bluuebunny/crossref_metadata_2025 huggingface dataset:
Mate Selection and Family Business Success
Authors: Kaye Kenneth
Published: April 2004

An index of a family's success is the caliber of talent it manages to attract and retain through marriage. This fundamental fact in sociology, anthropology, and history has received little attention in the family business field. Parents in Western societies have two windows of opportunity to enhance long-term family success through marriage: first, before their children reach puberty, and later, after they choose spouses for themselves.
Internationalization of Family Businesses: Evidence from Northwest Ohio, U.S.A
Authors: Okoroafo Sam C.
Published: April 2004

This study determines the extent of internationalization (i.e., global business attitudes and activities) of family businesses. A survey of 187 family businesses from northwest Ohio finds that family businesses do not regularly monitor the international marketplace or integrate global developments into domestic decisions. Although a small pool of businesses currently has ties with family businesses in foreign countries, many more would like to develop such ties. The study finds that if a family business does not get involved in foreign markets in the first and second generations, it is unlikely to do so in later generations. The majority of family businesses does not develop sources in foreign countries. The family businesses that do source from overseas markets do so mostly for cost and quality benefits. Approximately half of family businesses sold their products in foreign markets primarily via exporting and joint ventures.
Characteristics and Key Success Factors in Family Business: The Case of Korean Immigrant Businesses in Metro-Atlanta
Authors: Nam Young-Ho , Herbert James I.
Published: April 2004

Immigrant businesses in the United States are a vibrant and growing part of the economy, and their similarities and differences to other family businesses in the U.S. are worthy of investigation.This paper examines two elements of Korean immigrant businesses in Metro-Atlanta: characteristics (ethnic business, general family business, ownership and succession planning, strategic planning, and conflict and communication) and key success factors. There were 93 respondents in this exploratory study. This paper discusses the results and implications of the study.
Succession Experiences in Philippine Family Businesses
Authors: Santiago Andrea L.
Published: April 2004

Western research suggests that family business owners must prepare for leadership succession in a systematic manner to ensure continuity. A review of the succession experiences of eight family businesses in the Southeast Asian country of the Philippines seems to indicate that the key to smooth succession for group-oriented families is not entirely dependent on succession planning. Rather, a family business's smooth succession depends on the succession process being consistent with family values. In fact, valuing the preservation of the family unit helps to avoid the ill effects that normally accompany the absence of succession planning.
Limits to the Growth of Family-Owned Business? The Case of Chinese Transnational Corporations from Hong Kong
Authors: Yeung Henry Wai-chung
Published: April 2004

It has become conventional wisdom in management literature that family-owned business is restricted by its management practices and, therefore, cannot grow beyond a certain size. In the case of Chinese family firms, these practices are related to paternalism, nepotism, personalism, and fragmentation. This paper examines three detailed qualitative case studies of Chinese family firms from Hong Kong that have relentlessly pursued growth through internationalization. It argues that venturing into foreign markets and transnational operations has become an effective means for Chinese family firms to expand beyond the limits of domestic markets and centripetal management structures. International business strategies enable Chinese family firms to socialize trusted members into the corporate “family,” provide a training ground for the future heir to the patriarch, and consolidate networks of personal and business relationships. There are, therefore, no a priori reasons to support the alleged limits to the growth of Chinese family firms in their international context.
Social Embeddedness, Overt and Covert Power, and Their Effects on CEO Pay: An Empirical Examination Among Family Businesses in India
Authors: Veliyath Rajaram , Ramaswamy Kannan
Published: April 2004

The literature on CEO compensation reflects two common biases: (a) the dominant use of the agency theory perspective and (b) the almost exclusive use of U.S. and U.K samples. Agency theory views compensation as a consequence of the incentive contracts and the processes of corporate governance. However, little is known about the determinants of CEO compensation in developing countries. Considering that foreign direct investment of U.S. multinational enterprises increased 10-fold over the past decade, mostly in developing economies, there is a great need to understand the dynamics of pay setting in these foreign contexts. Overall, there is an imperative need to explore alternative theoretical perspectives as well as investigate nontraditional contexts to broaden existing theoretical premises.

In an attempt to address this need, this study investigates the CEO's social embeddedness and overt and covert power as determinants of CEO pay in a sample of Indian family-controlled firms. Using a time-series, cross-sectional regression analysis, we find family shareholding and the percentage of inside directors on the board (identified as bases of overt power for the CEO) to be the predominant influences on CEO pay. By contrast, some of the identified bases of covert power, such as the CEO's tenure, age, education, and firm diversification, are not significant. Surprisingly, controls for firm size and performance also exhibit no influence on CEO pay. These findings offer a useful point of reference against which results from western studies can be compared to formulate more holistic theories of CEO pay.
The Succession Process from a Resource- and Knowledge-Based View of the Family Firm
Authors: Cabrera-Suárez Katiuska , De Saá-Pérez Petra , García-Almeida Desiderio
Published: April 2004

A major challenge facing the family firm is the succession process. One reason for this challenge might involve the successor's ability to acquire the predecessor's key knowledge and skills adequately to maintain and improve the organizational performance of the firm. This paper uses two theoretical approaches from the strategic management field to explore this critical process and analyze how it can be managed effectively: the resource-based theory of the firm and the emergent knowledge-based view. This conceptual framework provides a powerful tool for understanding the nature and transfer of knowledge within the family business, which becomes the basis for developing competitive advantage over nonfamily businesses.
Coping with Growth Transitions: The Case of Chinese Family Businesses in Singapore
Authors: Tan Wee-Liang , Siew Tong Fock
Published: April 2004

Families control more than half of the corporations in East Asia (World Bank, 1999; World Bank, 1998). The contribution of family businesses to Asia's economic growth is predicated upon successfully growing their businesses. Many family businesses in East Asia, spanning countries such as Taiwan, Hong Kong, Indonesia, Singapore, and Malaysia, are Chinese owned and managed. Some claim that these businesses will never develop into full-fledged multinational enterprises because of their cultural heritage (Redding, 1990). However, some Chinese family businesses have successfully made the transition.

