bluuebunny/crossref_metadata_2025 huggingface dataset:
Reading and Carrying
Authors: James Kim Turnbull , Arroba Tanya
Published: August 2005

This article outlines a developmental framework for introducing systems psychodynamic concepts in the context of leadership development. The model focuses on two key aspects of the leadership role needed in today’s organizations. These are the ability to Read what is less obvious and below the surface in organizational systems, and the ability to manage what is Carried by those in leadership roles. These abilities inform choice of behaviours and intervention by leaders in their organization systems. We argue for the need for appreciation of the systems psychodynamics within organizations and identify the difficulties in including these aspects in leadership development programmes. This article provides a case study of a leadership development programme where we use the ‘Reading and Carrying’ model as a bridge to understanding the emotion/ality that impinges on the leadership role. We discuss the difficulties that learning about emotion in and of the system can bring, by looking at the emotion raised in the learning experience.
On Bodies, Rhinestones, and Pleasures
Authors: Swan Elaine
Published: August 2005

In this article I review what kinds of emotions might be felt by women who are teaching managers. I counterpoise arguments that women’s bodies are over-determined as motherly or lacking in masculinity, and therefore lack embodied authority, so leading to feelings of inadequacy, fear, and anxiety with the view that there are spaces, modes and moments when women can exceed, or interrupt these interpolations to produce most pleasurable relations. As a way into the debates, I examine ideas drawn from women’s studies on the emotions associated with pleasure—pleasure specifically based on women’s embodied erotics. Arguing that pleasure is not necessarily political resistance, or indeed, unproblematic, I argue that these ideas on pleasure and erotics can be applied to our understanding of women teaching in the management classroom. I conclude that an acknowledgement of some of these pleasures may provide us with a better platform for conceptualizing teaching than simply notions of nurturance, learner-centredness or disembodied rationality.
The Organization in Balance
Authors: Korthagen Fred A. J.
Published: August 2005

Two complementary processes that are important in learning within organizations, namely reflection and intuition, are analysed. This includes the introduction of a phase model for reflection. Intuition is examined using concepts borrowed from transpersonal psychology. Within this context, the work of Maslow is discussed and related to Wilber’s ideas about the higher stages of human consciousness. Our society places considerable emphasis on rationality and efficiency, which means that reflection often receives more attention than intuition. Both are important, however, and the author argues that in the end it is a question of integrating the reflective and intuitive processes. A concrete method useful for supporting that process is described.
The Book of Kings in Recent Research (Part I)
Authors: Avioz Michael
Published: August 2005

This article examines recent trends in the study of the book of Kings in the 1990s and in the beginning years of the third millennium. It focuses on issues pertaining to: composition and redaction; structure; sources; purpose; and date of the book. After a survey of recent commentaries, the studies on the book of Kings are presented in various circles and contexts, such as the Deuteronomistic History, the relation of the book of Kings with other biblical sources, and several disciplines, including text criticism, history and historiography, archaeology, cult and religion, society, and literary criticism. The second part of this article, scheduled to appear in a subsequent issue of Currents, will deal with specific literary units of the book of Kings.
Biblical Interpretation among African-American New Testament Scholars
Authors: Enis Larry L.
Published: August 2005

Given the small, but growing, number of ethnic minorities in the field of biblical studies, the issue of African-American biblical hermeneutics has received only marginal attention in scholarly journals. In an effort to discern major themes and objectives among these interpreters, this article surveys published works by African Americans who have attained either a PhD or ThD in the New Testament. In this study, six areas of particular interest emerged: hermeneutics, the black presence in the New Testament, Paul, the Gospels, the epistle of James, and Revelation. Moreover, this investigation will demonstrate that the phenomenon of African-American New Testament hermeneutics is a methodologically diverse one.
Jesus and the Gentiles After Jeremias: Patterns and Prospects
Authors: Bird Michael F.
Published: August 2005

Joachim Jeremias’s study, Jesus’ Promise to the Nations has significantly impacted scholarly estimations of Jesus’ view of the Gentiles. This study briefly surveys earlier works, critiques Jeremias’s position, identifies other contributors who have either followed Jeremias or have tried to erect an opposing viewpoint. As such, the validity of Jeremias’s conclusion is challenged particularly against the backdrop of an emerging alternative whereby Jesus’ view of the Gentiles is constructed in the context of Jewish restoration eschatology.
Application of Community-Based Participatory Research Methods to a Study of Complementary Medicine Interventions at End of Life
Authors: Williams Anna-leila , Selwyn Peter A. , McCorkle Ruth , Molde Susan , Liberti Lauren , Katz David L.
Published: August 2005

Community-based participatory research (CBPR) principles can be successfully applied to the design and implementation of a complementary medicine study for adults with end-stage AIDS. The Yale Prevention Research Center partnered with Leeway, Inc., an AIDS-dedicated nursing facility, and other academic and clinical entities to conduct a randomized, controlled pilot trial of meditation and massage on quality of life at the end of life. Using CBPR principles, a methodology was developed that was scientifically rigorous, highly respectful, and acceptable to the 91% minority study population. Using continuous, open communication among all involved parties, challenges were satisfactorily addressed in a timely manner. Fifty-eight residents (97% of those eligible) with end-stage AIDS participated from November 2001 to September 2003. Subjects received 1-month interventions of meditation, massage, combined meditation and massage, or standard care. The study of quality-of-life in end-stage AIDS poses unique challenges well met by applying CBPR principles to an academic-community research partnership.
Korean Oriental Medicine in Stroke Care
Authors: Kim Yong-Suk , Wang Jun , Mann Douglas , Gaylord Susan , Lee Hye-Jung , Lee Michael
Published: August 2005

