bluuebunny/crossref_metadata_2025 huggingface dataset:
GADD34 protein levels increase after transient ischemia in the cortex but not in the CA1 subfield: implications for post‐ischemic recovery of protein synthesis in ischemia‐resistant cells
Authors: Paschen Wulf , Hayashi Takeshi , Saito Atsushi , Chan Pak H.
Published: July 2004

Transient cerebral ischemia is a pathological process whereby an irreversible suppression of protein synthesis is believed to contribute to the extent of cell death in vulnerable neurons. Endoplasmic reticulum (ER) dysfunction has been identified as being responsible for ischemia‐induced shut‐down of translation. Recovery from ER dysfunction is facilitated by GADD34, a protein that dephosphorylates eukaryotic initiation factor (eIF)2α‐P and thus reactivates protein synthesis. We investigated ischemia‐induced changes in GADD34 levels in wild‐type and Cu2+/Zn2+SOD (SOD1) over‐expressing rats. Transient global cerebral ischemia was induced by common carotid artery occlusion. Tissue samples were taken from the vulnerable hippocampal CA1 subfield and the resistant cerebral cortex of the right and left hemispheres for evaluation of changes ingadd34mRNA and GADD34 protein levels. In wild‐type animals, we found significantly lower GADD34 levels than in SOD1 transgenes but no differences ingadd34mRNA levels, implying that superoxides regulategadd34translation. After ischemia, GADD34 protein levels were significantly increased in the cortex but not in the CA1 subfield, and these changes occurred earlier in SOD1 transgenic than in wild‐type animals. The rise ingadd34mRNA levels did not differ in the cortex and CA1 subfield, implying thatgadd34expression is regulated at the translational level.
Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury
Authors: Conte Valeria , Uryu Kunihiro , Fujimoto Scott , Yao Yuemang , Rokach Joshua , Longhi Luca , Trojanowski John Q. , Lee Virginia M‐Y. , McIntosh Tracy K. , Praticò Domenico
Published: July 2004

Traumatic brain injury is a well‐recognized environmental risk factor for developing Alzheimer's disease. Repetitive concussive brain injury (RCBI) exacerbates brain lipid peroxidation, accelerates amyloid (Aβ) formation and deposition, as well as cognitive impairments in Tg2576 mice. This study evaluated the effects of vitamin E on these four parameters in Tg2576 mice following RCBI. Eleven‐month‐old mice were randomized to receive either regular chow or chow‐supplemented with vitamin E for 4 weeks, and subjected to RCBI (two injuries, 24 h apart) using a modified controlled cortical impact model of closed head injury. The same dietary regimens were maintained up to 8 weeks post‐injury, when the animals were killed for biochemical and immunohistochemical analyses after behavioral evaluation. Vitamin E‐treated animals showed a significant increase in brain vitamin E levels and a significant decrease in brain lipid peroxidation levels. After RBCI, compared with the group on regular chow, animals receiving vitamin E did not show the increase in Aβ peptides, and had a significant attenuation of learning deficits. This study suggests that the exacerbation of brain oxidative stress following RCBI plays a mechanistic role in accelerating Αβ accumulation and behavioral impairments in the Tg2576 mice.
The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite ‘scavenger’?
Authors: Whiteman Matthew , Armstrong Jeffrey S. , Chu Siew Hwa , Jia‐Ling Siau , Wong Boon‐Seng , Cheung Nam Sang , Halliwell Barry , Moore Philip K.
Published: July 2004

Hydrogen sulfide (H2S) is a well‐known cytotoxic gas. Recently it has been shown to stimulate N‐methyl‐d‐aspartate (NMDA) receptors to enhance long‐term potentiation suggesting a novel neuromodulatory role in vivo. Endogenous levels of H2S in the brain are reported to range between 10 and 160 µm. Considerably lower H2S levels are reported in the brains of Alzheimer's disease (AD) patients, where levels of brain protein nitration (probably mediated by peroxynitrite) are markedly increased. Activation of NMDA receptors leads to intracellular tyrosine nitration by peroxynitrite. Because H2S and peroxynitrite are important mediators in brain function and disease, we investigated the effects of the H2S ‘donor’, sodium hydrogen sulfide (NaSH) on peroxynitrite‐mediated damage to biomolecules and to cultured human SH‐SY5Y cells. H2S significantly inhibited peroxynitrite‐mediated tyrosine nitration and inactivation of α1‐antiproteinase to a similar extent to reduced glutathione at each concentration tested (30–250 µm). H2S also inhibited peroxynitrite‐induced cytotoxicity, intracellular protein nitration and protein oxidation in human neuroblastoma SH‐SY5Y cells. These data suggest that H2S has the potential to act as an inhibitor of peroxynitrite‐mediated processes in vivo and that the potential antioxidant action of H2S deserves further study, given that extracellular GSH levels in the brain are very low.
Semicarbazide‐sensitive amine oxidase: role in the vasculature and vasodilation afterin situinhibition
Authors: Vidrio H.
Published: July 2004

1 The characteristics of semicarbazide‐sensitive amine oxidase (SSAO) are reviewed and the unknown physiological or pathological role of this enzyme emphasized.

2 The various mechanisms of action proposed for the vasodilator drug hydralazine are considered. In particular, the inhibitory action on various enzymes, related or not to cardiovascular function, are discussed.

