minutes before OP with subcutaneous dichlorvos. Differences in 10‐minute and 24‐hour mortality were assessed by the Fisher exact test. Results: Dichlorvos poisoning resulted in profound fasciculations without obvious seizure in all cohorts. In controls and animals treated with peripherally acting anticholinergics, fasciculations were followed by sedation and respiratory arrest (0% 10‐minute survival in all cohorts). In contrast, pretreatment with either atropine or diazepam significantly improved 10‐minute survival (100% and 44%, respectively). Although GLYC or IB afforded no protection when given alone, when delivered in conjunction with diazepam, the combination significantly improved survival (both groups 88% at 24 hours), suggesting a dual CNS/pulmonary muscarinic mechanism of lethality. Conclusions: The central respiratory depressant diazepam paradoxically attenuates organophosphate‐induced respiratory depression, and when combined with peripherally acting anticholinergic agents, reduces mortality in a rat model of severe acute OP poisoning.
Diagnosis Clusters for Emergency Medicine
Authors: Travers Debbie A. , Haas Stephanie W. , Waller Anna E. , Tintinalli Judith E.
Published: December 2003

Objectives:Aggregated emergency department (ED) data are useful for research, ED operations, and public health surveillance. Diagnosis data are widely available as The International Classification of Diseases, version, 9, Clinical Modification (ICD‐9‐CM) codes; however, there are over 24,000 ICD‐9‐CM code‐descriptor pairs. Standardized groupings (clusters) of ICD‐9‐CM codes have been developed by other disciplines, including family medicine (FM), internal medicine (IM), inpatient care (Agency for Healthcare Research and Quality [AHRQ]), and vital statistics (NCHS). The purpose of this study was to evaluate the coverage of four existing ICD‐9‐CM cluster systems for emergency medicine.Methods:In this descriptive study, four cluster systems were used to group ICD‐9‐CM final diagnosis data from a southeastern university tertiary referral center. Included were diagnoses for all ED visits in July 2000 and January 2001. In the comparative analysis, the authors determined the coverage in the four cluster systems, defined as the proportion of final diagnosis codes that were placed into clusters and the frequencies of diagnosis codes in each cluster.Results:The final sample included 7,543 visits with 19,530 diagnoses. Coverage of the ICD‐9‐CM codes in the ED sample was: AHRQ, 99%; NCHS, 88%; FM, 71%; IM, 68%. Seventy‐six percent of the AHRQ clusters were small, defined as grouping <1% of the diagnosis codes in the sample.Conclusions:The AHRQ system provided the best coverage of ED ICD‐9‐CM codes. However, most of the clusters were small and not significantly different from the raw data.
Determinants of Emergency Department Visits by Older Adults: A Systematic Review
Authors: McCusker Jane , Karp Igor , Cardin Sylvie , Durand Pierre , Morin Jacques
Published: December 2003

Objectives: To conduct a systematic review of the literature on the determinants of hospital emergency department (ED) visits by elders, using a modification of the Andersen behavioral model of health services, adapted to explain ED utilization. Methods: Relevant articles were identified through MEDLINE and a search of reference lists and personal files. Studies of populations aged 65 or older in which ED visits were a study outcome were included if they were: original, not restricted to a particular medical condition, written in English or French, and investigated one or more determinants. Data were abstracted and checked by two authors using a standard protocol. Results: Fourteen studies (reported in 15 articles) were reviewed, 10 community‐based and four using clinical samples. Among ten studies that measured multiple determinants, determinants reported from multivariate analyses included measures of need (perceived and evaluated health status, prior utilization), predisposing factors (health beliefs and sociodemographic variables), and enabling factors (physician availability, regular source of care, family resources, geographical access to services). Conclusions: Need is usually the primary determinant of ED visits in older people. Controlling for need, predisposing and enabling factors that promote access to primary medical care are associated with reduced ED utilization.
Contracting with Children and Helmet Distribution in the Emergency Department to Improve Bicycle Helmet Use
Authors: Bishai David , Qureshi Asma , Cantu Noelia , Parks Cheryl
Published: December 2003