This paper presents an in-depth study of five Chinese family businesses in Singapore that have successfully made the transition in growth and size and across national boundaries and family generations. Their business empires extend into the Asia Pacific region. This paper highlights the key success factors of these five noteworthy family businesses that enabled them to make these growth transitions.
Patterns in Serial Business Families: Theory Building Through Global Case Study Research
Authors: Kenyon-Rouvinez Denise
Published: April 2004

The sale of a family business often gives rise to emotions that can still haunt families years after the sale. However, some families—serial business families—combine generations of experience and succeed in turning it into a positive experience by re-creating a new family business venture. The objectives of this research are to demonstrate that serial business families constitute a global phenomenon and to identify patterns in how and why they re-create businesses. The compilation and analysis of in-depth interviews with nine serial business families from around the world show that they follow a three-stage process and that the original business, in terms of family, ownership, business, and governance, has a strong influence on what is re-created and how it is re-created. The fresh motivation and the strong commitment of serial business families, combined with renewed entrepreneurial spirit, could serve as an inspiration for all families in business to reconsider their strategic agendas in the context of the new economy.
Women's Role Involvement in Family Businesses, Business Tensions, and Business Success
Authors: Danes Sharon M. , Olson Patricia D.
Published: April 2004

This paper is based on a study of 391 family-business-owning couples where the husband is the business owner. The purpose of the study was to examine the work involvement of the wife in the business, the business tensions, and the impact of those tensions on family business success. Fifty-seven percent of wives worked in the business, 47% of whom were paid. Forty-two percent of wives were considered major decision makers. Having more than one decision maker in the business impacted certain types of inclusion tension. Business and family success outcomes varied by level of tensions. There was initial evidence of a threshold where business tensions begin to affect business success negatively.
In vivo expression patterns of MyoD, p21, and Rb proteins in myonuclei and satellite cells of denervated rat skeletal muscle
Authors: Ishido Minenori , Kami Katsuya , Masuhara Mitsuhiko
Published: April 2004

MyoD, a myogenic regulatory factor, is rapidly expressed in adult skeletal muscles in response to denervation. However, the function(s) of MyoD expressed in denervated muscle has not been adequately elucidated. In vitro, it directly transactivates cyclin-dependent kinase inhibitor p21 (p21) and retinoblastoma protein (Rb), a downstream target of p21. These factors then act to regulate cell cycle withdrawal and antiapoptotic cell death. Using immunohistochemical approaches, we characterized cell types expressing MyoD, p21, and Rb and the relationship among these factors in the myonucleus of denervated muscles. In addition, we quantitatively examined the time course changes and expression patterns among distinct myofiber types of MyoD, p21, and Rb during denervation. Denervation induced MyoD expression in myonuclei and satellite cell nuclei, whereas p21 and Rb were found only in myonuclei. Furthermore, coexpression of MyoD, p21, and Rb was induced in the myonucleus, and quantitative analysis of these factors determined that there was no difference among the three myofiber types. These observations suggest that MyoD may function in myonuclei in response to denervation to protect against denervation-induced apoptosis via perhaps the activation of p21 and Rb, and function of MyoD expressed in satellite cell nuclei may be negatively regulated. The present study provides a molecular basis to further understand the function of MyoD expressed in the myonuclei and satellite cell nuclei of denervated skeletal muscle.
Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells
Authors: Taniyama Yoshihiro , Ushio-Fukai Masuko , Hitomi Hirofumi , Rocic Petra , Kingsley Michael J. , Pfahnl Chun , Weber David S. , Alexander R. Wayne , Griendling Kathy K.
Published: April 2004

Angiotensin II activates a variety of signaling pathways in vascular smooth muscle cells (VSMCs), including the MAPKs and Akt, both of which are required for hypertrophy. However, little is known about the relationship between these kinases or about the upstream activators of Akt. In this study, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive kinase p38 MAPK and its substrate MAPKAPK-2 mediate Akt activation in VSMCs. In unstimulated VSMCs, Akt and p38 MAPK are constitutively associated and remain so after angiotensin II stimulation. Inhibition of p38 MAPK activity with SB-203580 dose-dependently inhibits Akt phosphorylation on Ser473, but not Thr308. Angiotensin II-induced phosphorylation of MAPKAPK-2 is also attenuated by SB-203580, as well as by inhibitors of ROS. In addition, angiotensin II stimulates the association of MAPKAPK-2 with the Akt-p38 MAPK complex, and an in vitro kinase assay shows that MAPKAPK-2 immunoprecipitates of VSMC lysates phosphorylate recombinant Akt in an angiotensin II-inducible manner. Finally, intracellular delivery of a MAPKAPK-2 peptide inhibitor blocks Akt phosphorylation on Ser473. These results suggest that the p38 MAPK-MAPKAPK-2 pathway mediates Akt activation by angiotensin II in these cells by recruiting active MAPKAPK-2 to a signaling complex that includes both Akt and p38 MAPK. Through this mechanism, p38 MAPK confers ROS sensitivity to Akt and facilitates downstream signaling. These results provide evidence for a novel signaling complex that may help to spatially organize hypertrophy-related, ROS-sensitive signaling in VSMCs.
Physiological concentrations of bile salts inhibit recovery of ischemic-injured porcine ileum
Authors: Campbell Nigel B. , Ruaux Craig G. , Shifflett Donnie E. , Steiner Jöerg M. , Williams David A. , Blikslager Anthony T.
Published: April 2004

