bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular-derived artemin: a determinant of vascular sympathetic innervation?
Authors: Damon Deborah H. , teRiele Jaclyn A. , Marko Stephen B.
Published: March 2007

Vascular sympathetic innervation is an important determinant of blood pressure and blood flow. The mechanisms that determine vascular sympathetic innervation are not well understood. The present study tests the hypothesis that vascular-derived artemin promotes the development of sympathetic innervation to blood vessels by promoting sympathetic axon growth. RT-PCR and Western analyses indicate that artemin is expressed by cultured vascular smooth muscle and arteries, and artemin coreceptors, glial cell-derived neurotrophic factor family receptor α3 and ret, are expressed by postganglionic sympathetic neurons. The effects of artemin on axon growth were assessed on explants of neonatal rat sympathetic ganglia. In the presence, but not in the absence, of nerve growth factor, exogenous artemin stimulated neurite growth. Femoral arteries (FA) from adult rats contain artemin, and these arteries stimulated sympathetic neurite growth. Growth in the presence of FA was 92.2 ± 11.9 mm, and that in the absence of FA was 26.3 ± 5.4 mm ( P < 0.05). FA stimulation of axon growth was reduced by an antibody that neutralized the activity of artemin ( P < 0.05). These data indicate that artemin is expressed in arteries, and its receptors are expressed and functional in the postganglionic sympathetic neurons that innervate them. This suggests that artemin may be a determinant of vascular sympathetic innervation.
Calf venous compliance in multiple system atrophy
Authors: Lipp A. , Sandroni P. , Ahlskog J. Eric , Maraganore D. M. , Shults C. W. , Low P. A.
Published: March 2007

In multiple system atrophy (MSA), increased venous compliance with excessive venous pooling is assumed to be a major contributor to orthostatic hypotension (OH); however, venous compliance has never been assessed in MSA patients. We evaluated the severity and distribution of adrenergic, cardiovagal, and sudomotor failure in 11 patients with probable MSA, 14 age- and sex-matched control subjects, and 8 patients with Parkinson's disease (PD) but not OH. Calf venous compliance, venous filling, and capillary filtration were measured using calf plethysmography. The response to the directly acting α-adrenergic stimulation (10 mg midodrine) on calf venous compliance was additionally evaluated. Contrary to our hypothesis, pressure-volume curves in the legs of MSA patients were flatter than in PD patients ( P < 0.05) or controls ( P < 0.001); this indicated reduced calf venous compliance in MSA. The MSA group had reduced venous filling compared with control ( P < 0.001) or PD subjects ( P < 0.001) but had a normal capillary filtration rate ( P = 0.73). Direct α-adrenergic stimulation resulted in a slight but significant reduction of calf venous compliance in controls ( P = 0.001) and PD subjects ( P < 0.001) but not in the MSA group. The compliance change in MSA significantly regressed with autonomic failure (composite autonomic severity scale, r2 = 0.56) but not with parkinsonism (Unified MSA Rating Scale, r2 = 0.12). Our data indicate that MSA patients with chronic OH have reduced, rather than increased, venous compliance in the lower leg. We postulate that chronic venous distension that is associated with OH results in structural remodeling of veins, leading to reduced compliance, a change which may protect patients against orthostatic stress.
Developmental regulation of DUOX1 expression and function in human fetal lung epithelial cells
Authors: Fischer Horst , Gonzales Linda K. , Kolla Venkatadri , Schwarzer Christian , Miot Françoise , Illek Beate , Ballard Philip L.
Published: March 2007

The purpose of this study was to determine the expression and cellular functions of the epithelial NADPH oxidase DUOX1 during alveolar type II cell development. When human fetal lung cells (gestational age 11–22 wk) were cultured to confluency on permeable filters, exposure of cells to a hormone mixture (dexamethasone, 8-Br-cAMP, and IBMX, together referred to as DCI) resulted in differentiation of cells into a mature type II phenotype as assessed by expression of lamellar bodies, surfactant proteins, and transepithelial electrical parameters. After 6 days in culture in presence of DCI, transepithelial resistance (2,616 ± 529 Ω·cm2) and potential (−8.5 ± 0.6 mV) indicated epithelial polarization. At the same time, treatment with DCI significantly increased the mRNA expression of DUOX1 (∼21-fold), its maturation factor DUOXA1 (∼12-fold), as well as DUOX protein (∼12-fold), which was localized near the apical cell pole in confluent cultures. For comparison, in fetal lung specimens, DUOX protein was not detectable at up to 27 wk of gestational age but was strongly upregulated after 32 wk. Function of DUOX1 was assessed by measuring H2O2 and acid production. Rates of H2O2 production were increased by DCI treatment and blocked by small interfering RNA directed against DUOX1 or by diphenylene iodonium. DCI-treated cultures also showed increased intracellular acid production and acid release into the mucosal medium, and acid production was largely blocked by knockdown of DUOX1 mRNA. These data establish the regulated expression of DUOX1 during alveolar maturation, and indicate DUOX1 in alveolar H2O2 and acid secretion by differentiated type II cells.
Gene cloning and expression of an aquaporin (AQP-h3BL) in the basolateral membrane of water-permeable epithelial cells in osmoregulatory organs of the tree frog
Authors: Akabane Gen , Ogushi Yuji , Hasegawa Takahiro , Suzuki Masakazu , Tanaka Shigeyasu
Published: March 2007

