bluuebunny/crossref_metadata_2025 huggingface dataset:
Xanthine Oxidoreductase Is an Endogenous Regulator of Cyclooxygenase-2
Authors: Ohtsubo Toshio , Rovira Ilsa I. , Starost Matthew F. , Liu Chengyu , Finkel Toren
Published: November 2004

Xanthine oxidoreductase (XOR) is the enzyme responsible for the final step in purine degradation resulting in the generation of uric acid. Here we have generated mice deficient in XOR. As expected, these animals lack tissue XOR activity and have low to undetectable serum levels of uric acid. Although normal at birth, XOR−/− mice fail to thrive after 10 to 14 days, and most die within the first month. The cause of death appears to be a form of severe renal dysplasia, a phenotype that closely resembles what has been observed previously in cyclooxygenase-2 (COX-2)–deficient mice. We further demonstrate that in the first month of life, a period in which the mouse kidney is undergoing rapid maturation and remodeling, wild-type mice exhibit an ≈30-fold increase in renal XOR activity, with a corresponding induction of COX-2 expression. In contrast, during this same period, XOR−/− animals fail to augment renal COX-2 expression. Finally, we show that in vitro and in vivo, uric acid can stimulate basal COX-2 expression. These results demonstrate that XOR activity is an endogenous physiological regulator of COX-2 expression and thereby provide insight into previous epidemiological evidence linking elevated serum uric levels with systemic hypertension and increased mortality from cardiovascular diseases. In addition, these results suggest a novel molecular link between cellular injury and the inflammatory response.
Proarrhythmic Consequences of a KCNQ1 AKAP-Binding Domain Mutation
Authors: Saucerman Jeffrey J. , Healy Sarah N. , Belik Mary E. , Puglisi Jose L. , McCulloch Andrew D.
Published: November 2004

The KCNQ1-G589D gene mutation, associated with a long-QT syndrome, has been shown to disrupt yotiao-mediated targeting of protein kinase A and protein phosphatase-1 to the I
Ks
channel. To investigate how this defect may lead to ventricular arrhythmia during sympathetic stimulation, we use integrative computational models of β-adrenergic signaling, myocyte excitation-contraction coupling, and action potential propagation in a rabbit ventricular wedge. Paradoxically, we find that the KCNQ1-G589D mutation alone does not prolong the QT interval. But when coupled with β-adrenergic stimulation in a whole-cell model, the KCNQ1-G589D mutation induced QT prolongation and transient afterdepolarizations, known cellular mechanisms for arrhythmogenesis. These cellular mechanisms amplified tissue heterogeneities in a three-dimensional rabbit ventricular wedge model, elevating transmural dispersion of repolarization and creating other T-wave abnormalities on simulated electrocardiograms. Increasing heart rate protected both single myocyte and the coupled myocardium models from arrhythmic consequences. These findings suggest that the KCNQ1-G589D mutation disrupts a critical link between β-adrenergic signaling and myocyte electrophysiology, creating both triggers of cardiac arrhythmia and a myocardial substrate vulnerable to such electrical disturbances.
ABCA1 Expression in Carotid Atherosclerotic Plaques
Authors: Albrecht C. , Soumian S. , Amey J.S. , Sardini A. , Higgins C.F. , Davies A.H. , Gibbs R.G.J.
Published: November 2004

Background and Purpose—

The ATP-binding cassette transporter A1 (ABCA1) facilitates cholesterol efflux from cells, a key process in reverse cholesterol transport. Whereas previous investigations focused on mutations causing impaired ABCA1 function, we assessed the role of ABCA1 in human carotid atherosclerotic disease.

Methods—

We compared the mRNA and protein levels of ABCA1, and one of its key regulators, the liver X receptor α (LXRα), between minimally and grossly atherosclerotic arterial tissue. We established
ABCA1
and
LXR
α gene expression by real-time quantitative polymerase chain reaction in 10 control and 18 atherosclerotic specimens. Presence of ABCA1 protein was assessed by immunoblotting. To determine whether differences observed at a local level were reflected in the systemic circulation, we measured ABCA1 mRNA in leukocytes of 10 patients undergoing carotid endarterectomy and 10 controls without phenotypic atherosclerosis.

Results—

ABCA1
and
LXR
α gene expression were significantly elevated in atherosclerotic plaques (
P
<0.0001 and 0.03, respectively). The increased mRNA levels of ABCA1 and LXRα were correlated in atherosclerotic tissue (
r
=0.85;
P
<0.0001). ABCA1 protein expression was significantly reduced in plaques compared with control tissues (
P
<0.0001). There were no differences in leukocyte ABCA1 mRNA expression (
P
=0.67).