Objectives: To determine whether injury prevention counseling and behavioral counseling delivered in the emergency department (ED) could result in increases in self‐reported bicycle helmet use. Methods: The authors undertook a trial of counseling in 222 children recruited in an urban ED between August 2000 and October 2001. All consenting patients in the ED aged 5 to 15 years who did not have life‐threatening conditions were eligible. One hundred nine children were assigned to the control group on the basis of attendance on an odd‐numbered day, and they received a photocopied photograph of the hospital. One hundred thirteen children were assigned to the intervention group, and they received a personal counseling session and signed a contract promising to wear their bicycle helmets. In addition, 57 of the intervention children were assigned (based on having an even‐numbered birthday) to be fitted with helmets if they did not already own them. Parents were telephoned four weeks after the ED encounter for follow‐up. Results: Follow‐up data were obtained for 148 children (67% follow‐up rate), of whom only 69 reported riding a bicycle in the four weeks after their ED visit. Of the final sample of 69 children, 38 belonged to one of the intervention groups, and 25 of these (66%) reported always wearing a helmet while cycling during the four weeks after their ED visit, versus 13 of 31 (42%) in the control group (odds ratio, 2.66; p < 0.05). The effect of the intervention was independent of whether the children owned a helmet at baseline. Conclusions: Injury prevention counseling in the ED using “The Injury Prevention Program” (TIPP) sheet, behavioral contracting, and helmet distribution may have a significant effect on reports of subsequent bike helmet use.
Phase II Trial of Carboxyamidotriazole in Patients With Relapsed Epithelial Ovarian Cancer
Authors: Hussain Mahrukh M. , Kotz Herbert , Minasian Lori , Premkumar Ahalya , Sarosy Gisele , Reed Eddie , Zhai Suoping , Steinberg Seth M. , Raggio Miranda , Oliver Vyta Kulpa , Figg William D. , Kohn Elise C.
Published: November 2003

Purpose: Carboxyamidotriazole (CAI) is a cytostatic inhibitor of nonvoltage-operated calcium channels and calcium channel–mediated signaling pathways. It inhibits angiogenesis, tumor growth, invasion, and metastasis. We hypothesized that CAI would promote disease stabilization lasting ≥ 6 months in patients with relapsed ovarian cancer.

Patients and Methods: Patients with epithelial ovarian cancer, good end-organ function, measurable disease, and three or fewer prior regimens were eligible. Oral CAI was given daily using a pharmacokinetic-dosing approach to maintain plasma concentrations between 2 and 4 μg/mL. Radiographic imaging to assess response was performed every 8 weeks. Positive outcome included stabilization or improvement of disease lasting ≥ 6 months. Plasma vascular endothelial growth factor (VEGF), interleukin (IL)-8, and matrix metalloproteinase (MMP)-2 were measured.

Results: Thirty-six patients were assessable for primary end point analysis, and 38 were assessable for toxicity. Forty-four percent of patients had three prior regimens, more than 50% had four or more disease sites, and 48% had liver metastases. Thirty-three patients reached the targeted concentration range during the first cycle. Eleven patients (31%) attained the ≥ 6-month outcome end point, with one partial response (8 months) and three minor responses (8, 12+, and 13 months). Median time to progression was 3.6 months (range, 1.6 to 13.3 months). CAI was well tolerated, with mostly grade 1 to 2 toxicity. Grade 3 events included fatigue (5%), vomiting (2%), neutropenic fever (2%), and neutropenia (2%). There were no grade 4 adverse events. No associations between VEGF, IL-8, and MMP-2 with CAI concentration or clinical outcome were observed.

Conclusion: CAI is a potential agent for additional study in the stabilization of relapsed ovarian cancer. Given a limited toxicity profile, it may have utility as a maintenance therapeutic agent for this disease.
Nonablative Allogeneic Stem-Cell Transplantation for Advanced/Recurrent Mantle-Cell Lymphoma
Authors: Khouri Issa F. , Lee Ming-S. , Saliba Rima M. , Jun Gu , Fayad Luis , Younes Anas , Pro Barbara , Acholonu Sandra , McLaughlin Peter , Katz Ruth L. , Champlin Richard E.
Published: November 2003

Purpose: Patients with relapsed mantle-cell lymphoma have poor prognosis and short survival. Our aim was to determine the efficacy of nonablative allogeneic stem-cell transplantation in patients with relapsed mantle-cell lymphoma.