An aquaporin (Hyla AQP-h3BL), consisting of 292 amino acid residues, has been cloned from the urinary bladder of Hyla japonica. In a swelling assay using Xenopus oocytes, AQP-h3BL cRNA-injected oocytes developed a sevenfold and 2.8-fold higher permeability to water and glycerol, respectively, than the water-injected oocytes. This permeability was inhibited by HgCl2. Immunofluorescence revealed that AQP-h3BL is localized in the basolateral plasma membrane of both granular cells in the ventral pelvic and dorsal skins and the secretory cells in the mucous glands. Immunopositive cells were also observed in the basolateral membrane of principal cells in the collecting ducts and in a portion of the late distal tubules in the kidneys, as well as in the principal cells of the urinary bladder. Sequence homology suggests that AQP-h3BL is a homolog to mammalian AQP3. This conclusion is supported by the observed localization of AQP-h3BL to the basolateral membrane in water- and glycerol-permeable epithelial cells. In ventral pelvic skins and urinary bladders, water enters into the cytoplasm through the apical plasma membrane at sites where AQP-h2, sometimes in association with AQP-h3, responds to stimulation by vasotocin; the water exits throughout AQP-h3BL to extracellular spaces. In the mucous glands, on the other hand, water enters throughout this AQP-h3BL and exits through AQP-x5, which is in the apical membrane of secretory cells. Thus, water homeostasis in the frog body is regulated by AQP-h3BL expressed in the basolateral membrane in concert with arginine vasotocin (AVT)-dependent or AVT-independent AQP.
Chemical reasonableness in Rietveld analysis; organics
Authors: Kaduk James A.
Published: March 2007

We know a lot about normal values of bond distances, bond angles, torsion angles, and other molecular parameters. This knowledge can be incorporated into the structure solution process and into Rietveld refinement through the use of restraints and rigid bodies. An important measure of the quality of the refined model is the chemical reasonableness of molecular geometry. Refinement of the structures of calcium tartrate tetrahydrate and guaifenesin is used to illustrate the importance of chemical reasonableness in determining the quality of a Rietveld refinement.
A new approach for instruction in powder crystallography
Authors: Toby B. H.
Published: March 2007

A series of Internet-distributed audio/visual recordings for learning crystallographic analysis of powder diffraction data is discussed. These recordings provide a compact mechanism for distributing educational information. Such presentations provide hands-on discussion beyond what is usually presented in instructional texts. In some cases similar material can be presented with HTML text, but recordings can be created with significantly less effort and are superior for software demonstration.
RIL, a LIM Gene on 5q31, Is Silenced by Methylation in Cancer and Sensitizes Cancer Cells to Apoptosis
Authors: Boumber Yanis A. , Kondo Yutaka , Chen Xuqi , Shen Lanlan , Gharibyan Vazganush , Konishi Kazuo , Estey Elihu , Kantarjian Hagop , Garcia-Manero Guillermo , Issa Jean-Pierre J.
Published: March 2007

Gene silencing associated with promoter methylation can inactivate tumor suppressor genes (TSG) in cancer. We identified RIL, a LIM domain gene mapping to 5q31, a region frequently deleted in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), as methylated in 55 of 79 (70%) of cancer cell lines tested. In a variety of primary tumors, we found RIL methylation in 55 of 92 (60%) cases, with highest methylation in AML and colon cancer, and in 30 of 83 (36%) MDS samples, whereas normal tissues showed either absence or substantially lower levels of methylation, which correlates with age. RIL is ubiquitously expressed but silenced in methylated cancers and could be reactivated by the hypomethylating agent 5-aza-2′-deoxycytidine. Restoring RIL expression in colon cancer cells by stable transfection resulted in reduced cell growth and clonogenicity and an ∼2.0-fold increase in apoptosis following UV exposure. In MDS, RIL methylation is a marker of adverse prognosis independent of chromosome 5 and 7 deletions. Our data suggest that RIL is a good candidate TSG silenced by hypermethylation in cancer. [Cancer Res 2007;67(5):1997–2005]
Attenuation of the Glucocorticoid Response during Ad5IL-12 Adenovirus Vector Treatment Enhances Natural Killer Cell–Mediated Killing of MHC Class I–Negative LNCaP Prostate Tumors
Authors: Raja Gabaglia Claudia , Diaz de Durana Yaiza , Graham Frank L. , Gauldie Jack , Sercarz Eli E. , Braciak Todd A.
Published: March 2007