Conclusions—

ABCA1 gene and protein are expressed in minimally atherosclerotic human arteries. Despite significant upregulation of ABCA1 mRNA, possibly mediated via LXRα, ABCA1 protein is markedly reduced in advanced carotid atherosclerotic lesions. No differences in leukocyte ABCA1 expression were found, suggesting the plaque microenvironment may contribute to the differential ABCA1 expression. We propose that the decreased level of ABCA1 protein is a key factor in the development of atherosclerotic lesions.
Carotid Intima-Media Thickness and Plaque Characteristics as a Risk Factor for Stroke in Japanese Elderly Men
Authors: Kitamura Akihiko , Iso Hiroyasu , Imano Hironori , Ohira Tetsuya , Okada Takeo , Sato Shinichi , Kiyama Masahiko , Tanigawa Takeshi , Yamagishi Kazumasa , Shimamoto Takashi
Published: November 2004

Background and Purpose—

Few cohort studies have examined the association of carotid intima-media thickness (IMT) and plaque characteristics with the risk of stroke in apparently healthy persons. We examined the relationship of carotid IMT and the surface, morphology, and calcification of carotid plaques with the incidence of stroke among Japanese men.

Methods—

Carotid IMT and plaque were evaluated bilaterally with ultrasonography in 1289 men aged 60 to 74 years without a previous stroke or coronary heart disease. In this cohort, the subsequent incidence of stroke was investigated.

Results—

During the 4.5-year follow-up, 34 strokes occurred. The multivariate-adjusted relative risk (95% CI) for the highest versus lowest quartiles of maximum IMT of the common carotid artery (CCA; ≥1.07 versus ≤0.77 mm) was 3.0 (1.1 to 8.3) for stroke. The combination of CCA and internal carotid artery (ICA) wall thickness was a better predictor of the risk of stroke than was CCA wall thickness alone. Men with a plaque, defined as a focal wall thickness of ≥1.5 mm, in the ICA had a 3-fold higher risk of stroke than those without a plaque, and the plaque surface irregularity further increased the stroke risk. A significant excess risk of stroke was confined to men with an uncalcified plaque.

Conclusions—

Increased IMT of the CCA and an uncalcified plaque in the ICA, as assessed by ultrasonography, are risk factors for stroke in elderly Japanese men.
Increased Expression of Hepatocyte Growth Factor in Cerebrospinal Fluid and Intracranial Artery in Moyamoya Disease
Authors: Nanba Rina , Kuroda Satoshi , Ishikawa Tatsuya , Houkin Kiyohiro , Iwasaki Yoshinobu
Published: November 2004

Background and Purpose—

The etiology of moyamoya disease still remains unknown. This study was aimed to explore the role of hepatocyte growth factor (HGF), a strong inducer of angiogenesis, in development of moyamoya disease.

Methods—

We studied cerebrospinal fluid (CSF) from 39 patients with moyamoya disease (24 children and 15 adults), 6 control patients with cervical spondylosis, and 7 control patients with internal carotid artery occlusion. CSF level of HGF was determined by enzyme-linked immunosorbent assay technique. We also evaluated the distribution of HGF and its cellular receptor c-Met in the carotid fork obtained from 2 patients with moyamoya disease and 2 control patients.

Results—

CSF level of HGF was 408.2±201.6 pg/mL and 443.2±193.5 pg/mL in patients with cervical spondylosis and internal carotid artery occlusion, respectively (mean±SD). On the other hand, CSF level of HGF was 820.3±319.0 pg/mL in patients with moyamoya disease, being significantly higher than those in 2 control groups (
P
<0.01). Both HGF and c-Met were widely distributed in the media and thickened intima of the carotid fork in patients with moyamoya disease but not in control patients.

