bluuebunny/crossref_metadata_2025 huggingface dataset:
Tips for Using a Peer Response System in a Large Introductory Physics Class
Authors: Milner-Bolotin Marina
Published: March 2004

Teaching a large introductory physics course can be a challenge for a young physics instructor, and making a large physics lecture interactive may seem almost impossible. The most difficult part about the large class is that due to its size there is very little real-time interaction between the students and the lecturer. The instructor often does not know how well the students understand the lecture or how actively they are involved in it. The lack of real-time communication might make it very difficult and misleading for both the students and the instructor. Fortunately, recently we witnessed the proliferation of technological tools that can help the instructor get instantaneous feedback during the lecture. One of these tools is the peer response system (PRS).1
The Little RNAs That Could
Authors: Leslie Mitch
Published: March 2004

Like many teenagers, stem cells won't grow up without a push. New research reveals that RNA snippets provide a shove, inciting brain stem cells to mature. The work suggests that RNAs instigate the process by changing a gene-blocking protein into a gene activator. The study is the first to show that the miniature molecules can turn genes on as well as off.
How Good Are Quantitative Complementation Tests?
Authors: Service Philip M.
Published: March 2004

Several recent studies have used quantitative complementation tests to identify relatively short chromosome regions that contain genes that influence life span and to screen for candidate life-span genes in flies. The methodology and logic of quantitative complementation tests are described. Arguments are presented that suggest that these tests may be misleading because there is a substantial, but unknown, likelihood of false positive results. The arguments are supported by the published results of quantitative complementation tests.
Reconstitution of Ca
2+
-Regulated Membrane Fusion by Synaptotagmin and SNAREs
Authors: Tucker Ward C. , Weber Thomas , Chapman Edwin R.
Published: March 2004

We investigated the effect of synaptotagmin I on membrane fusion mediated by neuronal SNARE proteins, SNAP-25, syntaxin, and synaptobrevin, which were reconstituted into vesicles. In the presence of Ca
2+
, the cytoplasmic domain of synaptotagmin I (syt) strongly stimulated membrane fusion when synaptobrevin densities were similar to those found in native synaptic vesicles. The Ca
2+
dependence of syt-stimulated fusion was modulated by changes in lipid composition of the vesicles and by a truncation that mimics cleavage of SNAP-25 by botulinum neurotoxin A. Stimulation of fusion was abolished by disrupting the Ca
2+
-binding activity, or by severing the tandem C2 domains, of syt. Thus, syt and SNAREs are likely to represent the minimal protein complement for Ca
2+
-triggered exocytosis.
Accessing Natural Products by Combinatorial Biosynthesis
Authors: Shen Ben
Published: March 2004

Enhancement and selective production of the protein phosphatase IIa inhibitor phoslactomycin (PLM) B by rational engineering of the PLM biosynthetic pathway highlights the effectiveness of combinatorial biosynthesis as a promising way to prepare complex natural products and their analogs.
Life Stress, Genes, and Depression: Multiple Pathways Lead to Increased Risk and New Opportunities for Intervention
Authors: Charney Dennis S. , Manji Husseini K.
Published: March 2004

Major depression is a common, severe, chronic, and often life-threatening illness. There is a growing appreciation that, far from being a disease with purely psychological manifestations, major depression is a systemic disease with deleterious effects on multiple organ systems. Stressful life events have a substantial causal association with depression, and there is now compelling evidence that even early life stress constitutes a major risk factor for the subsequent development of depression. The emerging evidence suggests that the combination of genetics, early life stress, and ongoing stress may ultimately determine individual responsiveness to stress and the vulnerability to psychiatric disorders, such as depression. It is likely that genetic factors and life stress contribute not only to neurochemical alterations, but also to the impairments of cellular plasticity and resilience observed in depression. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell plasticity and resilience are long-term targets for the actions of antidepressant agents. Agents capable of reversing the hypothesized impairments of cellular resilience, reductions in brain volume, and cell death or atrophy in depression have the potential of becoming new therapeutic classes of antidepressant drugs. Novel cellular targets include agents targeting neurotrophic pathways, glucocorticoid signaling, phosphodiesterase activity, and glutamatergic throughput. The future development of treatments that more directly target molecules in critical CNS (central nervous system) signaling pathways that regulate cellular plasticity thus hold promise as novel, improved long-term treatments for major depression.
Terminology used by pathologists in reporting on sudden infant deaths
Authors: Limerick S R , Bacon C J
Published: March 2004

Aim:To determine whether the terms used by pathologists in reporting on sudden infant deaths are applied consistently.

Method:Postal survey.

Results:Replies were received from 63 pathologists who carry out necropsies after sudden infant deaths. There was a pronounced variation in their use of the terms “sudden infant death syndrome” and “unascertained”, with the last term being applied not only when there were apparently suspicious features but also in various other circumstances. Opinions were divided as to whether the term “sudden infant death syndrome” still serves a useful purpose. Deaths that had occurred while bed sharing were categorised in several different ways. Many pathologists commented on the inadequacy of the history available to them at the time of their report.