Korean Oriental medicine (KOM), known as Hanbang in Korea, is the primary health care system for more than 20% of the population in Korea. Often integrated with allopathic Western medicine, it has been used and studied extensively in Korea for a variety of conditions, including stroke and Parkinson’s disease. Although KOM shares its origins with traditional Chinese medicine, its unique cultural contributions include a number of innovations in diagnosis and technique, such as Sasang constitutional medicine, Saam acupuncture, herbal acupuncture, and Korean hand acupuncture. This article reviews the development and use of KOM in Korea, focusing on a major component, Sasang constitutional medicine. It describes a preliminary study of effectiveness of Sasang constitutional medicine in the treatment of stroke and discusses the directions of future research in KOM.
Collecting Information About a CAM Practitioner’s Practice: A Preliminary Report of a Self-Interview Methodology
Authors: Elder William G. , Purdy Hunter , Bentley Andrew
Published: August 2005

To prepare allopathic providers to advise patients about complementary and alternative medicine (CAM) therapies, the University of Kentucky CAM curriculum integration project has identified and trained CAM practitioners to coteach, precept, and demonstrate their respective practices. This project is interested in integrating CAM practitioners as teachers into this university and has formed a multidisciplinary committee for advice. The committee has recognized the importance of increased understanding of CAM practices to enhance communication within itself and to decide to which CAM practices students should receive exposure. This article reports our attempt to create a CAM practice description, based on questions general to CAM practice and specific to a particular approach. Because there is limited existing systematic research on CAM practice characteristics, these questions may interest researchers conducting qualitative studies, especially those seeking an example of questions to ask CAM practitioners. We also believe this practice description will be of general interest.
Severity of Depressive Symptoms and Quality of Life in Patients with Amyotrophic Lateral Sclerosis
Authors: Kübler Andrea , Winter Susanne , Ludolph Albert C. , Hautzinger Martin , Birbaumer Niels
Published: August 2005

Objectives. The authors aimed at investigating the occurrence of depression and the level of quality of life in patients with amyotrophic lateral sclerosis (ALS), an incurable neurodegenerative disease leading to progressive motor paralysis. They further wished to elucidate correlates of depression and quality of life, such as physical impairment, time since diagnosis, age, sex, and education. Additionally, the authors attempted to confirm previous studies that had shown quality of life to be underestimated by partners or caregivers. Methods. To assess severity of depressive symptoms, the authors used Beck’s Depression Inventory (BDI) and the ALS-Depression Inventory. To assess the patients’ quality of life, they used the Scales to Assess Quality of Life. The same questionnaire was presented to partners or caregivers to estimate the patients’ quality of life. Results. Severity of depressive symptoms was everything from not depressed to clinically relevant depressed. On average, quality of life was rated as satisfactory. Severity of depressive symptoms and quality of life showed a moderate positive relation to physical impairment and a weak negative relation to time since diagnosis. Partners or caregivers rated patients’ quality of life significantly lower than did the patients. Conclusions. Although depression occurs among ALS patients, it is not inevitable. Patients can remain free of depression and maintain a good quality of life. Depression should be treated, and patients have to be provided with unbiased information, including their medical and palliative care options.
The EXCITE Trial: Attributes of the Wolf Motor Function Test in Patients with Subacute Stroke
Authors: Wolf Steven L. , Thompson Paul A. , Morris David M. , Rose Dorian K. , Winstein Carolee J. , Taub Edward , Giuliani Carol , Pearson Sonya L.
Published: August 2005

The Wolf Motor Function Test (WMFT) has been used in rehabilitation studies of chronic stroke patients, but until now its psychometric properties have not been evaluated in patients with subacute stroke. Two hundred twenty-nine participants with subacute stroke (3-9 months postinjury) at 7 research sites met inclusion criteria for the EXCITE Trial and were randomized into immediate or delayed (by 1 year) constraint-induced movement therapy treatment. All evaluations were undertaken by assessors standardized in the administration of the WMFT and masked to treatment designation. Participants were also assessed using the Fugl Meyer Motor Assessment (FMA). Delayed group members had measurements repeated 2 weeks following baseline assessment to determine learning or exposure effects. The results demonstrate that the WMFT differentiated higher from lower functioning participants across sites; scores were uninfluenced by hand dominance or affected side. Women exhibited slower performance times than men. The Functional Ability scale (FAS) portion of the WMFT also revealed lower scores among lower functioning participants and women. Minimal changes were observed after repeating the WMFT among delayed group participants 2 weeks later. The FMA revealed similar results when the total group was divided into higher and lower functional levels at its midpoint score of 33. The WMFT discriminates higher from lower functioning participants tested across research sites. Comparable findings using the FMA support the criterion validity of the WMFT.
Underappreciated Statin-Induced Myopathic Weakness Causes Disability
Authors: Dobkin Bruce H.
Published: August 2005