Tumor cells can evolve to evade immune responses by down-modulating surface MHC class I expression and become refractory to T cell–directed immunotherapy. We employed a strategy to bypass this escape mechanism using a recombinant adenovirus vector expressing interleukin-12 (Ad5IL-12) to target natural killer (NK) cell–mediated killing of human prostate tumors in NOD.scid mice. Fluorescence-activated cell sorting analysis revealed that LNCaP tumor cells bear negligible levels of MHC class I molecules; yet, they express MICA/B molecules, ligands for the NKG2D receptors found on NK cells. Transduction of LNCaP cells with the Ad5IL-12 vector prevented tumor formation in NOD.scid mice, indicating that NK cells alone can conduct tumor immunosurveillance and mediate protection. Intratumor injection of the Ad5IL-12 vector to established LNCaP tumors in NOD.scid mice resulted in a significant delay of tumor growth mediated by NK cell killing activity. The dependency of NK cells in this protective response was shown by the complete loss of Ad5IL-12 therapeutic efficacy on LNCaP tumors established in NOD.Cg-Rag1tm1MomPrf1tm1Sdz congenic mice, which are devoid of NK cell activity. More pronounced attenuation of tumor growth and enhanced NK killing activity was observed when pharmacologic adrenalectomy with mitotane was done in combination with Ad5IL-12 vector treatment. The Ad5IL-12 vector treatment also induced killing of MICA/B-negative MHC class I–positive PC3 tumors formed in NOD.scid mice. Together, these results indicate that a targeted NK cell response could provide a generic approach for cancer immunotherapy, and that enhancing the NK cell response via control of cortisol levels may provide an additional therapeutic avenue in cancer. [Cancer Res 2007;67(5):2290–7]
In vitro Biological Characterization of a Novel, Synthetic Diaryl Pyrazole Resorcinol Class of Heat Shock Protein 90 Inhibitors
Authors: Sharp Swee Y. , Boxall Kathy , Rowlands Martin , Prodromou Chrisostomos , Roe S. Mark , Maloney Alison , Powers Marissa , Clarke Paul A. , Box Gary , Sanderson Sharon , Patterson Lisa , Matthews Thomas P. , Cheung Kwai-Ming J. , Ball Karen , Hayes Angela , Raynaud Florence , Marais Richard , Pearl Laurence , Eccles Sue , Aherne Wynne , McDonald Edward , Workman Paul
Published: March 2007

The molecular chaperone heat shock protein 90 (HSP90) has emerged as an exciting molecular target. Derivatives of the natural product geldanamycin, such as 17-allylamino-17-demethoxy-geldanamycin (17-AAG), were the first HSP90 ATPase inhibitors to enter clinical trial. Synthetic small-molecule HSP90 inhibitors have potential advantages. Here, we describe the biological properties of the lead compound of a new class of 3,4-diaryl pyrazole resorcinol HSP90 inhibitor (CCT018159), which we identified by high-throughput screening. CCT018159 inhibited human HSP90β with comparable potency to 17-AAG and with similar ATP-competitive kinetics. X-ray crystallographic structures of the NH2-terminal domain of yeast Hsp90 complexed with CCT018159 or its analogues showed binding properties similar to radicicol. The mean cellular GI50 value of CCT018159 across a panel of human cancer cell lines, including melanoma, was 5.3 μmol/L. Unlike 17-AAG, the in vitro antitumor activity of the pyrazole resorcinol analogues is independent of NQO1/DT-diaphorase and P-glycoprotein expression. The molecular signature of HSP90 inhibition, comprising increased expression of HSP72 protein and depletion of ERBB2, CDK4, C-RAF, and mutant B-RAF, was shown by Western blotting and quantified by time-resolved fluorescent-Cellisa in human cancer cell lines treated with CCT018159. CCT018159 caused cell cytostasis associated with a G1 arrest and induced apoptosis. CCT018159 also inhibited key endothelial and tumor cell functions implicated in invasion and angiogenesis. Overall, we have shown that diaryl pyrazole resorcinols exhibited similar cellular properties to 17-AAG with potential advantages (e.g., aqueous solubility, independence from NQO1 and P-glycoprotein). These compounds form the basis for further structure-based optimization to identify more potent inhibitors suitable for clinical development. [Cancer Res 2007;67(5):2206–16]
Systemic Stromal Effects of Estrogen Promote the Growth of Estrogen Receptor–Negative Cancers
Authors: Gupta Piyush B. , Proia David , Cingoz Oya , Weremowicz Janusz , Naber Stephen P. , Weinberg Robert A. , Kuperwasser Charlotte
Published: March 2007

Numerous hormonal factors contribute to the lifetime risk of breast cancer development. These include inherited genetic mutations, age of menarche, age of menopause, and parity. Inexplicably, there is evidence indicating that ovariectomy prevents the formation of both estrogen receptor (ER)–positive and ER-negative breast cancers, suggesting that ER-negative breast cancers are dependent on ovarian hormones for their formation. To examine the mechanism(s) by which this may be occurring, we investigated the hypothesis that steroid hormones promote the outgrowth of ER-negative cancers by influencing host cell types distinct from the mammary epithelial cells. We used a novel xenograft mouse model of parturition-induced breast carcinoma formation, in which the tumors that arise following pregnancy lack the expression of nuclear hormone receptors, thereby recapitulating many clinical cases of this disease. Despite lacking ER expression, the tumors arising following pregnancy in this model require circulating estrogens for their formation. Moreover, increasing the levels of circulating estrogens sufficed to promote the formation and progression of ER-negative cancers, which was accompanied by a systemic increase in host angiogenesis and was attendant with the recruitment of bone marrow–derived stromal cells. Furthermore, bone marrow cells from estrogen-treated mice were sufficient to promote tumor growth. These results reveal a novel mechanism by which estrogens promote the growth of ER-negative cancers. [Cancer Res 2007;67(5):2062–71]
Inhibition of CXCR4-Mediated Breast Cancer Metastasis: A Potential Role for Heparinoids?
Authors: Harvey James R. , Mellor Paul , Eldaly Hesham , Lennard Thomas W.J. , Kirby John A. , Ali Simi
Published: March 2007

Purpose: The pattern of breast cancer metastasis may be determined by interactions between CXCR4 on breast cancer cells and CXCL12 within normal tissues. Glycosaminoglycans bind chemokines for presentation to responsive cells. This study was designed to test the hypothesis that soluble heparinoid glycosaminoglycan molecules can disrupt the normal response to CXCL12, thereby reducing the metastasis of CXCR4-expressing cancer cells.