Conclusions—

This study revealed that HGF is densely found in the carotid fork, and its CSF level is markedly elevated in moyamoya disease, suggesting that HGF may be a key protein for pathogenesis of moyamoya disease.
Life as Understanding
Authors: Figal Günter
Published: November 2004

In this paper I take up the "claim to universality" of hermeneutics, as put forth by Hans-Georg Gadamer; the aim is to grasp the "life that can understand," to grasp it in its essence and in terms of understanding. In this way I deal critically with Gadamer's (and Heidegger's) idea that all understanding is "self-understanding" and work out the dependence of understanding on the other, on the "hermeneutic object" (

Gegenstand

) of understanding. But a "hermeneutic object" (

Gegenstand

) is not a "mere object" (

Objekt

). On the basis of this distinction, I develop, in conclusion, a critical reflection on the selfobjectification of the human in those interpretations of human life that are oriented solely to natural science. Self-objectfication is a wrongly directed understanding and can therefore be corrected on the basis of a developed concept of life as understanding.
On the Incalculable: Language and Freedom from a Hermeneutic Point of View
Authors: Schmidt Dennis
Published: November 2004

In his celebrated "Letter on Humanism," Heidegger spoke of the need for an "original ethics" which did not submit itself to the ideal of something like a "subject" or the "human," two notions that he suggested were no longer serviceable for the task of thinking the problems of ethical life. The purpose of this article is to look at how Gadamer's hermeneutics might offer an avenue for developing this original ethics. To this end, Gadamer's discussion of language, in particular the relation of language and freedom, serves as the guideline for unpacking this claim.
A Global Tradition? Power and Historicity
Authors: Ziarek Krzysztof
Published: November 2004

To understand globalization, one needs to examine its provenance within the metaphysical tradition and, in particular, in relation to the ways in which power tends to operate in modernity. While its operations are necessary for shaping relations, the pervasiveness with which power invests beings tends to obscure the event, and in particular, temporality and historicity, which mark the possibility of undoing power's formative influence on beings and relations. The event becomes the site of a specific tension between power and the power-free, between changes intrinsic to power's intensification and a transformation indicative of a letting-go of power. In the face of our (post)modern tradition of increasingly intense macro and microflows of power, the power-free calls into question the metaphysical tradition of power that has underwritten the development of modernity. This transformation is neither a destruction nor an abandonment of modernity, but indicates an alternative to the prevalent and pervasive practices of power.
A Game Theoretical Approach of Price Negotiation and Coordination in an Innovative Firm-Supplier Context: An Experimental Analysis
Authors: Garapin Alexis , Duvallet Jeanne , Robin Stephane , Llerena Daniel
Published: November 2004

This article analyzes a sequential interaction between a firm and its supplier, involving negotiation in the first round and coordination between two different production activities in the second round. The evolution of the vertical relations in the manufacturing sectors reveals that the performance of the firms increasingly depends on these two dimensions. Price negotiation determines the share of the profits of the two actors, while coordination determines the performance of the overall chain. To model this sequential interaction between the supplier and the firm, we use the tools and concepts of game theory. While game theory usually considers the coordination problem as an isolated phenomenon, the originality of our work is that it examines the problem of in a context where coordination between agents is preceded by a negotiation phase. The model emphasizes the influence of the price negotiation on the coordination round. Several theoretical predictions are proposed, derived not only from the strict assumptions of game theory, but also from assumptions which relax those of game theory. These predictions are then experimentally tested. The results do not confirm the predictions of game theory. In fact, they are consistent with the predictions put forth as alternatives to the predictions of game theory. They show i) a propensity to maximize the performance of the chain, and ii) a propensity to arrive at an equitable share of the joint profit in the chain. Finally, though the experiment was not designed to study cross-cultural or international cases, the results suggest new research directions in this area.
Brain Angiotensin II and Synaptic Transmission
Authors: Pan Hui-Lin
Published: November 2004

The renin-angiotensin system is an enzymatic cascade by which angiotensinogen is cleaved by renin and then by angiotensin-converting enzyme to produce angiotensin II (Ang II) and subsequently other angiotensins. Biochemical and neurophysiological studies have documented the presence of the reninangiotensin system and specific Ang II receptors in the brain. Also, circulating Ang II can exert some of its actions, such as blood pressure control and body fluid homeostasis, through stimulation of Ang II receptors in the circumventricular organs that lack a normal blood-brain barrier. In addition to some of the post-synaptic effects of Ang II, recent studies have revealed that Ang II regulates synaptic transmission in several brain regions, especially the nucleus of the solitary tract, hypothalamic paraventricular nucleus, and hippocampus. This review summarizes emerging new evidence on the effect of brain Ang II on glutamatergic and GABAergic synaptic transmission. This previously unrecognized presynaptic action of Ang II is important for the control of neuronal excitability and many physiological functions including autonomic control, hormone secretion, and memory. Future research on the role of brain-derived Ang II and its receptors in synaptic transmission will further enhance our understanding of the cellular mechanisms of Ang II and the relationship between the renin-angiotensin system and brain functions.
Integration of Retrograde Axonal and Nuclear Transport Mechanisms in Neurons: Implications for Therapeutics
Authors: Hanz Shlomit , Fainzilber Mike
Published: November 2004

