bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene-Targeted Mice Reveal a Critical Role for Inducible Nitric Oxide Synthase in Vascular Dysfunction During Diabetes
Authors: Gunnett Carol A. , Heistad Donald D. , Faraci Frank M.
Published: December 2003

Background and Purpose—

Inducible nitric oxide synthase (iNOS) is a mediator of vascular dysfunction during inflammation. The purpose of this study was to test the hypothesis that vascular dysfunction during diabetes is dependent on expression of iNOS.

Methods—

Diabetes was produced in mice with streptozotocin (150 mg/kg IP). After 4 to 6 months of diabetes, vasomotor function was examined in vitro in carotid arteries from mice with targeted disruption of the gene for iNOS (iNOS-deficient mice) and from normal, wild-type (WT) mice.

Results—

Contractile responses of carotid arteries to U46619, a thromboxane A
2
analogue, were not altered by diabetes in WT mice. Responses to U46619 were increased in arteries from diabetic iNOS-deficient mice compared with diabetic WT and nondiabetic mice (iNOS-deficient and WT mice). These results indicate that expression of iNOS inhibits an increased vasoconstrictor response during diabetes. Arteries from nondiabetic WT mice relaxed 83±2% (mean±SE) in response to acetylcholine (1 μmol/L) compared with 58±6% in arteries from diabetic WT mice (
P
<0.05 versus nondiabetic mice). In contrast, relaxation of carotid arteries to acetylcholine was similar (81±4% versus 76±6%;
P
>0.05) in iNOS-deficient mice under nondiabetic and diabetic conditions, respectively. Thus, diabetes produced impairment of endothelium-dependent relaxation in arteries from WT but not iNOS-deficient mice. Endothelium-independent relaxation in response to nitroprusside was similar in arteries from all mice.

Conclusions—

These results provide the first direct evidence that impairment of endothelium-dependent relaxation during diabetes is dependent on expression of iNOS.
Is Diabetes Mellitus a Cardiovascular Disease Risk Equivalent for Fatal Stroke in Women?
Authors: Ho Jennifer E. , Paultre Furcy , Mosca Lori
Published: December 2003

Background and Purpose—

Diabetes mellitus is an independent risk factor for stroke and is associated with a 1.8- to ≈6-fold increased risk compared with nondiabetic subjects. Recent guidelines have classified diabetes as a coronary heart disease risk equivalent. Whether diabetes is a cardiovascular disease risk equivalent for stroke is not established.

Methods—

Data were pooled from 9 prospective epidemiological studies in the United States. We followed up 27 269 women (8.5% diabetic, 2.9% with prior myocardial infarction, 2.3% with prior stroke) for an average of 8.3 years, during which 238 stroke deaths were observed.

Results—

Both diabetic subjects without cardiovascular disease and nondiabetic subjects with history of prior stroke had a significantly increased risk of 10-year stroke mortality compared with nondiabetic subjects without prior cardiovascular disease (hazard ratio [HR], 6.77; 95% confidence interval [CI], 4.56 to 10.05; HR, 3.37; 95% CI, 2.38 to 4.77). History of prior myocardial infarction was not associated with long-term stroke mortality (HR, 0.66; 95% CI, 0.27 to 1.61). After adjustment for risk factors, diabetic subjects had similar risk compared with subjects with a history of prior stroke (HR, 1.29;
P
=0.43).

Conclusions—

Diabetic subjects without cardiovascular disease have a fatal stroke risk similar to that of nondiabetic subjects with a history of prior stroke and similar risk factor profile. This suggests that diabetes mellitus may be classified as a stroke risk equivalent and may warrant more aggressive treatment strategies in the future prevention of stroke.
How “Catholic” Was the Early Nazi Movement? Religion, Race, and Culture in Munich, 1919–1924
Authors: Hastings Derek
Published: December 2003

Amongthe more durable tenets of postwar West German historiography was the widespread conviction that Catholicism and Nazism were, at some most basic level, mutually exclusive entities. While a flood of critical studies in the 1960s began to erode this conviction at least around the edges — as scholars subjected to greater scrutiny the actual responses of Catholic opinion leaders, the German episcopate, and the Vatican to the Nazi regime — the image of a fundamental, albeit not quite perfect, incompatibility between Catholicism and Nazism has remained essentially intact to the present day. The durability of this image has been due to some degree to the steady stream of primarily apologetic monographs produced by a large and energetic Catholic scholarly community in Germany, whose works have stressed the heroic oppositional stance and victimhood of the Catholic Church during the Third Reich.
A New Perspective of Stratosphere–Troposphere Exchange
Authors: Stohl Andreas , Wernli Heini , James Paul , Bourqui Michel , Forster Caroline , Liniger Mark A. , Seibert Petra , Sprenger Michael
Published: December 2003