3 Studies linking inhibition of SSAO to hydralazine hypotension are reviewed and a general hypothesis relating both actions is presented. The hypothesis postulates that (a) vascular SSAO is involved in the regulation of vascular tone, and (b) hydralazine vasodilation is the consequence of vascular SSAO inhibition.

4 Evidence supporting these postulates is presented and vascular SSAO inhibition is proposed as a novel mechanism of vasodilation.
AT1‐receptor blockade and sympathetic neurotransmission in cardiovascular disease
Authors: Nap A. , Balt J. C. , Mathy M. J. , Van Zwieten P. A.
Published: July 2004

1 The present survey is dealing with the interactions between the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system (SNS) in various organs and tissues, with an emphasis on the angiotensin AT‐receptors located at the sympathetic nerve endings.

2 Angiotensin II, the main effector of the RAAS is known to stimulate sympathetic nerve traffic and its sequelae in numerous organs and tissues, such as the central nervous system, the adrenal medulla, the sympathetic ganglia and the sympathetic nerve endings. These stimulatory effects are mediated by AT1‐receptors and counteracted by AT1‐receptor antagonists.

3 Sympatho‐inhibition at the level of the sympathetic nerve ending appears to be a class effect of the AT1‐receptor blockers, mediated by presynaptic AT1‐receptors. With respect to the ratio pre‐/postsynaptic AT1‐receptor antagonism important quantitative differences between the various compounds were found.

4 Both the pre‐ and postjunctional receptors at the sympathetic nerve endings belong to the AT1‐receptor population. However, the presynaptic receptors belong to the AT1B‐subtype, whereas the postjunctional receptors probably belong to a different AT1‐receptor subpopulation.

5 Sympatho‐inhibition is a class effect of the AT1‐receptor antagonists. In conditions in which the SNS plays a pathophysiological role, such as hypertension and congestive heart failure, this property may well be of therapeutic relevance.
Differential regulation by Ca2+ of calmodulin‐ and PKC‐dependent contractile pathways in cat lower oesophageal sphincter
Authors: Sohn U. D. , Park J. H. , Lee T. S. , Shin C. Y. , Jeong J. H. , Kim J. H. , Je H. D. , Dartt D. A. , Zoukhri D. , Choi H. C. , Lee K. Y.
Published: July 2004

1 In the present investigation we examined the regulation of calmodulin (CaM)‐ and protein kinase C (PKC)‐dependent pathways by cytosolic Ca2+ in the contraction of cat lower oesophageal sphincter (LES).

2 Force developed in response to increasing doses of acetylcholine (ACh) was directly related to the increase of the [Ca2+]i measured by fura‐2. Thapsigargin, which depletes Ca2+ stores, reduced the contraction and the [Ca2+]i. In addition, contraction in response to maximal ACh was reduced by the CaM inhibitor CGS9343B but not by the PKC inhibitor chelerythrine. The contraction in response to submaximal ACh was reduced by chelerythrine but not by CGS9343B.

3 In permeabilized cells, the contraction in response to low Ca2+ (0.54 μm) was also reduced by CGS9343B.

4 The response to high Ca2+ (1.0 μm) was reduced by CGS9343B. ACh also inhibited PKC activation induced by diacylglycerol, which activation is inhibited by the N‐myristoylated peptide inhibitor derived from pseudosubstrate sequences of PKCαβγ (myr‐PKC‐αβγ), but not of myr‐PKC‐α.

5 These data are consistent with the view that activated CaM‐dependent pathways inhibit PKC‐dependent pathways, this switch mechanism might be regulated by Ca2+ in the LES.
Co‐localization of histamine and dopamine‐β‐hydroxylase in sympathetic ganglion and release of histamine from cardiac sympathetic terminals of guinea‐pig
Authors: Li M. , Luo X. , Chen L. , Zhang J. , Hu J. , Lu B.
Published: July 2004

1 The aim of this study was to investigate the co‐localization of histamine and dopamine‐β‐hydroxylase in the superior cervical ganglion of guinea‐pig and release of histamine from cardiac sympathetic terminals in guinea‐pig isolated atrium.

2 Histidine decarboxylase (a histamine‐synthesizing enzyme) mRNA signals were detected in the neurones of superior cervical ganglion of guinea‐pig by in situ hybridization. The results of double‐labelled immunofluorescence further confirmed the co‐localization of histamine and dopamine‐β‐hydroxylase in the large principle neurons and small intensely fluorescent cells in the superior cervical ganglion. The immunoreactivities of both histamine and dopamine‐β‐hydroxylase were significantly attenuated after 6‐hydroxydopamine‐induced lesion of sympathetic nerves.

3 The refractory electrical field stimulation caused the release of histamine from cardiac sympathetic terminals of guinea‐pig isolated atria (112.14 ± 40.34 ng ml−1), which was significantly attenuated to 35 ± 15.57 ng ml−1 by reserpine pretreatment. Following administering compound 48/80, a mast cell degranulator, electrical field stimulation induced a dramatic increase of endogenous histamine release from isolated atria (303.57 ±72.93 ng ml−1). When compound 48/80 was added to the reserpine‐treated atria, the release of histamine induced by field stimulation was decreased to 207.14 ± 76.39 ng ml−1.

