bluuebunny/crossref_metadata_2025 huggingface dataset:
Up‐regulation of the inward rectifier K+ current (IK1) in the mouse heart accelerates and stabilizes rotors
Authors: Noujaim Sami F. , Pandit Sandeep V. , Berenfeld Omer , Vikstrom Karen , Cerrone Marina , Mironov Sergey , Zugermayr Michelle , Lopatin Anatoli N. , Jalife José
Published: November 2006

Previous studies have suggested an important role for the inward rectifier K+ current (IK1) in stabilizing rotors responsible for ventricular tachycardia (VT) and fibrillation (VF). To test this hypothesis, we used a line of transgenic mice (TG) overexpressing Kir 2.1–green fluorescent protein (GFP) fusion protein in a cardiac‐specific manner. Optical mapping of the epicardial surface in ventricles showed that the Langendorff‐perfused TG hearts were able to sustain stable VT/VF for 350 ± 1181 s at a very high dominant frequency (DF) of 44.6 ± 4.3 Hz. In contrast, tachyarrhythmias in wild‐type hearts (WT) were short‐lived (3 ± 9 s), and the DF was 26.3 ± 5.2 Hz. The stable, high frequency, reentrant activity in TG hearts slowed down, and eventually terminated in the presence of 10 μm Ba2+, suggesting an important role for IK1. Moreover, by increasing IK1 density in a two‐dimensional computer model having realistic mouse ionic and action potential properties, a highly stable, fast rotor (≈45 Hz) could be induced. Simulations suggested that the TG hearts allowed such a fast and stable rotor because of both greater outward conductance at the core and shortened action potential duration in the core vicinity, as well as increased excitability, in part due to faster recovery of Na+ current. The latter resulted in a larger rate of increase in the local conduction velocity as a function of the distance from the core in TG compared to WT hearts, in both simulations and experiments. Finally, simulations showed that rotor frequencies were more sensitive to changes (doubling) in IK1, compared to other K+ currents. In combination, these results provide the first direct evidence that IK1 up‐regulation in the mouse heart is a substrate for stable and very fast rotors.
Brain–computer interface technology as a tool to augment plasticity and outcomes for neurological rehabilitation
Authors: Dobkin Bruce H.
Published: November 2006

Brain–computer interfaces (BCIs) are a rehabilitation tool for tetraplegic patients that aim to improve quality of life by augmenting communication, control of the environment, and self‐care. The neurobiology of both rehabilitation and BCI control depends upon learning to modify the efficacy of spared neural ensembles that represent movement, sensation and cognition through progressive practice with feedback and reward. To serve patients, BCI systems must become safe, reliable, cosmetically acceptable, quickly mastered with minimal ongoing technical support, and highly accurate even in the face of mental distractions and the uncontrolled environment beyond a laboratory. BCI technologies may raise ethical concerns if their availability affects the decisions of patients who become locked‐in with brain stem stroke or amyotrophic lateral sclerosis to be sustained with ventilator support. If BCI technology becomes flexible and affordable, volitional control of cortical signals could be employed for the rehabilitation of motor and cognitive impairments in hemiplegic or paraplegic patients by offering on‐line feedback about cortical activity associated with mental practice, motor intention, and other neural recruitment strategies during progressive task‐oriented practice. Clinical trials with measures of quality of life will be necessary to demonstrate the value of near‐term and future BCI applications.
A Complex Oscillating Network of Signaling Genes Underlies the Mouse Segmentation Clock
Authors: Dequéant Mary-Lee , Glynn Earl , Gaudenz Karin , Wahl Matthias , Chen Jie , Mushegian Arcady , Pourquié Olivier
Published: November 2006

The segmental pattern of the spine is established early in development, when the vertebral precursors, the somites, are rhythmically produced from the presomitic mesoderm. Microarray studies of the mouse presomitic mesoderm transcriptome reveal that the oscillator associated with this process, the segmentation clock, drives the periodic expression of a large network of cyclic genes involved in cell signaling. Mutually exclusive activation of the notch–fibroblast growth factor and Wnt pathways during each cycle suggests that coordinated regulation of these three pathways underlies the clock oscillator.
Neuropsychiatric symptoms in past users of sheep dip and other pesticides
Authors: Solomon Christine , Poole Jason , Palmer Keith T , Peveler Robert , Coggon David
Published: November 2006

Objectives:To explore the prevalence and pattern of neuropsychiatric symptoms in past users of sheep dip and other pesticides.

Methods:From a postal survey of men born between 1933 and 1977 and resident in three rural areas of England and Wales (response rate 31%), data were obtained on lifetime history of work with pesticides, neurological symptoms in the past month, current mental health and tendency to be troubled by non-neurological somatic symptoms (summarised as a somatising tendency score). Risk factors for current neuropsychiatric symptoms were assessed by modified Cox regression.