Stratosphere–troposphere exchange (STE) is important for the chemical composition of both the stratosphere and troposphere. Modifications of STE in a changing climate may affect stratospheric ozone depletion and the oxidizing capacity of the troposphere significantly. However, STE is still poorly understood and inadequately quantified, due to the involvement of physical and dynamical processes on local to global scales and to conceptual problems. In this study, a presentday global climatology of STE is developed that is based, from a data standpoint, on 15 yr of global meteorological reanalyses, and, from a conceptual standpoint, on a Lagrangian perspective that considers the pathways of exchange air parcels and their residence times in the troposphere and lowermost stratosphere. To this end, two complementary Lagrangian models are used. Particular consideration is given to “deep” exchange events that, through fast ascent of tropospheric or fast descent of stratospheric air masses, bring into contact air from the (potentially polluted) boundary layer and lower stratosphere. It is shown that they have different characteristics (strongly preferred geographical locations and a pronounced seasonal cycle) from that of the full set of exchange events. This result is important for accurately characterizing the effects of STE. In particular, it can be inferred that the well-documented springtime maximum of surface ozone cannot be explained primarily by STE.
Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels
Authors: Sim Derek S. , Merrill-Skoloff Glenn , Furie Barbara C. , Furie Bruce , Flaumenhaft Robert
Published: December 2003

Platelet accumulation at sites of vascular injury is the primary event in arterial thrombosis. Initial platelet accrual into thrombi is mediated by interactions of platelet adhesion receptors with ligands on the injured endothelium or in the sub-endothelial matrix. The role of intracellular signals in initial platelet accumulation at sites of endothelial injury, however, is the subject of debate. We have used a newly discovered inhibitor of phosphodiesterase 3A (PDE3A) and the well-characterized PDE3A inhibitor, cilostazol, to modulate 3′,5′-cyclic adenosine monophosphate (cAMP) levels in an in vivo model that enables the kinetic analysis of platelet accumulation. These studies demonstrate that elevation of basal cAMP levels results in an overall decline in platelet accumulation at the site of vascular injury. In particular, the initial rate of accumulation of platelets is inhibited by elevation of cAMP. Analysis of the kinetics of individual platelets at injury sites using intravital microscopy demonstrates that cAMP directs the rate at which platelets attach to and detach from thrombi. These studies demonstrate that cAMP in circulating platelets controls attachment to and detachment from sites of arteriolar injury. Thus, the status of the intracellular signaling machinery prior to engagement of platelet receptors influences the rate of platelet accumulation during thrombus formation.
A novel mechanism for imatinib mesylate–induced cell death of BCR-ABL–positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity
Authors: Okada Masayuki , Adachi Souichi , Imai Tsuyoshi , Watanabe Ken-ichiro , Toyokuni Shin-ya , Ueno Masaki , Zervos Antonis S. , Kroemer Guido , Nakahata Tatsutoshi
Published: December 2003

Caspase-independent programmed cell death can exhibit either an apoptosis-like or a necrosis-like morphology. The ABL kinase inhibitor, imatinib mesylate, has been reported to induce apoptosis of BCR-ABL–positive cells in a caspase-dependent fashion. We investigated whether caspases alone were the mediators of imatinib mesylate–induced cell death. In contrast to previous reports, we found that a broad caspase inhibitor, zVAD-fmk, failed to prevent the death of imatinib mesylate–treated BCR-ABL–positive human leukemic cells. Moreover, zVAD-fmk–preincubated, imatinib mesylate–treated cells exhibited a necrosis-like morphology characterized by cellular pyknosis, cytoplasmic vacuolization, and the absence of nuclear signs of apoptosis. These cells manifested a loss of the mitochondrial transmembrane potential, indicating the mitochondrial involvement in this caspase-independent necrosis. We excluded the participation of several mitochondrial factors possibly involved in caspase-independent cell death such as apoptosis-inducing factor, endonuclease G, and reactive oxygen species. However, we observed the mitochondrial release of the serine protease Omi/HtrA2 into the cytosol of the cells treated with imatinib mesylate or zVAD-fmk plus imatinib mesylate. Furthermore, serine protease inhibitors prevented the caspase-independent necrosis. Taken together, our results suggest that imatinib mesylate induces a caspase-independent, necrosis-like programmed cell death mediated by the serine protease activity of Omi/HtrA2.
Homer-3 regulates activation of serum response element in T cells via its EVH1 domain
Authors: Ishiguro Kazuhiro , Xavier Ramnik
Published: December 2003

Drosophila enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) homology 1 (EVH1) domain proteins regulate signal transduction at the neuronal and immunologic synapse. Despite shared cell biologic machinery at these synapses, the regulation of client proteins that transmit synaptic activity to the nucleus is likely to be different. Homer-3, a member of the EVH1 family, is expressed in the thymus, suggesting a role for this protein in T-cell signal transduction. Upon T-cell receptor (TCR) engagement, Homer-3 was recruited to the contact area of Jurkat cells to anti-CD3 and CD28 antibody–coated beads prior to actin accumulation and was subsequently translocated into the nucleus. Overexpression of Homer-3 reduced transcriptional activation via the serum response element (SRE) in response to anti-CD3 antibody, phorbol ester, or dominant active Ha-Ras. Consistent with these results, knockdown of Homer-3 increased SRE activation. Homer-3 coprecipitated with CCAAT/enhancer binding protein β (C/EBPβ), one of the transcription factors that binds to the SRE and has a consensus motif binding to EVH1 domain. Moreover, Homer-3 and its EVH1 domain fragment reduced transcriptional activation of C/EBPβ. These findings suggest that Homer-3 may be involved in the regulation of SRE activation in T cells via interaction between its EVH1 domain and C/EBPβ.
Short‐axis versus Long‐axis Approaches for Teaching Ultrasound‐guided Vascular Access on a New Inanimate Model
Authors: Blaivas Michael , Brannam Larry , Fernandez Eleanor
Published: December 2003