4 These results provide novel evidence that histamine co‐exists with noradrenaline in sympathetic nerves and might act as a neurotransmitter to modulate sympathetic neurotransmission.
Transforming Public Service in a World without Boundaries
Authors: Herbert Adam W.
Published: July 2004

In July 1995, the American Society for Public Administration's Endowment Board established the Donald C. Stone Fund to honor the memory of this public administration legend. Income from this fund is used to sponsor a lecture or symposium at ASPA's national conference, which reflects Stone's varied interests and contributions to the field. This year marked the ninth Donald C. Stone Lecture. On March 30, Adam W. Herbert was ASPA's Stone Lecturer and gave the following speech.
On Cooper's “Big Questions”
Authors: Rohr John A.
Published: July 2004

This is a commentary on Terry Cooper's effort to identify the “big questions” in administrative ethics to effect a more “focused, collaborative effort” in the ethics field. Although the author supports the thrust of Cooper's argument, he points out certain limitations therein.
A Partial Revolution: The Diplomatic Ethos and Transparency in Intergovernmental Organizations
Authors: Roberts Alasdair
Published: July 2004

The World Trade Organization and other intergovernmental organizations confront a crisis of legitimacy that is partly rooted in their perceived secretiveness. These organizations have attempted to address this crisis by promising “the maximum possible level of transparency,” but in fact, the improvements have been modest. Policies regarding access to information about intergovernmental organizations' operations continue to accommodate conventions of diplomatic confidentiality. Such conventions are more likely to be breached in areas where disclosure of information is essential to economic liberalization. A true revolution in transparency would require more rigorous policies on disclosure of information held by intergovernmental organizations such as the World Trade Organization, and could be justified as a prerequisite for the exercise of basic human rights, such as the right to participate fully in the policy‐making process.
Administration, Governance, and Policy Tools in Welfare Policy Implementation
Authors: Ewalt Jo Ann G. , Jennings Edward T.
Published: July 2004

Landmark welfare reform legislation passed in 1996 has been operating by legislative extensions since its expiration in September 2002. At this writing, reauthorization has been derailed by controversy over various legislative proposals. In this article, we contribute to the welfare policy debate by studying the importance of specific policy tools and the role of public administration in the dramatic fall in welfare caseloads from 1996 to 2000. Using administrative and survey data on welfare programs in 44 states, we test our theory that caseload reduction is a function of administrative commitments, policy design, and administrative actions linked to five sets of governance variables: environmental factors, client characteristics, treatments, administrative structures, and managerial roles and actions. We find strong evidence that administrative action to move clients into work, coupled with administrative commitments, can provide important links between policy goals and policy outcomes.
Establishing a Continuum from Minimizing to Maximizing Bureaucrats: State Agency Head Preferences for Governmental Expansion—A Typology of Administrator Growth Postures, 1964–98
Authors: Bowling Cynthia J. , Cho Chung‐Lae , Wright Deil S.
Published: July 2004

Scholars have long suspected the blanket description of bureaucrats as “budget maximizers” is simplistic and inaccurate. This article provides empirical grounds for questioning that description and enhances our understanding of bureaucratic fiscal preferences. Bureaucratic preferences for expansion are distributed along a continuum. A typology of agency heads' expansion preferences is developed and related to Downs's typology of bureaucrats. Data from eight surveys of state agency heads (1964–98) enable us to trace administrators' preferences for expansion over four decades. These preferences vary substantially in any single survey year and reflect trends across these years. Notably, a substantial proportion of agency heads opted for no expansion in their own agency's programs and expenditures or in the state's overall budget. This typology challenges conventional conceptions of bureaucrats' maximizing preferences, advances alternative interpretations about budget minimizing, and fills an important gap in budget and bureaucracy theory.
Building the Administrative State
Authors: Bertelli Anthony
Published: July 2004

Books reviewed in this article:

Daniel P. Carpenter, The Forging of Bureaucratic Autonomy: Reputations, Networks, and Policy Innovation in Executive Agencies, 1862–1928

David E. Lewis, Presidents and the Politics of Agency: Design Political Insulation in the United States Government Bureaucracy, 1946–1997
Solitude and the Restlessness of the Immemorial: Levinasian Traces in the Discourse of Patrick Modiano
Authors: Levy Karen D.
Published: July 2004

Emmanuel Levinas contested Western ontology's insistence on the importance of individual autonomy and systematized knowledge, developing a new description of how identity and intersubjectivity are constructed. In the early De l'existence à l'existant and Le Temps et l'autre, he explains how the effort of existing is assumed, creating a sense of mastery but also of solitude, for the ego and the self are tied to one another, but it is not until Totalité et Infini that he elaborates on the ethical encounter with the face as discourse. In his last major work Autrement qu’être ou au‐delà de l'essence, he focuses on the consequences of this epiphany for the subject, and relates this to the trace, a special kind of sign that focuses not so much on the relationship between sign and referent as on the irreversible passing of those who left them.