Conclusions:There is a serious need for greater consistency in the way pathologists report on sudden death in infants. Pathologists should be provided with a full history before they carry out the necropsy.
Carcinosarcoma with a large cell neuroendocrine epithelial component: first report of an unusual biphasic tumour of the urinary bladder
Authors: Li Yu , Outman J E , Mathur S C
Published: March 2004

This article describes the first reported case of carcinosarcoma of the urinary bladder with a large cell neuroendocrine epithelial component. A 61 year old man presented with gross haematuria and underwent resection of a biphasic bladder tumour. The malignant epithelial component showed large cell neuroendocrine differentiation with immunohistochemical reactivity for neurone specific enolase, synaptophysin, and chromogranin. The malignant mesenchymal component did not show specific differentiation by histological or immunohistochemical examination. The differential diagnosis of biphasic tumours in the urinary bladder is discussed, along with a review of the literature.
Gastric neuroendocrine carcinoma arising from heterotopic pancreatic tissue
Authors: Chetty R , Weinreb I
Published: March 2004

An 85 year old man presented with symptoms of dyspepsia and increase in stool frequency of two months duration. Upper endoscopy revealed an ulcer and the biopsy was interpreted as carcinoma with endocrine features. A formal distal gastrectomy was planned, but intraoperatively, because of the patient’s condition, a wedge resection was performed. Histology revealed a neuroendocrine tumour (grade 1), located mainly in the submucosa, which had caused mucosal attenuation and ulceration. Associated with the tumour and at its periphery was heterotopic pancreatic tissue composed of acini, ducts, and endocrine cells. The tumour was strongly positive for chromogranin and focally for synaptophysin. There was no associated chronic atrophic gastritis or G cell hyperplasia. A discrete focus of high grade neuroendocrine carcinoma (grade 3) within the typical (grade 1) neuroendocrine tumour was also present. This case illustrates a grade 1 neuroendocrine carcinoma, with a small grade 3 focus, arising within or intimately associated with heterotopic pancreatic tissue in the stomach. Although the two entities may be separate, their close topographical association favours the possibility of neuroendocrine carcinoma arising from the heterotopic pancreas. Pathologists should be aware of the occurrence of pancreatic heterotopia in the stomach and the association of carcinoma with it.
Amending the Standard Model of Particle Physics
Authors: Goldhaber Maurice
Published: March 2004

Some of my earlier arguments, suggesting modifications of the Standard Model of Particle Physics (see ref. 1), are elaborated and extended. Rules deduced from the known properties of elementary fermions are sharpened and extended in the first part. Conclusions drawn from the rules in the second part are also honed and expanded and an estimate of the neutrino mass eigenstates is added. In the third part, a tentative explanation of the rules is discussed. In my earlier paper, I suggested replacing the point-sources postulated by the Standard Model for each generation by finite 'source-shapes', equal for all elementary fermions of a generation and systematically decreasing in volume from the first to the third generation, thus increasing the effect of self-interactions. According to the rules a correlation exists between the mass of an elementary fermion and the strength of its self-interaction, thus an increase in self-interactions would resolve the problem of the hierarchical masses. A possible connection between the existence of only three generations and the three-dimensionality of space also is discussed. In the epilogue the question is explored whether finite source-shapes for the elementary fermions can be reconciled with fundamental theoretical tenets.
THEORETICAL STUDY OF ADIABATIC AND VERTICAL ELECTRON AFFINITY OF RADIOSENSITIZERS IN SOLUTION PART 2: ANALOGUES OF TIRAPAZAMINE
Authors: RAMALHO TEODORICO C. , DA CUNHA ELAINE F. F. , DE ALENCASTRO RICARDO BICCA
Published: March 2004

Tirapazamine is a radiosensitizer, whose biological activity is associated to its electron affinity (EA). The electron affinity can be divided in two main processes: Vertical and Adiabatic. In this work, we calculated the EAs of nitroimidazoles (Fig. 2) using HF and DFT methods and evaluated solvent effects (water and carbon tetrachloride) on EAs. For water, we combined the Polarized Continuum Model (PCM) and free energy perturbation (Finite Difference Thermodynamic Integration, FDTI) methods. For carbon tetrachloride, we used the FDTI method. The values of adiabatic EA obtained are in agreement with experimental data (deviations of 13.25 meV). The vertical EA were calculated according to Cederbaum's Outer Valence Green Function (OVGF) method. This study, which relays on theoretical aspects of free energy calculations on charged molecules in solution, could be helpful in the rational design of new and more selective bioreductive anticancer drugs.
PREDICTION OF THE TRANSPORT PROPERTIES OF SF6 WITH O2, CO2, CF4, N2 AND CH4 MIXTURES AT LOW DENSITY BY THE INVERSION METHOD (PART II)
Authors: HAGHIGHI BEHZAD , DJAVANMARDI ALIREZA HASSANI , PAPARI MOHAMAD MEHDI , NAJAFI MOHSEN
Published: March 2004

Viscosity and diffusion coefficients for five equimolar binary gas mixtures of SF 6 with O 2, CO 2, CF 4, N 2 and CH 4 gases are determined from the extended principle of corresponding states of viscosity by the inversion technique. The Lennard–Jones 12-6 (LJ 12-6) potential energy function is used as the initial model potential required by the technique. The obtained interaction potential energies from the inversion procedure reproduce viscosity within 1% and diffusion coefficients within 5%.
A New Selection Measure for Classification Using Decision Trees
Authors: Chandra B. , Saxena Gaurav
Published: March 2004

