bluuebunny/crossref_metadata_2025 huggingface dataset:
Knowledge and attitudes toward end-of-life care in veterans with symptomatic metastatic cancer
Authors: HWANG SHIRLEY S. , CHANG VICTOR T. , COGSWELL JANET , SRINIVAS SHANTHI , KASIMIS BASIL
Published: April 2004

Objectives:The purposes of this study were to study symptomatic metastatic cancer patients' knowledge and attitudes toward end-of-life (EOL) care and to examine how patient-perceived health status affects attitudes toward EOL care and survival.

Methods:From 1999 to 2002, 254 symptomatic metastatic cancer patients at the VA New Jersey Health Care System completed the Vermont Voices on Care of the Dying Questionnaire. Survival status and location of death were obtained. Descriptive statistics and the chi square method were used to assess the differences between African Americans (N= 109) and Caucasians (N= 135), and between different patient-perceived health status groups. A log-rank test was performed to assess for differences in median survival length between different patient-perceived health-status groups.

Results:Veterans' responses to the Vermont questionnaire showed knowledge deficits regarding EOL care. There was wide variation in self-rankings of health status: 45.6% of patients rated their illness as serious and life threatening, 18.9% considered their health problem significant but not life threatening, 2.8% thought they were in good health, and one-third of patients were unsure about their health status. Most patients (86.2%) preferred physician frankness when communicating bad news and 61.8% preferred family involvement in EOL discussions. African American patients were less likely to have completed advance directives (p< 0.0001), to have knowledge about hospice programs (p< 0.00001), and to feel capable of assessing their health situation (p= 0.04). Patient-rated health status affected completion rates of advance directives and survival.

Significance of the research:These findings demonstrate knowledge deficits and racial differences in attitudes and values toward EOL care in veterans with cancer. The Vermont questionnaire enables patients to state their EOL preferences but may not be detailed enough for clinical applications. Patient-rated health status may be an important explanatory variable for EOL preferences and length of survival.
Tachykinin NK2 receptor antagonists for the treatment of irritable bowel syndrome
Authors: Lecci Alessandro , Capriati Angela , Maggi Carlo Alberto
Published: April 2004

Tachykinin NK2 receptors are expressed in the gastrointestinal tract of both laboratory animals and humans. Experimental data indicate a role for these receptors in the regulation of intestinal motor functions (both excitatory and inhibitory), secretions, inflammation and visceral sensitivity. In particular, NK2 receptor stimulation inhibits intestinal motility by activating sympathetic extrinsic pathways or NANC intramural inhibitory components, whereas a modulatory effect on cholinergic nerves or a direct effect on smooth muscle account for the NK2 receptor‐mediated increase in intestinal motility. Accordingly, selective NK2 receptor antagonists can reactivate inhibited motility or decrease inflammation‐ or stress‐associated hypermotility. Intraluminal secretion of water is increased by NK2 receptor agonists via a direct effect on epithelial cells, and this mechanism is active in models of diarrhoea since selective antagonists reverse the increase in faecal water content in these models. Hyperalgesia in response to intraluminal volume signals is possibly mediated through the stimulation of NK2 receptors located on peripheral branches of primary afferent neurones. NK2 receptor antagonists reduce the hyper‐responsiveness that occurs following intestinal inflammation or application of stressful stimuli to animals. Likewise, NK2 receptor antagonists reduce intestinal tissue damage induced by chemical irritation of the intestinal wall or lumen. In healthy volunteers, the selective NK2 antagonist nepadutant reduced the motility‐stimulating effects and irritable bowel syndrome‐like symptoms triggered by intravenous infusion of neurokinin A, and displayed other characteristics that could support its use in patients. It is concluded that blockade of peripheral tachykinin NK2 receptors should be considered as a viable mechanism for decreasing the painful symptoms and altered bowel habits of irritable bowel syndrome patients.

British Journal of Pharmacology (2004) 141, 1249–1263. doi:10.1038/sj.bjp.0705751
Role of serotonin in the pathophysiology of the irritable bowel syndrome
Authors: Crowell Michael D
Published: April 2004

The irritable bowel syndrome (IBS) is a complex disorder that is associated with altered gastrointestinal motility, secretion, and sensation. Serotonin (5‐HT) is an important neurotransmitter and paracrine signalling molecule in the gastrointestinal tract. 5‐HT release from enterochromaffin (EC) cells initiates peristaltic, secretory, vasodilatory, vagal and nociceptive reflexes. The enteric nervous system (ENS) comprises a semiautonomous effector system that is connected to the central autonomic network. Parasympathetic and sympathetic nerves modulate the ENS via afferent and efferent communications. Ongoing, bidirectional brain–gut interactions involving 5‐HT pathways occur that significantly influence the effector systems. Altered 5‐HT signalling may lead to both intestinal and extraintestinal symptoms in IBS. 5‐HT directly and indirectly affects intestinal motor and secretory function and abnormalities may lead to either constipation or diarrhea. 5‐HT modulates sensation and perception of visceral stimulation at peripheral and central sites. Therapeutic agents targeting altered 5‐HT signalling may provide new, effective treatments for patients with IBS.