Introduction. Myopathic syndromes induced by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) include muscle complaints, myalgia, myositis, and rhabdomyolysis. No prospective study of statins, however, included tests of strength, so the incidence of weakness, with or without muscle symptoms and elevated enzymes, is unknown, and perhaps overlooked. Methods. From a convenience sample of patients referred to an outpatient neurorehabilitation clinic over the course of 1 year, 8 patients with hemiparetic stroke and 10 patients with other presumed neurologic diseases presented with new difficulty walking by 3 to 12 months after starting one of 3 statins. They reported no myalgias, exercise-induced aches, or weakness. Examination revealed proximal paresis graded 4/5 on the unaffected side in the hemiparetic patients and symmetrical bilateral proximal limb and neck flexor weakness graded 4/5 in the others. They stood up with difficulty and walked with bilateral hip drop and imbalance on turns. Results. Laboratory tests did not reveal myositis or other causes for paresis. No improvement in strength or mobility was found 6 weeks after initiating resistance exercises. The statin agent was stopped. By 3 months off statin, all recovered 5/5 proximal strength. Walking improved, and they arose from a chair without pushing off with their arms. Discussion. Serial manual muscle testing after initiating a statin may detect a reversible cause of disability. A genetic predisposition to statin-induced myopathic proximal weakness with normal creatine kinase is consistent with a continuum of previously reported symptoms and signs but may be underappreciated.
New Therapeutic Approaches to Parkinson’s Disease Including Neural Transplants
Authors: Kuan W. -L. , Barker R. A.
Published: August 2005

Parkinson’s disease (PD) is a common neurodegenerative disorder of the brain and typically presents with a disorder of movement. The core pathological event underlying the condition is the loss of the dopaminergic nigrostriatal pathway with the formation of alpha-synuclein positive Lewy bodies. As a result, drugs that target the degenerating dopaminergic network within the brain work well at least in the early stages of the disease. Unfortunately, with time these therapies fail and produce their own unique side-effect profile, and this, coupled with the more diffuse pathological and clinical findings in advancing disease, has led to a search for more effective therapies. In this review, the authors will briefly discuss the emerging new drug therapies in PD before concentrating on a more detailed discussion on the state of cell therapies to cure PD.
Individual Factors in Constraint-Induced Movement Therapy after Stroke
Authors: Rijntjes Michel , Hobbeling Verena , Hamzei Farsin , Dohse Stefanie , Ketels Gesche , Liepert Joachim , Weiller Cornelius
Published: August 2005

Objectives. Constraint-induced movement therapy (CIMT) has been shown to be effective in chronic stroke patients. It is worthwhile to investigate the influence of individual factors for two reasons: to find out whether they influence outcome and to see whether they support the theory underlying CIMT. Methods. Agroupof26 patients were treated with CIMT and followed over 6 months. In total, 14 individual factors were identified. Patients were assessed with 6 tests, including 2 commonly used after stroke (Frenchay Arm Test, 9 Hole Peg Test). Results. There were individual differences, but as a group, patients improved after therapy. There were no individual factors that influenced improvement in more than one test. Conclusions. CIMT is an effective therapy in patients with moderate impairment after stroke, also in tests commonly used in stroke rehabilitation. Factors that could have expected to make a difference on the basis of the theory behind CIMT (e.g., time since stroke, previous therapy, sensory deficit) did not influence results. Patients with hemorrhagic lesions and those with a high level of performance (Motor Activity Log > 2.5) profit as well. Pairwise therapy is as effective as individual therapy.
Transcription factor GATA-1 potently represses the expression of the HIV-1 coreceptor CCR5 in human T cells and dendritic cells
Authors: Sundrud Mark S. , VanCompernolle Scott E. , Eger Karla A. , Bruno Tullia C. , Subramaniam Arun , Mummidi Srinivas , Ahuja Sunil K. , Unutmaz Derya
Published: August 2005

CC chemokine receptor 5 (CCR5) is the major HIV-1 coreceptor and its expression levels are a critical determinant of HIV-1 infection. However, the molecular mechanisms of CCR5 regulation in primary targets of HIV-1 remain unknown. Despite binding to conserved DNA elements, we show that the transcription factors GATA binding protein 1 (GATA-1) and GATA-3 differentially suppress the expression of CCR5 in stem-cell–derived dendritic cells and primary human T-cell subsets. In addition, GATA-1 expression was also more potent than GATA-3 in suppressing T helper 1 (Th1)–associated genes, interferon-γ (IFNγ), and CXC chemokine receptor-3 (CXCR3). GATA-1, but not GATA-3, potently suppressed CCR5 transcription, thereby rendering human T cells resistant to CCR5-tropic HIV-1 infection. However, GATA-1 could also serve as a surrogate for GATA-3 in its canonic role of programming Th2 gene expression. These findings provide insight into GATA-3–mediated gene regulation during T-cell differentiation. Importantly, decoding the mechanisms of GATA-1–mediated repression of CCR5 may offer an opportunity to develop novel approaches to inhibit CCR5 expression in T cells.
High-dose factor VIII inhibits factor VIII–specific memory B cells in hemophilia A with factor VIII inhibitors
Authors: Hausl Christina , Ahmad Rafi U. , Sasgary Maria , Doering Christopher B. , Lollar Pete , Richter Günter , Schwarz Hans Peter , Turecek Peter L. , Reipert Birgit M.
Published: August 2005