The paper proposes a new selection measure for classification using decision trees for Data mining. Various algorithms have been proposed in the past for classification using decision trees viz. ID3, CART, SLIQ, etc. Selection measures like the Gain, Gain ratio, and Gini index have been proposed in these algorithms. However, none of the selection measures developed so far take into account the balancing of trees. This paper proposes a new selection measure which also takes into account the balancing of trees that will facilitate in improving the classification accuracy. The performance of the original SLIQ algorithm, C5 and the algorithm using the new selection measure (which takes into account the accuracy as well as the balance factor) was measured on the basis of the classification accuracy. Three real life data sets were chosen for this purpose.
Role and Contribution of Corporate Information Centers toward KM Initiatives: An Analysis of Managers' Perceptions
Authors: Marouf Laila
Published: March 2004

Knowledge, since the late 1990s, has been increasingly seen as a primary business asset, while knowledge management (KM) has been perceived to be the key differentiator between firms in terms of their sustainability, profitability, innovative capacity, and change management. The reason for this interest in knowledge management is the belief that knowledge and its applications are the means by which creativity can be fostered (Nonaka and Nishiguchi, 2000), innovation enabled (Hargadon, 1998), and competencies leveraged so as to improve overall organizational performance.

Since knowledge has become the driving force for economic development, attention to the organization and management of information and knowledge has increased tremendously. The knowledge management discourse has also captured the attention of professionals working in the library and information sector. In recent years, a body of literature has emerged that explicitly addresses knowledge management from the perspective of library and information professionals (Broadbent, 1997; Nicholson, 1997; Loughridge, 1999). This literature carries a key assumption that library and information professionals have an important role to play in knowledge management. KM is also assumed to be an instrument in enhancing professional image and role of the information professionals. Yunhua (1999) makes a clear case for library development from the perspective of knowledge management.
h-TechSight — A Next Generation Knowledge Management Platform
Authors: Stollberg Michael , Zhdanova Anna V. , Fensel Dieter
Published: March 2004

A new breed of Knowledge Management Systems (KMS), referred to as the Next Generation of Knowledge Management (NGKM), aims at overcoming the limitations of existing KMS regarding the range and quality of supportable Knowledge Management activities. Therefore, AI-based technologies are employed to enable automated knowledge item processing instead of the information retrieval functionality provided by conventional KMS. This paper presents the Knowledge Management Platform (KMP) developed in the h-TechSight project as an NGKM solution. It is designed to support organizations in technology intensive industries in monitoring changes in their external environment as an important factor in competitiveness. Therefore, the KMP combines NGKM enabling technologies for automatically observation of information resources on the Internet in order to notify users whenever a change in their domain of interest occurs. The aim of this paper is to position the KMP as a KMS of the next generation and to delineate the lessons learned in KMS design in the h-TechSight project. Thus, we illustrate the idea of NGKM with special emphasis on enabling technologies and, on this basis, expose the functional design and technical realization of the h-TechSight KMP.
Knowledge Management Initiatives in a Global IT Outsourcing Company: A Case Study of Infosys Technologies
Authors: Mayasandra N Ravi Shankar , Pan Shan L
Published: March 2004

Organizations position their formal Knowledge Management (KM) initiatives as a continuous process of deriving strategic benefits from the knowledge resources dispersed in the various internal constituencies. Thus, gaining a deeper awareness of the diverse viewpoints and attributes of their various units is a big challenge for organizations embracing formal KM strategies. Even with the challenges of organization-wide KM forming the theme of a number of studies, we see that these studies mostly feature organizations outside the Asian continent. The KM strategies of Asian organizations remain a relatively uncharted territory. This paper focuses on the KM strategies of Infosys Technologies, a leading Asian Information Technology (IT) firm. Adopting the case study methodology, we look at the consequences of initiating organization-wide formal KM, in four different organizational units within the company. Evidence from the case highlights the unfolding of unintended and intended consequences in the four units, and organizational efforts to reconcile them. Taking a subcultural perspective of the four units offers useful insights in understanding the consequences. The theoretical and managerial contributions of the study to the knowledge management arena are discussed.
Observing Spatial and Temporal Metadata in Hostnames
Authors: Lekeas Paraskevas V.
Published: March 2004

In this work we present some evidence showing that spatial and temporal metadata can be mined from hostnames. Hostnames map to IPs, and a set of IP addresses relative to a specific geographic region forms an IP map. If we choose a geographic region and obtain its IP map we can study the hostname representation of the map and mine spatial and temporal information that refer to the entities that use these hostnames (metadata). In this work we choose United Kingdom to be a region of interest and we take a random sample of its IP map. Using the hostname representation of this sample we compute the spatial distribution of the infrastructure of a British ISP and a snapshot of its Internet traffic. We also compute the rate of growth of another British ISP by introducing time in hostname's representation with the help of a partial order. At last we conclude that the above spatial and temporal information can serve as an independent source for the evaluation of these companies.
A comparison of adrenergic stress responses in three tropical teleosts exposed to acute hypoxia
Authors: Perry S. F. , Reid S. G. , Gilmour K. M. , Boijink C. L. , Lopes J. M. , Milsom W. K. , Rantin F. T.
Published: March 2004