British Journal of Pharmacology (2004) 141, 1285–1293. doi:10.1038/sj.bjp.0705762
On the use of low-frequency normal modes to enforce collective movements in refining macromolecular structural models
Authors: Delarue Marc , Dumas Philippe
Published: April 2004

As more and more structures of macromolecular complexes get solved in different conditions, it has become apparent that flexibility is an inherent part of their biological function. Normal mode analysis using simplified models of proteins such as the elastic network model has proved very effective in showing that many of the structural transitions derived from a survey of the Protein Data Bank can be explained by just a few of the lowest-frequency normal modes. In this work, normal modes are used to carry out medium- or low-resolution structural refinement, enforcing collective and large-amplitude movements that are beyond the reach of existing methods. Refinement is carried out in reciprocal space with respect to the normal mode amplitudes, by using standard conjugate-gradient minimization. Several tests on synthetic diffraction data whose mode concentration follows the one of real movements observed in the Protein Data Bank have shown that the radius of convergence is larger than the one of rigid-body refinement. Tests with experimental diffraction data for the same protein in different environments also led to refined structural models showing drastic reduction of the rms deviation with the target model. Because the structural transition is described by very few parameters, over-fitting of real experimental data is easily detected by using a cross-validation test. The method has also been applied to the refinement of atomic models into molecular envelopes and could readily be used to fit large macromolecular complex rearrangements into cryo-electron microscopy-reconstructed images as well as small-angle x-ray scattering-derived envelopes.
Rab13 regulates PKA signaling during tight junction assembly
Authors: Köhler Katja , Louvard Daniel , Zahraoui Ahmed
Published: April 2004

The GTPase Rab13 regulates the assembly of functional epithelial tight junctions (TJs) through a yet unknown mechanism. Here, we show that expression of the GTP-bound form of Rab13 inhibits PKA-dependent phosphorylation and TJ recruitment of the vasodilator-stimulated phosphoprotein, an actin remodelling protein. We demonstrate that Rab13GTP directly binds to PKA and inhibits its activity. Interestingly, activation of PKA abrogates the inhibitory effect of Rab13 on the recruitment of vasodilator-stimulated phosphoprotein, ZO-1, and claudin1 to cell–cell junctions. Rab13 is, therefore, the first GTPase that controls PKA activity and provides an unexpected link between PKA signaling and the dynamics of TJ assembly.
Alternative topogenesis of Mgm1 and mitochondrial morphology depend on ATP and a functional import motor
Authors: Herlan Mark , Bornhövd Carsten , Hell Kai , Neupert Walter , Reichert Andreas S.
Published: April 2004

Mitochondrial morphology and inheritance of mitochondrial DNA in yeast depend on the dynamin-like GTPase Mgm1. It is present in two isoforms in the intermembrane space of mitochondria both of which are required for Mgm1 function. Limited proteolysis of the large isoform by the mitochondrial rhomboid protease Pcp1/Rbd1 generates the short isoform of Mgm1 but how this is regulated is unclear. We show that near its NH2 terminus Mgm1 contains two conserved hydrophobic segments of which the more COOH-terminal one is cleaved by Pcp1. Changing the hydrophobicity of the NH2-terminal segment modulated the ratio of the isoforms and led to fragmentation of mitochondria. Formation of the short isoform of Mgm1 and mitochondrial morphology further depend on a functional protein import motor and on the ATP level in the matrix. Our data show that a novel pathway, to which we refer as alternative topogenesis, represents a key regulatory mechanism ensuring the balanced formation of both Mgm1 isoforms. Through this process the mitochondrial ATP level might control mitochondrial morphology.
CIN85 Associates with Multiple Effectors Controlling Intracellular Trafficking of Epidermal Growth Factor Receptors
Authors: Kowanetz Katarzyna , Husnjak Koraljka , Höller Daniela , Kowanetz Marcin , Soubeyran Philippe , Hirsch Dianne , Schmidt Mirko H.H , Pavelic Kresimir , De Camilli Pietro , Randazzo Paul A. , Dikic Ivan
Published: April 2004

CIN85 is a multidomain adaptor protein involved in Cbl-mediated down-regulation of epidermal growth factor (EGF) receptors. CIN85 src homology 3 domains specifically bind to a proline-arginine (PxxxPR) motif in Cbl, and this association seems to be important for EGF receptor endocytosis. Here, we report identification of novel CIN85 effectors, all containing one or more PxxxPR motifs, that are indispensable for their mutual interactions. These effectors include phosphatidyl-inositol phosphatases SHIP-1 and synaptojanin 2B1, Arf GTPase-activating proteins ASAP1 and ARAP3, adaptor proteins Hip1R and STAP1, and a Rho exchange factor, p115Rho GEF. Acting as a molecular scaffold, CIN85 clusters its effectors and recruits them to high-molecular-weight complexes in cytosolic extracts of cells. Further characterization of CIN85 binding to ASAP1 revealed that formation of the complex is independent on cell stimulation. Overexpression of ASAP1 increased EGF receptor recycling, whereas ASAP1 containing mutated PxxxPR motif failed to promote this event. We propose that CIN85 functions as a scaffold molecule that binds to numerous endocytic accessory proteins, thus controlling distinct steps in trafficking of EGF receptors along the endocytic and recycling pathways.
Members of the Toc159 Import Receptor Family Represent Distinct Pathways for Protein Targeting to Plastids
Authors: Ivanova Yordanka , Smith Matthew D. , Chen Kunhua , Schnell Danny J.
Published: April 2004