The paired texts of Patrick Modiano's Voyage de noces and Dora Bruder most strikingly inscribe the simultaneous self‐absorption and tedium of existing, but also depict how traces from the immemorial shatter the subject's autonomy. Modiano is haunted by the missing person ad's description of a runaway girl who disappeared in December 1941, was interned in Drancy the following summer and then deported to Auschwitz. He first wrote Voyage de noces to exorcise the spell the ad cast upon him, was eventually compelled to respond directly to the summons by composing Dora Bruder. Modiano tries to retrieve fragments of the adolescent Dora's past and rescue her from oblivion, but his efforts prove largely futile, for there is no memory to retrieve. His insistence on Dora's decision to remain in Drancy with her father makes it possible for him to forgive his own father's failings and acknowledge his admiration both for him and all those who defied Occupation hypocrisy. Lastly, Modiano's text calls upon us as readers to become the guardians of the pleas that French authorities ignored and thereby accept the summons of the immemorial ourselves.
Description, description d'actions et itération: réflexions à partir de l'exemple de Julien Gracq1
Authors: Killander Carla Cariboni
Published: July 2004

Le récit itératif, dont Genette a montré le fonctionnement à partir du texte proustien, occupe une place centrale dans les récits de Gracq. La question qui est soulevée dans cet article est celle du statut théorique qu'il revêt. L'indication fournie par une pratique courante chez les critiques de Gracq, consistant à traiter les passages itératifs comme descriptifs, invite à formuler l'hypothèse que le récit itératif doit être considéré comme une forme de description. La pertinence de la catégorie théorique de la « description d'actions » s'avère cependant faible lorsqu'il s'agit de rendre compte de la forme et du fonctionnement des passages itératifs chez Gracq. La nécessité apparaît d’élargir la notion théorique de description élaborée par des théoriciens de la description.
Abnormally elevated intramuscular pressure impairs muscle blood flow at rest after exercise
Authors: Zhang Q. , Styf J.
Published: July 2004

We used photoplethysmography (PPG) to measure the relative changes in the anterior tibial muscle blood flow (MBF) in response to exercise when intramuscular pressure (IMP) was elevated (the test leg) or when IMP was normal (the control leg). The elevated IMP was induced by applying venous obstruction of 40 mmHg or 65 mmHg (thigh tourniquet) of a casted leg in eight healthy subjects. Subjects performed dorsiflexion of both feet in sitting position with or without venous obstruction. IMP at rest after exercise increased to 39.4±7.9 mmHg or to 58.3±8.4 mmHg, respectively. MBF at rest before exercise was 100%. At rest after exercise, it increased to 184±52.6% in the test leg when IMP was 39.4 mmHg, and to 279±108.3% in the control leg. MBF at rest after exercise was 156±58.2% in the test leg when IMP was 58.3 mmHg and 303±95.3% in the control leg. The abnormally elevated IMP induced by venous obstruction of a casted leg reduced MBF at rest after exercise. PPG seems to be a suitable method to measure changes in MBF in response to exercise and in experimental conditions with abnormally elevated IMP.
Prointegrin Maturation Follows Rapid Trafficking and Processing of MT1‐MMP in Furin‐Negative Colon Carcinoma LoVo Cells
Authors: Deryugina Elena I. , Ratnikov Boris I. , Yu Qing , Baciu Peter C. , Rozanov Dmitri V. , Strongin Alex Y.
Published: July 2004

Understanding the function of invasion‐promoting membrane type‐1 matrix metalloproteinase (MT1‐MMP) is of paramount importance for understanding cancer biology. MT1‐MMP is synthesized in cells as a latent zymogen that requires the cleavage of its prodomain to exert the proteolytic activity. The mature αv integrin subunit is also generated by endoproteolytic cleavage of the αv subunit precursor (pro‐αv). Cleavage by furin is considered to be a principal event in the activation of both MT1‐MMP and pro‐αv. To elucidate the alternative activation pathway of MT1‐MMP and pro‐αv, we employed furin‐negative LoVo cells, which co‐express MT1‐MMP with integrin αvβ3. In these cells the MT1‐MMP proenzyme was rapidly trafficked to the plasma membrane via an unconventional Brefeldin A‐resistant pathway and, then, autocatalytically processed on the cell surface. Next, the MT1‐MMP activity converted the cell surface‐associated pro‐αv into the mature αv integrin, represented by the disulfide‐bonded heavy and light chains, and promoted the formation of the functional integrin αvβ3 heterodimer. These events stimulated cell motility in vitro, and malignant invasion and tumor growth in vivo. Our data suggest that in furin‐negative colon carcinoma cells MT1‐MMP is autocatalytically processed and the active protease then operates as a prointegrin convertase. Our findings argue strongly that the processing by furin is not a prerequisite for the activation of MT1‐MMP.
Annexin–Actin Interactions
Authors: Hayes Matthew J. , Rescher Ursula , Gerke Volker , Moss Stephen E.
Published: July 2004

The actin cytoskeleton is a malleable framework of polymerised actin monomers that may be rapidly restructured to enable diverse cellular activities such as motility, endocytosis and cytokinesis. The regulation of actin dynamics involves the coordinated activity of numerous proteins, among which members of the annexin family of Ca2+‐ and phospholipid‐binding proteins play an important role. Although the roles of annexins in actin dynamics are not understood at a mechanistic level, annexins have the requisite properties to integrate Ca2+‐signaling with actin dynamics at membrane contact sites. In this review we discuss the current state of knowledge on this topic, and consider how and where annexins may fit into the complex molecular machinery that regulates the actin cytoskeleton.
Strain softening behaviour in nonviable rat right‐ventricular trabeculae, in the presence and the absence of butanedione monoxime
Authors: Kirton R. S. , Taberner A. J. , Nielsen P. M. F. , Young A. A. , Loiselle D. S.
Published: July 2004