Experiments were performed to assess the afferent and efferent limbs of the hypoxia-mediated humoral adrenergic stress response in selected hypoxia-tolerant tropical fishes that routinely experience environmental O2depletion. Plasma catecholamine (Cat) levels and blood respiratory status were measured during acute aquatic hypoxia [water Po2(PwO2) = 10–60 mmHg] in three teleost species, the obligate water breathers Hoplias malabaricus (traira) and Piaractus mesopotamicus (pacu) and the facultative air breather Hoplerythrinus unitaeniatus (jeju). Traira displayed a significant increase in plasma Cat levels (from 1.3 ± 0.4 to 23.3 ± 15.1 nmol/l) at PwO2levels below 20 mmHg, whereas circulating Cat levels were unaltered in pacu at all levels of hypoxia. In jeju denied access to air, plasma Cat levels were increased markedly to a maximum mean value of 53.6 ± 19.1 nmol/l as PwO2was lowered below 40 mmHg. In traira and jeju, Cat release into the circulation occurred at abrupt thresholds corresponding to arterial Po2(PaO2) values of approximately 8.5–12.5 mmHg. A comparison of in vivo blood O2equilibration curves revealed low and similar P50values (i.e., PaO2at 50% Hb-O2saturation) among the three species (7.7–11.3 mmHg). Thus Cat release in traira and jeju occurred as blood O2concentration was reduced to approximately 50–60% of the normoxic value. Intravascular injections of nicotine (600 nmol/kg) elicited pronounced increases in plasma Cat levels in traira and jeju but not in pacu. Thus the lack of Cat release during hypoxia in pacu may reflect an inoperative or absent humoral adrenergic stress response in this species. When allowed access to air, jeju did not release Cats into the circulation at any level of aquatic hypoxia. The likeliest explanation for the absence of Cat release in these fish was that air breathing, initiated by aquatic hypoxia, prevented PaO2values from falling to the critical threshold required for Cat secretion. The ventilatory responses to hypoxia in each species were similar, consisting generally of increases in both frequency and amplitude. These responses were not synchronized with or influenced by plasma Cat levels. Thus the acute humoral adrenergic stress response does not appear to stimulate ventilation during acute hypoxia in these tropical species.
Characterization of blood pressure and morphological traits in cardiovascular-related organs in 13 different inbred mouse strains
Authors: Deschepper Christian F. , Olson Jean L. , Otis Melissa , Gallo-Payet Nicole
Published: March 2004

To better understand the contributions of various genetic backgrounds to complex quantitative phenotypes, we have measured several quantitative traits of cardiovascular interest [i.e., systolic blood pressure, weight (corrected by body weight) of several cardiac compartments and adrenals and kidneys, and histological correlates for kidneys and adrenals] in male and female mice from 13 different inbred strains. We selected strains so that each major genealogical group would be represented and to conform to priorities set by the Mouse Phenome Database project. Interstrain comparisons of phenotypes made it possible to identify strains that displayed values that belonged to either the low or the high end of the interstrain variance for quantitative traits, such as systolic blood pressure, body weight, left ventricular weight, and/or adrenocortical structure. For instance, both male and female C3H/HeJ and A/J mice displayed either low systolic blood pressure or low cardiac ventricular mass, respectively, and male C57BL6/J displayed low adrenal weight. Likewise, intersex comparisons made it possible to identify phenotypic values that were sexually dimorphic for some of the same traits. For instance, female AKR/J mice had relatively higher body weight and systolic blood pressure values than their male counterparts, perhaps constituting an animal model of the metabolic X syndrome. These strain- and sex-specific features will be of value both for future genetic and/or developmental studies and for the development of new animal models that will help in the generation of mechanistic hypotheses. All data have been deposited to the Mouse Phenome Database for future integration with the Mouse Genome Database and can be further analyzed and compared with tools available on the site.
Muscarinic Modulation of the Trigemino-Reticular Pathway in Lampreys
Authors: Le Ray Didier , Brocard Frédéric , Dubuc Réjean
Published: March 2004

In lampreys, reticulospinal neurons integrate sensory inputs to adapt their control onto the spinal locomotor networks. Whether and how sensory inputs to reticulospinal neurons are modulated remains to be determined. We showed recently that cholinergic inputs onto reticulospinal neurons play a key role in the initiation of locomotion elicited by stimulation of the mesencephalic locomotor region in semi intact lampreys. Here, we examined the possible role of muscarinic acetylcholine receptors in modulating trigeminal inputs to reticulospinal neurons. A local application of muscarinic agonists onto an intracellularly recorded reticulospinal cell depressed the disynaptic responses to trigeminal stimulation. A depression was also observed when muscarinic agonists were pressure ejected over the brain stem region containing second-order neurons relaying trigeminal inputs to reticulospinal neurons. Conversely, muscarinic antagonists increased the trigeminal-evoked responses, suggesting that a muscarinic depression of sensory inputs to RS neurons is exerted tonically. The muscarinic modulation affected predominantly the N-methyl-d-aspartate (NMDA) component of the trigeminal-evoked responses. Moreover, atropine perfusion facilitated the occurrence of sustained depolarizations induced by stimulation of the trigeminal nerve, and it revealed NMDA-induced intrinsic oscillations in reticulospinal neurons. The functional significance of a muscarinic modulation of a sensory transmission to reticulospinal neurons is discussed.
Remnant Lipoproteins from Patients with Sudden Cardiac Death Enhance Coronary Vasospastic Activity Through Upregulation of Rho-Kinase
Authors: Oi Keiji , Shimokawa Hiroaki , Hiroki Junko , Uwatoku Toyokazu , Abe Kohtaro , Matsumoto Yasuharu , Nakajima Yasuhiro , Nakajima Katsuyuki , Takeichi Sanae , Takeshita Akira
Published: March 2004

Objective—

Sudden cardiac death (SCD) still remains a serious problem. We have previously shown that remnant-like particles (RLP) are the major risk factor for SCD and that Rho-kinase plays a central role in the molecular mechanism of coronary vasospasm. In this study, we examined whether RLP from patients with SCD upregulate Rho-kinase associated with an enhanced coronary vasospastic activity.