Hemophilia A in its severe form is a life-threatening hemorrhagic disease that is caused by mutations in the factor VIII (FVIII) gene (symbol F8). About 25% of patients who receive replacement therapy develop neutralizing antibodies that inhibit the function of substituted FVIII. Long-term application of high doses of FVIII has evolved as an effective therapy to eradicate the antibodies and to induce long-lasting immune tolerance. Little is known, however, about the immunologic mechanisms that cause the down-modulation of anti-FVIII antibodies by high doses of FVIII. We report that high doses of FVIII inhibit the restimulation of FVIII-specific memory B cells and their differentiation into antibody-secreting plasma cells in vitro and in vivo in a murine model of hemophilia A. The inhibition of memory B-cell responses is irreversible and not mediated by FVIII-specific T cells. Furthermore, it seems to involve the activation of caspases. We conclude that the inhibition of FVIII-specific memory B cells might be an early event in the down-modulation of anti-FVIII antibodies in patients with hemophilia A who receive high doses of FVIII.
Functional consequences of the human DMT1 (SLC11A2) mutation on protein expression and iron uptake
Authors: Priwitzerova Monika , Nie Guangjun , Sheftel Alex D. , Pospisilova Dagmar , Divoky Vladimir , Ponka Prem
Published: August 2005

We have previously described a case of severe hypochromic microcytic anemia caused by a homozygous mutation in the divalent metal transporter 1 (DMT1 1285G > C). This mutation encodes for an amino acid substitution (E399D) and causes preferential skipping of exon 12 during processing of the DMT1 mRNA. To examine the functional consequences of this mutation, full-length DMT1 transcript with the patient's point mutation or a DMT1 transcript with exon 12 deleted was expressed in Chinese hamster ovary (CHO) cells. Our results demonstrate that the E399D substitution has no effect on protein expression and function. In contrast, deletion of exon 12 led to a decreased expression of the protein and disruption of its subcellular localization and iron uptake activity. We hypothesize that the residual protein in hematopoietic cells represents the functional E399D DMT1 variant, but because of its quantitative reduction, the iron uptake activity of DMT1 in the patient's erythroid cells is severely suppressed.
Intrabodies targeting the Kaposi sarcoma–associated herpesvirus latency antigen inhibit viral persistence in lymphoma cells
Authors: Corte-Real Sofia , Collins Chris , da Silva Frederico Aires , Simas J. Pedro , Barbas Carlos F. , Chang Yuan , Moore Patrick , Goncalves Joao
Published: August 2005

Kaposi sarcoma–associated herpesvirus (KSHV) latency-associated nuclear antigen-1 (LANA1) is essential for the maintenance and segregation of viral episomes in KSHV latently infected B cells. We report development of intracellular, rabbit-derived antibodies generated by phage display technology, which bind to N-terminal LANA1 epitopes and neutralize the chromosome-binding activity of LANA1. Although these cloned single-chain variable fragments (scFvs) show relatively low binding affinities for the LANA1 viral antigen in in vitro assays, they nonetheless outcompete KSHV-seropositive human sera for LANA1 epitope binding. In heterologous cells, intracellular intrabody expression inhibits LANA1-dependent plasmid maintenance of both an artificial plasmid containing KSHV LANA1 binding sequences and a bacterial artificial chromosome containing the entire KSHV genome. In KSHV naturally infected primary effusion lymphoma cells, intracellular intrabody expression causes a reduction or loss of the typical LANA1 punctate, nuclear pattern. This morphologically apparent LANA1 dispersion correlates to loss of viral episome by molecular analysis. These data suggest a novel approach to antiherpes viral therapy and confirm LANA1 is critical target for neutralization of KSHV viral latency.
The macular mapping test: a reliability study
Authors: Bartlett Hannah , Davies Leon N , Eperjesi Frank
Published: August 2005

Background

Age-related macular degeneration (ARMD) is the leading cause of visual disability in people over 60 years of age in the developed world. The success of treatment deteriorates with increased latency of diagnosis. The purpose of this study was to determine the reliability of the macular mapping test (MMT), and to investigate its potential as a screening tool.

Methods

The study population comprised of 31 healthy eyes of 31 participants. To assess reliability, four macular mapping test (MMT) measurements were taken in two sessions separated by one hour by two practitioners, with reversal of order in the second session. MMT readings were also taken from 17 age-related maculopathy (ARM), and 12 AMD affected eyes.

Results

For the normal cohort, average MMT scores ranged from 85.5 to 100.0 MMT points. Scores ranged from 79.0 to 99.0 for the ARM group and from 9.0 to 92.0 for the AMD group. MMT scores were reliable to within ± 7.0 points. The difference between AMD affected eyes and controls (z = 3.761, p = < 0.001) was significant. The difference between ARM affected eyes and controls was not significant (z = -0.216, p = 0.829).