Plastids represent a diverse group of organelles that perform essential metabolic and signaling functions within all plant cells. The differentiation of specific plastid types relies on the import of selective sets of proteins from among the ∼2500 nucleus-encoded plastid proteins. The Toc159 family of GTPases mediates the initial targeting of proteins to plastids. In Arabidopsis thaliana, the Toc159 family consists of four genes: atTOC159, atTOC132, atTOC120, and atTOC90. In vivo analysis of atToc159 function indicates that it is required specifically for the import of proteins necessary for chloroplast biogenesis. In this report, we demonstrate that atToc120 and atToc132 represent a structurally and functionally unique subclass of protein import receptors. Unlike atToc159, mutants lacking both atToc120 and atToc132 are inviable. Furthermore, atToc120 and atToc132 exhibit preprotein binding properties that are distinct from atToc159. These data indicate that the different members of the Toc159 family represent distinct pathways for protein targeting to plastids and are consistent with the hypothesis that separate pathways have evolved to ensure balanced import of essential proteins during plastid development.
Denaturation of replication protein A reveals an alternative conformation with intact domain structure and oligonucleotide binding activity
Authors: Nuss Jonathan E. , Alter Gerald M.
Published: April 2004

Replication protein A (RPA) is a heterotrimeric, multidomain, single‐stranded DNA‐binding protein. Using spectroscopic methods and methylene carbene‐based chemical modification methods, we have identified conformational intermediates in the denaturation pathway of RPA. Intrinsic protein fluorescence studies reveal unfolding profiles composed of multiple transitions, with midpoints at 1.5, 2.7, 4.2, and 5.3 M urea. CD profiles of RPA unfolding are characterized by a single transition. RPA is stabilized with respect to the CD‐monitored transition when bound to a dA15 oligonucleotide. However, oligonucleotide binding appears to exert little, if any, effect on the first fluorescence transition. Methylene carbene chemical modification, coupled with MALDI‐TOF mass spectrometry analysis, was also used to monitor unfolding of several specific RPA folds of the protein. The unfolding profiles of the individual structures are characterized by single transitions similar to the CD‐monitored transition. Each fold, however, unravels with different individual characteristics, suggesting significant autonomy. Based on results from chemical modification and spectroscopic analyses, we conclude the initial transition observed in fluorescence experiments represents a change in the juxtaposition of binding folds with little unraveling of the domain structures. The second transition represents the unfolding of the majority of fold structure, and the third transition observed by fluorescence correlates with the dissociation of the 70‐ and 32‐kD subunits.
Variations in high‐density lipoprotein cholesterol in relation to physical activity and Taq 1B polymorphism of the cholesteryl ester transfer protein gene
Authors: Mukherjee M , Shetty KR
Published: April 2004

The aim of the study was to determine any association of physical activity and Taq 1B polymorphism in the cholesteryl ester transfer protein gene on high‐density lipoprotein (HDL) cholesterol. Five hundred and four subjects, 390 males and 114 females consisting of an equal number of age‐ and sex‐matched healthy controls and patients with coronary artery disease, were included. The mean age (±SD) of the patients and controls were 57.5 ± 10.6 years and 56.8 ± 11.0 years, respectively. All the patients underwent coronary angiography; 33, 58, 63, and 98 patients had normal coronaries, single‐, two‐, or triple‐vessel disease, respectively. A third of the patients had suffered from a myocardial infarction. The genotype distribution conforming to Hardy–Weinberg equilibrium was similar for cases and controls. The mean HDL cholesterol increased from B1B1 through B2B2 genotype in controls and sedentary male patients. Self‐reported leisure time physical activity, consisting mostly of an hour of morning walk daily, was associated with a rise in mean HDL cholesterol in male controls (33.6 ± 7.9 mg/dl to 36.2 ± 8.9 mg/dl, p = 0.037) and patients (32.4 ± 7.9 mg/dl to 35.7 ± 11.0 mg/dl; p = 0.018). The exercise‐associated rise in HDL cholesterol was most pronounced in controls (32.1 ± 9.1 mg/dl to 36.8 ± 9.3 mg/dl, p = 0.05) and male patients (30.5 ± 7.4 mg/dl to 37.2 ± 9.7 mg/dl, p = 0.007) with B1B1 rather than B1B2 or B2B2 genotype. The results suggest a possible gene‐environment interaction in the regulation of HDL cholesterol that needs to be confirmed in other populations and larger samples to rule out a chance occurrence.
Construction of Preferences by Constraint Satisfaction
Authors: Simon Dan , Krawczyk Daniel C. , Holyoak Keith J.
Published: April 2004

Participants were given a choice between two multi-attribute alternatives (job offers). Preferences for the attributes were measured before, during, and after the choices were made. We found that over the course of decision making, the preferences shifted to cohere with the choice: The attributes of the option that was eventually chosen came to be rated more favorably than they had been rated initially, while the attributes of the rejected option received lower preference ratings than before. These coherence shifts were triggered by a single attribute that decisively favored one option (Experiment 1), and occurred spontaneously in the absence of a decisive attribute (Experiment 2). The coherence shift preceded commitment to choice. These findings favor constraint-satisfaction models of decision making.
Do Dogs Resemble Their Owners?
Authors: Roy Michael M. , Nicholas J.S. Christenfeld
Published: April 2004