Methods and Results—

We isolated RLP and non-RLP in very-low-density lipoprotein (VLDL) fraction from SCD patients without coronary stenosis. We performed in vivo study in which we treated the coronary artery with RLP or non-RLP fraction at the adventitia in pigs. After 1 week, intracoronary serotonin caused marked coronary hyperconstriction at the segment treated with RLP fraction but not with non-RLP fraction (
P
<0.001, n=6), and hydroxyfasudil, a selective Rho-kinase inhibitor, dose-dependently inhibited the spasm in vivo. In organ chamber experiments, serotonin caused hypercontraction of vascular smooth muscle cells (VSMC) from RLP-treated segment, which was significantly inhibited by hydroxyfasudil (
P
<0.001, n=6). In cultured human coronary VSMC, the treatment with RLP significantly enhanced the expression and activity of Rho-kinase (
P
<0.05, n=6).

Conclusions—

These results indicate that RLP from SCD patients upregulate Rho-kinase in coronary VSMC and markedly enhance coronary vasospastic activity.
Hemodilution With Stoma-Free Hemoglobin at Physiologically Maintained Viscosity Delays the Onset of Vasoconstriction
Authors: Rochon Géraldine , Caron Alexis , Toussaint-Hacquard Marie , Alayash Abdu I. , Gentils Monique , Labrude Pierre , Stoltz Jean François , Menu Patrick
Published: March 2004

Solutions of modified cell-free hemoglobin, prepared from outdated red blood cells, have been developed during the past decade to circumvent the increasing need for allogeneic blood. Despite improvements in the safety and efficacy of these solutions, undesirable effects such as an increase in vascular tone leading to hypertension have not been fully resolved, which might hinder their clinical usefulness. To discriminate between the pharmacological and rheological effects of cell-free hemoglobin, we compared the effects of blood/cell-free hemoglobin mixtures of high versus low viscosity on hemodynamics and vascular hindrance, an index of vascular tone, which was normalized for blood viscosity. Anesthetized rats were subjected to 50% exchange transfusion with (1) high-viscosity solutions: whole blood (n=5) or red blood cells mixed with cell-free hemoglobin (Hb-Hv group, n=5); (2) low-viscosity solutions: cell-free hemoglobin (Hb-Lv group, n=5) or human albumin (n=5). Two hours after hemodilution, vascular hindrance remained unchanged in animals transfused with whole blood and albumin. Hb-Lv induced an immediate and sustained increase in vascular hindrance (208%). Conversely, in Hb-Hv animals, the vascular hindrance increase was delayed and smaller (27% to 147%), whereas peripheral resistance increased gradually (94% after 2 hours). Our results demonstrate the beneficial effects of cell-free hemoglobin in the presence of the animals’ own red blood cells in maintaining physiological viscosity and limiting vasoconstriction because of the pharmacological properties of cell-free hemoglobin.
Angiotensin II Impairs the Insulin Signaling Pathway Promoting Production of Nitric Oxide by Inducing Phosphorylation of Insulin Receptor Substrate-1 on Ser
312
and Ser
616
in Human Umbilical Vein Endothelial Cells
Authors: Andreozzi Francesco , Laratta Emanuela , Sciacqua Angela , Perticone Francesco , Sesti Giorgio
Published: March 2004

It has been suggested that serine (Ser) phosphorylation of insulin receptor substrate-1 (IRS-1) decreases the ability of IRS-1 to be phosphorylated on tyrosine, thereby attenuating insulin signaling. There is evidence that angiotensin II (AII) may impair insulin signaling to the IRS-1/phosphatydilinositol 3-kinase (PI 3-kinase) pathway by enhancing Ser phosphorylation. Insulin stimulates NO production by a pathway involving IRS-1/PI3-kinase/Akt/endothelial NO synthase (eNOS). We addressed the question of whether AII affects insulin signaling involved in NO production in human umbilical vein endothelial cells and tested the hypothesis that the inhibitory effect of AII on insulin signaling was caused by increased site-specific Ser phosphorylation in IRS-1. Exposure of human umbilical vein endothelial cells to AII resulted in inhibition of insulin-stimulated production of NO. This event was associated with impaired IRS-1 phosphorylation at Tyr
612
and Tyr
632
, two sites essential for engaging the p85 subunit of PI3-kinase, resulting in defective activation of PI 3-kinase, Akt, and eNOS. This inhibitory effect of AII was reversed by the type 1 receptor antagonist losartan. AII increased c-Jun N-terminal kinase (JNK) and extracellular signal–regulated kinase (ERK) 1/2 activity, which was associated with a concomitant increase in IRS-1 phosphorylation at Ser
312
and Ser
616
, respectively. Inhibition of JNK and ERK1/2 activity reversed the negative effects of AII on insulin-stimulated NO production. Our data suggest that AII, acting via the type 1 receptor, increases IRS-1 phosphorylation at Ser
312
and Ser
616
via JNK and ERK1/2, respectively, thus impairing the vasodilator effects of insulin mediated by the IRS-1/PI 3-kinase/Akt/eNOS pathway.
Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms
Authors: Dai Yun , Rahmani Mohamed , Pei Xin-Yan , Dent Paul , Grant Steven
Published: March 2004