Results:Data were available for 9844 men, including 1913 who had worked with sheep dip, 832 with other insecticides but not sheep dip and 990 with other pesticides but never with sheep dip or insecticides. Neurological symptoms were consistently 20–60% more common in past users of sheep dip than in men who had never worked with pesticides, but their prevalence was also higher in men who had worked only with pesticides other than sheep dip or insecticides. They clustered strongly within individuals, but this clustering was not specific to men who had worked with sheep dip. Reporting of three or more neurological symptoms was associated with somatising tendency (prevalence ratio (PR) 15.0, 95% CI 11.4 to 19.5, for the highest vs the lowest category of somatisation) and was more common in users of sheep dip (PR 1.3, 95% CI 1.0 to 1.6), other insecticides (PR 1.4, 95% CI 1.0 to 1.8) and other pesticides (PR 1.3, 95% CI 1.0 to 1.7) than in non-users. Among users of sheep dip, prevalence was higher in men who had dipped most often, but not in those who had worked with sheep dip concentrate. Past use of pesticides was not associated with current anxiety or depression.

Conclusion:Neurological symptoms are more common in men who have worked with sheep dip, but the association is not specific to sheep dip or insecticides. A toxic cause for the excess cannot be ruled out, but several features of our observations suggest that psychological mechanisms have a role.
Should office workers spend fewer hours at their computer? A systematic review of the literature
Authors: IJmker S , Huysmans M A , Blatter B M , van der Beek A J , van Mechelen W , Bongers P M
Published: November 2006

Worldwide, millions of office workers use a computer. Reports of adverse health effects due to computer use have received considerable media attention. This systematic review summarises the evidence for a relationship between the duration of work time spent using the computer and the incidence of hand–arm and neck–shoulder symptoms and disorders. Several databases were systematically searched up to 6 November 2005. Two reviewers independently selected articles that presented a risk estimate for the duration of computer use, included an outcome measure related to hand–arm or neck–shoulder symptoms or disorders, and had a longitudinal study design. The strength of the evidence was based on methodological quality and consistency of the results. Nine relevant articles were identified, of which six were rated as high quality. Moderate evidence was concluded for a positive association between the duration of mouse use and hand–arm symptoms. For this association, indications for a dose–response relationship were found. Risk estimates were in general stronger for the hand–arm region than for the neck–shoulder region, and stronger for mouse use than for total computer use and keyboard use. A pathophysiological model focusing on the overuse of muscles during computer use supports these differences. Future studies are needed to improve our understanding of safe levels of computer use by measuring the duration of computer use in a more objective way, differentiating between total computer use, mouse use and keyboard use, attaining sufficient exposure contrast, and collecting data on disability caused by symptoms.
Risk of prematurity, low birthweight and pre-eclampsia in relation to working hours and physical activities: a systematic review
Authors: Bonzini Matteo , Coggon David , Palmer Keith T
Published: November 2006

Background:Occupational activities are suspected of having an adverse impact on outcomes of pregnancy.

Aim:To assess the evidence relating three major adverse outcomes (preterm delivery, low birthweight (LBW) and pre-eclampsia/gestational hypertension) to five common occupational exposures (prolonged working hours, shift work, lifting, standing and heavy physical workload).

Methods:A systematic search of Medline and Embase (1966–December 2005) using combinations of keywords and medical subject heading terms was conducted. For each relevant paper, standard details were abstracted that were then used to summarise the design features of studies, to rate their methodological quality (completeness of reporting and potential for important bias or confounding) and to provide estimates of effect. For studies with similar definitions of exposure and outcome, pooled estimates of relative risk (RR) in meta-analysis were calculated.

Results:53 reports were identified—35 on preterm delivery, 34 on birth weight and 9 on pre-eclampsia or gestational hypertension. These included 21 cohort investigations. For pre-term delivery, extensive evidence relating to each of the exposures of interest was found. Findings were generally consistent and tended to rule out a more than moderate effect size (RR >1.4). The larger and most complete studies were less positive, and pooled estimates of risk pointed to only modest or null effects. For small-for-gestational age, the position was similar, but the evidence base was more limited. For pre-eclampsia and gestational hypertension, it was too small to allow firm conclusions.

Conclusions:The balance of evidence is not sufficiently compelling to justify mandatory restrictions on any of the activities considered in this review. However, given some uncertainties in the evidence base and the apparent absence of important beneficial effects, it may be prudent to advise against long working hours, prolonged standing and heavy physical work, particularly late in pregnancy. Our review identifies several priorities for future investigation.
Increased interleukin-6 receptor expression in the paraventricular nucleus of rats with heart failure
Authors: Helwig Bryan G. , Musch Timothy I. , Craig Robin A. , Kenney Michael J.
Published: November 2006

Activation of the hypothalamic-pituitary-adrenal (HPA) axis and augmented plasma and tissue levels of IL-6 are hallmarks of heart failure (HF). Within the forebrain, cardiovascular homeostasis is mediated in part by the paraventricular nucleus (PVN) of the hypothalamus. IL-6, via binding to the IL-6 receptor (IL-6R)/glycoprotein 130 (gp130) complex influences cellular and physiological responses. Thus, in the current study, we hypothesized that PVN IL-6R protein and gene expression are upregulated in HF vs. sham-operated rats, whereas gp130 levels in the same tissues remain stable. Six weeks after coronary ligation surgery, hemodynamic measurements were obtained, and HF rats were divided into moderate noncongestive and severe chronic congestive groups based on cardiac indices. Plasma IL-6 levels were determined and changes in gene and protein expression of IL-6R and gp130 between sham-operated and HF rats were determined via real-time PCR and Western blot analyses, respectively. Plasma levels of IL-6 were elevated in rats with severe, but not moderate, HF compared with sham-operated controls. In both moderate and severe HF rats, protein but not gene expression of IL-6R was significantly increased in PVN tissue but not in non-PVN tissue, compared with sham-operated controls. Gene and protein levels of the gp130 subunit were not altered by HF in either tissue analyzed. Collectively, these data suggest that within the brain of HF rats, IL-6R expression is not a global change. Rather the increased IL-6 levels characteristic of HF may alter PVN-mediated physiological responses via enhanced expression of the IL-6R.
Effects of bovine colostrum supplementation on immune variables in highly trained cyclists
Authors: Shing Cecilia M. , Peake Jonathan , Suzuki Katsuhiko , Okutsu Mitsuharu , Pereira Rosie , Stevenson Lesley , Jenkins David G. , Coombes Jeff S.
Published: November 2006