We examined whether the frequent casual reports of people resembling their pets are accurate by having observers attempt to match dogs with their owners. We further explored whether any ability of observers to make such matches is due to people selecting dogs who resemble them, in which case the resemblance should be greater for predictable purebreds than for nonpurebreds, or is due to convergence, in which case the resemblance should grow with duration of ownership. Forty-five dogs and their owners were photographed separately, and judges were shown one owner, that owner's dog, and one other dog, with the task of picking out the true match. The results were consistent with a selection account: Observers were able to match only purebred dogs with their owners, and there was no relation between the ability to pair a person with his or her pet and the time they had cohabited. The ability to match people and pets did not seem to rely on any simple trait matching (e.g., size or hairiness). The results suggest that when people pick a pet, they seek one that, at some level, resembles them, and when they get a purebred, they get what they want.
An efficient and highly selective deprotection of N‐Fmoc‐α‐amino acid and lipophilic N‐Fmoc‐dipeptide methyl esters with aluminium trichloride and N,N‐dimethylaniline
Authors: Di Gioia M.L. , Leggio A. , Le Pera A. , Siciliano C. , Liguori A. , Sindona G.
Published: April 2004

Abstract:  A novel procedure for the deprotection of the carboxyl group of amino acid methyl esters is presented. The process is carried out by the reagent system aluminium trichloride/N,N‐dimethylaniline that can successfully be applied to unblock the carboxyl moiety either of N‐Fmoc‐protected amino acid methyl esters and N‐Fmoc‐protected short dipeptide methyl esters. The chiralities of the optically pure amino acid or peptide precursors are maintained totally unchanged.
A protective effect of pyrrolidine dithiocarbamate in a rat model of liver cirrhosis
Authors: Bruck Rafael , Schey Ron , Aeed Hussein , Hochman Ayala , Genina Olga , Pines Mark
Published: April 2004

Abstract: Background: Nuclear factor kappa B (NF‐κB) activation, proinflammatory cytokines, and reactive oxygen species have been implicated as mediators of liver injury and fibrogenesis. We have shown recently that pyrrolidine dithiocarbamate (PDTC), an antioxidant and inhibitor of NF‐κB activation, was protective in a rat model of acute liver failure. The aim of the present study was to examine the efficacy of PDTC in a chronic rat model of thioacetamide (TAA)‐induced hepatic fibrosis.

Methods: Liver cirrhosis was induced by intraperitoneal injections of TAA (200 mg/kg) twice weekly for 12 weeks. Two groups of rats also received PDTC (either 20 or 60 mg/kg, i.p. for 12 weeks).

Results: TAA administration induced liver cirrhosis, which was inhibited by PDTC in a dose‐dependent manner. The histopathologic score of fibrosis, the spleen weight, and hepatic hydroxyproline were significantly lower in the rats treated with TAA+PDTC compared with TAA only (P<0.001). The hepatic levels of thiobarbituric acid reactive substances and protein carbonyls after 12 weeks of treatment were also lower in the rats treated with TAA+PDTC (P=0.02 and 0.01, respectively), indicating reduced oxidative stress. Immunohistochemical studies and in situ hybridization demonstrated inhibition of stellate cell (α smooth muscle actin positive) activation, tissue inhibitor of metalloproteinase‐2, and collagen α1(I) gene expression in the livers of the PDTC‐treated rats. As determined by Northern blot analysis, PDTC had no inhibitory effect on collagen α1(I) gene expression in the rat hepatic stellate cells‐T6 cells in vitro.

Conclusions: PDTC inhibits the development of liver cirrhosis in TAA‐treated rats. The mechanism of action is associated with decreased oxidative stress and hepatic necroinflammation.
Factors Related to Adult Patient Decision Making About Withholding or Withdrawing Nutrition and/or Hydration
Authors: Riley Joan M. , Mahoney Margaret Ann , Fry Sara T. , Feild Lucy
Published: April 2004

(1) End‐of‐life decisions that focus on withholding or withdrawing nutrition and/or hydration present difficult choices at particularly vulnerable times for patients and families. Clinical ethics studies published in the last twenty years provide insight about the decision making process that can be useful to all parties involved. The purpose of the systematic research review is to synthesize empirical data about patient/surrogate decision making related to withholding or withdrawing nutritional sustenance toward the end of life, and contextual factors that influence their decision making. Future topics for clinical ethics research and clinical practice implications are posed.
Smoking Cessation: The State of the Science
Authors: Andersen Susan , Keller Colleen , McGowan Nancy
Published: April 2004

(1) Smoking remains the most significant modifiable risk factor for the leading causes of death in the United States. The most frequently used theoretical model used to guide interventions directed toward smoking cessation has been the Transtheoretical Model (TTM) (Prochaska & DiClemente, 1983 [24]), although the effectiveness and efficacy of the model's use in guiding smoking cessation interventions has not been fully evaluated. A non‐statistical meta‐analytic approach was used to examine reports of the use of the TTM in smoking cessation interventions. Three elements were considered for inclusion in this integrated review: the clear specification of the use of a theoretical framework, a specified intervention directed towards changing smoking behavior, and a specified outcome of smoking behavior change. From 1,500 research articles, 16 reports fit these criteria. The assessment of the research reviewed indicates that the TTM has not been fully tested in smoking cessation interventions, nor have process mediators been used to determine the mechanism of smoking behavior change.
Evidence‐Based Best Practice: The Common Knowledge of Ethical Clinical Scholarship
Authors: Ledbetter Carol A.
Published: April 2004