Experimental Design: Inhibition of the response of CXCR4-expressing Chinese hamster ovary cells to CXCL12 was assessed by measurement of calcium flux and chemotaxis. Radioligand binding was also assessed to quantify the potential of soluble heparinoids to prevent specific receptor ligation. The human breast cancer cell line MDA-MB-231 and a range of sublines were assessed for their sensitivity to heparinoid-mediated inhibition of chemotaxis. A model of hematogenous breast cancer metastasis was established, and the potential of clinically relevant doses of heparinoids to inhibit CXCL12 presentation and metastatic disease was assessed.

Results: Unfractionated heparin and the low-molecular-weight heparin tinzaparin inhibited receptor ligation and the response of CXCR4-expressing Chinese hamster ovary cells and human breast cancer cell lines to CXCL12. Heparin also removed CXCL12 from its normal site of expression on the surface of parenchymal cells in the murine lung. Both heparin and two clinically relevant dose regimens of tinzaparin reduced hematogenous metastatic spread of human breast cancer cells to the lung in a murine model.

Conclusions: Clinically relevant concentrations of tinzaparin inhibit the interaction between CXCL12 and CXCR4 and may be useful to prevent chemokine-driven breast cancer metastasis.
Translating Expression Profiling into a Clinically Feasible Test to Predict Neuroblastoma Outcome
Authors: Schramm Alexander , Vandesompele Jo , Schulte Johannes H. , Dreesmann Sabine , Kaderali Lars , Brors Benedikt , Eils Roland , Speleman Frank , Eggert Angelika
Published: March 2007

Purpose: To assess the feasibility of predicting neuroblastoma outcome using highly parallel quantitative real-time PCR data.

Experimental Design: We generated expression profiles of 63 neuroblastoma patients, 47 of which were analyzed by both Affymetrix U95A microarrays and highly parallel real-time PCR on microfluidic cards (MFC; Applied Biosystems). Top-ranked genes discriminating patients with event-free survival or relapse according to high-level analysis of Affymetrix chip data, as well as known neuroblastoma marker genes (MYCN and NTRK1/TrkA), were quantified simultaneously by real-time PCR. Analysis of PCR data was accomplished using high-level bioinformatics methods including prediction analysis of microarray, significance analysis of microarray, and Computerized Affected Sibling Pair Analyzer and Reporter.

Results: Internal validation of the MFC method proved it highly reproducible. Correlation of MFC and chip expression data varied markedly for some genes. Outcome prediction using prediction analysis of microarray on real-time PCR data resulted in 80% accuracy, which is comparable to results obtained using the Affymetrix platform. Real-time PCR data were useful for risk assessment of relapsing neuroblastoma (P = 0.0006, log-rank test) when Computerized Affected Sibling Pair Analyzer and Reporter analysis was applied.

Conclusions: These data suggest that multiplex real-time PCR might be a promising approach to reduce the complexity of information obtained from whole-genome array experiments. It could provide a more convenient and less expensive tool for routine application in a clinical setting.
Virus-Associated Tumor Imaging by Induction of Viral Gene Expression
Authors: Fu De-Xue , Tanhehco Yvette C. , Chen Jianmeng , Foss Catherine A. , Fox James J. , Lemas Victor , Chong Ja-Mun , Ambinder Richard F. , Pomper Martin G.
Published: March 2007

Purpose: EBV and other herpesviruses are associated with a variety of malignancies. The EBV thymidine kinase (TK) is either not expressed or is expressed at very low levels in EBV-associated tumors. However, EBV-TK expression can be induced in vitro with several chemotherapeutic agents that promote viral lytic induction. The goal of this study is to image EBV-associated tumors by induction of viral TK expression with radiolabeled 2′-fluoro-2′-deoxy-β-d-5-iodouracil-arabinofuranoside (FIAU).

Experimental Design: Immunoblot, luciferase reporter assay, and in vitro assay with [14C]FIAU were used to show the effects of bortezomib on the induction of lytic gene expression of EBV-associated tumor cells. In vivo imaging and ex vivo biodistribution studies with [125I]FIAU on EBV-associated tumors were done to visualize and confirm, respectively, the EBV(+) tumor–specific effects of bortezomib.

Results: In vitro assays with [14C]FIAU and ex vivo biodistribution studies with [125I]FIAU showed that uptake and retention of radiolabeled FIAU was specific for cells that express EBV-TK. Planar gamma imaging of EBV(+) Burkitt's lymphoma xenografts in severe combined immunodeficient mice showed [125I]FIAU localization within tumors following treatment with bortezomib.