Interactions between the cyclin-dependent kinase (CDK) inhibitor flavopiridol and the proteasome inhibitor bortezomib were examined in Bcr/Abl+ human leukemia cells. Coexposure of K562 or LAMA84 cells to subtoxic concentration of flavopiridol (150-200 nM) and bortezomib (5-8 nM) resulted in a synergistic increase in mitochondrial dysfunction and apoptosis. These events were associated with a marked diminution in nuclear factor κB (NF-κB)/DNA binding activity; enhanced phosphorylation of SEK1/MKK4 (stress-activated protein kinase/extracellular signal-related kinase 1/mitogen-activated protein kinase kinase 4), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK); down-regulation of Bcr/Abl; and a marked reduction in signal transducer and activator of transcription 3 (STAT3) and STAT5 activity. In imatinib mesylate-resistant K562 cells displaying increased Bcr/Abl expression, bortezomib/flavopiridol treatment markedly increased apoptosis in association with down-regulation of Bcr/Abl and BclxL, and diminished phosphorylation of Lyn, Hck, CrkL, and Akt. Parallel studies were performed in imatinib mesylate-resistant LAMA84 cells exhibiting reduced expression of Bcr/Abl but a marked increase in expression/activation of Lyn and Hck. Flavopiridol/bortezomib effectively induced apoptosis in these cells in association with Lyn and Hck inactivation. The capacity of flavopiridol to promote bortezomib-mediated Bcr/Abl down-regulation and apoptosis was mimicked by the positive transcription elongation factor-b (P-TEFb) inhibitor DRB (5,6-dichloro 1-β-d-ribofuranosylbenzinida-sole). Finally, the bortezomib/flavopiridol regimen also potently induced apoptosis in Bcr/Abl- human leukemia cells. Collectively, these findings suggest that a strategy combining flavopiridol and bortezomib warrants further examination in chronic myelogenous leukemia and related hematologic malignancies. (Blood. 2004;104:509-518)
Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension
Authors: Bresser P. , Fedullo P.F. , Auger W.R. , Channick R.N. , Robbins I.M. , Kerr K.M. , Jamieson S.W. , Rubin L.J.
Published: March 2004

Pathophysiological findings in chronic thromboembolic pulmonary hypertension (CTEPH) have suggested that a secondary small vessel arteriopathy may contribute to the haemodynamic impairment observed in these patients. It was hypothesised that this element of the elevated vascular resistance may be responsive to continuous intravenous epoprostenol therapy.

Retrospectively, the clinical and haemodynamic responses to continuous intravenous epoprostenol were evaluated in nine CTEPH patients who subsequently underwent pulmonary thromboendarterectomy (PTE). Cardiopulmonary haemodynamics were determined prior to the initiation of epoprostenol, while on epoprostenol, prior to PTE, and after PTE.

Six patients, treated for 2–26 months prior to PTE, experienced either clinical stability or improvement that was associated with a mean reduction in pulmonary vascular resistance (PVR) of 28% (median 33%, range 0–46%). Three patients, treated for 3–9 months, experienced clinical deterioration during epoprostenol administration, with a significant increase in PVR in two patients. Subsequent PTE resulted in a highly significant improvement of cardiac index, mean pulmonary artery pressure and total pulmonary resistance.

To conclude, selected patients with chronic thromboembolic pulmonary hypertension may benefit clinically and haemodynamically from continuous intravenous epoprostenol treatment prior to pulmonary thromboendarterectomy. Factors predictive of a beneficial response, and whether this intervention influences either morbidity or mortality associated with pulmonary thromboendarterectomy, remain to be established.
Significance of precipitins and asymptomatic lymphocytic alveolitis: a 20‐yr follow-up
Authors: Cormier Y. , Létourneau L. , Racine G.
Published: March 2004

What is the significance of serum preciptins and lymphocytic alveolitis in a healthy subject exposed to antigens responsible for hypersensitivity pneumonitis (HP)? This study was done to evaluate the 20‐yr outcome of asymptomatic dairy farmers with or without precipitins or lymphocytic alveolitis in their bronchoalveolar lavage (BAL).

Twenty-seven of the initial 43 farmers were restudied. Of the missing 16, 11 refused the follow-up, three had died and two could not be located. The restudied farmers had a clinical evaluation, lung function tests and a high resolution computed tomography (HRCT).

Only one subject, an asthmatic, had dyspnoea, none described present or past symptoms suggestive of HP. Of those who were no longer on the farm, none had quit because of respiratory problems. Lung function changes were as expected with aging. The only difference was that farmers with positive precipitins had a statistically significant greater decrease in their forced expiratory volume in one second than the sero-negative farmers. Four HRCTs showed signs of minimal parenchymal abnormalities; these were not more prevalent for subjects with or without precipitins or BAL lymphocytosis.