…A university does not fully discharge its responsibilities to its students or to the community at large if it hands out knowledge (and the power which knowledge eventually yields) without posing questions about its responsible uses [2].
A Synthesis of What We Know About the Use of Physical Restraints and Seclusion with Patients in Psychiatric and Acute Care Settings
Authors: Bower Fay L. , McCullough Cynthia S. , Timmons Mae E.
Published: April 2004

Purpose

(1) This article synthesizes research findings on the use of restraint and seclusion with patients in psychiatric and acute care settings.

Conclusions

(2) The little that is known about restraint/seclusion use with these populations is inconsistent. Attitudes and perceptions of patients, family, and staff differ. However, all patients had very negative feelings about both, whether they were restrained/secluded or observed by others who were not restrained. The reasons for restraint/seclusion use vary with no accurate use rate for either. What precipitates the use of restraint/seclusion also varies but professionals claim they are necessary to prevent/treat violent or unruly behavior. Some believe seclusion/restraint is effective but there is no empirical evidence to support this belief. Many less restrictive alternatives have been tested with varying outcomes. Several educational programs to help staff learn about different ways to handle violent/confused patients have been successful.

Implications

(3) Until more is known about restraint/seclusion use from prospective controlled research, the goal to use least restrictive methods must be pursued. More staff educational programs must be offered and the evaluation of alternatives to restraint/seclusion pursued. When seclusion/restraint is necessary it should be used less arbitrarily, less frequently, and with less trauma.
Bilateral Head Flattening in Hospitalized Premature Infants
Authors: Hemingway Martha , Oliver Sandra
Published: April 2004

(1) Asymmetrical headshape in infants has increased markedly since the 1992 recommendation of the American Academy of Pediatrics to reduce the risk of sudden infant death syndrome by avoiding the prone sleeping position. Cranial molding correlated to restrictive intrauterine environment, birth trauma, torticollis, positioning, lack of full bone mineralization, neurological deficits, and any combination of the above. Nursing interventions to prevent cranial molding include alternative mattress surfaces and repositioning. The research strongly supports repositioning of infants to improve cranial vault symmetry.
Normal concentrations of essential and toxic elements in pregnant baboons and fetuses (Papio species)
Authors: Schlabritz‐Loutsevitch N.E. , Hubbard G.B. , Dammann M.J. , Jenkins S.L. , Frost P.A. , McDonald T.J. , Nathanielsz P.W.
Published: April 2004

Abstract:  Heavy metals are essential for the normal progression of maternal and fetal tissue growth and metabolism in pregnancy. Considerable data have been collected for concentrations of various elements in pregnant women, but no comprehensive evaluation of element concentrations in any non‐human primate model has been performed. Baboons were studied at the second half of pregnancy. Forty essential and toxic element concentrations were analyzed by absorption spectrophotometry in paired maternal and fetal blood samples; hair and nail samples in pregnant baboons; in placenta, amniotic fluid; and fetal femur, lymph nodes, and liver. Concentrations demonstrated an excellent correlation with concentrations reported in late human pregnancy. Twenty‐four elements were below detectable limits in various specimens. We conclude that the pregnant baboon offers unique opportunities to study both normal maternal, fetal, and placental physiology as well as the environmental toxicology of these elements. This information and the ability to use the pregnant baboon as a model is important because essential and toxic elements are key components of the diet as well as major products of manufacturing processes within our industrialized society.
Examination of the signal transduction pathways leading to activation of gelatinolytic activity by interleukin‐1α and Porphyromonas gingivalis in human osteosarcoma cells
Authors: Chang Yu‐Chao , Chu Shu‐Chen , Yang Shun‐Fa , Hsieh Yih‐Shou , Yang Li‐Chiu , Huang Fu‐Mei
Published: April 2004

Background:  Recently, evidence show that matrix metalloproteinases (MMP) play an important role in the pathogenesis of periodontal diseases. However, the mechanisms and signal transduction pathways involved in the production of MMPs in human osteosarcoma cells are not fully understood.

Objectives:  The purpose of this study was to investigate the gelatinolytic activity in human osteosarcoma cells stimulated with interleukin‐1α (IL‐1α) or Porphyromonas gingivalis in the absence or presence of SB203580 (p38 inhibitor), U0126 [mitogen‐activated protein kinase kinase (MEK) inhibitor], and LY294002 [phosphatidylinositaol 3‐kinase (PI3K) inhibitor].

Methods:  IL‐1α and the supernatants of P. gingivalis were used to evaluate gelatinolytic activity in human osteosarcoma cells using gelatin zymography. Furthermore, to search possible signal transduction pathways, SB203580, U0126, and LY294002 were added to test how they modulated the gelatinolytic activity.