Objectives: To determine whether a short‐axis (SA) or long‐axis (LA) ultrasound (US) approach to guidance for line placement results in faster vascular access for novice US users. Also, to assess if there was a difference in the number of skin penetrations and needle redirections between the two guidance techniques. Methods: This was a prospective, randomized, observational study of emergency medicine (EM) residents at a Level I trauma center. A gelatin dessert and dietary fiber supplement mixture, providing a realistic US image, were placed inside a synthetic arm skin that is used for training phlebotomists and contains a rubber vein filled with red fluid at a depth of 1.5 cm. After a 30‐minute tutorial on US‐guided vascular access, EM residents were randomized to one of two groups. Group one attempted SA first and then the LA. Group two tried LA first followed by the SA. Time from skin break to vein cannulation, number of skin breaks and needle redirections, and difficulty of access on a 10‐point Likert scale as reported by residents were recorded. Statistical analysis included paired Student's t‐test with 95% confidence intervals (95% CIs). Results: Seventeen EM residents participated. The mean times to vein cannulation in SA and LA were 2.36 minutes (95% CI = 1.15 to 3.58) and 5.02 minutes (95% CI = 2.90 to 7.13), respectively (p = 0.03). The mean numbers of skin breaks for SA and LA were 4.18 (95% CI = 1.18 to 7.17) and 5.76 (95% CI = 1.83 to 9.69), respectively (p = 0.49). The mean numbers of needle redirections in the SA and LA were 13.71 (95% CI = 4.51 to 22.89) and 18.17 (95% CI = 7.95 to 28.40), respectively (p = 0.51). The mean difficulty scores for SA and LA were 3.99 (95% CI = 2.42 to 5.67) and 5.86 (95% CI = 4.32 to 7.40), respectively (p = 0.17). Conclusions: Novice US users obtain vascular access faster with an SA approach on an inanimate model.
A Risk Score to Predict Arrhythmias in Patients with Unexplained Syncope
Authors: Sarasin François P. , Hanusa Barbara H. , Perneger Thomas , Louis‐Simonet Martine , Rajeswaran Anand , Kapoor Wishwa N.
Published: December 2003

Objectives: To develop and validate a risk score predicting arrhythmias for patients with syncope remaining unexplained after emergency department (ED) noninvasive evaluation. Methods: One cohort of 175 patients with unexplained syncope (Geneva, Switzerland) was used to develop and cross‐validate the risk score; a second cohort of 269 similar patients (Pittsburgh, PA) was used to validate the system. Arrhythmias as a cause of syncope were diagnosed by cardiac monitoring or electrophysiologic testing. Data from the patient's history and 12‐lead emergency electrocardiography (ECG) were used to identify predictors of arrhythmias. Logistic regression was used to identify predictors for the risk‐score system. Risk‐score performance was measured by comparing the proportions of patients with arrhythmias at various levels of the score and receiver operating characteristic (ROC) curves. Results: The prevalence of arrhythmic syncope was 17% in the derivation cohort and 18% in the validation cohort. Predictors of arrhythmias were abnormal ECG (odds ratio [OR]: 8.1, 95% confidence interval [CI] = 3.0 to 22.7), a history of congestive heart failure (OR: 5.3, 95% CI = 1.9 to 15.0), and age older than 65 (OR: 5.4, 95% CI = 1.1 to 26.0). In the derivation cohort, the risk of arrhythmias ranged from 0% (95% CI = 0 to 6) in patients with no risk factors to 6% (95% CI = 1 to 15) for patients with one risk factor, 41% (95% CI = 26 to 57) for patients with two risk factors, and 60% (95% CI = 32 to 84) for those with three risk factors. In the validation cohort, these proportions varied from 2% (95% CI = 0 to 7) with no risk factors to 17% (95% CI = 10 to 27) with one risk factor, 35% (95% CI = 24 to 46) with two risk factors, and 27% (95% CI = 6 to 61) with three risk factors. Areas under the ROC curves ranged from 0.88 (95% CI = 0.84 to 0.91) for the derivation cohort to 0.84 (95% CI = 0.77 to 0.91) after cross‐validation within the same cohort and 0.75 (95% CI = 0.68 to 0.81) for the external validation cohort. Conclusions: In patients with unexplained syncope, a risk score based on clinical and ECG factors available in the ED identifies patients at risk for arrhythmias.
Training of Residents for Their Role as Flight Physicians: A Survey of Emergency Medicine Training Programs
Authors: Hoyle John D. , Loos Scott A. , Jones Jeffrey S.
Published: December 2003