Serum precipitins and asymptomatic lymphocytic alveolitis in an asymptomatic, exposed dairy farmer have no clinically meaningful long-term consequences.
3‐Min step test and treadmill exercise for evaluating exercise-induced asthma
Authors: Tancredi G. , Quattrucci S. , Scalercio F. , De Castro G. , Zicari A.M. , Bonci E. , Cingolani S. , Indinnimeo L. , Midulla F.
Published: March 2004

A simple exercise test would be useful for detecting exercise-induced asthma, a common problem in asthmatic children. The current study compared the 3‐min step test with treadmill exercise for evaluating exercise-induced asthma in asthmatic children and assessed whether responses to both tests are influenced by baseline lung function and habitual physical activity.

A series of 154 asthmatic children (84 male children; mean age 12.9±0.9 yrs) underwent a 3‐min step-test and treadmill testing on different days within a week at least 24 h apart. Before both tests each subject did spirometry to obtain the baseline forced expiratory volume in one second (FEV1). After both exercise challenges all subjects did serial spirometry and the lowest FEV1recorded over time was used to calculate the fall in FEV1expressed as a percentage of the measured pre-exercise (baseline) value (% fall in FEV1) and the area above the FEV1curve (AAC0–30 min) expressed as a percentage of the pre-exercise value. Changes in both exercise variables were also analysed in percentile subgroups defined by questionnaire answers on habitual physical activity in hours.

The mean % fall in FEV1was significantly higher for treadmill exercise than for the step test (15.0±7.5versus11.7±5.9); and the AAC0–30 minwas larger for treadmill than for the step test (−261.6±139.9%versus−197.3±105.0% min). In all subgroups defined by habitual physical activity the mean % fall in FEV1decreased more after treadmill exercise than after the step test. After step test and treadmill exercise no significant correlation was found between % fall in FEV1and baseline lung function, or between % fall in FEV1among groups defined by habitual physical activity.

Although the 3‐min step test yields a lower % fall in forced expiratory volume in one second (FEV1) and a lower value of the area above the FEV1curve than treadmill testing, it is a quick, economical, reproducible and portable alternative procedure for identifying exercise-induced asthma in outpatients and epidemiological studies. Baseline lung function and habitual physical activity have no influence on the amount or duration of exercise-induced asthma.
Scintigraphic measurement of tracheal mucus velocityin vivo
Authors: Morgan L. , Pearson M. , de Iongh R. , Mackey D. , van der Wall H. , Peters M. , Rutland J.
Published: March 2004

Mucociliary clearance (MCC) is an important mechanism for removing inhaled particles, secretions and cellular debris from the respiratory tract. Here, a direct measurement of tracheal mucus velocity (TMV) for assessment of MCC, suitable for clinical and research use, is reported, and a comparison is made of TMV in normal subjects and patients with chronic obstructive pulmonary disease (COPD).

A 0.1‐mL bolus of radiolabelled (2–5 MBq), technetium-labelled macroaggregated human albumin (99mTc MAA) was injected through the cricothyroid membrane into the trachea of 20 young (<50 yrs) and 12 older (>50 yrs) normal subjects and 34 patients with COPD. Repeat studies were carried out in 13 normal subjects and 16 COPD patients. Movement of the bolus in the trachea was recorded (15 min) using a gamma camera interfaced to a computer. Data were analysed using specifically designed software.

The test was well tolerated by subjects and patients, and no significant adverse events were reported. No significant differences were observed between data recorded from different regions of the bolus (leading edge, peak, trailing edge) by analysis of variance (ANOVA). Bland-Altman plots of the repeat studies indicated that data were more variable in normal subjects (coefficient of repeatability (COR) 10.3 mm·min−1) than in COPD patients (COR 5.5 mm·min−1). TMV (mean±sd) in young normal subjects (n=20) was 10.7±3.5 mm·min−1. TMV was reduced in older normal subjects (n=12; 6.5±2.6 mm·min−1) and further reduced in COPD (n=34; 2.1±2.7 mm·min−1).

In conclusion, this technique can be used to measure tracheal mucus velocity rapidly and safely in healthy subjects and patients with respiratory tract disease. This study has confirmed that tracheal mucus velocity declines with age and is further impaired in patients with chronic obstructive pulmonary disease.
Does systemic inflammation trigger local exercise-induced oxidative stress in COPD?
Authors: Koechlin C. , Couillard A. , Cristol J.P. , Chanez P. , Hayot M. , Le Gallais D. , Préfaut C.
Published: March 2004

Inflammatory abnormalities may be involved in the inadequate basal oxidant/antioxidant balance and local exercise-induced oxidative stress in chronic obstructive pulmonary disease (COPD) patients.

The time course of oxidative stress and inflammation was investigated in 10 COPD patients and seven healthy subjects before and after local dynamic quadriceps endurance exercise at 40% of maximal strength. Venous samples were collected before, immediately after and up to 48 h after exercise.

At rest, levels of an oxidant released by stimulated phagocytes, the superoxide anion, were significantly higher in patients, as were plasma levels of C‐reactive protein, tumour necrosis factor‐α and interleukin‐6, inflammatory markers. An inverse relationship was found between baseline C‐reactive protein levels and endurance time in patients. Six hours after exercise, superoxide anion release and levels of protein oxidation products, an index of oxidative stress, increased similarly in both groups, whereas thiobarbituric acid reactive substance levels, another index of oxidative stress, increased significantly only in patients. Plasma nonenzymatic antioxidant and inflammatory cytokine levels were unchanged by the exercise protocol.