Patients and Methods: Eighteen patients were treated in one of two consecutive trials. Thirteen patients underwent a conditioning regimen of fludarabine (30 mg/m2 daily for 3 days), cyclophosphamide (750 mg/m2 daily for 3 days), and high-dose rituximab. For the remaining five patients, the conditioning regimen consisted of cisplatin (25 mg/m2 daily for 4 days), fludarabine (30 mg/m2 daily for 2 days), and cytarabine (1,000 mg/m2 daily for 2 days). Tacrolimus and methotrexate were used for graft-versus-host disease prophylaxis.

Results: The median age was 56.5 years. Patients underwent a median of three prior chemotherapy regimens. Prior autologous transplantation failed in five (28%) patients and 16 (89%) had chemosensitive disease. Donor cell engraftment occurred in all patients. Eight patients (44%) required no platelet or RBC transfusion, and acute graft-versus-host disease of greater than grade 2 did not develop in any patient. The day-100 mortality was 0%. Complete remission (CR) occurred in 17 patients. Three patients progressed, and one was reinduced into continuous CR with donor lymphocyte infusion. With a median follow-up period of 26 months, the actuarial probability of current-event-free-survival at 3 years was 82% (95% CI, 65% to 99%).

Conclusion:Our data suggest that nonablative allogeneic transplantation is a safe and potentially effective strategy for patients with relapsed and chemosensitive mantle-cell lymphoma.
High Risk of Subsequent Neoplasms Continues With Extended Follow-Up of Childhood Hodgkin’s Disease: Report From the Late Effects Study Group
Authors: Bhatia Smita , Yasui Yutaka , Robison Leslie L. , Birch Jillian M. , Bogue Monica K. , Diller Lisa , DeLaat Cyndi , Fossati-Bellani Franca , Morgan Elaine , Oberlin Odile , Reaman Gregory , Ruymann Frederick B. , Tersak Jean , Meadows Anna T.
Published: November 2003

Purpose: We present an update of a previously reported Late Effects Study Group cohort of 1,380 children with Hodgkin’s disease (HD) diagnosed between 1955 and 1986 in patients aged 16 years or younger. We describe the pattern and incidence of subsequent neoplasms (SNs) occurring with extended follow-up.

Patients and Methods: Median age at diagnosis of HD was 11.7 years (range, 0.3 to 16.9 years) and at last follow-up was 27.8 years. Median length of follow-up was 17.0 years.

Results: An additional 103 SNs were ascertained (total SNs = 212). The cohort was at an 18.5-fold increased risk of developing SNs compared with the general population (standardized incidence ratio [SIR], 18.5, 95% CI, 15.6 to 21.7). The cumulative incidence of any second malignancy was 10.6% at 20 years, increasing to 26.3% at 30 years; and of solid malignancies was 7.3% at 20 years, increasing to 23.5% at 30 years. Breast cancer was the most common solid malignancy (SIR, 56.7). Other commonly occurring solid malignancies included thyroid cancer (SIR, 36.4), bone tumors (SIR, 37.1), and colorectal (SIR, 36.4), lung (SIR, 27.3), and gastric cancers (SIR, 63.9). Risk factors for solid tumors included young age at HD and radiation-based therapy. Thirty-two patients developed third neoplasms, with the cumulative incidence approaching 21% at 10 years from diagnosis of second malignancy.

Conclusion: Additional follow-up of this large cohort of HD survivors documents an increasing occurrence of known radiation-associated solid tumors, (breast and thyroid cancers), as well as emergence of epithelial neoplasms common in adults, (colon and lung cancers) at a younger age than expected in the general population, necessitating ongoing surveillance of this high risk population.
Photoperiodic Regulation of Leptin Sensitivity in the Siberian Hamster, Phodopus sungorus, Is Reflected in Arcuate Nucleus SOCS-3 (Suppressor of Cytokine Signaling) Gene Expression
Authors: Tups Alexander , Ellis Claire , Moar Kim M. , Logie Tracy J. , Adam Clare L. , Mercer Julian G. , Klingenspor Martin
Published: December 2003