Objective: To determine the number of emergency medicine (EM) residency programs in which residents serve as helicopter emergency medical services (HEMS) crew, the extent of training provided for this role, and how HEMS residents are evaluated. Methods: Accredited EM residency programs were contacted by telephone to determine which programs had residents serving as HEMS physicians. A self‐administered survey was then mailed to the medical directors of the HEMS programs. Descriptive statistics were determined for each question. Results: Surveys were returned by 18 of the 20 residency programs (90%) where residents served as HEMS physicians. In the majority (94%), residents work with one other crew member, typically a nurse or paramedic. The amount of flight hours for a resident ranged from 25 to 500. The number of flights ranged from five to 225. The amount of HEMS training was highly variable. Four programs (22%) did not require any orientation flights with patients; 12 (67%) did not require any proficiency testing; direct attending supervision was rare (6%); and written feedback occurred in only 28% of programs. Conclusions: The training of residents for their role as flight physicians is highly variable, considering the amount of air transport time they perform. Direct faculty supervision, proficiency testing, and written feedback are rarely utilized.
Satellite and Mobile Wireless Transmission of Focused Assessment with Sonography in Trauma
Authors: Strode Christofer A. , Rubal Bernard J. , Gerhardt Robert T. , Christopher Frank L. , Bulgrin James R. , Kinkler E. Sterling , Bauch Terry D. , Boyd Sheri Y. N.
Published: December 2003

Objectives: Focused assessment with sonography in trauma (FAST) can define life‐threatening injuries in austere settings with remote real‐time review by experienced physicians. This study evaluates vest‐mounted microwave, satellite, and LifeLink communications technology for image clarity and diagnostic accuracy during remote transmission of FAST examinations. Methods: Using a SonoSite, FAST was obtained on three patients with pericardial and intraperitoneal effusions and two control subjects in a remotely located U.S. Army Combat Support Hospital. A miniature vest‐mounted video transmitter attached to the SonoSite sent wireless ultrasound video 20 m to a receiving antenna. The signal was then transferred over VSAT satellite systems at 512 kilobaud per second (kbps), INMARSAT satellite systems at 64 kbps, and over LifeLink on a moving ambulance through a metropolitan wireless traffic–management network. Clarity and absence or presence of effusions were recorded by 15 staff emergency physicians. Results: Average sensitivity, specificity, and accuracy were 87% (95% confidence interval [CI] = 79% to 95%), 85% (95% CI = 81% to 89%), and 86% (95% CI = 82% to 90%) for the Premier Wireless Vest; 98% (95% CI = 97% to 99%), 83% (95% CI = 75% to 91%), and 86% (95% CI = 82% to 90%) for VSAT; 95% (95% CI = 94% to 96%), 70% (95% CI = 58% to 82%), and 75% (95% CI = 70% to 80%) for INMARSAT; and 82% (95% CI = 73% to 91%), 83% (95% CI = 74% to 92%), and 82% (95% CI = 78% to 86%) for LifeLink with clarity of 3.0 (95% CI = 2.7 to 3.3), 2.9 (95% CI = 2.6 to 3.2), 1.3 (95% CI = 1.2 to 1.4), and 2.1 (95% CI = 1.8 to 2.4), respectively. Conclusions: Accuracy correlated with clarity. Roaming vest transmission of FAST provides interpretable, diagnostic imagery at the distances used in this study. VSAT provided the best clarity and diagnostic value with the lighter, more portable INMARSAT serving a lesser role for remote clinical interpretation. LifeLink performed well, and further infrastructure improvements may increase clarity and accuracy.
Faculty Development: What Is Faculty Development?
Authors: Hamilton Glenn C. , Brown James E.
Published: December 2003

Faculty development is an organized, goal‐directed process to achieve career progression and growth. Inherent in this process is the acquisition of skills that enable one to contribute in a meaningful way to the advancement of a field of interest, whether educational, operational, or scientific. The process requires attention to technical skills, personal attributes, and explicit goals. Supportive mentorship is optimal. This document outlines important concepts and identifies helpful resources for academic faculty members. Additional resources are available at http://www.saem.orgfacdevindex.htm
HandiStroke: A Handheld Tool for the Emergent Evaluation of Acute Stroke Patients
Authors: Shapiro Jason , Bessette Michael , Levine Steven R. , Baumlin Kevin
Published: December 2003

Background: The management of acute stroke is time‐sensitive. Clinical decision making requires data not only from laboratory testing and neuroimaging, but also from a detailed history and neurologic examination. The neurologic examination provides baseline information and assists in differentiating acute stroke from its mimickers. There is a need for tools to facilitate the evaluation and decision making in the acute stroke patient to make the correct diagnosis and, when indicated, to properly administer intravenous thrombolytic therapy. Objectives: The goals of this project were to create a standardized, handheld software program to aid physicians in their evaluation of patients presenting to the emergency department (ED) with acute ischemic stroke, and to create an educational tool with which residents and other health care professionals can gain a level of proficiency in treating these patients. Results: A comprehensive handheld tool was created that incorporates a National Institutes of Health Stroke Scale (NIHSS) calculator, inclusion criteria, absolute contraindications, and relative warnings for thrombolytic use (i.e., recombinant tissue plasminogen activator), and a weight‐based dosing calculator that flows in a logical and clinically relevant format. Additionally, the program includes reference materials and guidelines for clinical management to further assist the clinician. Conclusions: Applications of this program include reformatting for use as a data‐gathering tool in future clinical studies investigating the treatment of stroke patients, increasing the use and documentation of the NIHSS within the ED in acute ischemic stroke patients, and improving protocol adherence for rt‐PA use.
Purα, a Single-Stranded Deoxyribonucleic Acid Binding Protein, Augments Placental Lactogen Gene Transcription
Authors: Limesand Sean W. , Jeckel Kimberly M. , Anthony Russell V.
Published: December 2003