Conclusions: These results indicate the feasibility of imaging chemotherapy-mediated viral lytic induction by radiopharmaceutical-based techniques such as single photon emission computed tomography and positron emission tomography.
Mitochondrial Dysfunction in Atherosclerosis
Authors: Madamanchi Nageswara R. , Runge Marschall S.
Published: March 2007

Increased production of reactive oxygen species in mitochondria, accumulation of mitochondrial DNA damage, and progressive respiratory chain dysfunction are associated with atherosclerosis or cardiomyopathy in human investigations and animal models of oxidative stress. Moreover, major precursors of atherosclerosis—hypercholesterolemia, hyperglycemia, hypertriglyceridemia, and even the process of aging—all induce mitochondrial dysfunction. Chronic overproduction of mitochondrial reactive oxygen species leads to destruction of pancreatic β-cells, increased oxidation of low-density lipoprotein and dysfunction of endothelial cells—factors that promote atherosclerosis. An additional mechanism by which impaired mitochondrial integrity predisposes to clinical manifestations of vascular diseases relates to vascular cell growth. Mitochondrial function is required for normal vascular cell growth and function. Mitochondrial dysfunction can result in apoptosis, favoring plaque rupture. Subclinical episodes of plaque rupture accelerate the progression of hemodynamically significant atherosclerotic lesions. Flow-limiting plaque rupture can result in myocardial infarction, stroke, and ischemic/reperfusion damage. Much of what is known on reactive oxygen species generation and modulation comes from studies in cultured cells and animal models. In this review, we have focused on linking this large body of literature to the clinical syndromes that predispose humans to atherosclerosis and its complications.
Regulation of Phosphodiesterase 3 and Inducible cAMP Early Repressor in the Heart
Authors: Yan Chen , Miller Clint L. , Abe Jun-ichi
Published: March 2007

Growing evidence suggests that multiple spatially, temporally, and functionally distinct pools of cyclic nucleotides exist and regulate cardiac performance, from acute myocardial contractility to chronic gene expression and cardiac structural remodeling. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing cAMP and cyclic GMP, regulate the amplitude, duration, and compartmentation of cyclic nucleotide-mediated signaling. In particular, PDE3 enzymes play a major role in regulating cAMP metabolism in the cardiovascular system. PDE3 inhibitors, by raising cAMP content, have acute inotropic and vasodilatory effects in treating congestive heart failure but have increased mortality in long-term therapy. PDE3A expression is downregulated in human and animal failing hearts. In vitro, inhibition of PDE3A function is associated with myocyte apoptosis through sustained induction of a transcriptional repressor ICER (inducible cAMP early repressor) and thereby inhibition of antiapoptotic molecule Bcl-2 expression. Sustained induction of ICER may also cause the change of other protein expression implicated in human and animal failing hearts. These data suggest that the downregulation of PDE3A observed in failing hearts may play a causative role in the progression of heart failure, in part, by inducing ICER and promoting cardiac myocyte dysfunction. Hence, strategies that maintain PDE3A function may represent an attractive approach to circumvent myocyte apoptosis and cardiac dysfunction.
Distinct Roles of Autophagy in the Heart During Ischemia and Reperfusion
Authors: Matsui Yutaka , Takagi Hiromitsu , Qu Xueping , Abdellatif Maha , Sakoda Hideyuki , Asano Tomoichiro , Levine Beth , Sadoshima Junichi
Published: March 2007

Autophagy is an intracellular bulk degradation process for proteins and organelles. In the heart, autophagy is stimulated by myocardial ischemia. However, the causative role of autophagy in the survival of cardiac myocytes and the underlying signaling mechanisms are poorly understood. Glucose deprivation (GD), which mimics myocardial ischemia, induces autophagy in cultured cardiac myocytes. Survival of cardiac myocytes was decreased by 3-methyladenine, an inhibitor of autophagy, suggesting that autophagy is protective against GD in cardiac myocytes. GD-induced autophagy coincided with activation of AMP-activated protein kinase (AMPK) and inactivation of mTOR (mammalian target of rapamycin). Inhibition of AMPK by adenine 9-β-
d
-arabinofuranoside or dominant negative AMPK significantly reduced GD-induced autophagy, whereas stimulation of autophagy by rapamycin failed to cause an additive effect on GD-induced autophagy, suggesting that activation of AMPK and inhibition of mTOR mediate GD-induced autophagy. Autophagy was also induced by ischemia and further enhanced by reperfusion in the mouse heart, in vivo. Autophagy resulting from ischemia was accompanied by activation of AMPK and was inhibited by dominant negative AMPK. In contrast, autophagy during reperfusion was accompanied by upregulation of Beclin 1 but not by activation of AMPK. Induction of autophagy and cardiac injury during the reperfusion phase was significantly attenuated in
beclin 1
+/−
mice. These results suggest that, in the heart, ischemia stimulates autophagy through an AMPK-dependent mechanism, whereas ischemia/reperfusion stimulates autophagy through a Beclin 1–dependent but AMPK-independent mechanism. Furthermore, autophagy plays distinct roles during ischemia and reperfusion: autophagy may be protective during ischemia, whereas it may be detrimental during reperfusion.
Autonomic Ganglionic Blockade Does Not Prevent Reduction in Cerebral Blood Flow Velocity During Orthostasis in Humans
Authors: Zhang Rong , Levine Benjamin D.
Published: March 2007

Background and Purpose—

The underlying mechanisms for reductions in cerebral blood flow (CBF) during orthostasis are not completely understood. This study tested the hypothesis that sympathetic activation causes cerebral vasoconstriction leading to reductions in CBF during lower body negative pressure (LBNP).

Methods—

CBF velocity, arterial pressure, and end-tidal CO
2
were measured during LBNP (−30 to −50 mm Hg) in 11 healthy subjects before and after autonomic ganglionic blockade with trimethaphan. Arterial partial pressure of CO
2
also was measured in a subgroup of 5 subjects. Mean arterial pressure during LBNP after blockade was maintained by infusion of phenylephrine.