Strain softening is commonly reported during mechanical testing of passive whole hearts. It is typically manifested as a stiffer force–extension relationship in the first deformation cycle relative to subsequent cycles and is distinguished from viscoelasticity by a lack of recovery of stiffness, even after several hours of rest. The cause of this behaviour is presently unknown. In order to investigate its origins, we have subjected trabeculae to physiologically realistic extensions (5–15% of muscle length at 26°C and 0.5 mm Ca2+), while measuring passive force and dynamic stiffness. While we did not observe strain softening in viable trabeculae, we found that it was readily apparent in nonviable (electrically inexcitable) trabeculae undergoing the same extensions. This result was obtained in both the presence and absence of 2,3‐butanedione monoxime (BDM). Furthermore, BDM had no effect on the passive compliance of viable specimens, while its presence partly inhibited, but could not prevent, stiffening of nonviable specimens. Loss of viability was accompanied by a uniform increase of dynamic stiffness over all frequencies examined (0.2–100 Hz). The presence of strain softening during length extensions of nonviable tissue resulted in a comparable uniform decrease of dynamic stiffness. It is therefore concluded that strain softening is neither intrinsic to viable rat right ventricular trabeculae nor influenced by BDM but, rather, reflects irreversible damage of tissue in partial, or full, rigor.
Long‐term structural and functional consequences of cardiac ischaemia–reperfusion injury in vivo in mice
Authors: Celle Tijl De , Cleutjens Jack P. , Blankesteijn W. Matthijs , Debets Jacques J. , Smits Jos F. , Janssen Ben J.
Published: July 2004

The short‐term (<24 h) consequences of oxidative stress induced by ischaemia–reperfusion (IR) have been studied extensively in the mouse heart. However, much less is known about the long‐term effects inflicted by a brief ischaemic period on the murine heart. We therefore examined the structural and functional consequences of a 30 min ischaemic period after 2 and 8 weeks of reperfusion and compared these to the effects induced by permanent occlusion of the left anterior descending coronary artery (LAD). The latter procedure resulted in transmural myocardial infarcts of about 52% of the left ventricle. In contrast, the single 30 min ischaemic period led to infarct sizes of about 13% of the left ventricle (range, 4–23%) at 2 and 8 weeks after reperfusion. Maximal cardiac contractility responses (+dP/dt) to dobutamine infusion and volume loading were depressed at 2, but not at 8 weeks after IR. The restoration of cardiac contractility at 8 weeks after IR was associated with a significant 20% enlargement of the end‐diastolic volume and 16% increase of the left ventricular wall thickness. These changes in cardiac geometry were less pronounced at 2 weeks after IR. Histological examination revealed that the IR injury was associated with prominent calcification. At 2 and at 8 weeks after IR, 25 ± 5 and 38 ± 5% of the injured area was calcified as observed in 69 and 73% of the animals, respectively. After permanent occlusion of the LAD, calcification was not observed and healing of the affected area was characterized by thinning and dilatation of the infarcted myocardium. These data indicate that, in mice, a single 30 min period of ischaemia reduced ventricular contractility up to at least 2 weeks after reperfusion. However, 8 weeks after IR, cardiac function was restored by eccentric hypertrophy associated with calcification of the injured ventricular wall.
Spontaneous changes in guinea‐pig respiratory pattern during barometric plethysmography: role of catecholamines and nitric oxide
Authors: Bazán‐Perkins Blanca , Vargas Mario H. , Sánchez‐Guerrero Edgar , Chávez Jaime , Montaño Luis M.
Published: July 2004

Barometric plethysmography for unrestrained animals is a non‐invasive method that allows repetitive measurements of pulmonary function, but habituation of the conscious animal to this technique has not been explored. Respiratory frequency (fR) and ‘enhanced pause’ (Penh) were measured by barometric plethysmography for a period of 8 h in guinea‐pigs. Compared with basal values, during the first hour of recording a progressive increase in Penh (up to 25–50%) and a corresponding decrease in fR were recorded, followed by a relative plateau in each for up to 8 h. These changes were avoided by a 30‐min pretreatment with propranolol and l‐NAME (nitric oxide synthase inhibitor), with Penh values as high as this plateau phase since the beginning of recording. Atropine, salbutamol or budesonide did not modify the progressive increment in Penh. We concluded that catecholamines and nitric oxide are released when guinea‐pigs are introduced into the plethysmographic chamber, leading to initial low Penh values. These mediators probably diminish owing to habituation of the animal to the new environment, with an apparent progressive increment in Penh. These spontaneous changes in Penh and fR must be taken into account during barometric plethysmography in order to avoid misinterpretation of the results.
Modular Construction of Early Ediacaran Complex Life Forms
Authors: Narbonne Guy M.
Published: July 2004

Newly discovered, exceptionally preserved, soft-bodied fossils near Spaniard's Bay in eastern Newfoundland exhibit features not previously described from Ediacaran (terminal Neoproterozoic) fossils. All of the Spaniard's Bay taxa were composed of similar architectural elements—centimeter-scale frondlets exhibiting three orders of fracticality in branching. Frondlets were combined as modules atop semi-rigid organic skeletons to form a wide array of larger constructions, including frondose and plumose structures. This architecture and construction define the “rangeomorphs,” a biological clade that dominated the Mistaken Point assemblage (575 to 560 million years ago) but does not appear to be ancestral to any Phanerozoic or modern organisms.
Crystal Structures of Human Cytochrome P450 3A4 Bound to Metyrapone and Progesterone
Authors: Williams Pamela A. , Cosme Jose , Vinković Dijana Matak , Ward Alison , Angove Hayley C. , Day Philip J. , Vonrhein Clemens , Tickle Ian J. , Jhoti Harren
Published: July 2004