Placental lactogen (PL) is thought to alter maternal metabolism to increase the pool of nutrients available for the fetus and to stimulate fetal nutrient uptake. The ovine (o) PL gene is expressed in chorionic binucleate cells (oBNC) and cis-elements located within the proximal promoter (−124 to +16 bp) are capable of trophoblast-specific expression in human (BeWo) and rat (Rcho-1) choriocarcinoma cells. Protein-DNA interactions were identified with oBNC nuclear extracts, and mutational analysis of these regions revealed a previously undefined cis-element from −102/−123 bp that enhances promoter activity in BeWo cells but not Rcho-1 cells. Characterization of this region identified the nucleotide sequence CCAGCA (−105/−110; o110) as the responsible cis-acting element. Southwestern analysis with this element identified a binding protein with an apparent Mr of approximately 41,000. Expression screening of an ovine placental cDNA library identified six homologous cDNAs, which shared identity with human (97%) and mouse (95%) Purα, a single-stranded DNA binding protein. The Purα-o110 interaction was confirmed by electrophoretic mobility-supershift assays with oBNC and BeWo extracts but was absent with Rcho-1 extracts. Furthermore, overexpression of ovine Purα enhanced transactivation of the oPL gene proximal promoter in both choriocarcinoma cell lines through this novel cis-element. This study identified a previously undefined cis-element, which interacts with Purα to augment PL gene transcription.
FGF-dependent generation of oligodendrocytes by a hedgehog-independent pathway
Authors: Chandran Siddharthan , Kato Hidemasa , Gerreli Dianne , Compston Alastair , Svendsen Clive N. , Allen Nicholas D.
Published: December 2003

During development, spinal cord oligodendrocyte precursors (OPCs) originate from the ventral, but not dorsal, neuroepithelium. Sonic hedgehog (SHH) has crucial effects on oligodendrocyte production in the ventral region of the spinal cord; however, less is known regarding SHH signalling and oligodendrocyte generation from neural stem cells (NSCs). We show that NSCs isolated from the dorsal spinal cord can generate oligodendrocytes following FGF2 treatment, a MAP kinase dependent phenomenon that is associated with induction of the obligate oligogenic gene Olig2. Cyclopamine, a potent inhibitor of hedgehog signalling, did not block the formation of oligodendrocytes from FGF2-treated neurosphere cultures. Furthermore,neurospheres generated from SHH null mice also produced oligodendrocytes, even in the presence of cyclopamine. These findings are compatible with the idea of a hedgehog independent pathway for oligodendrocyte generation from neural stem cells.
Integration of complex larval chemosensory organs into the adult nervous system ofDrosophila
Authors: Gendre Nanaë , Lüer Karin , Friche Sandrine , Grillenzoni Nicola , Ramaekers Ariane , Technau Gerhard M. , Stocker Reinhard F.
Published: December 2003

The sense organs of adult Drosophila, and holometabolous insects in general, derive essentially from imaginal discs and hence are adult specific. Experimental evidence presented here, however, suggests a different developmental design for the three largely gustatory sense organs located along the pharynx. In a comprehensive cellular analysis, we show that the posteriormost of the three organs derives directly from a similar larval organ and that the two other organs arise by splitting of a second larval organ. Interestingly, these two larval organs persist despite extensive reorganization of the pharynx. Thus, most of the neurons of the three adult organs are surviving larval neurons. However, the anterior organ includes some sensilla that are generated during pupal stages. Also, we observe apoptosis in a third larval pharyngeal organ. Hence, our experimental data show for the first time the integration of complex, fully differentiated larval sense organs into the nervous system of the adult fly and demonstrate the embryonic origin of their neurons. Moreover, they identify metamorphosis of this sensory system as a complex process involving neuronal persistence, generation of additional neurons and neuronal death. Our conclusions are based on combined analysis of reporter expression from P[GAL4] driver lines, horseradish peroxidase injections into blastoderm stage embryos, cell labeling via heat-shock-induced flip-out in the embryo, bromodeoxyuridine birth dating and staining for programmed cell death. They challenge the general view that sense organs are replaced during metamorphosis.
Recruitment ofC. elegansdosage compensation proteins for gene-specific versus chromosome-wide repression
Authors: Yonker Stephanie A. , Meyer Barbara J.
Published: December 2003

In C. elegans, an X-chromosome-wide regulatory process compensates for the difference in X-linked gene dose between males (XO) and hermaphrodites(XX) by equalizing levels of X-chromosome transcripts between the sexes. To achieve dosage compensation, a large protein complex is targeted to the X chromosomes of hermaphrodites to reduce their expression by half. This repression complex is also targeted to a single autosomal gene, her-1. By silencing this male-specific gene, the complex induces hermaphrodite sexual development. Our analysis of the atypical dosage compensation gene dpy-21 revealed the first molecular differences in the complex that achieves gene-specific versus chromosome-wide repression. dpy-21 mutations, shown here to be null, cause elevated X-linked gene expression in XX animals, but unlike mutations in other dosage compensation genes, they do not cause extensive XX-specific lethality or disrupt the stability or targeting of the dosage compensation complex to X. Nonetheless,DPY-21 is a member of the dosage compensation complex and localizes to X chromosomes in a hermaphrodite-specific manner. However, DPY-21 is the first member of the dosage compensation complex that does not also associate with her-1. In addition to a difference in the composition of the complex at her-1 versus X, we also found differences in the targeting of the complex to these sites. Within the complex, SDC-2 plays the lead role in recognizing X-chromosome targets, while SDC-3 plays the lead in recognizing her-1 targets.
Developmental origin of wiring specificity in the olfactory system ofDrosophila
Authors: Jefferis Gregory S. X. E. , Vyas Raj M. , Berdnik Daniela , Ramaekers Ariane , Stocker Reinhard F. , Tanaka Nobuaki K. , Ito Kei , Luo Liqun
Published: December 2003