Conclusion

The reliability data shows that a change of 14 points or more is required to indicate a clinically significant change. This value is required for use of the MMT as an outcome measure in clinical trials. Although there was no difference between MMT scores from ARM affected eyes and controls, the MMT has the advantage over the Amsler grid in that it uses a letter target, has a peripheral fixation aid, and it provides a numerical score. This score could be beneficial in office and home monitoring of AMD progression, as well as an outcome measure in clinical research.
Controlled, double-blind, randomized clinical trial to evaluate the impact of fruit juice consumption on the evolution of infants with acute diarrhea
Authors: Valois Sandra , Costa-Ribeiro Hugo , Mattos Ângela , Ribeiro Tereza Cristina , Mendes Carlos Maurício , Lifshitz Fima
Published: August 2005

In order to assess the effects of juice feedings during acute diarrhea a double-blind, randomized study was performed in 90 children, mean age of 10 ± 4.28 months. Thirty patients with acute diarrhea were fed twice-daily 15 ml/kg of Apple Juice (AJ), 30 received White Grape Juice (WGJ), and 30 were given colored and flavored water (WA) as part of their age appropriate dietary intake. The duration and severity of diarrhea were the main endpoint variables of the study performed in a metabolic unit. The patients were similar among the 3 groups, had diarrhea for 50–64 hours prior to admission, and were dehydrated when admitted to the unit for study. Half of the patients in each group were well nourished and the others had mild to moderate degrees of malnutrition. Rotavirus infection was the agent causing the illness in 63% of the patients. The infants fed juice ingested 14–17% more calories than those given WA, (those receiving AJ and WGJ ingested 95 and 98 Calories/Kg/d respectively) whereas those receiving WA consumed 81 cal/kg/d). The increased energy intake was not at the expense of other foods or milk formula. The mean body weight gain was greater among patients receiving WGJ (+ 50.7 gm) as compared with the patients in the AJ group (+ 18.3 gm) or the patients fed WA (- 0.7 gm) (p = 0.08). The duration of the illness was longer in the infants fed juice as compared with those given WA (p = 0.006), the mean +/- SD duration in hours was 49.4 ± 32.6, 47.5 ± 38.9 and 26.5 ± 27.4 in patients fed AJ, WGJ and WA respectively. All patients improved while ingesting juice and none of them developed persistent diarrhea; most recovered within 50 hours of the beginning of treatment and less than one fourth had diarrhea longer than 96 hours in the unit. The fecal losses were also increased among the juice fed patients (p = 0.001); the mean ± SD fecal excretion in g/kg/h was 3.94 ± 2.35, 3.59 ± 2.35, and 2.19 ± 1.63 in AJ, WGJ and WA respectively. The stool output was highest during the first day of treatment among all the patients, though those fed AJ had the highest volume of fecal losses and those who received WA had the lowest stool excretion. After the first day of treatment the differences in fecal excretion were not significant. The ability to tolerate carbohydrates during the illness and immediately after recovery was similar among the 3 groups of patients. Intake of juices with different fructose/glucose ratios and osmolarities resulted in more fecal losses and more prolonged diarrhea as compared with water feedings, but the patients given juice ingested more calories and gained more weight, particularly among those being fed the juice with equimolar concentrations of fructose and glucose.
Reversal of High dietary fructose-induced PPARα suppression by oral administration of lipoxygenase/cyclooxygenase inhibitors
Authors: Kelley Glen L , Azhar Salman
Published: August 2005

High fructose feeding causes diet-induced alterations of lipid metabolism and decreased insulin sensitivity, hallmark of which is a rapid and profound hypertriglyceridemia. One of the mechanisms that contribute to serum hypertriglyceridemia in this model is suppression of hepatic PPARα. HMG-CoA inhibitors, which reduce serum triglycerides in these animals, also elevate/restore hepatic PPARα. Previously we demonstrated that two known lipoxygenase/cyclooxygenase inhibitors reversed diet-induced hypertriglyceridemia in this model and that reversal of certain inflammatory markers in the liver correlated with the metabolic benefit. In this paper we extended these studies by examining the impact of these compounds on expression of PPARα, both at the level of transcription and expression. Our data show that diet-induced suppression of hepaic PPARα is reversed upon treatment with lipoxygenase/cyclooxygenase compounds. We then tested one of these compounds, BW-755c, over a range of doses from 10 mg/kg to 100 mg/kg to establish a dose-response relationship with the reduction of serum hypertriglyceridemia in this model. These experiments support the concept of using anti-inflammatory medications as one method to correct metabolic dysfunction.
Differentiation Pathways in Human Embryonic Stem Cell‐Derived Cardiomyocytes
Authors: LEV SOPHIE , KEHAT IZHAK , GEPSTEIN LIOR
Published: August 2005

Abstract: Human embryonic stem (hES) cells are pluripotent cell lines derived from the inner cell mass of the blastocyst‐stage embryo. These unique cell lines can be propagated in the undifferentiated state in culture, while retaining the capacity to differentiate into derivatives of all three germ layers, including cardiomyocytes. The derivation of the hES cell lines presents a powerful tool to explore the early events of cardiac progenitor cell specification and differentiation, and it also provides a novel cell source for the emerging field of cardiovascular regenerative medicine. A spontaneous differentiation system of these stem cells to cardiomyocytes was established and the generated myocytes displayed molecular, structural, and functional properties of early‐stage heart cells. In order to follow the in vitro differentiation process, the temporal expression of signaling molecules and transcription factors governing early cardiac differentiation was examined throughout the process. A characteristic pattern was noted recapitulating the normal in vivo cardiac differentiation scheme observed in other model systems. This review discusses the known pathways involved in cardiac specification and the possible factors that may be used to enhance cardiac differentiation of hES cells, as well as the steps required to fully harness the enormous potential of these unique cells.
Calcium Signaling in Cardiac Ventricular Myocytes
Authors: BERS DONALD M. , GUO TAO
Published: August 2005