We have previously shown rapid in vitro recovery of barrier function in porcine ischemic-injured ileal mucosa, attributable principally to reductions in paracellular permeability. However, these experiments did not take into account the effects of luminal contents, such as bile salts. Therefore, the objective of this study was to evaluate the role of physiological concentrations of deoxycholic acid in recovery of mucosal barrier function. Porcine ileum was subjected to 45 min of ischemia, after which mucosa was mounted in Ussing chambers and exposed to varying concentrations of deoxycholic acid. The ischemic episode resulted in significant reductions in transepithelial electrical resistance (TER), which recovered to control levels of TER within 120 min, associated with significant reductions in mucosal-to-serosal3H-labeled mannitol flux. However, treatment of ischemic-injured tissues with 10−5M deoxycholic acid significantly inhibited recovery of TER with significant increases in mucosal-to-serosal3H-labeled mannitol flux, whereas 10−6M deoxycholic acid had no effect. Histological evaluation at 120 min revealed complete restitution regardless of treatment, indicating that the breakdown in barrier function was due to changes in paracellular permeability. Similar effects were noted with the application of 10−5M taurodeoxycholic acid, and the effects of deoxycholic acid were reversed with application of the Ca2+-mobilizing agent thapsigargin. Deoxycholic acid at physiological concentrations significantly impairs recovery of epithelial barrier function by an effect on paracellular pathways, and these effects appear to be Ca2+dependent.
Exercise response after rapid intravenous infusion of saline in healthy humans
Authors: Robertson H. Thomas , Pellegrino Riccardo , Pini Daniela , Oreglia Jacopo , DeVita Stefano , Brusasco Vito , Agostoni PierGiuseppe
Published: April 2004

Patients with chronic heart failure have an abnormal pattern of exercise ventilation (V̇e), characterized by small tidal volumes (Vt), increased alveolar ventilation, and elevated physiological dead space (Vd/Vt). To investigate whether increased lung water in isolation could reproduce this pattern of exercise ventilation, 30 ml/kg of saline were rapidly infused into nine normal subjects, immediately before a symptom-limited incremental exercise test. Saline infusion significantly reduced forced vital capacity, 1-s forced expiratory volume, and alveolar volume ( P < 0.01 for all). After saline, exercise ventilation assessed by the V̇e/V̇co2 slope increased from 24.9 ± 2.4 to 28.0 ± 2.9 l/l, ( P < 0.0002), associated with a small decrease in arterial Pco2, but without changes in Vt, Vd/Vt, or alveolar-arterial O2 difference. A reduction in maximal O2 uptake of 175 ± 184 ml/min ( P < 0.02) was observed in the postsaline infusion exercise studies, associated with a consistent reduction in maximal exercise heart rate (8.1 ± 5.9 beats/min, P < 0.01), but without a change in the O2 pulse. Therefore, infusion of saline to normal subjects before exercise failed to reproduce either the increase in Vd/Vt or the smaller exercise Vt described in heart failure patients. The observed increase in V̇e can be attributed to dilution acidosis from infusion of the bicarbonate-free fluid and/or to afferent signals from lung and exercising muscles. The reduction in maximal power output, maximal O2 uptake, and heart rate after saline infusion may be linked to accumulation of edema fluid in exercising muscle, impairing the diffusion of O2 to muscle mitochondria.
Noradrenergic Induction of Selective Plasticity in the Frequency Tuning of Auditory Cortex Neurons
Authors: Manunta Yves , Edeline Jean-Marc
Published: April 2004

Neuromodulators have long been viewed as permissive factors in experience-induced cortical plasticity, both during development and in adulthood. Experiments performed over the last two decades have reported the potency of acetylcholine to promote changes in functional properties of cortical cells in the auditory, visual, and somatosensory modality. In contrast, very few attempts were made with the monoaminergic systems. The present study evaluates how repeated presentation of brief pulses of noradrenaline (NA) concomitant with presentation of a particular tone frequency changes the frequency tuning curves of auditory cortex neurons determined at 20 dB above threshold. After 100 trials of NA-tone pairing, 28% of the cells (19/67) exhibited selective tuning modifications for the frequency paired with NA. All the selective effects were obtained when the paired frequency was within 1/4 of an octave from the initial best frequency. For these cells, selective decreases were prominent (15/19 cases), and these effects lasted ≥15 min after pairing. No selective effects were observed under various control conditions: tone alone ( n = 10 cells), NA alone ( n = 11 cells), pairing with ascorbic acid ( n = 6 cells), or with GABA ( n = 20 cells). Selective effects were observed when the NA-tone pairing was performed in the presence of propranolol (4/10 cells) but not when it was performed in the presence phentolamine (0/13 cells), suggesting that the effects were mediated by alpha receptors. These results indicate that brief increases in noradrenaline concentration can trigger selective modifications in the tuning curves of cortical neurons that, in most of the cases, go in opposite direction compared with those usually reported with acetylcholine.
Microarray analysis of the rat lacrimal gland following the loss of parasympathetic control of secretion
Authors: Nguyen Doan H. , Toshida Hiroshi , Schurr Jill , Beuerman Roger W.
Published: April 2004