The aim of this study was to investigate the influence of low-dose bovine colostrum protein concentrate (CPC) supplementation on selected immune variables in cyclists. Twenty-nine highly trained male road cyclists completed an initial 40-km time trial (TT40) and were then randomly assigned to either a supplement ( n = 14, 10 g bovine CPC/day) or placebo group ( n = 15, 10 g whey protein concentrate/day). After 5 wk of supplementation, the cyclists completed a second TT40. They then completed 5 consecutive days of high-intensity training (HIT) that included a TT40, followed by a final TT40 in the following week. Venous blood and saliva samples were collected immediately before and after each TT40, and upper respiratory illness symptoms were recorded over the experimental period. Compared with the placebo group, bovine CPC supplementation significantly increased preexercise serum soluble TNF receptor 1 during the HIT period (bovine CPC = 882 ± 233 pg/ml, placebo = 468 ± 139 pg/ml; P = 0.039). Supplementation also suppressed the postexercise decrease in cytotoxic/suppressor T cells during the HIT period (bovine CPC = −1.0 ± 2.7%, placebo = −9.2 ± 2.8%; P = 0.017) and during the following week (bovine CPC = 1.4 ± 2.9%, placebo = −8.2 ± 2.8%; P = 0.004). Bovine CPC supplementation prevented a postexercise decrease in serum IgG2 concentration at the end of the HIT period (bovine CPC = 4.8 ± 6.8%, P = 0.88; placebo = −9.7 ± 6.9%, P = 0.013). There was a trend toward reduced incidence of upper respiratory illness symptoms in the bovine CPC group ( P = 0.055). In summary, low-dose bovine CPC supplementation modulates immune parameters during normal training and after an acute period of intense exercise, which may have contributed to the trend toward reduced upper respiratory illness in the bovine CPC group.
Ozone induces clear cellular and molecular responses in the mouse lung independently of the transcription-coupled repair status
Authors: Kooter Ingeborg M. , Pennings Jeroen L. A. , Fokkens Paul H. B. , Leseman Daan L. A. C. , Boere A. John F. , Gerlofs-Nijland Miriam E. , Cassee Flemming R. , Schalk Johanna A. C. , Orzechowski Tom J. H. , Schaap Mirjam M. , Breit Timo M. , Dormans Jan A. M. A. , van Oostrom Conny T. M. , de Vries Annemieke , van Steeg Harry
Published: November 2006

The oxidant ozone is a well-known air pollutant, inhalation of which is associated with respiratory tract inflammation and functional alterations of the lung. It is well established as an inducer of intracellular oxidative stress. We investigated whether Cockayne syndrome B, transcription-coupled, repair-deficient mice ( Csb−/−), known to be sensitive to oxidative stressors, respond differently to ozone than repair-proficient controls ( Csb+/−). Mice were exposed to 0.8 parts/million ozone for 8 h, and we examined a wide range of biological parameters in the lung at the gene expression, protein, and cellular level 4 h after the ozone exposure. Relevant biological responses to ozone for both repair-deficient Csb−/− and repair-proficient Csb+/− mice, as determined by biochemical analysis of bronchoalveolar lavage fluid (e.g., increases of polymorphonuclear neutrophils, alkaline phosphatase, macrophage-inflammatory protein-2, and tumor necrosis factor-α), pathological examinations, and gene expression (upregulation of oxidative-stress-related genes) analyses were observed. The bronchoalveolar lavage fluid showed significantly more tumor necrosis factor-α in repair-deficient Csb−/− mice than in repair-proficient Csb+/− mice after ozone exposure. In addition, a clear trend was observed toward fewer differentially expressed genes with a lower fold ratio in repair-deficient Csb−/− mice than in repair-proficient Csb+/− mice. However, repair-deficient Csb−/− mice do not respond significantly more sensitively to ozone compared with repair-proficient Csb+/− mice at the level of gene expression. We conclude that, under the conditions employed here, although small differences at the transcriptional level exist between repair-proficient Csb+/− mice and transcription-coupled repair defective Csb−/− mice, these do not have a significant effect on the ozone-induced lung injury.
Dysfunction of the canine respiratory muscle pump in ascites
Authors: Leduc Dimitri , De Troyer André
Published: November 2006