Abstract: Calcium (Ca) is a multifunctional regulator of diverse cellular functions. In cardiac muscle Ca is a direct central mediator of electrical activation, ion channel gating, and excitation‐contraction (E‐C) coupling that all occur on the millisecond time scale. The key amplification step in E‐C coupling is under tight control of very local [Ca]. Ca also directly activates signaling via kinases and phosphatases (e.g., Ca‐calmodulin‐dependent protein kinase [CaMKII] and calcineurin) that occur over a longer time scale (seconds to minutes), and the co‐localization of these Ca‐dependent modulators to their targets and to Ca is also critical in distinct signaling pathways. Finally, Ca‐dependent signaling is also involved in long‐term (minutes to hours/days) alterations in gene expression (or excitation‐transcription coupling). These pathways are involved in hypertrophy and heart failure, and they can alter the expression of some of the key Ca regulatory proteins involved in E‐C coupling and their regulation by kinases and phosphatases. There may again be physical microenvironments involved in this nuclear transcription, such that they sense a discrete Ca signal that is distinct from that involved in E‐C coupling. In this way cells can use Ca signaling in multiple ways that function in spatially and temporally distinct manners.
The Murine Cardiac 26S Proteasome: An Organelle Awaiting Exploration
Authors: GOMES ALDRIN V. , ZONG CHENGGONG , EDMONDSON RICKY D. , BERHANE BENIAM T. , WANG GUANG‐WU , LE STEVEN , YOUNG GLEN , ZHANG JUN , VONDRISKA THOMAS M. , WHITELEGGE JULIAN P. , JONES RICHARD C. , JOSHUA IRVING G. , THYPARAMBIL SHEENO , PANTALEON DAWN , QIAO JOE , LOO JOSEPH , PING PEIPEI
Published: August 2005

Abstract: Multiprotein complexes have been increasingly recognized as essential functional units for a variety of cellular processes, including the protein degradation system. Selective degradation of proteins in eukaryotes is primarily conducted by the ubiquitin proteasome system. The current knowledge base, pertaining to the proteasome complexes in mammalian cells, relies largely upon information gained in the yeast system, where the 26S proteasome is hypothesized to contain a 20S multiprotein core complex and one or two 19S regulatory complexes. To date, the molecular structure of the proteasome system, the proteomic composition of the entire 26S multiprotein complexes, and the specific designated function of individual components within this essential protein degradation system in the heart remain virtually unknown. A functional proteomic approach, employing multidimensional chromatography purification combined with liquid chromatography tandem mass spectrometry and protein chemistry, was utilized to explore the murine cardiac 26S proteasome system. This article presents an overview on the subject of protein degradation in mammalian cells. In addition, this review shares the limited information that has been garnered thus far pertaining to the molecular composition, function, and regulation of this important organelle in the cardiac cells.
Metabolic Energetics and Genetics in the Heart
Authors: TAEGTMEYER HEINRICH , WILSON CHRISTOPHER R. , RAZEGHI PETER , SHARMA SAUMYA
Published: August 2005

Abstract: From the first stages of differentiation in the embryo to the end of life, energy substrate metabolism and function are inextricably linked features of the heart. The principle of energy substrate metabolism is simple. For a given developmental stage and for a given environment, the heart oxidizes the most efficient fuel on the path to ATP. The “multitasking” of energy substrate metabolism in the heart entails more than the generation of reducing equivalents for oxidative phosphorylation of ADP in the respiratory chain. In the postnatal heart, substrate switching and metabolic flexibility are features of normal function. In the stressed heart, metabolic remodeling precedes, triggers, and sustains functional and structural remodeling. This manuscript reviews the pleiotropic actions of metabolism in energy transfer, signal transduction, cardiac growth, gene expression, and viability. Examples are presented to illustrate that metabolic signals of stressed and failing heart are the product of complex cellular processes. An early feature of the maladapted heart is a loss of metabolic flexibility. The example of lipotoxic heart failure illustrates the concept of sustained metabolic dysregulation as a cause of contractile dysfunction of the heart. Thus, a paradigm emerges in which metabolic signals not only regulate fluxes through enzyme catalyzed reactions in existing metabolic pathways, but also regulate transcriptional, translational, and post‐translational signaling in the heart. As new insights are gained into metabolic adaptation and maladaptation of the heart, metabolic modulation may become an effective strategy for the treatment of heart failure.
Structure‐Function Relation of the Myosin Motor in Striated Muscle
Authors: RECONDITI MASSIMO , LINARI MARCO , LUCII LEONARDO , STEWART ALEX , SUN YIN‐BIAO , NARAYANAN THEYENCHERI , IRVING TOM , PIAZZESI GABRIELLA , IRVING MALCOLM , LOMBARDI VINCENZO
Published: August 2005