Cytochromes P450 (P450s) metabolize a wide range of endogenous compounds and xenobiotics, such as pollutants, environmental compounds, and drug molecules. The microsomal, membrane-associated, P450 isoforms CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2E1, and CYP1A2 are responsible for the oxidative metabolism of more than 90% of marketed drugs. Cytochrome P450 3A4 (CYP3A4) metabolizes more drug molecules than all other isoforms combined. Here we report three crystal structures of CYP3A4: unliganded, bound to the inhibitor metyrapone, and bound to the substrate progesterone. The structures revealed a surprisingly small active site, with little conformational change associated with the binding of either compound. An unexpected peripheral binding site is identified, located above a phenylalanine cluster, which may be involved in the initial recognition of substrates or allosteric effectors.
Host-to-Parasite Gene Transfer in Flowering Plants: Phylogenetic Evidence from Malpighiales
Authors: Davis Charles C. , Wurdack Kenneth J.
Published: July 2004

Horizontal gene transfer (HGT) between sexually unrelated species has recently been documented for higher plants, but mechanistic explanations for HGTs have remained speculative. We show that a parasitic relationship may facilitate HGT between flowering plants. The endophytic parasites Rafflesiaceae are placed in the diverse order Malpighiales. Our multigene phylogenetic analyses of Malpighiales show that mitochrodrial (matR) and nuclear loci (18Sribosomal DNA andPHYC) place Rafflesiaceae in Malpighiales, perhaps near Ochnaceae/Clusiaceae. Mitochondrialnad1B-C, however, groups them within Vitaceae, near their obligate hostTetrastigma. These discordant phylogenetic hypotheses strongly suggest that part of the mitochondrial genome in Rafflesiaceae was acquired via HGT from their hosts.
Emergent Human Pathogen Simian Virus 40 and Its Role in Cancer
Authors: Vilchez Regis A. , Butel Janet S.
Published: July 2004

The polyomavirus simian virus 40 (SV40) is a known oncogenic DNA virus which induces primary brain and bone cancers, malignant mesothelioma, and lymphomas in laboratory animals. Persuasive evidence now indicates that SV40 is causing infections in humans today and represents an emerging pathogen. A meta-analysis of molecular, pathological, and clinical data from 1,793 cancer patients indicates that there is a significant excess risk of SV40 associated with human primary brain cancers, primary bone cancers, malignant mesothelioma, and non-Hodgkin's lymphoma. Experimental data strongly suggest that SV40 may be functionally important in the development of some of those human malignancies. Therefore, the major types of tumors induced by SV40 in laboratory animals are the same as those human malignancies found to contain SV40 markers. The Institute of Medicine recently concluded that “the biological evidence is of moderate strength that SV40 exposure could lead to cancer in humans under natural conditions.” This review analyzes the accumulating data that indicate that SV40 is a pathogen which has a possible etiologic role in human malignancies. Future research directions are considered.
Pathogenesis of Malaria and Clinically Similar Conditions
Authors: Clark Ian A. , Alleva Lisa M. , Mills Alison C. , Cowden William B.
Published: July 2004

There is now wide acceptance of the concept that the similarity between many acute infectious diseases, be they viral, bacterial, or parasitic in origin, is caused by the overproduction of inflammatory cytokines initiated when the organism interacts with the innate immune system. This is also true of certain noninfectious states, such as the tissue injury syndromes. This review discusses the historical origins of these ideas, which began with tumor necrosis factor (TNF) and spread from their origins in malaria research to other fields. As well the more established proinflammatory mediators, such as TNF, interleukin-1, and lymphotoxin, the roles of nitric oxide and carbon monoxide, which are chiefly inhibitory, are discussed. The established and potential roles of two more recently recognized contributors, overactivity of the enzyme poly(ADP-ribose) polymerase 1 (PARP-1) and the escape of high-mobility-group box 1 (HMGB1) protein from its normal location into the circulation, are also put in context. The pathogenesis of the disease caused by falciparum malaria is then considered in the light of what has been learned about the roles of these mediators in these other diseases, as well as in malaria itself.
Clonorchiasis and Cholangiocarcinoma: Etiologic Relationship and Imaging Diagnosis
Authors: Choi Byung Ihn , Han Joon Koo , Hong Sung Tae , Lee Kyoung Ho
Published: July 2004

Despite a gradual decrease in prevalence, clonorchiasis is still prevalent in East Asia. A large and compelling body of evidence links clonorchiasis and cholangiocarcinoma, although the mechanisms involved are not completely understood. Clonorchiasis induces biliary epithelial hyperplasia and metaplasia, and this could facilitate at least one stage of the carcinogenesis, which is promoting effect. In areas of endemic infection, more clonorchiasis cases are now diagnosed incidentally during radiological examinations such as cholangiography, ultrasonography, and computed tomography. Radiological findings are regarded as pathognomonic for clonorchiasis since they reflect the unique pathological changes of this disorder. These radiological examinations currently play important roles in the diagnosis, staging, and decision-making process involved in the treatment of cholangiocarcinoma. The morphological features and radiological findings of clonorchiasis-associated cholangiocarcinoma are essentially combinations of the findings for the two diseases. The morphological features of clonorchiasis- associated cholangiocarcinoma, observed in radiological examinations, do not differ from those of the usual cholangiocarcinoma. In patients diagnosed with or suspected to have clonorchiasis, radiological findings should be carefully scrutinized for occult cholangiocarcinoma.
Emerging from Obscurity: Biological, Clinical, and Diagnostic Aspects of
Dientamoeba fragilis
Authors: Johnson Eugene H. , Windsor Jeffrey J. , Clark C. Graham
Published: July 2004