Results—

Before blockade, mean arterial pressure did not change during LBNP. However, CBF velocity was reduced in all subjects by 14% (
P
<0.05). Systolic and pulsatile (systolic–diastolic) CBF velocity were reduced by 18% and 28%, respectively, associated with significant reductions in pulse arterial pressure and end-tidal CO
2
(all
P
<0.05). After blockade, mean arterial pressure during LBNP was well-maintained and even increased slightly with infusion of phenylephrine. However, reductions in mean, systolic, and pulsatile CBF velocity, pulse arterial pressure, and ETCO
2
were similar to those before blockade. In contrast to reductions in end-tidal CO
2
, arterial partial pressure of CO
2
did not change during LBNP.

Conclusions—

These data, contrary to our hypothesis, demonstrate that sympathetic vasoconstriction is not the primary mechanism underlying reductions in CBF during moderate LBNP. We speculate that diminished pulse arterial pressure or pulsatile blood flow may reduce cerebral vessel wall shear stress and contribute to reductions in CBF during orthostasis through flow mediated regulatory mechanisms.
TRAF-1, -2, -3, -5, and -6 Are Induced in Atherosclerotic Plaques and Differentially Mediate Proinflammatory Functions of CD40L in Endothelial Cells
Authors: Zirlik Andreas , Bavendiek Udo , Libby Peter , MacFarlane Lindsey , Gerdes Norbert , Jagielska Joanna , Ernst Sandra , Aikawa Masanori , Nakano Hiroyasu , Tsitsikov Erdyni , Schönbeck Uwe
Published: March 2007

Objective—

Several lines of evidence implicate CD40 ligand (CD40L, CD154) as a mediator and marker of atherosclerosis. This study investigated the involvement of tumor necrosis factor receptor-associated factors (TRAFs) in CD40 signaling in endothelial cells (ECs) and their expression in atheromata and cells involved in atherogenesis.

Methods and Results—

CD40L enhanced the basal expression of TRAF-1, -2, -3, and 6, but not TRAF-5 in ECs. TRAFs associated with CD40 on ligation by CD40L. Study of ECs from TRAF-1, -2, and -5-deficient mice demonstrated functional involvement of TRAFs in proinflammatory CD40 signaling. Whereas TRAF-1 deficiency enhanced CD40L-induced IL-6 and MCP-1 expression, TRAF-2 and TRAF-5 deficiency inhibited CD40L-inducible IL-6 but not MCP-1 expression. Gene silencing in human ECs further delineated functions of TRAFs in CD40 signaling. TRAF-3 silencing in ECs showed increased CD40L-induced IL-6, MCP-1, and IL-8 expression, whereas TRAF-6 silencing increased selectively CD40L-induced MCP-1 expression. Enhanced TRAF levels in atherosclerotic lesions further supports involvement of members of this family of signaling molecules in arterial disease.

Conclusions—

These results implicate endothelial TRAF-1, -2, -3, -5, and -6 in CD40 signaling in atherogenesis, identifying these molecules as potential targets for selective therapeutic intervention.
Brain Activation for Lexical Decision and Reading Aloud: Two Sides of the Same Coin?
Authors: Carreiras Manuel , Mechelli Andrea , Estévez Adelina , Price Cathy J.
Published: March 2007

This functional magnetic resonance imaging study compared the neuronal implementation of word and pseudoword processing during two commonly used word recognition tasks: lexical decision and reading aloud. In the lexical decision task, participants made a finger-press response to indicate whether a visually presented letter string is a word or a pseudoword (e.g., “paple”). In the reading-aloud task, participants read aloud visually presented words and pseudowords. The same sets of words and pseudowords were used for both tasks. This enabled us to look for the effects of task (lexical decision vs. reading aloud), lexicality (words vs. nonwords), and the interaction of lexicality with task. We found very similar patterns of activation for lexical decision and reading aloud in areas associated with word recognition and lexical retrieval (e.g., left fusiform gyrus, posterior temporal cortex, pars opercularis, and bilateral insulae), but task differences were observed bilaterally in sensorimotor areas. Lexical decision increased activation in areas associated with decision making and finger tapping (bilateral postcentral gyri, supplementary motor area, and right cerebellum), whereas reading aloud increased activation in areas associated with articulation and hearing the sound of the spoken response (bilateral precentral gyri, superior temporal gyri, and posterior cerebellum). The effect of lexicality (pseudoword vs. words) was also remarkably consistent across tasks. Nevertheless, increased activation for pseudowords relative to words was greater in the left precentral cortex for reading than lexical decision, and greater in the right inferior frontal cortex for lexical decision than reading. We attribute these effects to differences in the demands on speech production and decision-making processes, respectively.
An Event-related fMRI Study of Exogenous Facilitation and Inhibition of Return in the Auditory Modality
Authors: Mayer Andrew R. , Harrington Deborah L. , Stephen Julia , Adair John C. , Lee Roland R.
Published: March 2007