The elongated morphology of neuronal processes imposes a significant challenge for effective intracellular communication between the neurites and the cell body. This problem is especially acute upon injury, when the cell body must receive accurate and timely information on the site and extent of axonal damage to mount an appropriate response. Recent work has demonstrated that nuclear import factors from the importin (karyopherin) α and β families provide a mechanism for retrograde injury signaling. Importins are found throughout axons and dendrites at significant distances from the cell body, and importin β protein is increased after nerve lesion by local translation of axonal mRNA. This leads to formation of a high-affinity nuclear localization signal (NLS) binding complex that traffics retrogradely due to an interaction of importin α with the motor protein dynein. Disruption of the complex with excess NLS peptides delays regeneration of injured sensory neurons. The dual role of importins in retrograde transport in axons and nuclear import in cell bodies suggests new avenues for manipulating intrinsic regeneration mechanisms in the nervous system and may provide a novel route for drug delivery to the CNS.
Quantitative Analysis of Connectivity in the Visual Cortex: Extracting Function from Structure
Authors: Vezoli Julien , Falchier Arnaud , Jouve Bertrand , Knoblauch Kenneth , Young Malcolm , Kennedy Henry
Published: November 2004

It is generally agreed that information flow through the cortex is constrained by a hierarchical architecture. Lack of precise data on areal connectivity leads to indeterminacy of existing models. The authors introduce two quantitative parameters (SLN and FLN) that hold the promise of resolving such indeterminacy. In the visual system, using a very incomplete database, provisional hierarchies are in line with the recent proposal of higher functions of area V1 and suggest a hitherto unsuspected central function of the frontal eye field.
In vitro maturation of nascent reticulocytes to erythrocytes
Authors: Koury Mark J. , Koury Stephen T. , Kopsombut Prapaporn , Bondurant Maurice C.
Published: November 2004

Most studies of mammalian reticulocyte maturation have used blood reticulocytes.Nascent reticulocytes, as found in bone marrow, have not been available in developmentally synchronized populations. Nascent murine reticulocytes formed in vitro by enucleation of Friend virus–infected erythroblasts were purified and recultured for 110 hours. At 0 hours, all recultured cells were lobulated and contained dense, centralized reticulin. By 110 hours, about 20% to 25% of the cells became biconcave erythrocytes. Most ribosomes and cellular RNAs were degraded within 20 hours, and during that period, heme synthesis declined from a rate equal to that of late erythroblasts to less than 10% of that rate. Many mitochondria appeared normal until they showed outer membrane swelling, degradation, and apparent fusion with intracellular vacuoles at 40 hours of culture. During the period of mitochondrial loss, Bcl-XL, an antiapoptotic protein that accumulates during erythroblast differentiation and maintains mitochondrial membrane integrity, demonstrated progressive decreases and changes consistent with deamidation. Nevertheless, the reticulocytes did not undergo apoptosis, because their apoptotic machinery was degraded. This experimental system that provides a developmentally synchronized population of nascent murine reticulocytes that mature into biconcave erythrocytes in vitro should be useful in further investigations of the cellular events involved in reticulocyte maturation.
Membrane receptors are not required to deliver granzyme B during killer cell attack
Authors: Kurschus Florian C. , Bruno Roxana , Fellows Edward , Falk Christine S. , Jenne Dieter E.
Published: November 2004

Granzyme B (GzmB), a serine protease of cytotoxic T lymphocytes and natural killer (NK) cells, induces apoptosis by caspase activation after crossing the plasma membrane of target cells. The mechanism of this translocation during killer cell attack, however, is not understood. Killer cells release GzmB and the membrane-disturbing perforin at the contact site after target recognition. Receptor-mediated import of glycosylated GzmB and release from endosomes were suggested, but the role of the cation-independent mannose 6-phosphate receptor was recently refuted. Using recombinant nonglycosylated GzmB, we observed binding of GzmB to cellular membranes in a cell type–dependent manner. The basis and functional impact of surface binding were clarified. GzmB binding was correlated with the surface density of heparan sulfate chains, was eliminated on treatment of target cells with heparinase III or sodium chlorate, and was completely blocked by an excess of catalytically inactive GzmB or GzmK. Although heparan sulfate–bound GzmB was taken up rapidly into intracellular lysosomal compartments, neither of the treatments had an inhibitory influence on apoptosis induced by externally added streptolysin O and GzmB or by natural killer cells. We conclude that membrane receptors for GzmB on target cells are not crucial for killer cell–mediated apoptosis.
Punish the parent not the progeny
Authors: Elrick Lucy J. , Jorgensen Heather G. , Mountford Joanne C. , Holyoake Tessa L.
Published: November 2004