Previous studies showed that loss of muscarinic parasympathetic input to the lacrimal gland (LG) leads to a dramatic reduction in tear secretion and profound changes to LG structure. In this study, we used DNA microarrays to examine the regulation of the gene expression of the genes for secretory function and organization of the LG. Long-Evans rats anesthetized with a mixture of ketamine/xylazine (80:10 mg/kg) underwent unilateral sectioning of the greater superficial petrosal nerve, the input to the pterygopalatine ganglion. After 7 days, tear secretion was measured, the animals were killed, and structural changes in the LG were examined by light microscopy. Total RNA from control and experimental LGs ( n = 5) was used for DNA microarray analysis employing the U34A GeneChip. Three statistical algorithms (detection, change call, and signal log ratio) were used to determine differential gene expression using the Microarray Suite (5.0) and Data Mining Tools (3.0). Tear secretion was significantly reduced and corneal ulcers developed in all experimental eyes. Light microscopy showed breakdown of the acinar structure of the LG. DNA microarray analysis showed downregulation of genes associated with the endoplasmic reticulum and Golgi, including genes involved in protein folding and processing. Conversely, transcripts for cytoskeleton and extracellular matrix components, inflammation, and apoptosis were upregulated. The number of significantly upregulated genes (116) was substantially greater than the number of downregulated genes ( 49 ). Removal of the main secretory input to the rat LG resulted in clinical symptoms associated with severe dry eye. Components of the secretory pathway were negatively affected, and the increase in cell proliferation and inflammation may lead to loss of organization in the parasympathectomized lacrimal gland.
Capillary regression in vascular endothelial growth factor-deficient skeletal muscle
Authors: Tang Kechun , Breen Ellen C. , Gerber Hans-Peter , Ferrara Napoleone M. A. , Wagner Peter D.
Published: April 2004

Skeletal muscle angiogenesis is an important physiological adaptation to increased metabolic demand, possibly dependent on vascular endothelial growth factor (VEGF), the increased expression of which is a known early response to exercise. To test the hypothesis that VEGF is essential to muscle capillary maintenance, we evaluated the consequences of targeted skeletal muscle inhibition of VEGF expression in postnatal, cage-confined VEGF loxP(+/+) mice. To delete VEGF, cre recombinase expression was accomplished using direct intramuscular injection of a recombinant adeno-associated cre recombinase expressing viral vector. Four weeks postinfection, VEGF-inactivated regions revealed 64% decreases in capillary density and capillary-to-fiber ratio. Substantial apoptosis was also observed in VEGF-depleted regions. There was no evidence of rescue at 8 wk, with a persistent 67% reduction in capillary-to-fiber ratio and a 69% decrease in capillary density. These data implicate VEGF as an essential survival factor for muscle capillarity and also demonstrate insufficient VEGF-dependent signaling leads to apoptosis in mouse skeletal muscle.
MEK1-ERK2 Signaling Pathway Protects Myocardium From Ischemic Injury In Vivo
Authors: Lips Daniel J. , Bueno Orlando F. , Wilkins Benjamin J. , Purcell Nicole H. , Kaiser Robert A. , Lorenz John N. , Voisin Laure , Saba-El-Leil Marc K. , Meloche Sylvain , Pouysségur Jacques , Pagès Gilles , De Windt Leon J. , Doevendans Pieter A. , Molkentin Jeffery D.
Published: April 2004

Background—

Myocardial infarction causes a rapid and largely irreversible loss of cardiac myocytes that can lead to sudden death, ventricular dilation, and heart failure. Members of the mitogen-activated protein kinase (MAPK) signaling cascade have been implicated as important effectors of cardiac myocyte cell death in response to diverse stimuli, including ischemia-reperfusion injury. Specifically, activation of the extracellular signal–regulated kinases 1/2 (ERK1/2) has been associated with cardioprotection, likely through antagonism of apoptotic regulatory pathways.

Methods and Results—

To establish a causal relationship between ERK1/2 signaling and cardioprotection, we analyzed
Erk1
nullizygous gene-targeted mice,
Erk2
heterozygous gene-targeted mice, and transgenic mice with activated MEK1-ERK1/2 signaling in the heart. Although MEK1 transgenic mice were largely resistant to ischemia-reperfusion injury,

Erk2
+/−

gene-targeted mice showed enhanced infarction areas, DNA laddering, and terminal deoxynucleotidyl transferase–mediated dUTP biotin nick-end labeling (TUNEL) compared with littermate controls. In contrast, enhanced MEK1-ERK1/2 signaling protected hearts from DNA laddering, TUNEL, and preserved hemodynamic function assessed by pressure-volume loop recordings after ischemia-reperfusion injury.