The orienting of attention to different locations in space is fundamental to most organisms and occurs in all sensory modalities. Orienting has been extensively studied in vision, but to date, few studies have investigated neuronal networks underlying automatic orienting of attention and inhibition of return to auditory signals. In the current experiment, functional magnetic resonance imaging and behavioral data were collected while healthy volunteers performed an auditory orienting task in which a monaurally presented tone pip (cue) correctly or incorrectly cued the location of a target tone pip. The stimulus onset asynchrony (SOA) between the cue and target was 100 or 800 msec. Behavioral results were consistent with previous studies showing that valid auditory cues produced facilitation at the short SOA and inhibition of return at the long SOA. Functional results indicated that the reorienting of attention (100 msec SOA) and inhibition of return (800 msec SOA) were mediated by both common and distinct neuronal structures. Both attention mechanisms commonly activated a network consisting of fronto-oculomotor areas, the left postcentral gyrus, right premotor area, and bilateral tonsil of the cerebellum. Several distinct areas of frontal and parietal activation were identified for the reorienting condition, whereas the right inferior parietal lobule was the only structure uniquely associated with inhibition of return.
Effects of rTMS Conditioning over the Fronto-parietal Network on Motor versus Visual Attention
Authors: Rounis Elisabeth , Yarrow Kielan , Rothwell John C.
Published: March 2007

Many studies have shown that visuospatial orienting attention depends on a network of frontal and parietal areas in the right hemisphere. Rushworth et al. [Rushworth, M. F., Krams, M., & Passingham, R. E. The attentional role of the left parietal cortex: The distinct lateralization and localization of motor attention in the human brain. Journal of Cognitive Neuroscience, 13, 698–710, 2001] have recently provided evidence for a left-lateralized network of parietal areas involved in motor attention. Using two variants of a cued reaction time (RT) task, we set out to investigate whether high-frequency repetitive transcranial magnetic stimulation (rTMS; 5 Hz) delivered “off-line” in a virtual lesion paradigm over the right or left dorsolateral prefrontal cortex (DLPFC) or the posterior parietal cortex (PPC) would affect performance in a motor versus a visual attention task. Although rTMS over the DLPFC on either side did not affect RT performance on a spatial orienting task, it did lead to an increase in the RTs of invalidly cued trials in a motor attention task when delivered to the left DLPFC. The opposite effect was found when rTMS was delivered to the PPC: In this case, conditioning the right PPC led to increased RTs in invalidly cued trials located in the left hemispace, in the spatial orienting task. rTMS over the PPC on either side did not affect performance in the motor attention task. This double dissociation was evident in the first 10 min after rTMS conditioning. These results enhance our understanding of the networks associated with attention. They provide evidence of a role for the left DLPFC in the mechanisms of motor preparation, and confirm Mesulam's original proposal for a right PPC dominance in spatial attention [Mesulam, M. M. A cortical network for directed attention and unilateral neglect. Annals of Neurology, 10, 309–325, 1981].
Long-term Expertise with Artificial Objects Increases Visual Competition with Early Face Categorization Processes
Authors: Rossion Bruno , Collins Daniel , Goffaux Valérie , Curran Tim
Published: March 2007

The degree of commonality between the perceptual mechanisms involved in processing faces and objects of expertise is intensely debated. To clarify this issue, we recorded occipito-temporal event-related potentials in response to faces when concurrently processing visual objects of expertise. In car experts fixating pictures of cars, we observed a large decrease of an evoked potential elicited by face stimuli between 130 and 200 msec, the N170. This sensory suppression was much lower when the car and face stimuli were separated by a 200-msec blank interval. With and without this delay, there was a strong correlation between the face-evoked N170 amplitude decrease and the subject's level of car expertise as measured in an independent behavioral task. Together, these results show that neural representations of faces and nonface objects in a domain of expertise compete for visual processes in the occipito-temporal cortex as early as 130–200 msec following stimulus onset.
Indications for Repair of Full-Thickness Rotator Cuff Tears
Authors: Wolf Brian R. , Dunn Warren R. , Wright Rick W.
Published: March 2007

Rotator cuff repair surgery for full-thickness tears is common and accepted in orthopaedics today. Given that a significant number of people have asymptomatic rotator cuff tears, the indications for surgery are, however, somewhat unclear. Multiple factors such as duration of symptoms, acuity and size of the tear, patient age, and others require consideration and can influence the decision to perform surgery. This article reviews these variables and the indications for surgery to repair full-thickness rotator cuff tears.
Effectiveness of Bioabsorbable Arrows Compared with Inside-Out Suturing for Vertical, Reparable Meniscal Lesions
Authors: Bryant Dianne , Dill James , Litchfield Robert , Amendola Annunziato , Giffin Robert , Fowler Peter , Kirkley Alexandra
Published: March 2007

Background

Techniques for repairing the meniscus include both open and arthroscopic techniques using sutures and bioabsorbable implants. The purpose of this study was to compare the effectiveness of inside-out suturing and bioabsorbable arrows for repair of vertical meniscal lesions.

Study Design

Randomized controlled clinical trial; Level of evidence, 1.

Methods

One hundred consecutive patients were randomly assigned to arrows (n = 51) or sutures (n = 49). Sixty-five percent of patients (31 sutures, 34 arrows) underwent a concomitant anterior cruciate ligament reconstruction. A blinded research associate conducted assessments at 6 weeks and 3, 6, 12, and 24 months postoperatively. The primary outcome was retear rate. Secondary outcomes included the Western Ontario Meniscal Evaluation Tool, Anterior Cruciate Ligament Quality of Life Outcome Measure, and side-to-side comparisons of flexion and extension.