Ascites, a complicating feature of many diseases of the liver and peritoneum, commonly causes dyspnea. The mechanism of this symptom, however, is uncertain. In the present study, progressively increasing ascites was induced in anesthetized dogs, and the hypothesis was initially tested that ascites increases the impedance on the diaphragm and, so, adversely affects the lung-expanding action of the muscle. Ascites produced a gradual increase in abdominal elastance and an expansion of the lower rib cage. Concomitantly, the caudal displacement of the diaphragm and the fall in airway opening pressure during isolated stimulation of the phrenic nerves decreased markedly; transdiaphragmatic pressure during phrenic stimulation also decreased. To assess the adaptation to ascites of the respiratory system overall, we subsequently measured the changes in lung volume, the arterial blood gases, and the electromyogram of the parasternal intercostal muscles during spontaneous breathing. Tidal volume and minute ventilation decreased progressively as ascites increased, leading to an increase in arterial Pco2 and parasternal intercostal inspiratory activity. It is concluded that 1) ascites, acting through an increase in abdominal elastance and an expansion of the lower rib cage, impairs the lung-expanding action of the diaphragm; 2) this impairment elicits a compensatory increase in neural drive to the inspiratory muscles, but the compensation is not sufficient to maintain ventilation; and 3) dyspnea in this setting results in part from the dissociation between increased neural drive and decreased ventilation.
The role of free radicals in the pathophysiology of muscular dystrophy
Authors: Tidball James G. , Wehling-Henricks Michelle
Published: November 2006

Null mutation of any one of several members of the dystrophin protein complex can cause progressive, and possibly fatal, muscle wasting. Although these muscular dystrophies arise from mutation of a single gene that is expressed primarily in muscle, the resulting pathology is complex and multisystemic, which shows a broader disruption of homeostasis than would be predicted by deletion of a single-gene product. Before the identification of the deficient proteins that underlie muscular dystrophies, such as Duchenne muscular dystrophy (DMD), oxidative stress was proposed as a major cause of the disease. Now, current knowledge supports the likelihood that interactions between the primary genetic defect and disruptions in the normal production of free radicals contribute to the pathophysiology of muscular dystrophies. In this review, we focus on the pathophysiology that results from dystrophin deficiency in humans with DMD and the mdx mouse model of DMD. Current evidence indicates three general routes through which free radical production can be disrupted in dystrophin deficiency to contribute to the ensuing pathology. First, constitutive differences in free radical production can disrupt signaling processes in muscle and other tissues and thereby exacerbate pathology. Second, tissue responses to the presence of pathology can cause a shift in free radical production that can promote cellular injury and dysfunction. Finally, behavioral differences in the affected individual can cause further changes in the production and stoichiometry of free radicals and thereby contribute to disease. Unfortunately, the complexity of the free radical-mediated processes that are perturbed in complex pathologies such as DMD will make it difficult to develop therapeutic approaches founded on systemic administration of antioxidants. More mechanistic knowledge of the specific disruptions of free radicals that underlie major features of muscular dystrophy is needed to develop more targeted and successful therapeutic approaches.
Short oxygen prebreathing and intravenous perfluorocarbon emulsion reduces morbidity and mortality in a swine saturation model of decompression sickness
Authors: Dainer Hugh , Nelson John , Brass Kathryn , Montcalm-Smith Elizabeth , Mahon Richard
Published: November 2006

Disabled submarine (DISSUB) survivors will achieve inert gas tissue saturation within 24 h. Direct ascent to the surface when saturated carries a high risk of decompression sickness (DCS) and death, yet may be necessary during rescue or escape. O2 has demonstrated benefits in decreasing morbidity and mortality resulting from DCS by enhancing inert gas elimination. Perfluorocarbons (PFCs) also mitigate the effects of DCS by decreasing bubble formation and increasing O2 delivery. Our hypothesis is that combining O2 prebreathing (OPB) and PFC administration will reduce the incidence of DCS and death following saturation in an established 20-kg swine model. Yorkshire swine (20 ± 6.5 kg) were compressed to 5 atmospheres (ATA) in a dry chamber for 22 h before randomization into one of four groups: 1) air and saline, 2) OPB and saline, 3) OPB with PFC given at depth, 4) OPB with PFC given after surfacing. OPB animals received >90% O2 for 9 min at depth. All animals were returned to the surface (1 ATA) without decompression stops. The incidence of severe DCS < 2 h after surfacing was 96%, 63%, 82%, and 29% for groups 1, 2, 3, and 4, respectively. The incidence of death was 88%, 41%, 54%, and 5% for groups 1, 2, 3, and 4, respectively. OPB combined with PFC administration after surfacing provided the greatest reduction in DCS morbidity and mortality in a saturation swine model. O2-related seizure activity before reaching surface did not negatively affect outcome, but further safety studies are warranted.
Comparative Efficacy of Acetazolamide and Apraclonidine in the Control of Intraocular Pressure following Phacoemulsification
Authors: Scuderi Gianluca , Regine Federico , Perdicchi Andrea , Mannino Giuseppe , Recupero Santi M.
Published: November 2006