Chronic myeloid leukemia (CML) is sustained by a rare population of primitive, quiescent, BCR-ABL+ cells and represents an excellent example of a malignancy in which tumor-initiating cells represent the key to disease eradication. CML is also the first malignancy for which targeted therapy has replaced conventional chemotherapy. Within a vast excess of proliferating progenitor cells that express breakpoint cluster region-abelson (BCR-ABL) and are exquisitely sensitive to the tyrosine kinase inhibitor imatinib mesylate (IM) resides a small population of quiescent leukemic cells that, despite higher levels of BCR-ABL transcripts, exhibits innate insensitivity to IM. These cells remain after IM therapy, even when apparently complete responses are achieved, and they probably explain molecular disease persistence. Although it can be argued that patients may survive for many years with low levels of leukemia still present, it is possible to achieve disease clearance at the molecular level following an allogeneic stem cell transplantation. The emergence of drug resistance with IM monotherapy also argues in favor of complete disease eradication that we believe should remain the ultimate therapeutic goal in CML. New approaches to the elimination of these primitive CML cells may thus be crucial to the development of curative strategies.
Immunotherapy of autoimmune encephalomyelitis with redirected CD4+CD25+ T lymphocytes
Authors: Mekala Divya J. , Geiger Terrence L.
Published: November 2004

We developed an approach that increases CD4+CD25+ regulatory T-cell potency by antigen-specifically redirecting them against pathologic T lymphocytes. The regulatory cells are transgenically modified with chimeric receptors that link antigen–major histocompatibility complex (MHC) extracellular and transmembrane domains with the cytoplasmic signaling tail of T-cell receptor ζ (TCR-ζ). The receptors' antigen-MHC recognizes the TCR of cognate T lymphocytes. Receptor engagement stimulates the receptor-modified T cell (RMTC) through the linked ζ chain. CD4+CD25+ RMTCs expressing a myelin basic protein (MBP) 89-101-IAs-ζ receptor, unlike unmodified CD4+CD25+ T cells or CD4+CD25- RMTCs, prevented and treated experimental allergic encephalomyelitis (EAE) induced with MBP89-101. The RMTCs were effective even after the autoreactive T-cell repertoire had diversified to include specificities not directly targeted by the chimeric receptor. Remissions were sustained and mortality was decreased from more than 50% to 0%. These results provide proof of principal for a novel approach to enforce the interaction of regulatory and pathologic T lymphocytes, thereby facilitating the treatment of autoimmune disease.
Generation of Globular Fragment of Adiponectin by Leukocyte Elastase Secreted by Monocytic Cell Line THP-1
Authors: Waki Hironori , Yamauchi Toshimasa , Kamon Junji , Kita Shunbun , Ito Yusuke , Hada Yusuke , Uchida Shoko , Tsuchida Atsushi , Takekawa Sato , Kadowaki Takashi
Published: November 2004