Results:  Gelatin zymography demonstrated that the latent proforms of gelatinases MMP‐2 and MMP‐9 were released by human osteosarcoma cells. Secretion of MMP‐9 was time‐dependent by stimulating with IL‐1α or P. gingivalis. In addition, SB203580, U0126, and LY294002 significantly reduced the IL‐1α or P. gingivalis‐stimulated MMP‐9 production, respectively (p < 0.05). However, none of the kinase inhibitors affected the MMP‐2 level compared with the control during the 4‐day culture period (p > 0.05).

Conclusions:  Our findings demonstrated that IL‐1α and P. gingivalis enhance MMP‐9 production in human osteosarcoma cells, and the signal transduction pathways p38, MEK, and PI3K are involved in the inhibition of MMP‐9. SB203580, U0126, and LY294002 suppress MMP‐9 production and/or activity and may therefore be valuable therapeutics in MMP‐mediated periodontal destruction, and might be proved clinically useful agents, in combination with standard treatment modalities, in the treatment of periodontitis.
Integrating Professional Management into a Family Owned Business
Authors: Dyer W. Gibb
Published: April 2004

Under which conditions can professional knowledge and values be integrated successfully into the organization and management of a family firm?
Do Family-Owned Businesses Have a Strategic Advantage in International Joint Ventures?
Authors: Swinth Robert L. , Vinton Karen L.
Published: April 2004

In an increasingly turbulent global economic environment, companies are searching for winning ways of doing business internationally. One frequently discussed type of business is the joint venture. In this article, we argue that the likelihood of success for an international joint venture increases when both partners are family-owned businesses. These firms have shared values and goals that enable them to bridge cultural barriers more effectively than publicly held corporations.
The Impact of Family Ownership and Involvement on the Process of Management Succession
Authors: Welsch Johannes H. M.
Published: April 2004

The exploratory investigation on which this article builds seeks to link the field of family business with the field of human resource management. The research asks the question, Are family firms less rational, less bureaucratic, and more political in the management of their human resources? An in-depth analysis of the process of management succession in more than two hundred industrial firms shows the differences to be very subtle.
The Influence of Going Public on Investment Policy: An Empirical Study of French Family-Owned Businesses
Authors: Mahérault Loïc
Published: April 2004

This article focuses on the lack of capital available to small, private, family-owned businesses or businesses in which the manager and his or her family hold more than 51% of the total number of shares. It claims that being listed might be the best way to overcome this lack of capital.

The article starts from the established view that access to financial resources is not easy for small family-owned businesses (Coleman & Carsky, 1999; De Visscher, Aronoff, & Ward 1995; Harvey & Evans 1995). In questioning the generally admitted frontier between investment and financing policies (Modigliani & Miller, 1958, 1963), this empirical work is on the fringe of standard financial theory.

The study is carried out on two samples of small French family firms. The first is composed of 46 private companies, the second of 49 listed companies. All companies are SMEs (small and medium-size enterprises) and are nearly the same size. Empirical results are based on two cross-sectional analyses (1992, 1993). Linear regressions between investment and financial constraints are presented for the two samples separately. Results are very different, depending on whether the firm is listed. The description of private firms' investment is consistent with the pecking order theory (Myers & Majluf, 1984) and financial constraints clearly appear. The description of listed family firms is more classical: investment and financing policies seem to be independent. Finally, quoted family-owned businesses do not seem to suffer from lack of capital.
Family CEOs vs. Nonfamily CEOs in the Family-Controlled Firm: An Examination of the Level and Sensitivity of Pay to Performance
Authors: McConaughy Daniel L.
Published: April 2004

This study examines CEO compensation in 82 founding-family-controlled firms; 47 CEOs are members of the founding family and 35 are not. It tests the family incentive alignment hypothesis, which predicts that family CEOs have superior incentives for maximizing firm value and, therefore, need fewer compensation-based incentives. Univariate and multivariate analyses show that family CEOs' compensation levels are lower and that they receive less incentive-based pay—confirming the family incentive alignment hypothesis and suggesting the possible need for family firms to increase CEO compensation when they replace a founding family CEO with a nonfamily-member CEO.
Strategic Decision Making in Intergenerational Successions of Small- and Medium-Size Family-Owned Businesses
Authors: Bjuggren Per-Olof , Sund Lars-Göran
Published: April 2004

This paper deals with intergenerational successions of small and medium-size enterprises (SMEs). Entrepreneurs face an unavoidable succession dilemma: they must make either explicit or implicit strategic decisions about transitioning ownership of the family business. The main alternatives are to sell the company to someone outside the family or to make arrangements for an interfamily succession. In the latter case, there are many transition modes, e.g., through a gift of shares or a will. This paper uses decision trees to analyze intergenerational successions problems. One conclusion of the paper is that it is important for a society to provide a legal system that facilitates transitions of family companies within the family because the legal system will, among other positive factors connected with family businesses, preserve idiosyncratic knowledge of family character.
Venture Capitalists and Closely Held IPOs: Lessons for Family-Controlled Firms
Authors: Astrachan Joseph H. , McConaughy Daniel L.
Published: April 2004