Conclusions—

These data are the first to demonstrate that ERK2 signaling is required to protect the myocardium from ischemia-reperfusion injury in vivo.
Macrophage-Targeted Overexpression of Urokinase Causes Accelerated Atherosclerosis, Coronary Artery Occlusions, and Premature Death
Authors: Cozen Aaron E. , Moriwaki Hideaki , Kremen Michal , DeYoung Mary Beth , Dichek Helén L. , Slezicki Katherine I. , Young Stephen G. , Véniant Murielle , Dichek David A.
Published: April 2004

Background—

Human atherosclerotic lesions contain elevated levels of urokinase plasminogen activator (uPA), expressed predominantly by macrophages.

Methods and Results—

To test the hypothesis that macrophage-expressed uPA contributes to the progression and complications of atherosclerosis, we generated transgenic mice with macrophage-targeted overexpression of uPA. The uPA transgene was bred into the apolipoprotein E–null background, and transgenic mice and nontransgenic littermate controls were fed an atherogenic diet. uPA-transgenic mice had significantly elevated uPA activity in the atherosclerotic artery wall, of a magnitude similar to elevations reported in atherosclerotic human arteries. Compared with littermate controls, uPA-transgenic mice had accelerated atherosclerosis, dilated aortic roots, occlusive proximal coronary artery disease, myocardial infarcts, and early mortality.

Conclusions—

These data support the hypothesis that overexpression of uPA by artery wall macrophages is atherogenic and suggest that uPA inhibitors might be therapeutically useful.
Adrenomedullin Can Protect Against Pulmonary Vascular Remodeling Induced by Hypoxia
Authors: Matsui Hiromitsu , Shimosawa Tatsuo , Itakura Kanami , Guanqun Xing , Ando Katsuyuki , Fujita Toshiro
Published: April 2004

Background—

Chronic hypoxia is one of the major causes of pulmonary vascular remodeling associated with stimulating reactive oxygen species (ROS) production. Recent studies have indicated that hypoxia upregulates expression of adrenomedullin (AM), which is not only a potent vasodilator but also an antioxidant. Thus, using heterozygous AM-knockout (AM
+/−
) mice, we examined whether AM could attenuate pulmonary vascular damage induced by hypoxia.

Methods and Results—

Ten-week-old male wild-type (AM
+/+
) or AM
+/−
mice were housed under 10% oxygen conditions for 3 to 21 days. In AM
+/+
mice, hypoxia enhanced AM mRNA expression, which was reduced by the administration of a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-
N
-oxyl (hydroxy-TEMPO). Hypoxia induced pulmonary vascular remodeling, which was associated with the increased production of oxidative stress measured by electron spin resonance and immunostaining of 3-nitrotyrosine. The media wall thickness of the pulmonary arteries was significantly greater in AM
+/−
mice housed under hypoxia than in AM
+/+
mice under hypoxia. Concomitantly, pulmonary ROS production induced by hypoxia was more enhanced in AM
+/−
mice than in AM
+/+
mice. The administration of both exogenous AM and hydroxy-TEMPO normalized pulmonary vascular media wall thickness in not only AM
+/+
but also AM
+/−
mice under hypoxic conditions associated with the normalization of ROS overproduction in the lung.

Conclusions—

The present results suggest that an endogenous AM is a potential protective peptide against hypoxia-induced vascular remodeling, possibly through the suppression of ROS generation, which might provide an effective therapeutic strategy.
Multisite Phosphorylation Mechanism for Protein Kinase A Activation of the Smooth Muscle ATP-Sensitive K
+
Channel
Authors: Quinn Kathryn V. , Giblin Jonathan P. , Tinker Andrew
Published: April 2004

The activation of ATP-sensitive K
+
channels by protein kinase A in vascular smooth muscle is an important component of the action of vasodilators. In this study, we examine the molecular mechanisms of regulation of the cloned equivalent of this channel comprising the sulfonylurea receptor 2B and the inward rectifier 6.1 subunit (SUR2B/Kir6.1). Specifically, we focus on whether the channel is directly phosphorylated and the sites at which this occurs in the protein complex. We identify one site in Kir6.1 (S385) and two sites in SUR2B (T633 and S1465) using a combination of biochemical and functional assays. Our work supports a model in which multiple sites in the channel complex have to be phosphorylated before activation occurs.
Clinimetric Properties of the Motor Activity Log for the Assessment of Arm Use in Hemiparetic Patients
Authors: van der Lee J.H. , Beckerman H. , Knol D.L. , de Vet H.C.W. , Bouter L.M.
Published: April 2004

Background and Purpose—

The Motor Activity Log (MAL) is a semistructured interview for hemiparetic stroke patients to assess the use of their paretic arm and hand (amount of use [AOU]) and quality of movement [QOM]) during activities of daily living. Scores range from 0 to 5. The following clinimetric properties of the MAL were quantified: internal consistency (Cronbach α), test-retest agreement (Bland and Altman method), cross-sectional construct validity (correlation between AOU and QOM and with the Action Research Arm [ARA] test), longitudinal construct validity (correlation of change on the MAL during the intervention with a global change rating [GCR] and with change on the ARA), and responsiveness (effect size).

Methods—

Two baseline measurements 2 weeks apart and 1 follow-up measurement immediately after 2 weeks of intensive exercise therapy either with or without immobilization of the unimpaired arm (forced use) were performed in 56 chronic stroke patients.