Purpose: The purpose of our study was to compare the effects of systemically administered acetazolamide and topical apraclonidine 0.5% in the control of intraocular pressure (IOP) following phacoemulsification of senile cataracts. Setting: The study was conducted on patients affected by cataract and followed at the Department of Ophthalmology. Methods: Seventy-eight eyes in 78 patients were selected. Twenty-six eyes were randomly assigned to postoperative treatment with topical apraclonidine 0.5%, 26 received oral acetazolamide and the remaining 26 received no hypotensive treatment (control group). Statistical analyses were performed mainly by means of analyis of variance. Results: IOPs measured 24 h after surgery were significantly (p = 0.01) lower in the apraclonidine group compared to the control group. Conclusions: Our double-blind prospective study conducted on patients randomly assigned to treatment with apraclonidine or acetazolamide shows that the former drug is undoubtedly effective in the prevention of IOP increases following phacoemulsification. IOPs recorded in patients treated with this drug were lower than those observed in the acetazolamide and the control groups. Considering the lower risk of toxicity associated with topical administration, apraclonidine 0.5% seems to be preferable to oral acetazolamide in this postoperative setting.
Acute Optic Neuropathy in Patients with Behçet’s Disease
Authors: Voros Gerasimos M. , Sandhu Sukhpal S. , Pandit Ranjeet
Published: November 2006

Although acute optic neuropathy has been rarely reported in patients with Behçet’s disease, a detailed description of its clinical course is lacking. We report in detail the course of acute optic neuropathy in two patients with Behçet’s disease. Our experience suggests that it can be bilateral, can affect both eyes simultaneously, and can be recurrent. The severity of the visual loss and its recovery can be very variable even in the same patient. Early recognition of this entity and treatment with high-dose systemic corticosteroids may limit the degree of permanent visual loss. However, the optimal treatment has not been established.
Hb Jambol: A New Hyperunstable Hemoglobin Causing Severe Hemolytic Anemia
Authors: Efremov G.D. , Simjanovska L. , Plaseska-Karanfilska D. , Stanojevic E. , Petkov G.H.
Published: November 2006

We describe a new hyperunstable β-chain variant due to a complex genomic rearrangement. The abnormal hemoglobin (Hb) was found as a de novo mutation in a 2-year-old Bulgarian girl with severe hemolytic anemia. The mutation was detected through RNA/DNA analysis. It represents a complex genomic rearrangement involving an insertion of 23 nts after IVS-II-535 (derived by triplication of the 12-nts adjacent sequence and subsequent deletion of 1 nt), a deletion of 310 nts extending from IVS-II-550 to the first nt of Cd 108 and an insertion of 28 nts at the deletion junctions (derived from the inverted sequence between nts +3,707 and +3,734 3′ to the β-globin gene termination codon). At the protein level this mutation leads to a deletion of 4 amino acid residues (Leu-Leu-Glu-Asn) at positions 105–108 and an insertion of 9 residues (Val-Pro-Ser-Val-Thr-Leu-Phe-Phe-Asp) at the same location, creating an abnormal elongated β-chain of 151 amino acid residues. This highly unstable variant was named ‘Hb Jambol’ after the geographic location in which the patient resides.
Immune Thrombocytopenia after Renal Transplantation for IgA Nephropathy
Authors: Talaulikar Dipti , Falk Michael , Talaulikar Girish , Pidcock Michael
Published: November 2006

Immune thrombocytopenic purpura associated with renal disease is usually therapy-related, occurring after administration of intravenous immunoglobulin therapy or anti-D. Secondary cases occurring after renal transplantation are extremely rare. We present the second reported case of immune thrombocytopenic purpura occurring after renal transplantation for IgA nephropathy. Primary IgA nephropathy is the most common form of primary glomerulonephritis and although the pathogenesis of the disease remains incompletely understood, recent evidence suggests that the basic abnormality lies within the IgA immune system rather than in the kidney. We postulate a novel mechanism for thrombocytopenia occurring in such cases.
Rho Kinase Inhibition Improves Endothelial Function in Human Subjects With Coronary Artery Disease
Authors: Nohria Anju , Grunert Matthew E. , Rikitake Yoshiyuki , Noma Kensuke , Prsic Adnan , Ganz Peter , Liao James K. , Creager Mark A.
Published: November 2006

Investigations from basic biology suggest that activation of the Rho/Rho kinase pathway reduces the bioavailability of nitric oxide (NO) and thereby promotes atherosclerosis and its clinical complications. Yet, little information is available about the relationship of the Rho/Rho kinase pathway to NO bioavailability in humans with atherosclerosis. Accordingly, we determined whether inhibition of Rho kinase augments NO bioavailability and improves endothelial function in human subjects with coronary artery disease (CAD). Thirteen CAD subjects and 16 age- and sex-matched healthy controls were randomly assigned to receive the Rho kinase inhibitor, fasudil, or placebo for 1 month each in a double-blind crossover trial. Flow-mediated, endothelium-dependent and nitroglycerin-induced, endothelium-independent vasodilation were assessed by brachial artery ultrasonography. Rho kinase activity was measured in peripheral leukocytes. Fasudil increased endothelium-dependent vasodilation in CAD subjects from 9.4±1.9% to 13.4±1.9% (
P
=0.001) but not in healthy controls (from 11.3±1.4% to 7.7±1.1%;
P
=0.07). Endothelium-independent vasodilation was not affected by fasudil in either CAD or healthy subjects. Fasudil reduced Rho kinase activity by 59±18% in CAD subjects (
P
=0.001) but not in healthy subjects (by 3±6%;
P
=0.60). The change in endothelium-dependent vasodilation achieved with fasudil relative to placebo was inversely proportional to Rho kinase inhibition (ie, greater Rho kinase inhibition was associated with larger improvement in endothelium-dependent vasodilation) (
r
=−0.48;
P
=0.01). These findings suggest that Rho/Rho kinase activation promotes endothelial dysfunction in humans with atherosclerosis. Inhibition of the Rho/Rho kinase pathway should provide a useful strategy to restore NO bioavailability in humans with atherosclerosis.
Integrin Activation in the Heart
Authors: Valencik Maria L. , Zhang Dongfang , Punske Bonnie , Hu Ping , McDonald John A. , Litwin Sheldon E.
Published: November 2006