This study examines how the presence of venture capitalists (VCs) in closely held IPOs relates to their performance. It also identifies other factors that are related to the performance of closely held IPOs. Closely held firms in this study had an average of 88% insider ownership before the IPO. In general, we find that closely held IPOs benefit from associations with VCs. This finding suggests that VCs' outside expertise and connections are valuable assets. Because it takes time for VCs to effect changes and because beneficial changes generally occur gradually, firms contemplating IPOs must plan well in advance to maximize firm value. Family-controlled firms contemplating growth or liquidity options through the IPO, VCs, or other outside capital should consider the findings of this study because it identifies factors that are associated with more successful IPO outcomes.
Your Old Men Shall Dream Dreams, Your Young Men Shall See Visions: Toward a Theory of Family Firm Innovation with Help from the Brubeck Family
Authors: Litz Reginald A. , Kleysen Robert F.
Published: April 2004

Despite significant advances, a conspicuous gap remains in family business research concerning the practice of innovation in family firms. After reviewing innovation and family business literature, we offer coarse- and fine-grained conceptualizations of intergenerational innovation in the family enterprise. Given the fine-grained distinctions inherent in our resulting definition of family firm innovation, we move on to an in-depth study of one family involved in the innovative activity of jazz improvisation. After offering our analysis of the core dynamics apparent in this family's interactions, we conclude this paper with a research agenda for future work on family firm innovation.
The Development of Family Companies: Management and Ownership Imperatives
Authors: Westhead Paul , Cowling Marc , Howorth Carole
Published: April 2004

This study explores management and ownership imperatives facing 427 independent unquoted (i.e., nonpublic) companies in the United Kingdom. To detect real rather than sample differences, the study used a matched pairs methodology. Chi-square and student's T-tests confirmed several similarities among the 73 family companies and the comparable 73 nonfamily companies. The tenure periods of CEOs in both groups of firms before being appointed to the CEO position were similar. CEOs in family firms had not remained in this position for significantly longer periods than CEOs in nonfamily firms, and the majority of directors in family and nonfamily firms did not hold outside directorships in other companies. Several significant differences were also detected. CEOs from the kinship group owning the family business had been in the CEO position for much longer than “outside” CEOs in family firms. Furthermore, the proportion of total shares owned by directors in family firms was significantly more than the proportion owned by directors in nonfamily firms. A significantly larger proportion of nonfamily rather than family firms had employed a nonexecutive director. In concluding, it is highlighted that a firm's identification of itself as a family firm is important in defining family firms and that firms that do not currently perceive themselves to be family firms may in the future.
The Succession Transition Process: A Longitudinal Perspective
Authors: Murray Barbara
Published: April 2004

Based on longitudinal case study analysis, this paper provides a metaview of the succession process as it unfolds during the generational transition periods in family enterprise systems. The results indicate that the transition period contains a sequence of phases, here called the transition cycle, during which time the system has an opportunity to do the work or tasks required when changing from one archetypal form of ownership and leadership to another. Each phase in the transition period has a distinct task that the system needs to address, and the whole process requires between three to eight years to complete. Three distinct types of transition “journeys” are identified, based on the extent to which the system was able to make progress with and achieve the tasks required within the transition cycle. One of these journey types was most likely to lead to continuity of the family enterprise, whereas the other two journey types were more likely to lead to disintegration of the system.
Succession and Nonsuccession Concerns of Family Firms and Agency Relationship with Nonfamily Managers
Authors: Chua Jess H. , Chrisman James J. , Sharma Pramodita
Published: April 2004

This article consists of two parts. The first part reports findings from a survey of the issues facing top executives in 272 Canadian family firms. Results show that succession is their No. 1 concern, thus supporting the predominant focus of family business researchers on succession issues. Results also show that concern about relationships with nonfamily managers is a close second in importance. The second part of the article uses Agency Theory to explain why relationships with nonfamily managers are so important. Empirical results show that both the extent and the criticality of a firm's dependence on nonfamily managers are statistically significant determinants of the importance. This study implies that relationships with nonfamily managers is a neglected research topic and points to a new direction for research in family business management.
Cl− uptake promoting depolarizing GABA actions in immature rat neocortical neurones is mediated by NKCC1
Authors: Yamada Junko , Okabe Akihito , Toyoda Hiroki , Kilb Werner , Luhmann Heiko J. , Fukuda Atsuo
Published: April 2004

GABA is the principal inhibitory neurotransmitter in the mature brain, but during early postnatal development the elevated [Cl−]i in immature neocortical neurones causes GABAA receptor activation to be depolarizing. The molecular mechanisms underlying this intracellular Cl− accumulation remain controversial. Therefore, the GABA reversal potential (EGABA) or [Cl−]i in early postnatal rat neocortical neurones was measured by the gramicidin‐perforated patch‐clamp method, and the relative expression levels of the cation−Cl− cotransporter mRNAs (in the same cells) were examined by semiquantitative single‐cell multiplex RT‐PCR to look for statistical correlations with [Cl−]i. The mRNA expression levels were positively (the Cl− accumulating Na+,K+−2Cl− cotransporter NKCC1) or negatively (the Cl− extruding K+−Cl− cotransporter KCC2) correlated with [Cl−]i. NKCC1 mRNA expression was high in early postnatal days, but decreased during postnatal development, whereas KCC2 mRNA expression displayed the opposite pattern. [Cl−]i and NKCC1 mRNA expression were each higher in cortical plate (CP) neurones than in the presumably older layer V/VI pyramidal neurones in a given slice. The pharmacological effects of bumetanide on EGABA were consistent with the different expression levels of NKCC1 mRNA. These data suggest that NKCC1 may play a pivotal role in the generation of GABA‐mediated depolarization in immature CP cells, while KCC2 promotes the later maturation of GABAergic inhibition in the rat neocortex.
The human tumour suppressor gene SLC5A8 expresses a Na+–monocarboxylate cotransporter
Authors: Coady Michael J. , Chang Min‐Hwang , Charron Francois M. , Plata Consuelo , Wallendorff Bernadette , Sah Jerome Frank , Markowitz Sanford D. , Romero Michael F. , Lapointe Jean‐Yves
Published: April 2004