In both insects and mammals, olfactory receptor neurons (ORNs) expressing specific olfactory receptors converge their axons onto specific glomeruli,creating a spatial map in the brain. We have previously shown that second order projection neurons (PNs) in Drosophila are prespecified by lineage and birth order to send their dendrites to one of ∼50 glomeruli in the antennal lobe. How can a given class of ORN axons match up with a given class of PN dendrites? Here, we examine the cellular and developmental events that lead to this wiring specificity. We find that, before ORN axon arrival,PN dendrites have already created a prototypic map that resembles the adult glomerular map, by virtue of their selective dendritic localization. Positional cues that create this prototypic dendritic map do not appear to be either from the residual larval olfactory system or from glial processes within the antennal lobe. We propose instead that this prototypic map might originate from both patterning information external to the developing antennal lobe and interactions among PN dendrites.
Isthmus-to-midbrain transformation in the absence of midbrain-hindbrain organizer activity
Authors: Jászai József , Reifers Frank , Picker Alexander , Langenberg Tobias , Brand Michael
Published: December 2003

In zebrafish acerebellar (ace) embryos, because of a point mutation in fgf8, the isthmic constriction containing the midbrain-hindbrain boundary (MHB) organizer fails to form. The mutants lack cerebellar development by morphological criteria, and they appear to have an enlarged tectum, showing no obvious reduction in the tissue mass at the dorsal mesencephalic/metencephalic alar plate. To reveal the molecular identity of the tissues located at equivalent rostrocaudal positions along the neuraxis as the isthmic and cerebellar primordia in wild-types, we undertook a detailed analysis of ace embryos. In ace mutants, the appearance of forebrain and midbrain specific marker genes (otx2, dmbx1, wnt4) in the caudal tectal enlargement reveals a marked rostralized gene expression profile during early somitogenesis, followed by the lack of early and late cerebellar-specific gene expression (zath1/atoh1, gap43,tag1/cntn2, neurod, zebrin II). The Locus coeruleus(LC) derived from rostral rhombomere 1 is also absent in the mutants. A new interface between otx2 and epha4a suggests that the rostralization stops at the caudal part of rhombomere 1. The mesencephalic basal plate is also affected in the mutant embryos, as indicated by the caudal expansion of the diencephalic expression domains of epha4a,zash1b/ashb, gap43 and tag1/cntn2, and by the dramatic reduction of twhh expression. No marked differences are seen in cell proliferation and apoptotic patterns around the time the rostralization of gene expression becomes evident in the mutants. Therefore,locally distinct cell proliferation and cell death is unlikely to be the cause of the fate alteration of the isthmic and cerebellar primordia in the mutants. Dil cell-lineage labeling of isthmic primordial cells reveals that cells, at the location equivalent of the wild-type MHB, give rise to caudal tectum in ace embryos. This suggests that a caudalto-rostral transformation leads to the tectal expansion in the mutants. Fgf8-coated beads are able to rescue morphological MHB formation, and elicit the normal molecular identity of the isthmic and cerebellar primordium in ace embryos. Taken together, our analysis reveals that cells of the isthmic and cerebellar primordia acquire a more rostral, tectal identity in the absence of the functional MHB organizer signal Fgf8.
Cell behaviour on micropatterned substrata: limits of extracellular matrix geometry for spreading and adhesion
Authors: Lehnert Dirk , Wehrle-Haller Bernhard , David Christian , Weiland Ulrich , Ballestrem Christoph , Imhof Beat A. , Bastmeyer Martin
Published: December 2003

Cell adhesion, spreading and migration require the dynamic formation and dispersal of contacts with the extracellular matrix (ECM). In vivo, the number, availability and distribution of ECM binding sites dictate the shape of a cell and determine its mobility. To analyse the geometrical limits of ECM binding sites required for cell attachment and spreading, we used microcontact printing to produce regular patterns of ECM protein dots of defined size separated by nonadhesive regions. Cells cultured on these substrata adhere to and spread on ECM regions as small as 0.1 μm2, when spacing between dots is less than 5 μm. Spacing of 5-25 μm induces a cell to adapt its shape to the ECM pattern. The ability to spread and migrate on dots ≥1 μm2 ceases when the dot separation is ≥30 μm. The extent of cell spreading is directly correlated to the total substratum coverage with ECM-proteins, but irrespective of the geometrical pattern. An optimal spreading extent is reached at a surface coating above 15%. Knowledge of these geometrical limits is essential for an understanding of cell adhesion and migration, and for the design of artificial surfaces that optimally interact with cells in a living tissue.
NF-κB signaling in lymphocytes: a new cast of characters
Authors: Lucas Peter C. , McAllister-Lucas Linda M. , Nuñez Gabriel
Published: December 2003