Integrins mechanically link the cytoskeleton to the extracellular matrix in cardiac myocytes and are thereby involved in mechanotransduction. Integrins appear to be necessary for cardiac myocyte hypertrophy. To determine the effect of increased integrin ligation and signaling on adult cardiac function, a heart-specific truncated α
5
integrin (gain of function) was conditionally expressed in mice. Four days later, we observed an 80% reduction in amplitude of the QRS complex, profound systolic dysfunction, decreased connexin43, loss of gap junctions, and abnormal intercalated discs. Surprisingly, isolated left ventricular myocytes contracted normally and exhibited normal Ca
2+
transients. This suggested that cell/cell electrical and/or mechanical coupling was disrupted. To distinguish electrical from mechanical coupling deficits, we compared the papillary muscle force generated by electrically stimulated versus rapid cooling contractions in which intracellular Ca
2+
is released without electrical depolarization. Both were decreased in the transgenic muscle. However, electrically stimulated contractions were more significantly reduced than rapid cooling contractures. This suggests a component of cell/cell electrical uncoupling. Optical mapping revealed a loss of the normal elliptical isochronal activation pattern implying a loss of preferential conduction through gap junctions. For the first time, we have shown that integrins can regulate both mechanical and electrical coupling in the adult heart, even in the absence of primary hemodynamic alterations. Furthermore, we demonstrated that unregulated integrin activation leads to both contractile dysfunction and arrhythmias.
The Impact of Participative and Directive Leadership on Teachers' Performance: The Intervening Effects of Job Structuring, Decision Domain, and Leader-Member Exchange
Authors: Somech Anit , Wenderow Maayan
Published: November 2006

Purpose: The contingency model theory suggests that the effects of a leadership style cannot be studied without explicit attention to the given situation. Accordingly, the authors propose a model that allows them to examine simultaneously the relative impact of participative leadership and directive leadership on teachers' performance through the intervening effects of three factors: job structuring (bureaucratic job structuring vs. person-job integration), decision domain (technical vs. managerial), and leader-member exchange (LMX).

Method: Data were collected from a survey of 100 teachers and their principals at seven elementary schools in northern Israel.

Results: The mixed models analysis shows that although the impact of directive leadership on teachers' performance was contingent in nature, the positive effect of participative leadership on their performance was above and beyond the specific conditions studied. Regarding the impact of directive leadership on teachers' performance, job structuring, decision domain, and LMX served as moderators in the directive leadership–teachers' performance relationship.

Implications: These results offer a basis for ongoing conceptual development by helping researchers and practitioners to move from an either/or to a both/and leadership approach. Moreover, these interpretations take direction and participation to be interpersonal processes rather than stable personality traits.
Leadership for Social Justice and Equity: Evaluating a Transformative Framework and Andragogy
Authors: Brown Kathleen M.
Published: November 2006

Purpose: This study explores the effects of an alternative, transformative andragogy (i.e., the art and science of helping others to learn) designed to be responsive to the challenges of preparing educational leaders committed to social justice and equity.

Design: Within the context of preparation programs, the three theoretical perspectives of adult learning theory, transformative learning theory, and critical social theory are interwoven with the three andragogical processes of critical reflection, rational discourse, and policy praxis to form an alternative, transformative framework. Forty graduate students of educational administration (two cohorts of preservice leaders) participated in this study. Quantitative methods are used to assess the possible effects of transformative learning strategies on preservice leaders' attitudes toward issues of diversity in education. Qualitative research methods are then employed to further explore the possible effects of andragogical approaches on preservice leaders' personal beliefs and their reported ability to connect theory to practice.

Findings: Findings indicate that participation in transformative learning processes and strategies can increase students' perceived growth in awareness, acknowledgement, and action toward social justice.

Implications: The strategies used were created to help future leaders develop as transformative, reflective scholars and practitioners actively engaged in political, emancipatory interests. By participating in a number of assignments requiring the examination of ontological and epistemological assumptions, values and beliefs, context and experience, and competing worldviews, transformation is possible.
Assessing School Achievement Progress: Comparing Alternative Approaches
Authors: Heck Ronald H.
Published: November 2006

Purpose: Currently under the No Child Left Behind Act, cut scores of successive cohorts of students are used to identify schools that are successful and others that are failing. For many schools, however, this score does not provide an accurate, fair, or comprehensive performance assessment. The focus of this study is to compare three alternative approaches for estimating student progress with respect to their accuracy, equity, and usefulness in making inferences about school effectiveness.

Research Design: The study compares achievement estimates compiled across a 4-year period from successive and longitudinal cohorts in a multilevel sample of 123 elementary schools and several thousand students.