Abstract: Force and shortening in striated muscle are driven by a structural working stroke in the globular portion of the myosin molecules—the myosin head—that cross‐links the myosin‐containing filaments and the actin‐containing filaments. We use time‐resolved X‐ray diffraction in single fibers from frog skeletal muscle to link the conformational changes in the myosin head determined at atomic resolution in crystallographic studies with the kinetic and mechanical features of the molecular motor in the preserved sarcomeric structure. Our approach exploits the improved brightness and collimation of the X‐ray beams of the third generation synchrotrons by using X‐ray interference between the two arrays of myosin heads in each bipolar myosin filament to measure with Å sensitivity the axial motions of myosin heads in situ during the synchronous execution of the working stroke elicited by rapid decreases in length or load imposed during an active isometric contraction. Changes in the intensity and interference‐fine structure of the axial X‐ray reflections following the mechanical perturbation allowed to establish the average conformation of the myosin heads during the active isometric contraction and the extent of tilt during the elastic response and during the subsequent working stroke. The myosin working stroke is 12 nm at low loads, which is consistent with crystallographic studies, while it is smaller and slower at higher loads. The load dependence of the size and speed of the myosin working stroke is the molecular determinant of the macroscopic performance and efficiency of muscle.
Ryanodine Receptor‐Targeted Anti‐Arrhythmic Therapy
Authors: WEHRENS XANDER H.T. , LEHNART STEPHAN E. , MARKS ANDREW R.
Published: August 2005

Abstract: Cardiac arrhythmia is an important cause of death in patients with heart failure (HF) and inherited arrhythmia syndromes, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). Alterations in intracellular calcium handling play a prominent role in the generation of arrhythmias in the failing heart. Diastolic calcium leak from the sarcoplasmic reticulum (SR) via cardiac ryanodine receptors (RyR2) may initiate delayed afterdepolarizations and triggered activity leading to arrhythmias. Similarly, SR Ca2+ leak through mutant RyR2 channels may cause triggered activity during exercise in patients with CPVT. Novel therapeutic approaches, based on recent advances in the understanding of the cellular mechanisms underlying arrhythmias in HF and CPVT, are currently being evaluated to specifically correct defective Ca2+ release in these lethal syndromes.
Calmodulin-dependent protein kinase II, and not protein kinase C, is sufficient for triggering cell-cycle resumption in mammalian eggs
Authors: Madgwick Suzanne , Levasseur Mark , Jones Keith T.
Published: August 2005

Mouse eggs arrest at metaphase II following ovulation and are only triggered to complete meiosis when fertilized. Sperm break the cell-cycle arrest by a long-lasting series of Ca2+ spikes that lead to an activation of the anaphase-promoting complex/cyclosome. The signal transduction pathway is not fully resolved but both protein kinase C (PKC) and calmodulin-dependent protein kinase II (CamKII) activities increase at fertilization and previous pharmacological studies have implicated both in cell-cycle resumption. We have used a combination of pharmacological inhibitors and constitutively active cRNA constructs of PKCα and CamKIIα microinjected into mouse eggs to show that it is CamKII and not PKC that is the sufficient trigger for cell-cycle resumption from metaphase II arrest.

Constitutively active PKC constructs had no effect on the resumption of meiosis but caused an immediate and persistent elevation in intracellular Ca2+ when store-operated Ca2+ entry was stimulated. With respect to resumption of meiosis, the effects of constitutively active CamKII on eggs were the same as sperm. Eggs underwent second polar body extrusion and pronucleus formation with normal timings; while both securin and cyclin B1 destruction, visualised by coupling to fluorescent protein tags, were complete by the time of polar body extrusion. Induction of a spindle checkpoint by overexpression of Mad2 or by spindle poisons blocked CamKII-induced resumption of meiosis, but the Ca2+ chelator BAPTA did not. Furthermore direct measurement of Ca2+ levels showed that CamKII did not induce exit from metaphase II arrest by raising Ca2+. Therefore, we conclude that PKCs may play an important role in maintaining Ca2+ spiking at fertilization by promoting store-operated Ca2+ entry, while CamKII transduces cell-cycle resumption, and lies downstream of sperm-induced Ca2+ release but upstream of a spindle checkpoint. These data, combined with the knowledge that CamKII activity increase at fertilization, suggest that mouse eggs undergo cell-cycle resumption through stimulation of CamKII.
Different intracellular trafficking of FGF1 endocytosed by the four homologous FGF receptors
Authors: Haugsten Ellen Margrethe , Sørensen Vigdis , Brech Andreas , Olsnes Sjur , Wesche Jørgen
Published: August 2005