Cell-surface antigen receptors on B and T lymphocytes are complex, multisubunit assemblies that must recruit several accessory proteins and activate multiple signaling pathways in order to illicit a proper immune response. One pathway culminates in the activation of specific protein kinase C (PKC) isoforms, which is necessary for the ultimate activation of the NF-κB transcription factor. Since NF-κB plays a crucial role in the adaptive immune response (e.g. in lymphocyte proliferation and cytokine production), it is important to understand the molecular mechanisms by which NF-κB is regulated. Nevertheless, the connection between PKC activation and NF-κB has remained a mystery that has now been at least partly solved. Recent findings implicate a new scaffolding protein, Bimp3/CARMA1/CARD11, as a key factor in bridging PKC activation with the downstream activation of Bcl10 and MALT1, which ultimately stimulates NF-κB. Since some of these signaling components are lymphocyte specific, therapeutic agents that block this pathway could blunt the inappropriate proliferation of lymphocytes associated with certain inflammatory and neoplastic disorders. Alternatively, agents that specifically augment this pathway, thereby enhancing immune function in immunodeficiency, may be developed.
Junctional adhesion molecules (JAMs): more molecules with dual functions?
Authors: Ebnet Klaus , Suzuki Atsushi , Ohno Shigeo , Vestweber Dietmar
Published: December 2003

Junctional adhesion molecules (JAMs) are members of an immunoglobulin subfamily expressed by leukocytes and platelets as well as by epithelial and endothelial cells, in which they localize to cell-cell contacts and are specifically enriched at tight junctions. The recent identification of extracellular ligands and intracellular binding proteins for JAMs suggests two functions for JAMs. JAMs associate through their extracellular domains with the leukocyte β2 integrins LFA-1 and Mac-1 as well as with the β1 integrin α4β1. All three integrins are involved in the regulation of leukocyte-endothelial cell interactions. Through their cytoplasmic domains, JAMs directly associate with various tight junction-associated proteins including ZO-1, AF-6, MUPP1 and the cell polarity protein PAR-3. PAR-3 is part of a ternary protein complex that contains PAR-3, atypical protein kinase C and PAR-6. This complex is highly conserved through evolution and is involved in the regulation of cell polarity in organisms from Caenorhabditis elegans and Drosophila to vertebrates. These findings point to dual functions for JAMs: they appear to regulate both leukocyte/platelet/endothelial cell interactions in the immune system and tight junction formation in epithelial and endothelial cells during the acquisition of cell polarity.
The socio-economic impact of telehealth: A systematic review
Authors: Jennett P A , Hall L Affleck , Hailey D , Ohinmaa A , Anderson C , Thomas R , Young B , Lorenzetti D , Scott R E
Published: December 2003

We reviewed the socio-economic impact of telehealth, focusing on nine main areas: paediatrics, geriatrics, First Nations (i.e. indigenous peoples), home care, mental health, radiology, renal dialysis, rural/remote health services and rehabilitation. A systematic search led to the identification of 4646 citations or abstracts; from these, 306 sources were analysed. A central finding was that telehealth studies to date have not used socioeconomic indicators consistently. However, specific telehealth applications have been shown to offer significant socio-economic benefit, to patients and families, health-care providers and the health-care system. The main benefits identified were: increased access to health services, cost-effectiveness, enhanced educational opportunities, improved health outcomes, better quality of care, better quality of life and enhanced social support. Although the review found a number of areas of socio-economic benefit, there is the continuing problem of limited generalizability.
Potential effect of patient-assisted teledermatology on outpatient referral rates
Authors: Eminović N , Witkamp L , Ravelli A C J , Bos J D , Van Den Akker Th W , Bousema M T , Henquet C J M , Koopman R J J , Zeegelaar J E , Wyatt J C
Published: December 2003

We carried out a pilot study on the feasibility and accuracy of store-and-forward teledermatology based on patient-provided images and history as a triage tool for outpatient consultation. Patients referred by their general practitioner provided a history and images via the Internet. The information was reviewed by one of 12 teledermatologists and the patient then visited a different dermatologist in person within two days. Three independent dermatologists compared the remote and in-person diagnoses in random order to determine diagnostic agreement. Broader agreement was also measured, by comparing the main disease groups into which the two diagnoses fell. The teledermatologists indicated whether an in-person consultation or further investigations were necessary. There were 105 eligible patients, aged four months to 72 years, who were willing to participate. For the 96 cases included in the analysis, complete diagnostic agreement was found in 41% ( n= 39), partial diagnostic agreement in 10% ( n= 10) and no agreement in 49% ( n= 47). There was disease group agreement in 66% of cases ( n= 63). Nearly a quarter (23%) of participating patients could have safely been managed without an in-person visit to a dermatologist.
The reality of applying an assessment guideline to a telemedicine mental health programme
Authors: Hailey David , Bulger Tim , Stayberg Sharlene , Urness Douglas
Published: December 2003

A guideline for assessment of telemedicine applications was used by the Alberta Mental Health Board (AMHB) in its evaluation of a telemedicine mental health (TMH) service. Many attributes referred to in the guideline were well covered in the AMHB evaluation. However, there were limitations on the assessment of outcomes and cost-effectiveness. From the perspective of the AMHB, the guideline was helpful, although more so in the earlier stages of the TMH service than for its appraisal as it reached maturity. The measures of performance suggested by the guideline did not fully match local operational conditions. Constraints on the assessment of the mature TMH service included the complexity of the network, the limited resources available for evaluation and the routine administrative demands of decision makers. This experience points to the usefulness of standardized assessment approaches to telemedicine, but also to their limitations.
The Impact of Vertical Coordination on Ex Post Transaction Costs in Domestic and International Buyer–Seller Relationships
Authors: Buvik Arnt , Andersen Otto
Published: December 2003