Ever since its first description in 1918,
Dientamoeba fragilis
has struggled to gain recognition as a significant pathogen. There is little justification for this neglect, however, since there exists a growing body of case reports from numerous countries around the world that have linked this protozoal parasite to clinical manifestations such as diarrhea, abdominal pain, flatulence, and anorexia. A number of studies have even incriminated
D. fragilis
as a cause of irritable bowel syndrome, allergic colitis, and diarrhea in human immunodeficiency virus patients. Although
D. fragilis
is most commonly identified using permanently stained fecal smears, recent advances in culturing techniques are simplifying as well as improving the ability of investigators to detect this organism. However, there are limitations in the use of cultures since they cannot be performed on fecal samples that have been fixed. Significant progress has been made in the biological classification of this organism, which originally was described as an ameba. Analyses of small-subunit rRNA gene sequences have clearly demonstrated its close relationship to
Histomonas
, and it is now known to be a trichomonad. How the organism is transmitted remains a mystery, although there is some evidence that
D. fragilis
might be transmitted via the ova of the pinworm,
Enterobius vermicularis
. Also, it remains to be answered whether the two distinct genotypes of
D. fragilis
recently identified represent organisms with differing virulence.
Rapid Diagnosis of Pharyngitis Caused by Group A Streptococci
Authors: Gerber Michael A. , Shulman Stanford T.
Published: July 2004

Although commercial rapid antigen detection tests (RADTs) are more expensive than blood agar plate (BAP) cultures, the advantage they offer is the speed with which they provide results. Rapid identification and consequent prompt treatment of patients with pharyngitis due to group A beta-hemolytic streptococci (GABHS) can reduce the risk of spread of GABHS, can allow patients to return to school or work sooner, and may reduce the acute morbidity of this illness. In most studies, RADTs have been compared with BAP cultures as the criterion standard. However, these comparisons are complicated by the fact that there is no universally accepted procedure for performing a BAP culture. The great majority of the RADTs that are currently available have a high specificity (i.e., 95% or greater) and a sensitivity of between 70 and 90% compared with BAP cultures. Few published studies have compared the performance of various RADTs to each other or examined the performance of various RADTs in the office setting. There is also relatively little published information about how physicians in practice actually use RADTs, but the available information suggests that many physicians do not follow recommended guidelines. While the development of easy-to-perform RADTs for the diagnosis of GABHS pharyngitis has altered clinical practice substantially, only limited data about cost-effectiveness are currently available.
Clinical Microbiology of Bacterial and Fungal Sepsis in Very-Low-Birth-Weight Infants
Authors: Kaufman David , Fairchild Karen D.
Published: July 2004

Twenty percent of very-low-birth-weight (<1500 g) preterm infants experience a serious systemic infection, and despite advances in neonatal intensive care and antimicrobials, mortality is as much as threefold higher for these infants who develop sepsis than their counterparts without sepsis during their hospitalization. Outcomes may be improved by preventative strategies, earlier and accurate diagnosis, and adjunct therapies to combat infection and protect the vulnerable preterm infant during an infection. Earlier diagnosis on the basis of factors such as abnormal heart rate characteristics may offer the ability to initiate treatment prior to the onset of clinical symptoms. Molecular and adjunctive diagnostics may also aid in diagnosing invasive infection when clinical symptoms indicate infection but no organisms are isolated in culture. Due to the high morbidity and mortality, preventative and adjunctive therapies are needed. Prophylaxis has been effective in preventing early-onset group B streptococcal sepsis and late-onsetCandidasepsis. Future research in prophylaxis using active and passive immunization strategies offers prevention without the risk of resistance to antimicrobials. Identification of the differences in neonatal intensive care units with low and high infection rates and implementation of infection control measures remain paramount in each neonatal intensive care unit caring for preterm infants.
Increased urinary excretion of 8-hydroxydeoxyguanosine in engine room personnel exposed to polycyclic aromatic hydrocarbons
Authors: Nilsson R , Nordlinder R , Moen B E , Øvrebø S , Bleie K , Skorve A H , Hollund B E , Tagesson C
Published: July 2004

Background:Previous investigations indicate that engine room personnel on ships are exposed to polycyclic aromatic hydrocarbons (PAH) from oil and oil products, with dermal uptake as the major route of exposure. Several PAH are known carcinogens and mutagens.

Aims:To investigate the urinary excretion of a marker for oxidative DNA damage, 8-hydroxydeoxy-guanosine (8OHdG), in engine room personnel, and to study the association between 8OHdG and 1-hydroxypyrene (1OHP), a biological marker for PAH exposure.

Methods:Urine samples were collected from engine room personnel (n = 36) on 10 Swedish and Norwegian ships and from unexposed controls (n = 34) with similar age and smoking habits. The exposure to oils, engine exhaust, and tobacco smoke 24 hours prior to sampling was estimated from questionnaires. The urinary samples were frozen for later analyses of 8OHdG and 1OHP by high performance liquid chromatography.