Results—

Internal consistency was high (AOU: α=0.88; QOM: α=0.91). The limits of agreement were −0.70 to 0.85 and −0.61 to 0.71 for AOU and QOM, respectively. The correlation with the ARA score (Spearman ρ) was 0.63 (AOU and QOM). However, the improvement on the MAL during the intervention was only weakly related to the GCR and to the improvement on the ARA, Spearman ρ was between 0.16 and 0.22. The responsiveness ratio was 1.9 (AOU) and 2.0 (QOM).

Conclusion—

The MAL is internally consistent and relatively stable in chronic stroke patients not undergoing an intervention. The cross-sectional construct validity of the MAL is reasonable, but the results raise doubt about its longitudinal construct validity.
Nandrolone Decanoate and Load Increase Remodeling and Strength in Human Supraspinatus Bioartificial Tendons
Authors: Triantafillopoulos Ioannis K. , Banes Albert J. , Bowman Karl F. , Maloney Melissa , Garrett William E. , Karas Spero G.
Published: April 2004

Background

To date, no studies document the effect of anabolic steroids on rotator cuff tendons.

Study Design

Controlled laboratory study.

Hypothesis

Anabolic steroids enhance remodeling and improve the biomechanical properties of bioartificially engineered human supraspinatus tendons.

Methods

Bioartificial tendons were treated with either nandrolone decanoate (nonload, steroid, n = 18), loading (load, nonsteroid, n = 18), or both (load, steroid, n = 18). A control group received no treatment (nonload, nonsteroid [NLNS], n = 18). Bioartificial tendons’ remodeling was assessed by daily scanning, cytoskeletal organization by staining, matrix metalloproteinase-3 levels by ELISA assay, and biomechanical properties by load-to-failure testing.

Results

The load, steroid group showed the greatest remodeling and the best organized actin cytoskeleton. Matrix metallo-proteinase-3 levels in the load, steroid group were greater than those of the nonload, nonsteroid group (P < .05). Ultimate stress and ultimate strain in the load, steroid group were greater than those of the nonload, nonsteroid and nonload, steroid groups (P < .05). The strain energy density in the load, steroid group was greater when compared to other groups (P < .05).

Conclusions

Nandrolone decanoate and load acted synergistically to increase matrix remodeling and biomechanical properties of bioartificial tendons.

Clinical Relevance

Data suggest anabolic steroids may enhance production of bioartificial tendons and rotator cuff tendon healing in vitro. More research is necessary before such clinical use is recommended.
Long-Term Functional and Anatomical Follow-Up of Early Detected Spondylolysis in Young Athletes
Authors: Miller Stephen F. , Congeni Joseph , Swanson Kenneth
Published: April 2004

Background

Spondylolysis defects detected by nuclear scintigraphy but not by plain radiographs represent early lesions. Functional outcome and eventual bony union of these defects are unknown.

Hypothesis

Defects with greater degree of healing shortly after treatment will proceed to full bony union and better long-term functional outcome.

Study Design

Longitudinal cohort study.

Methods

Forty young athletes with early detected spondylolysis (radiograph negative, nuclear scintigraphy positive) were divided into 3 stages of healing by computed tomography scan. Functional outcome was assessed 7 to 11 years later using the low back outcome score and other factors. Degree of bony healing was assessed in volunteers.

Results

Thirty-two of 40 subjects (80%) completed the survey. Twenty-nine of 32 (91%) had good or excellent low back outcome scores. None required spinal fusion, but 1 required partial diskectomy. Functional outcome did not differ based on initial computed tomography results. Radiographic follow-up was obtained in 11 volunteers. None of the 7 bilateral defects healed, and 3 of these progressed to grade 1 spondylolisthesis. All 4 unilateral defects healed fully with bone.

Conclusions

Most young athletes conservatively treated for early spondylolysis maintain good functional outcome up to 11 years later. Unilateral defects can undergo full bony healing but may take longer than 12 weeks. Bilateral defects may undergo further degeneration and slip with time.
Characterization of plasminogen as an adhesive ligand for integrins αMβ2 (Mac-1) and α5β1 (VLA-5)
Authors: Lishko Valeryi K. , Novokhatny Valery V. , Yakubenko Valentin P. , Skomorovska-Prokvolit Helen V. , Ugarova Tatiana P.
Published: April 2004

Plasminogen (Pg) has been implicated in many biologic processes involving extracellular proteolysis. We investigated whether Pg, by virtue of its capacity to be deposited within the extracellular matrix, can serve as a ligand for cell surface integrins. We report here that Pg supports cell adhesion by engaging integrins αMβ2 and α5β1. The immobilized Glu-Pg, but not its derivatives with the N-terminal peptide lacking, plasmin and Lys-Pg, supported efficient adhesion that was abolished by anti-αMβ2 and anti-α5β1 integrin-specific monoclonal antibodies (mAbs). In addition, lysine binding sites of Glu-Pg contributed to cell adhesion inasmuch as tranexamic acid and ϵ-aminocaproic acid inhibited cell adhesion. The involvement of αMβ2 and α5β1 in adhesion to Glu-Pg was demonstrable with blood neutrophils, U937 monocytoid cells, and genetically engineered αMβ2-transfected human embryonic kidney (HEK) 293 cells. In αMβ2, the αMI-domain is the binding site for Glu-Pg because the “I-less” form of αMβ2 did not support cell adhesion and the recombinant αMI-domain bound Glu-Pg directly. In comparison with cell adhesion, the binding of soluble Glu-Pg to cells and the concomitant generation of plasmin activity was inhibited by anti-α5β1 but not by anti-αMβ2. These findings identify Glu-Pg as an adhesive ligand for integrins αMβ2 and α5β1 and suggest that α5β1 may participate in the binding of soluble Glu-Pg and assist in its activation.
Large-scale in vitro expansion of polyclonal human CD4+CD25high regulatory T cells
Authors: Hoffmann Petra , Eder Ruediger , Kunz-Schughart Leoni A. , Andreesen Reinhard , Edinger Matthias
Published: April 2004