Even though the transaction costs framework has evolved considerably in the past decade, there is still only modest empirical knowledge about the governance performance implications of the theory. This article focuses on the governance performance of vertical coordination in relationships between manufacturing firms. On the basis of transaction cost analysis and related works in international marketing, the authors examine the impact of asset specificity and vertical coordination on ex post transaction costs in domestic and international buyer–seller relationships. In accordance with current literature in international marketing, performance measurement problems are expected to be more evident in international business trade than in domestic business-to-business relationships. The empirical findings show that under conditions with substantial asset specificity, vertical coordination reduces ex post transaction significantly more in international buyer–seller relationships than in domestic channel dyads.
On Distributor Commitment in Marketing Channels for Industrial Products: Contrast between the United States and Japan
Authors: Kim Keysuk , Oh Changho
Published: December 2003

Previous studies have highlighted task environmental factors as the sole drivers of a distributor's commitment to its supplier and have found positive consequences of distributor commitment. The authors propose institutional factors as another motive for distributor commitment in channel relationships. Specifically, the authors suggest that long-term orientation is an essential institutional environment to consider for a comparative study of distributor commitment. The authors hypothesize that distributor commitment is driven by both task environmental factors and institutional factors. The authors conduct national surveys of industrial distributors in the United States and Japan to test the hypotheses. The hypothesis test results indicate that task environmental factors are related significantly to distributor commitment regardless of the channel contexts and that the effect of an institutional factor varies across the channel contexts.
Brand Name Translation: Language Constraints, Product Attributes, and Consumer Perceptions in East and Southeast Asia
Authors: Hong F.C. (Frank) , Pecotich Anthony , Shultz Clifford J.
Published: December 2003

The primary purpose of this study is to examine the relationship between foreign brand name translation and product-related cues—such as physical quality, perceived origin, and brand name—on consumers’ perceived quality, price, and purchase intentions. In translations from alphabetic to character-based languages such as Mandarin, two generic methods of brand name translation are available: (1) direct translation for the meaning of the brand name and (2) phonetic translation for the pronunciation of the brand name. The results from a series of structurally related experiments designed to investigate the effects of brand name translation in a cross-cultural context indicate that for an unknown brand, a phonetic translation may be mandatory, whereas for an existing strong brand name, it may be best to retain the original name.
Identifying Brand Image Dimensionality and Measuring the Degree of Brand Globalization: A Cross-National Study
Authors: Hsieh Ming H.
Published: December 2003

The author aims to answer two questions related to brand globalization: (1) whether the pattern of brand image dimensionality is similar across international markets and (2) how cohesive a brand image perception is in a global market. Results from a 20-country, 70-region study provide concrete evidence that supports the applicability of the proposed benefit-based multidimensional image structure that corresponds to consumers’ sensory, utilitarian, and symbolic and economic need at both the global and the national level. On the basis of the identified image dimensions, the author proposes an alternative approach to measuring the degree of global brand image cohesiveness as an indicator of brand globalization. Global brand image cohesiveness is calculated on the basis of the summation of Euclidean distances between the column score of image dimensions of the home country (i.e., initial market) and that of foreign countries. Furthermore, nations are clustered on the basis of these column scores, and the resultant clusters correspond approximately to groups of countries that share similar levels of economic development, cultural dimension, or geographic distance, which suggests that national characteristics affect brand image perceptions. The findings provide implications for the practice of global brand image management.
Integrating Transfer Pricing Policy and Activity-Based Costing
Authors: Stevenson Thomas H. , Cabell David W.E.
Published: December 2003

The activity-based costing approach justifies the transfer prices a multinational corporation uses to transfer unique company parts or services among its divisions located in different countries. This article illustrates how this approach reduces the probability of costly tax audits and assists in obtaining an advanced pricing agreement.
Educator Insights: Standardization or Adaptation of the International Marketing Mix: The Role of the Local Subsidiary/Representative
Authors: Solberg Carl Arthur
Published: December 2003

In this article, the author suggests that the standardization versus customization issue in international marketing has important organizational aspects that are often neglected in the literature. The author parts from the traditional culture and economies of scale approaches by introducing a taxonomy of international marketing organizations based on headquarters versus subsidiary decision power and on market knowledge at headquarters. The author then suggests a typology of organizational solutions—local baronies, civil war, confederation, and federation—and describes two case studies to illustrate how firms “travel” in the model. Finally, the author develops several propositions and discusses managerial implications.
Entrepreneurship and Marketing Strategy: The SME under Globalization
Authors: Knight Gary
Published: December 2003

Globalization and the emergence of internationally active small and medium-sized enterprises (SMEs) are key worldwide trends. The author investigates the interrelationships of entrepreneurial orientation, marketing strategy, tactics, and firm performance among SMEs affected by globalization. The author offers empirical findings and conclusions on the critical roles of entrepreneurship and marketing to assist SME managers.