The orphan cotransport protein expressed by the SLC5A8 gene has been shown to play a role in controlling the growth of colon cancers, and the silencing of this gene is a common and early event in human colon neoplasia. We expressed this protein in Xenopus laevis oocytes and have found that it transports small monocarboxylic acids. The electrogenic activity of the cotransporter, which we have named SMCT (sodium monocarboxylate transporter), was dependent on external Na+ and was compatible with a 3 : 1 stoichiometry between Na+ and monocarboxylates. A portion of the SMCT‐mediated current was also Cl− dependent, but Cl− was not cotransported. SMCT transports a variety of monocarboxylates (similar to unrelated monocarboxylate transport proteins) and most transported monocarboxylates demonstrated Km values near 100 μm, apart from acetate and d‐lactate, for which the protein showed less affinity. SMCT was strongly inhibited by 1 mm probenecid or ibuprofen. In the absence of external substrate, a Na+‐independent leak current was also observed to pass through SMCT. SMCT activity was strongly inhibited after prolonged exposure to high external concentrations of monocarboxylates. The transport of monocarboxylates in anionic form was confirmed by the observation of a concomitant alkalinization of the cytosol. SMCT, being expressed in colon and kidney, represents a novel means by which Na+, short‐chain fatty acids and other monocarboxylates are transported in these tissues. The significance of a Na+–monocarboxylate transporter to colon cancer presumably stems from the transport of butyrate, which is well known for having anti‐proliferative and apoptosis‐inducing activity in colon epithelial cells.
Hereditary Early-Onset Parkinson's Disease Caused by Mutations in
PINK1
Authors: Valente Enza Maria , Abou-Sleiman Patrick M. , Caputo Viviana , Muqit Miratul M. K. , Harvey Kirsten , Gispert Suzana , Ali Zeeshan , Del Turco Domenico , Bentivoglio Anna Rita , Healy Daniel G , Albanese Alberto , Nussbaum Robert , González-Maldonado Rafael , Deller Thomas , Salvi Sergio , Cortelli Pietro , Gilks William P. , Latchman David S. , Harvey Robert J. , Dallapiccola Bruno , Auburger Georg , Wood Nicholas W.
Published: April 2004

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in
PINK1
(PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.
FUZZY TRANSDUCTIVE SUPPORT VECTOR MACHINES FOR HYPERTEXT CLASSIFICATION
Authors: LIU HONG , HUANG SHANG-TENG
Published: April 2004

A method to assign fuzzy labels to unlabeled hypertext documents based on hyperlink structure information is first proposed. Then, the construction of the fuzzy transductive support vector machines is described. Also, an algorithm to train the fuzzy transductive support vector machines is presented. While in the transductive support vector machines all the test examples are treated equally, in the fuzzy transductive support vector machines, test examples are treated discriminatively according to their fuzzy labels, hence a more reliable decision function. Experimental results on the WebKB corpus show that, by fusing the plain text information and the hyperlink structure information, much better classification performance can be achieved.
Inorganic phosphate speeds loaded shortening in rat skinned cardiac myocytes
Authors: Hinken Aaron C. , McDonald Kerry S.
Published: April 2004

Force generation in striated muscle is coupled with inorganic phosphate (Pi) release from myosin, because force falls with increasing Pi concentration ([Pi]). However, it is unclear which steps in the cross-bridge cycle limit loaded shortening and power output. We examined the role of Pi in determining force, unloaded and loaded shortening, power output, and rate of force development in rat skinned cardiac myocytes to discern which step in the cross-bridge cycle limits loaded shortening. Myocytes ( n = 6) were attached between a force transducer and position motor, and contractile properties were measured over a range of loads during maximal Ca2+ activation. Addition of 5 mM Pi had no effect on maximal unloaded shortening velocity ( Vo) (control 1.83 ± 0.75, 5 mM added Pi 1.75 ± 0.58 muscle lengths/s; n = 6). Conversely, addition of 2.5, 5, and 10 mM Pi progressively decreased force but resulted in faster loaded shortening and greater power output (when normalized for the decrease in force) at all loads greater than ∼10% isometric force. Peak normalized power output increased 16% with 2.5 mM added Pi and further increased to a plateau of ∼35% with 5 and 10 mM added Pi. Interestingly, the rate constant of force redevelopment ( ktr) progressively increased from 0 to 10 mM added Pi, with ktr ∼360% greater at 10 mM than at 0 mM added Pi. Overall, these results suggest that the Pi release step in the cross-bridge cycle is rate limiting for determining shortening velocity and power output at intermediate and high relative loads in cardiac myocytes.