The increased baseline systemic inflammation in chronic obstructive pulmonary disease patients could be related to disturbed oxidant/antioxidant balance, and, together, these may have triggered the exercise-induced oxidative stress. The absence, however, of local exercise-induced systemic inflammation suggests that additional mechanisms explain local exercise-induced oxidative stress.
Dose-response relationship of inhaled budesonide in adult asthma: a meta-analysis
Authors: Masoli M. , Holt S. , Weatherall M. , Beasley R.
Published: March 2004

The aim of this study was to examine the dose-response relationship of inhaled budesonide in adolescents and adults with asthma.

A meta-analysis was carried out on placebo-controlled, randomised clinical trials, presenting data on at least one outcome measure of asthma and using at least two doses of budesonide, delivered by turbuhaler or metered-dose inhaler+spacer twice daily.

A total of six studies of 1,435 adolescents and adults, with mild to moderately severe asthma, met the inclusion criteria for the meta-analysis. A negative exponential model indicated that 80% of the benefit at 1,600 µg·day−1was achieved at doses of ∼200–400 µg·day−1and 90% by 300–600 µg·day−1. Meta-regression with a quadratic term in dose showed that the maximum effect was obtained with doses of ∼1,000 µg·day−1.

In conclusion, the available published data indicate that, in adolescents and adults with mild to moderate asthma, most of the therapeutic benefit of budesonide delivered by turbuhaler or metered-dose inhaler+spacer is achieved with a dose of ∼400 µg·day−1and the maximum effect is achieved at ∼1,000 µg·day−1. This conclusion is qualified by the recognition that there is considerable individual variability in the response to inhaled corticosteroids and that the subjects included in this meta-analysis had predominantly mild to moderate asthma.
Chronic thromboembolic pulmonary hypertension
Authors: Dartevelle P. , Fadel E. , Mussot S. , Chapelier A. , Hervé P. , de Perrot M. , Cerrina J. , Ladurie F.L. , Lehouerou D. , Humbert M. , Sitbon O. , Simonneau G.
Published: March 2004

Pulmonary arterial hypertension is a severe disease that has been ignored for a long time. However, over the past 20 yrs chest physicians, cardiologists and thoracic surgeons have shown increasing interest in this disease because of the development of new therapies, that have improved both the outcome and quality of life of patients, including pulmonary transplantation and prostacyclin therapy.

Chronic thromboembolic pulmonary arterial hypertension (CTEPH) can be cured surgically through a complex surgical procedure: the pulmonary thromboendarterectomy. Pulmonary thromboendarterectomy is performed under hypothermia and total circulatory arrest.

Due to clinically evident acute-pulmonary embolism episodes being absent in >50% of patients, the diagnosis of CTEPH can be difficult. Lung scintiscan showing segmental mismatched perfusion defects is the best diagnostic tool to detect CTEPH.

Pulmonary angiography confirms the diagnosis and determines the feasability of endarterectomy according to the location of the disease, proximalversusdistal. The technique of angiography must be perfect with the whole arterial tree captured on the same picture for each lung. The lesions must start at the level of the pulmonary artery trunk, or at the level of the lobar arteries, in order to find a plan for the endarterectomy.

When the haemodynamic gravity corresponds to the degree of obliteration, pulmonary thromboendarterectomy can be performed with minimal perioperative mortality, providing definitive, excellent functional results in almost all cases.
Reduced spontaneous apoptosis in peripheral blood neutrophils during exacerbation of COPD
Authors: Pletz M.W.R. , Ioanas M. , de Roux A. , Burkhardt O. , Lode H.
Published: March 2004

A major feature of acute exacerbation of chronic obstructive pulmonary disease (COPD) is the accumulation of activated neutrophils in the bronchial tree. This phenomenon can be explained by an increased migration and/or by a prolonged survival due to an inhibition of spontaneous apoptosis. The aim of this study was to assess the apoptotic behaviour of peripheral blood neutrophils in COPD patients during an acute exacerbation.

Thirty-six hospitalised COPD patients with an acute exacerbation and 10 healthy volunteers were included. Blood samples were obtained at admission, after 3–5 days and at discharge. Spontaneous apoptosis of isolated neutrophils was measured based on Annexin V‐PE binding and nuclear morphology after culturing for 18 h.

At admission, significantly lower rates of spontaneous apoptosis were noted in COPD patients compared with healthy volunteers (mean±sd 31±13%versus44±18%). The mean percentages of apoptotic neutrophils were 31±13% at admission, 39±15% after 3–5 days and 47±18% at discharge. There was a statistically significant difference between the rates of spontaneous apoptosis on the first day and at discharge. Neither forced expiratory volume in one second <35% predicted, smoking habit, corticosteroid therapy nor evidence of bacterial infection showed any influence on the spontaneous apopotosis in this study.

In conclusion, during acute exacerbations of chronic obstructive pulmonary disease, neutrophil granulocytes show a reduced spontaneous apoptosis that increases progressively after treatment and clinical remission. This raises the question of the importance of neutrophil apoptosis in the development and resolution of exacerbations of chronic obstructive pulmonary disease.