CD4+CD25+ regulatory T (Treg) cells are pivotal for the maintenance of self-tolerance, and their adoptive transfer gives protection from autoimmune diseases and pathogenic alloresponses after solid organ or bone marrow transplantation in murine model systems. In vitro, human CD4+CD25+ Treg cells display phenotypic and functional characteristics similar to those of murine CD4+CD25+ Treg cells: namely, hyporesponsiveness to T-cell receptor (TCR) stimulation and suppression of CD25- T cells. Thus far, the detailed characterization and potential clinical application of human CD4+CD25+ Treg cells have been hampered by their paucity in peripheral blood and the lack of appropriate expansion protocols. Here we describe the up to 40 000-fold expansion of highly purified human CD4+CD25high T cells in vitro through the use of artificial antigen-presenting cells for repeated stimulation via CD3 and CD28 in the presence of high-dose interleukin 2 (IL-2). Expanded CD4+CD25high T cells were polyclonal, maintained their phenotype, exceeded the suppressive activity of freshly isolated CD4+CD25high T cells, and maintained expression of the lymph node homing receptors L-selectin (CD62L) and CCR7. The ability to rapidly expand human CD4+CD25high Treg cells on a large scale will not only facilitate their further exploration but also accelerate their potential clinical application in T cell–mediated diseases and transplantation medicine.
A molecular basis for nonsecretory myeloma
Authors: Coriu Daniel , Weaver Kristal , Schell Maria , Eulitz Manfred , Murphy Charles L. , Weiss Deborah T. , Solomon Alan
Published: April 2004

The biosynthesis of aberrant immunoglobulin polypeptides by monoclonal plasma cells has been implicated in the pathogenesis of nonsecretory myeloma. Our studies of a patient with this disorder indeed have demonstrated the presence of abnormal κ light chains that resulted from a frameshift mutation in nucleotides encoding the constant region of the molecule. As a consequence of a 2-base deletion in codon 187 and loss of the normal stop codon, this portion of the κ chain was composed of 128 amino acids (rather than the expected 106), with a completely anomalous sequence after position 187 that included absence of the cysteines required for intrachain and interchain disulfide bonds. The unusual primary structure of this component was confirmed by mass spectrometric and amino acid sequence analyses of cytoplasmic protein extracts. Our studies provide the first evidence that human nonsecretory myeloma may result from an alteration in the light-chain constant region.
Blood concentrations of alemtuzumab and antiglobulin responses in patients with chronic lymphocytic leukemia following intravenous or subcutaneous routes of administration
Authors: Hale Geoff , Rebello Peppy , Brettman Lee R. , Fegan Chris , Kennedy Ben , Kimby Eva , Leach Mike , Lundin Jeanette , Mellstedt Håkan , Moreton Paul , Rawstron Andy C. , Waldmann Herman , Osterborg Anders , Hillmen Peter
Published: April 2004

Alemtuzumab is a humanized anti-CD52 antibody licensed for refractory B-cell chronic lymphocytic leukemia (B-CLL), when given intravenously at 30 mg thrice weekly. However, the intravenous route is associated with infusion-related reactions and is inconvenient. We measured blood concentrations in 30 relapsed patients treated with intravenous alemtuzumab and in 20 patients from a previously untreated group who received similar doses subcutaneously. Highest trough samples in the intravenous group were less than 0.5 μg/mL to 18.3 μg/mL (mean 5.4 μg/mL). The cumulative dose required to reach 1.0 μg/mL was 13 mg to 316 mg (mean 90 mg). Higher blood concentrations correlated with the achievement of better clinical responses and minimal residual disease. The highest measured concentrations in the subcutaneous group were similar (0.6 μg/mL to 24.8 μg/mL, mean 5.4 μg/mL). However, the cumulative dose to reach 1.0 μg/mL was higher: 146 mg to 1106 mg (mean 551 mg). No antiglobulin responses were detected in 30 patients given intravenous alemtuzumab whereas 2 of 32 patients given subcutaneous alemtuzumab made substantial anti-idiotype responses. Thus, subcutaneous alemtuzumab achieved concentrations similar to those for intravenous alemtuzumab, although with slightly higher cumulative doses. Subcutaneous alemtuzumab is more convenient and better tolerated but may be associated with some patients forming anti–alemtuzumab antibodies, particularly those patients who were previously untreated.
Extended Lymph Node Dissection for Gastric Cancer: Who May Benefit? Final Results of the Randomized Dutch Gastric Cancer Group Trial
Authors: Hartgrink H.H. , van de Velde C.J.H. , Putter H. , Bonenkamp J.J. , Klein Kranenbarg E. , Songun I. , Welvaart K. , van Krieken J.H.J.M. , Meijer S. , Plukker J.T.M. , van Elk P.J. , Obertop H. , Gouma D.J. , van Lanschot J.J.B. , Taat C.W. , de Graaf P.W. , von Meyenfeldt M.F. , Tilanus H. , Sasako M.
Published: April 2004

Purpose

The extent of lymph node dissection appropriate for gastric cancer is still under debate. We have conducted a randomized trial to compare the results of a limited (D1) and extended (D2) lymph node dissection in terms of morbidity, mortality, long-term survival and cumulative risk of relapse. We have reviewed the results of our trial after follow-up of more than 10 years.