Many growth factors and cytokines bind to more than one receptor, but in many cases the different roles of the separate receptors in signal transduction are unclear. Intracellular sorting of ligand-receptor complexes may modulate the signalling, and we have here studied the intracellular trafficking of ligand bound to receptors for fibroblast growth factors (FGFs). For this purpose, we transfected HeLa cells with any one of the four tyrosine kinase FGF receptors (FGFR1-4). In cells expressing any one of these receptors, externally added FGF1 was localized to sorting/early endosomes after 15 minutes at 37°C. After longer incubation times, FGF1 internalized in cells expressing FGFR1 was localized mainly to late endosomes/lysosomes, similarly to EGF. By contrast, FGF1 internalized in cells expressing FGFR4 followed largely the same intracellular pathway as the recycling ligand, transferrin. In cells expressing FGFR2 or FGFR3, sorting of FGF1 to lysosomes was somewhat less efficient than that observed for FGFR1. Furthermore, FGF1 was more slowly degraded in cells expressing FGFR4 than in cells expressing FGFR1-3 and in addition, internalized FGFR4 as such was more slowly degraded than the other receptors. The data indicate that after endocytosis, FGFR4 and its bound ligand are sorted mainly to the recycling compartment, whereas FGFR1-3 with ligand are sorted mainly to degradation in the lysosomes. Alignment of the amino acid sequence of the intracellular part of the four FGFRs revealed several lysines conserved in FGFR1-3 but absent in FGFR4. Lysines are potential ubiquitylation sites and could thus target a receptor to lysosomes for degradation. Indeed, we found that FGFR4 is less ubiquitylated than FGFR1, which could be the reason for the different sorting of the receptors.
Extra-mitochondrial localisation of frataxin and its association with IscU1 during enterocyte-like differentiation of the human colon adenocarcinoma cell line Caco-2
Authors: Acquaviva Fabio , De Biase Irene , Nezi Luigi , Ruggiero Giuseppina , Tatangelo Fabiana , Pisano Carmela , Monticelli Antonella , Garbi Corrado , Acquaviva Angela Maria , Cocozza Sergio
Published: August 2005

Friedreich's ataxia is a recessive neurodegenerative disease due to insufficient expression of the mitochondrial protein frataxin. Although it has been shown that frataxin is involved in the control of intracellular iron metabolism, by interfering with the mitochondrial biosynthesis of proteins with iron/sulphur (Fe/S) clusters its role has not been well established. We studied frataxin protein and mRNA expression and localisation during cellular differentiation. We used the human colon adenocarcinoma cell line Caco-2, as it is considered a good model for intestinal epithelial differentiation and the study of intestinal iron metabolism. Here we report that the protein, but not the mRNA frataxin levels, increase during the enterocyte-like differentiation of Caco-2 cells, as well as in in-vivo-differentiated enterocytes at the upper half of the crypt-villus axis. Furthermore, subcellular fractionation and double immunostaining, followed by confocal analysis, reveal that frataxin localisation changes during Caco-2 cell differentiation. In particular, we found an extramitochondrial localisation of frataxin in differentiated cells. Finally, we demonstrate a physical interaction between extramitochondrial frataxin and IscU1, a cytoplasmic isoform of the human Fe/S cluster assembly machinery. Based on our data, we postulate that frataxin could be involved in the biosynthesis of iron-sulphur proteins not only within the mitochondria, but also in the extramitochondrial compartment. These findings might be of relevance for the understanding of both the pathogenesis of Friedreich's ataxia and the basic mechanism of Fe/S cluster biosynthesis.
Antidepressant-Induced Adverse Reactions in a Patient with Hemorrhagic Stroke
Authors: Bogdanovic Zoran , Nalamati Jhansi R , Kilcullen John K , Dhuper Sunil
Published: August 2005

Objective:

To report a case of antidepressant-induced adverse drug reactions in a patient with hemorrhagic stroke.

Case Summary:

A 56-year-old man developed life-threatening adverse reactions after fluoxetine was added to his previously prescribed regimen of buspirone and olanzapine. One week after starting fluoxetine 60 mg/day, the patient developed syndrome of inappropriate antidiuretic hormone secretion and serotonin syndrome concurrently. The patient had experienced a hemorrhagic stroke before the adverse drug reactions occurred.

DISCUSSION:

A patient with a history of hemorrhagic stroke developed serious adverse drug reactions when fluoxetine was added to his drug therapy. When the combination therapy was stopped, all adverse effects gradually disappeared and laboratory abnormalities were corrected. The likelihood that the adverse reactions were caused by fluoxetine is probable according to the Naranjo probability scale. In addition, a history of stroke may be a risk factor for the development of such reactions.

CONCLUSIONS:

Today, patients with depression after experiencing a stroke are treated more effectively, but antidepressant-induced adverse drug reactions may be serious. A growing number of patients are treated for post-stroke depression; they require close supervision and careful dosing of antidepressants to prevent full-blown adverse reactions from occurring.
Keto-Enol Tautomerism of Dimedone Studied by Dynamic NMR
Authors: Martínez-Richa Antonio , Mendoza-Díaz Guillermo , Joseph-Nathan Pedro
Published: August 2005

The keto-enol tautomeric equilibrium of dimedone has been investigated by high-resolution 13C NMR spectroscopy. Kinetic information of the solution keto-enol tautomerism for dimedone in DMSO, in the temperature range of 25–85 °C, was derived from line shape measurements in a 75-MHz spectrometer. A value of 3.43 Kcal/mol was found for the Arrhenius activation energy Ea and of 1.07 × 106 s−1 for the pre-exponential factor A. With the use of the observed chemical shifts in the high-resolution 13C-NMR spectra of dimedone in the solid state, an estimate coalescence temperature of 240 K for dimedone in DMSO was obtained by extrapolation of the experimental curve. The estimated free energy of activation at the coalescence temperature, Δ Gc≠, is 10.8 Kcal/mol. Finally, the 13C spin-lattice relaxation times, T1(13C), in solid dimedone were measured as a function of temperature in the range of 25 to 90 °C. The data are discussed in terms of the different motional environments that result from the geometric restrictions imposed by hydrogen bonding in the crystal structure.