We present the first evidence that suppressor of cytokine signaling-3 (SOCS3), a protein inhibiting Janus kinase/signal transducer and activator of transcription (STAT) signaling distal of the leptin receptor, conveys seasonal changes in leptin sensitivity in the Siberian hamster. Food deprivation (48 h) reduced SOCS3 gene expression in hamsters acclimated to either long (LD) or short (SD) photoperiods, suggesting that leptin signals acute starvation regardless of photoperiod. However, SOCS3 mRNA levels were substantially lower in the hypothalamic arcuate nucleus of hamsters acclimated to SD than in those raised in LD. In juveniles raised in LD, a rapid increase in SOCS3 mRNA was observed within 4 d of weaning, which was completely prevented by transfer to SD on the day of weaning. The early increase in SOCS3 gene expression in juvenile hamsters in LD clearly preceded the establishment of different body weight trajectories in LD and SD. In adult LD hamsters, SOCS3 mRNA was maintained at an elevated level despite the chronic food restriction imposed to lower body weight and serum leptin to or even below SD levels. A single injection of leptin in SD hamsters elevated SOCS3 mRNA to LD levels, whereas leptin treatment had no effect on SOCS3 gene expression in LD hamsters. Our results suggest that the development of leptin resistance in LD-acclimated hamsters involves SOCS3-mediated suppression of leptin signaling in the arcuate nucleus. Increased SOCS3 expression in LD hamsters is independent of body fat and serum leptin levels, suggesting that the photoperiod is able to trigger the biannual reversible switch in leptin sensitivity.
Mitf expression is sufficient to direct differentiation of medaka blastula derived stem cells to melanocytes
Authors: Béjar Julia , Hong Yunhan , Schartl Manfred
Published: December 2003

Embryonic stem (ES) cell lines have provided very useful models to analyse differentiation processes. We present here the development of a differentiation system using ES-like cell lines from medaka. These cells were transfected with the melanocyte specific isoform of the microphtalmia-related transcription factor (Mitf). Mitf is a basic helix-loop-helix-leucine zipper transcription factor whose M isoform is restricted to neural crest derived melanocytes and is essential for the development of these cells in vertebrates from mammals to fish. What is not clear yet is whether Mitf is a downstream factor or a master regulator of melanocyte commitment and differentiation. Expression of Mitf in the ES-like cells from medaka led to the induction of cells that, by morphology, physiology and gene expression pattern, were confirmed to be fully differentiated pigment cells. Mitf expression is therefore sufficient for the proper differentiation of medaka pluripotent stem cells into melanocytes.
Information display by transcriptional enhancers
Authors: Kulkarni Meghana M. , Arnosti David N.
Published: December 2003

Transcriptional enhancers integrate positional and temporal information to regulate the complex expression of developmentally controlled genes. Current models suggest that enhancers act as computational devices, receiving multiple inputs from activators and repressors and resolving them into a single positive or a negative signal that is transmitted to the basal transcriptional machinery. We show that a simple, compact enhancer is capable of representing both repressed and activated states at the same time and in the same nucleus. This finding suggests that closely apposed factor binding sites, situated within compact cis-elements, can be independently interpreted by the transcriptional machinery, possibly through successive enhancer-promoter interactions. These results provide clear evidence that the computational functions usually ascribed to the enhancer itself are actually shared with the basal machinery. In contrast to the autonomous computer model of enhancer function, an information-display or `billboard' model of enhancer activity may better describe many developmentally regulated transcriptional enhancers.
The pro-apoptotic gene Bax is required for the death of ectopic primordial germ cells during their migration in the mouse embryo
Authors: Stallock James , Molyneaux Kathy , Schaible Kyle , Knudson C. Michael , Wylie Christopher
Published: December 2003

In the mouse embryo, significant numbers of primordial germ cells (PGCs)fail to migrate correctly to the genital ridges early in organogenesis. These usually die in ectopic locations. In humans, 50% of pediatric germ line tumors arise outside the gonads, and these are thought to arise from PGCs that fail to die in ectopic locations. We show that the pro-apoptotic gene Bax,previously shown to be required for germ cell death during later stages of their differentiation in the gonads, is also expressed during germ cell migration, and is required for the normal death of germ cells left in ectopic locations during and after germ cell migration. In addition, we show that Bax is downstream of the known cell survival signaling interaction mediated by the Steel factor/Kit ligand/receptor interaction. Together, these observations identify the major mechanism that removes ectopic germ cells from the embryo at early stages.
Atrophin 2 recruits histone deacetylase and is required for the function of multiple signaling centers during mouse embryogenesis
Authors: Zoltewicz J. Susie , Stewart Nicola J. , Leung Ricky , Peterson Andrew S.
Published: December 2003