Findings: First, method effects associated with the designs interact with estimates of school effectiveness. Less than 20% of the schools are similarly identified as meeting performance standards across all three designs investigated. Second, in each approach, contextual indicators (e.g., student composition) dominate in explaining between-school differences in proficiency levels. Third, the longitudinal-cohort approach provides more comprehensive results about performance because of the simultaneous focus on student proficiency and growth. Equity and usefulness are also increased in comparisons of student growth because student composition and context effects are diminished and, conversely, process effects (e.g., academic expectations) are increased in explaining school differences.

Conclusions: The comparisons suggest caution in making decisions about schools based on proficiency levels because both method effects and extraneous variables interact with the validity of estimates obtained. Modeling students' growth trajectories, however, can uncover positive school results that are missed in the current proficiency-status approach.
Sacred Journeys of Nurse Healers
Authors: Hemsley Martin , Glass Nel
Published: November 2006

This article reports on a hermeneutic phenomenological investigation of the transformational and extraordinary experiences, or sacred journeys, of 11 nurse healers. The study was guided by Watson’s conceptual model. An overarching theme, “walking two worlds,” was identified, along with five essential themes: belonging and connecting, opening to spirit, summoning, wounding and healing journey, and living as a healer. The importance of these phenomenologically uncovered holistic understandings to the teaching, practice, administration, knowledge development, and theoretical evolvement of nursing is argued.
Designing Student Groupwork in Management Education: Widening the Palette of Options
Authors: Holtham Clive W. , Melville Robert R. , Sodhi ManMohan S.
Published: November 2006

The authors describe innovation in practice through the unusual deployment of teams in a master’s in management core course. Two parallel uses of teams were made, both drawing on the jigsaw team method, in one case with the team supporting individual work. The experiences support the idea of widening the palette of types of groupwork used in management education, as well as the need for this to be addressed by faculty teams and individual academics.
Exploring the Connections between Adult and Management Education
Authors: Brookfield Stephen D. , Kalliath Thomas , Laiken Marilyn
Published: November 2006

Stephen Brookfield has written and edited 10 books on adult learning, teaching, and critical thinking. He is a recipient of a number of awards, including the World Award for Literature in Adult Education (in 1986, 1989, 1996, and 2005), the Imogene Okes Award for Outstanding Research in Adult Education (in 1986), and the Leadership Award from the Association for Continuing Higher Education (in 2001). In this interview, Stephen Brookfield responds to questions from Thomas Kalliath and Marilyn Laiken on a range of topics, including connections between adult education and management education, lifelong learning, team learning, organizational and workplace learning, and corporate social responsibility.1
Transplantation of vascular endothelial cells mediates the hematopoietic recovery and survival of lethally irradiated mice
Authors: Chute John P. , Muramoto Garrett G. , Salter Alice B. , Meadows Sarah K. , Rickman Dennis W. , Chen Benny , Himburg Heather A. , Chao Nelson J.
Published: November 2006

Flk-1+ endothelial progenitors contribute critically to the definitive onset of hematopoiesis during embryogenesis. Recent studies have suggested that adult sources of endothelial cells also possess hematopoietic activity. In this study, we sought to determine whether transplantation of primary vascular endothelial cells (ECs) could enhance the hematopoietic recovery and survival of irradiated mice. C57Bl6 mice were exposed to sublethal and lethal doses of irradiation and were subsequently given transplants of either primary murine brain–derived ECs (MBECs) or fetal blood-derived ECs (FBECs). Mice that received a transplant with MBECs alone demonstrated accelerated BM cellular recovery, radioprotection of BM c-kit+sca-1−lin− progenitors and enhanced regeneration of c-kit+sca-1+lin− (KSL) stem/progenitor cells following irradiation compared with controls. MBEC transplantation also facilitated the recovery of circulating white blood cell and platelet counts following radiation exposure. Remarkably, 57% of mice that received a transplant with MBECs alone survived long term following 1050 cGy exposure, which was 100% lethal in control mice. FBEC transplantation was also associated with increased survival compared with controls, although these mice did not survive in the long term. These data suggest that reestablishment of endothelial cell activity can improve the hematopoietic recovery and survival of irradiated mice.
Cytokine and integrin stimulation synergize to promote higher levels of GATA-2, c-myb, and CD34 protein in primary human hematopoietic progenitors from bone marrow
Authors: Dao Mo A. , Nolta Jan A.
Published: November 2006

We have previously shown that engagement of the integrins VLA-4 and VLA-5 to the fibronectin fragment CH-296 in combination with cytokines sustained the capacity of cultured human CD34+ cells to undergo hematopoiesis in immunodeficient mice for 7 to 12 months, whereas this capacity was rapidly lost in cells cultured in suspension with the same cytokines. In the current study, we assessed the molecular pathways that might explain the loss of long-term engraftment capacity in cells cultured in suspension. Although the cell cycle profile was similar between cells cultured in suspension versus on fibronectin, levels of cell death were higher in the suspended cultures. While the CDK inhibitors p27Kip1 and p57Kip2 were present at equal levels in cells from both cultures, low levels of p21Cip1 were detectable only in the cytoplasmic compartment of cells cultured in suspension. Cytoplasmic location of p21Cip1 has been linked to monocytic differentiation. The levels of c-myb and GATA-2, transcription factors associated with stem cell maintenance, were higher in cells cultured on fibronectin as compared with suspension. In contrast, the levels of PU.1, which is induced during myeloid differentiation, were higher in cells cultured in suspension. There were no significant differences in surface expression of CD34 on the cells after culture, but total CD34 protein, assessed by immunoblotting, was significantly higher in cells cultured on fibronectin. Our data suggest that, in the presence of cytokines, the engagement of VLA-4 and VLA-5 integrins to the fibronectin fragment CH-296 preserves the expression of specific transcription factors associated with primitive stem cell maintenance. In contrast, a lack of integrin engagement leads to the induction of cellular markers associated with myeloid differentiation.
Src family kinases mediate neutrophil adhesion to adherent platelets
Authors: Evangelista Virgilio , Pamuklar Zehra , Piccoli Antonio , Manarini Stefano , Dell'Elba Giuseppe , Pecce Romina , Martelli Nicola , Federico Lorenzo , Rojas Mauricio , Berton Giorgio , Lowell Clifford A. , Totani Licia , Smyth Susan S.
Published: November 2006