Results:Excretion in urine of 8OHdG (adjusted to density 1.022) was similar for controls (mean 18.0 nmol/l, n = 33), and for those who had been in the engine room without skin contact with oils (mean 18.7 nmol/l, n = 15). Engine room personnel who reported skin contact with oil had increased excretion of 8OHdG (mean 23.2 nmol/l, n = 19). The difference between this group and the unexposed controls was significant. The urinary levels of ln 1OHP and ln 8OHdG were significantly correlated, and the association was still highly significant when the effects of smoking and age were accounted for in a multiple regression analysis.

Conclusion:Results indicate that exposure to PAH or possibly other compounds from skin contact with oils in engine rooms may cause oxidative DNA damage.
Determination of serum IgG antibodies toBacillus anthracisprotective antigen in environmental sampling workers using a fluorescent covalent microsphere immunoassay
Authors: Biagini R E , Sammons D L , Smith J P , Page E H , Snawder J E , Striley C A F , MacKenzie B A
Published: July 2004

Aims:To evaluate potential exposure toBacillis anthracis(Ba) spores in sampling/decontamination workers in the aftermath of an anthrax terror attack.

Methods:Fifty six serum samples were obtained from workers involved in environmental sampling forBaspores at the American Media, Inc. (AMI) building in Boca Raton, FL after the anthrax attack there in October 2001. Nineteen sera were drawn from individuals both pre-entry and several weeks after entrance into the building. Nine sera each were drawn from unique individuals at the pre-entry and follow up blood draws. Thirteen donor control sera were also evaluated. Individuals were surveyed forBaexposure by measurement of serumBaanti-protective antigen (PA) specific IgG antibodies using a newly developed fluorescent covalent microsphere immunoassay (FCMIA).

Results:Four sera gave positive anti-PA IgG results (defined as anti-PA IgG concentrations ⩾ the mean μg/ml anti-PA IgG from donor control sera (n = 13 plus 2 SD which were also inhibited ⩾ 85% when the serum was pre-adsorbed with PA). The positive sera were the pre-entry and follow up samples of two workers who had received their last dose of anthrax vaccine in 2000.

Conclusion:It appears that the sampling/decontamination workers of the present study either had insufficient exposure toBaspores to cause the production of anti-PA IgG antibodies or they were exposed to anthrax spores without producing antibody. The FCMIA appears to be a fast, sensitive, accurate, and precise method for the measurement of anti-PA IgG antibodies.
Urinary excretion half life of trichloroacetic acid as a biomarker of exposure to chlorinated drinking water disinfection by-products: Figure 1
Authors: Bader E L , Hrudey S E , Froese K L
Published: July 2004

Aims:To measure accurately urinary elimination half life of trichloroacetic acid (TCAA).

Methods:A longitudinal pilot exposure/intervention study measured the elimination half life of TCAA in urine. Beverage consumption was limited to a public water supply and bottled water of known TCAA concentration, and ingestion volume was managed. The five participants limited fluid consumption to only the water provided. Consumption journals were kept by each participant and their daily first morning urine (FMU) samples were analysed for TCAA and creatinine. TCAA elimination half life curves were generated from a two week washout period using TCAA-free bottled water.

Results:Individual elimination half lives ranged from 2.1 to 6.3 days, for single compartment exponential decay, the model which fit the data.

Conclusion:Urinary TCAA is persistent enough to be viable as a biomarker of medium term (days) exposure to drinking water TCAA ingestion within a range of realistic concentrations.
Reactive airways dysfunction syndrome caused by bromochlorodifluoromethane from fire extinguishers: Table 1
Authors: Matrat M , Laurence M F , Iwatsubo Y , Hubert C , Joly N , Legrand-Cattan K , L’Huillier J P , Villemain C , Pairon J C
Published: July 2004

Although the neurological and cardiovascular effects of Freons have been extensively described, the respiratory effects have been less well documented. We report four cases of occupational asthma following accidental exposure to bromochlorodifluoromethane (Halon 1211) due to release of the contents of a fire extinguisher. All subjects developed an irritative reaction of the upper airways and lower respiratory symptoms immediately after exposure. Non-specific bronchial hyperreactivity was present for at least two months in all subjects and was still present more than two years after exposure in one case. The diagnosis of reactive airways dysfunction syndrome can be adopted in at least three of these four cases.
Excess risk of kidney disease in a population living near industrial plants
Authors: Hodgson S , Nieuwenhuijsen M J , Hansell A , Shepperd S , Flute T , Staples B , Elliott P , Jarup L
Published: July 2004

Runcorn has been a site of chemical industry activity for over a century, where tons of toxic chemicals are released annually to air and water. Excess kidney disease mortality (nephritis, nephrotic syndrome, and nephrosis) was found in the population living within 2 km of the industrial plants (standardised mortality ratio (SMR) in males 131 (95% CI 90 to 185) and females 161 (95% CI 118 to 214)) compared to a reference population (northwest England)). Risk of hospital admissions for kidney disease in Halton (comprising the towns of Runcorn and Widnes) was higher than in the less industrial, nearby town of Warrington. The standardised admission ratio (SAR) in Halton was 115 (95% CI 107 to 124) for males and 126 (95% CI 117 to 137) for females; and in Warrington 91 (95% CI 85 to 97) for males and 84 (95% CI 78 to 91) for females compared to the Warrington and Halton area as a whole. The excess risk of kidney disease in the Runcorn area requires further investigation.