Atrophins are evolutionarily conserved proteins that are thought to act as transcriptional co-repressors. Mammalian genomes contain two atrophin genes. Dominant polyglutamine-expanded alleles of atrophin 1 have been identified as the cause of dentatorubralpallidoluysian atrophy, an adult-onset human neurodegenerative disease with similarity to Huntington's. In a screen for recessive mutations that disrupt patterning of the early mouse embryo, we identified a line named openmind carrying a mutation in atrophin 2. openmind homozygous embryos exhibit a variety of patterning defects that first appear at E8.0. Defects include a specific failure in ventralization of the anterior neural plate, loss of heart looping and irregular partitioning of somites. In mutant embryos, Shh expression fails to initiate along the anterior midline at E8.0, and Fgf8 is delocalized from the anterior neural ridge at E8.5,revealing a crucial role for atrophin 2 in the formation and function of these two signaling centers. Atrophin 2 is also required for normal organization of the apical ectodermal ridge, a signaling center that directs limb pattern. Elevated expression of atrophin 2 in neurons suggests it may interact with atrophin 1 in neuronal development or function. We further show that atrophin 2 associates with histone deacetylase 1 in mouse embryos, providing a biochemical link between Atr2 and a chromatin-modifying enzyme. Based on our results, and on those of others, we propose that atrophin proteins act as transcriptional co-repressors during embryonic development.
VARICOSE, a WD-domain protein, is required for leaf blade development
Authors: Deyholos Michael K. , Cavaness G. Frank , Hall Branden , King Ed , Punwani Jayson , Van Norman Jaimie , Sieburth Leslie E.
Published: December 2003

To gain insight into the processes controlling leaf development, we characterized an Arabidopsis mutant, varicose(vcs), with leaf and shoot apical meristem defects. The vcsphenotype is temperature dependent; low temperature growth largely suppressed defects, whereas high growth temperatures resulted in severe leaf and meristem defects. VCS encodes a putative WD-domain containing protein,suggesting a function involving protein-protein interactions. Temperature shift experiments indicated that VCS is required throughout leaf development,but normal secondary vein patterning required low temperature early in leaf development. The low-temperature vcs phenotype is enhanced in axr1-3 vcs double mutants and in vcs mutants grown in the presence of polar auxin transport inhibitors, however, vcs has apparently normal auxin responses. Taken together, these observations suggest a role for VCS in leaf blade formation.
A distinct patterning mechanism of O and P cell fates in the development of the rostral segments of the leechHelobdella robusta: implications for the evolutionary dissociation of developmental pathway and morphological outcome
Authors: Kuo Dian-Han , Shankland Marty
Published: December 2003

Despite a high degree of homonomy in the segmental organization of the ectoderm, the body plan of the leech is divided into two zones based on the distinct cell lineage patterns that give rise to the O/P portion of the segmental ectoderm. In the midbody and caudal segments, each segmental repeat of ectoderm arises in part from one o' blast cell and one `p' blast cell. These two blast cells are positionally specified to distinct O and P fates,and give rise to differentiated descendant cells called O and P pattern elements, respectively. In the rostral segments, each segmental repeat of O and P pattern elements arises from a single `op' blast cell. Based on their developmental fates and their responses to the ablation of neighboring cells,the granddaughters of the primary op blast cell are categorized into two O-type cells and two P-type cells. The O-type cells do not require the presence of the rest of the op blast cell clone for their normal development. By contrast, normal development of the P-type cells depends upon interactions with the other OP sublineages. Additional experiments showed that the O-type cells are the source of a repressive signal involved in the normal fate specification of the P-type cells. Our data suggest that the cell interactions involved in fate specification differ substantially in the rostral and midbody segments, even though the set of differentiated descendants produced by the rostral OP pathway and the midbody O and P pathways are very similar.