Polymorphonuclear leukocyte (PMN)–platelet interactions at sites of vascular damage contribute to local and systemic inflammation. We sought to determine the role of “outside-in” signaling by Src-family tyrosine kinases (SFKs) in the regulation of αMβ2-integrin–dependent PMN recruitment by activated platelets under (patho)physiologic conditions. Activation-dependent epitopes in β2 integrin were exposed at the contact sites between PMNs and platelets and were abolished by SFK inhibitors. PMNs from αMβ2−/−, hck−/−fgr−/−, and hck−/−fgr−/−lyn−/− mice had an impaired capacity to adhere with activated platelets in suspension. Phosphorylation of Pyk2 accompanied PMN adhesion to platelets and was blocked by inhibition as well as by genetic deletion of αMβ2 integrin and SFKs. A Pyk2 inhibitor reduced platelet-PMN adhesion, indicating that Pyk2 may be a downstream effector of SFKs. Analysis of PMN-platelet interactions under flow revealed that SFK signaling was required for αMβ2-mediated shear-resistant adhesion of PMNs to adherent platelets, but was dispensable for P-selectin–PSGL-1–mediated recruitment and rolling. Finally, SFK activity was required to support PMN accumulation along adherent platelets at the site of vascular injury, in vivo. These results definitely establish a role for SFKs in PMN recruitment by activated platelets and suggest novel targets to disrupt the pathophysiologic consequences of platelet-leukocyte interactions in vascular disease.
MRP8/MRP14 impairs endothelial integrity and induces a caspase-dependent and -independent cell death program
Authors: Viemann Dorothee , Barczyk Katarzyna , Vogl Thomas , Fischer Ute , Sunderkötter Cord , Schulze-Osthoff Klaus , Roth Johannes
Published: November 2006

Activated phagocytes express considerable amounts of MRP8 and MRP14, 2 calcium-binding S100 proteins forming stable heterodimers that are specifically secreted at inflammatory sites in many diseases. We previously reported that treatment of human microvascular endothelial cells with purified MRP8/MRP14 leads to loss of endothelial cell contacts. In this study, we demonstrate that MRP8/MRP14 complexes furthermore trigger cell death of endothelial cells after the onset of cell detachment. Morphologic analysis of dying endothelial cells revealed characteristic features of both apoptosis and necrosis. Furthermore, MRP8/MRP14 induced apoptotic caspase-9 and caspase-3 activation, DNA fragmentation, and membrane phosphatidylserine exposure in target cells. These events were independent of death receptor signaling and in part controlled by a mitochondrial pathway. Consistently, overexpression of antiapoptotic Bcl-2 abrogated caspase activation and externalization of phosphatidylserine; however, MRP8/MRP14 still induced plasma membrane damage and even DNA fragmentation. Thus, our results demonstrate that MRP8/MRP14 triggers cell death via caspase-dependent as well as -independent mechanisms. Excessive release of cytotoxic MRP8/MRP14 by activated phagocytes might therefore present an important molecular pathomechanism contributing to endothelial damage during vasculitis and other inflammatory diseases.
End points to establish the efficacy of new agents in the treatment of acute leukemia
Authors: Appelbaum Frederick R. , Rosenblum Daniel , Arceci Robert J. , Carroll William L. , Breitfeld Philip P. , Forman Stephen J. , Larson Richard A. , Lee Stephanie J. , Murphy Sharon B. , O'Brien Susan , Radich Jerald , Scher Nancy S. , Smith Franklin O. , Stone Richard M. , Tallman Martin S.
Published: November 2006

Federal regulations provide 2 pathways for approval of new agents for the treatment of acute leukemia, regular and accelerated approval. Regular approval requires evidence of clinical benefit, which is generally defined as either prolongation of life or improved quality of life, or an effect on an end point established as a surrogate for clinical benefit. Accelerated approval can be obtained based on demonstration of an effect on a surrogate measure “reasonably likely” to predict clinical benefit, but requires demonstration of clinical benefit after approval as well. The acute leukemias are a heterogeneous and relatively uncommon group of diseases. The design and execution of prospective randomized clinical trials demonstrating prolongation of life or improved quality of life for patients with these disorders can be difficult and costly and require lengthy follow-up. Thus, the development of novel trial design and inclusion of validated surrogate markers for clinical benefit are needed. To explore some of the issues pertinent to the choice of end points for drug approval in acute leukemia, the Food and Drug Administration invited the American Society of Hematology to participate in the organization and conduct of a joint workshop. In this report, we present the results of that effort.