Patients and Methods

Between August 1989 and June 1993, 1,078 patients with gastric adenocarcinoma were randomly assigned to undergo a D1 or D2 lymph node dissection. Data were collected prospectively, and patients were followed for more than 10 years.

Results

A total of 711 patients (380 in the D1 group and 331 in the D2 group) were treated with curative intent. Morbidity (25% v 43%; P < .001) and mortality (4% v 10%; P = .004) were significantly higher in the D2 dissection group. After 11 years there is no overall difference in survival (30% v 35%; P = .53). Of all subgroups analyzed, only patients with N2 disease may benefit of a D2 dissection. The relative risk ratio for morbidity and mortality is significantly higher than one for D2 dissections, splenectomy, pancreatectomy, and age older than 70 years.

Conclusion

Overall, extended lymph node dissection as defined in this study generated no long-term survival benefit. The associated higher postoperative mortality offsets its long-term effect in survival. For patients with N2 disease an extended lymph node dissection may offer cure, but it remains difficult to identify patients who have N2 disease. Morbidity and mortality are greatly influenced by the extent of lymph node dissection, pancreatectomy, splenectomy and age. Extended lymph node dissections may be of benefit if morbidity and mortality can be avoided.
Large-scale preparation and purification of polyacrylamide-free RNA oligonucleotides
Authors: LUKAVSKY PETER J. , PUGLISI JOSEPH D.
Published: April 2004

We present a fast and simple protocol for large-scale preparation and purification of RNA oligonucleotides. RNA oligonucleotides are prepared by in vitro transcription with T7 RNA polymerase from linearized plasmid DNA templates constructed by PCR. In place of denaturing polyacrylamide gel electrophoresis (PAGE), size-exclusion chromatography is employed to purify the RNA oligonucleotide from the transcription mixture yielding >99% pure RNA product. In contrast to PAGE-based purification, the gel filtration method does not require denaturation of the RNA oligonucleotide, which is desirable for larger RNAs, and the product is free of low-molecular-weight acrylamide contaminants, which greatly benefits NMR, crystallographic, and other biophysical studies of large RNAs and RNA–protein complexes.
New-Product Strategy and Industry Clockspeed
Authors: Souza Gilvan C. , Bayus Barry L. , Wagner Harvey M.
Published: April 2004

We study how industry clockspeed, internal firm factors, such as product development, production, and inventory costs, and competitive factors determine a firm's optimal new-product introduction timing and product-quality decisions. We explicitly model market demand uncertainty, a firm's internal cost structure, and competition, using an infinite-horizon Markov decision process. Based on a large-scale numerical analysis, we find that more frequent new-product introductions are optimal under faster clockspeed conditions. In addition, we find that a firm's optimal product-quality decision is governed by a firm's relative costs of introducing new products with incremental versus more substantial improvements. We show that a time-pacing product introduction strategy results in a production policy with a simple base-stock form and performs well relative to the optimal policy. Our results thus provide analytical support for the managerial belief that industry clockspeed and time to market are closely related.
Retailer- vs. Vendor-Managed Inventory and Brand Competition
Authors: Mishra Birendra K. , Raghunathan Srinivasan
Published: April 2004

Vendor-managed inventory (VMI) is emerging as a significant development in the recent trend towards collaboration and information sharing in supply chain management. Transfer of inventory monitoring and other overhead costs to manufacturers and continuous replenishment of retailer inventory are commonly cited as potential benefits that VMI offers to retailers. We provide a new explanation in this paper for why retailers might be interested in VMI. We show that VMI intensifies the competition between manufacturers of competing brands and that the increased competition benefits a retailer that stocks these brands. Competition arises because of brand substitution; that is, some consumers may switch to another brand if their “preferred” brand is out of stock. The manufacturer whose brand is out of stock thus risks losing sales from those consumers who buy the competing brand. Consequently, each manufacturer has an incentive to keep a higher stock of its own brand, not only to satisfy the demand from its customers, but also the spillover demand that arises if a competing brand goes out of stock. When the retailer makes the stocking-level decisions, the competition is mitigated by the pooling of demands at the retailer. VMI restores the competition between the manufacturers and benefits the retailer.
Picturing Efficiency: Precisionism, Scientific Management, and the Effacement of Labor
Authors: CORWIN SHARON
Published: April 2004

ABSTRACT In the early decades of the twentieth century, the pursuit of efficiency came to dominate instances of industrial and artistic production: the engineering consultants Frank and Lillian Gilbreth attempted to visualize a language of minimal waste, while Precisionist art achieved its own aesthetic of efficiency. This essay examines the Precisionist project alongside the discourses of the rationalized factory and suggests a relationship between the formal economy of Precisionism and the rhetoric of scientific management. For Precisionist art and the Gilbreths' time-motion studies, the representation of efficiency ultimately entailed the elision of artist and worker as producers of labor.