Results

At baseline, groups were similar in age, gender, time from injury to surgery, and length and location of tear. Mean follow-up was 28.0 ± 8.4 months. There were 22 failed meniscal repairs (11 in each group), which did not represent a significant difference in the rate of failure between groups (P = .92). The mean quality of life scores and side-to-side differences in extension and flexion measurements were not significantly different between groups. Two patients from the arrow group crossed over into the suture group at the time of surgery because of technical difficulties with the device, and in 3 instances, a single suture was needed to keep the tear reduced while arrows were introduced. Two patients required reoperation for removal of a prominent, subcutaneous arrow, and 1 patient in the suture group suffered a transient peroneal nerve palsy during revision suturing.

Conclusion

At intermediate follow-up, there were no statistically significant differences in measured outcomes between meniscal suturing and arrows. Longer term follow-up is necessary to identify differences between these 2 treatments, particularly to estimate the incidence of articular surface damage in patients whose meniscal tear was repaired using arrows.
Evaluation Practice Among Community-Based Organizations
Authors: Carman Joanne G.
Published: March 2007

Increasingly, government, foundations, and others are asking community-based organizations for more evaluation information. Although the demand for this information may be increasing, the field knows very little about the way organizations are responding to this demand. Using data collected from interviews and a mail survey of community-based organizations, this article addresses five research questions: (a) What types of activities do community-based organizations use to evaluate their programs? (b) What types of data do they collect? (c) How do they collect data? (d) Who has the primary responsibility for conducting evaluation? and (e) Where does the funding come from? The answers to these questions are intended to serve as the basis for future discussions about building evaluation capacity and improving community-based services.
Program Evaluation: The Board Game
Authors: Febey Karen , Coyne Molly
Published: March 2007

The field of program evaluation lacks interactive teaching tools. To address this pedagogical issue, the authors developed a collaborative learning technique called Program Evaluation: The Board Game. The authors present the game and its development in this practitioner-oriented article. The evaluation board game is an adaptable teaching tool designed to familiarize players with basic history, theories, approaches, and tasks associated with conducting program evaluations. The basis of the game design came from an evaluation skills taxonomy and a review of popular texts in the evaluation field. The authors piloted the game and administered a postgame survey to assess its effectiveness. Results of the survey provided specific information about how the game contributed to learning and led to significant modifications and improvements in the game. The authors’ experience demonstrates that the board game can generate useful discussion about evaluation issues and teach foundational knowledge in the program evaluation field.
Sins of Omission and Commission
Authors: Birman Dina
Published: March 2007

The article addresses a hypothetical dilemma confronted by an evaluator of a transition from welfare program regarding inclusion of a small immigrant/language minority group in the study. The article advocates for inclusion of diverse groups. Three important aspects of diversity are discussed that have particular relevance to transition from welfare for immigrants and refuges: legal status, the relative size and concentration of the ethnic/language community, and the specific cultural and historical circumstances. Legal status is a factor that affects eligibility for welfare and incentives for transitioning to work. Smaller groups may be particularly important to include because their access to culturally sensitive resources may be especially limited. Historical circumstances in the country of origin shape the attitudes of an immigrant or refugee group toward use of government aid. The ethical dilemma is discussed in relation to the AEA’s Guiding Principles for Evaluators of Diversity, Competence, and Honesty and Integrity.
Reported Influence of Evaluation Data on Decision Makers’ Actions
Authors: Christie Christina A.
Published: March 2007

Using a set of scenarios derived from actual evaluation studies, this simulation study examines the reported influence of evaluation information on decision makers’ potential actions. Each scenario described a context where one of three types of evaluation information (large-scale study data, case study data, or anecdotal accounts) is presented and a specific decision needs to be made. Participants were asked to indicate which type of data presented would influence their decision making. Results from 131 participants indicate that participants were influenced by all types of information, yet large-scale and case study data are more influential relative to anecdotal accounts; certain types of evaluation data are more influential among certain groups of decision makers; and choosing to use one type of evaluation data over the other two depends on the independent influence of other types of evaluation data on the decision maker, as well as prior beliefs about program efficacy.
Asymmetric cell division within the human hematopoietic stem and progenitor cell compartment: identification of asymmetrically segregating proteins
Authors: Beckmann Julia , Scheitza Sebastian , Wernet Peter , Fischer Johannes C. , Giebel Bernd
Published: March 2007

The findings that many primitive human hematopoietic cells give rise to daughter cells that adopt different cell fates and/or show different proliferation kinetics suggest that hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) can divide asymmetrically. However, definitive experimental demonstration is lacking due to the current absence of asymmetrically segregating marker molecules within the primitive hematopoietic cell compartment. Thus, it remains an open question as to whether HSCs/HPCs have the capability to divide asymmetrically, or whether the differences that have been observed are established by extrinsic mechanisms that act on postmitotic progenitors. Here, we have identified 4 proteins (CD53, CD62L/L-selectin, CD63/lamp-3, and CD71/transferrin receptor) that segregate differentially in about 20% of primitive human hematopoietic cells that divide in stroma-free cultures. Therefore, this indicates for the first time that HSCs/HPCs have the capability to divide asymmetrically. Remarkably, these proteins, in combination with the surrogate stem-cell marker CD133, help to discriminate the more primitive human cultivated HSCs/HPCs. Since 3 of these proteins, the transferrin receptor and the tetraspanins CD53 and CD63, are endosomal-associated proteins, they may provide a link between the endosomal compartment and the process of asymmetric cell division within the HSC/HPC compartment.