Previous studies revealed that carboxyl-terminal fragment containing the globular domain of adiponectin exists in human plasma. Although it is proposed that the globular fragment is generated by proteolytic cleavage, the place and responsible enzyme of the cleavage are still unclear. In this study, we evaluated the activity to cleave adiponectin in culture medium of several cell lines in vitro. Adiponectin cleavage into several carboxyl-terminal fragments containing the globular domain was observed in the medium of phorbol 12-myristate 13-acetate-stimulated monocytic cell lines THP-1 and U937. The molecular masses of the major products were 25, 20, and 18 kDa. The cleavage was thought to be mediated by leukocyte elastase (also known as neutrophil elastase) based on the following observations. First, the cleavage was inhibited by serine-protease inhibitors [phenylmethylsulfonylfluoride, Pefabloc SC (Roche Diagnostics, Basel, Switzerland) and aprotinin] and by the leukocyte elastase-specific peptide inhibitor MeOSuc-AAPV-CMK. Second, no activity was detected after THP-1 cells had fully differentiated into macrophages. Third, purified leukocyte elastase cleaved adiponectin with the same cleavage pattern as THP-1 cells. Finally, leukocyte elastase secreted by activated neutrophils cleaved adiponectin into the globular fragments. Amino-terminal sequence analysis revealed that cleavage sites of adiponectin by purified leukocyte elastase were between 38Thr and 39Cys, 40Ala and 41Gly, 44Ala and 45Gly, 91Ala and 92Glu, and 110Ala and 111Ala (the numbering of the positions of the amino acids starts at the signal sequence), suggesting that the cleavage occurs in the collagenous domain. These data indicate that the cleavage of adiponectin by leukocyte elastase secreted from activated monocytes and/or neutrophils could be a candidate for the mechanism of the generation of the globular fragment of adiponectin.
Evidence for an Association between Metabolic Cardiovascular Syndrome and Coronary and Aortic Calcification among Women with Polycystic Ovary Syndrome
Authors: Talbott E. O. , Zborowski J. V. , Rager J. R. , Boudreaux M. Y. , Edmundowicz D. A. , Guzick D. S.
Published: November 2004

Women with polycystic ovary syndrome (PCOS) exhibit an adverse cardiovascular risk profile, characteristic of the metabolic cardiovascular syndrome (MCS). The aim of this study was to determine the prevalence of coronary artery (CAC) and aortic (AC) calcification among middle-aged PCOS cases and controls and to explore the relationship among calcification, MCS, and other cardiovascular risk factors assessed 9 yr earlier. This was a prospective study of 61 PCOS cases and 85 similarly aged controls screened in 1993–1994 for risk factors and reevaluated in 2001–2002. The main outcome measures were CAC and AC, measured by electron beam tomography. Women with PCOS had a higher prevalence of CAC (45.9% vs. 30.6%) and AC (68.9% vs. 55.3%) than controls. After adjustment for age and body mass index, PCOS was a significant predictor of CAC (odds ratio = 2.31; P = 0.049). PCOS subjects were also 4.4 times more likely to meet the criteria for MCS than controls. High-density lipoprotein cholesterol and insulin appeared to mediate the PCOS influence on CAC. Interestingly, total testosterone was an independent risk factor for AC in all subjects after controlling for PCOS, age, and body mass index (P = 0.034). We conclude that women with PCOS are at increased risk of MCS and demonstrate increased CAC and AC compared with controls. Components of MCS mediate the association between PCOS and CAC, independently of obesity.
Serum Parathyroid Hormone Is Associated with Increased Mortality Independent of 25-Hydroxy Vitamin D Status, Bone Mass, and Renal Function in the Frail and Very Old: A Cohort Study
Authors: Sambrook P. N. , Chen J. S. , March L. M. , Cameron I. D. , Cumming R. G. , Lord S. R. , Schwarz J. , Seibel M. J.
Published: November 2004

Very frail older people constitute an increasing proportion of the aging population and often have vitamin D deficiency and impaired renal function. Primary hyperparathyroidism has been associated with increased mortality, but it is unclear whether secondary hyperparathyroidism is associated with increased mortality independent of renal function and vitamin D status. This study aimed to examine the effect of vitamin D deficiency and secondary hyperparathyroidism on mortality in frail older people after accounting for renal function and general measures of health. We evaluated 842 subjects (182 men with a mean age of 81.9 yr and 660 women with a mean age of 86.2 yr) living in residential aged care facilities in Sydney, Australia in a prospective, cohort study. Over a mean duration of follow-up of 31 months, 345 subjects died. Baseline serum 25-hydroxy vitamin D, serum PTH, and bone ultrasound attenuation were significantly associated with mortality in univariate and multivariate analyses (for PTH, a hazard ratio of 1.39 for time to death) after correcting for age and gender. In multivariate analyses that corrected for health status, nutritional status, and renal function, PTH remained a significant predictor of mortality but not 25-hydroxy vitamin D or bone ultrasound attenuation. Serum PTH appears to be associated with increased mortality in the frail elderly independent of vitamin D status, renal function, bone mass, and measures of general health. The mechanism of this effect requires further investigation.
Erosion of Endogenous Testosterone-Driven Negative Feedback on Pulsatile Luteinizing Hormone Secretion in Healthy Aging Men
Authors: Veldhuis Johannes D. , Iranmanesh Ali , Keenan Daniel M.
Published: November 2004

The present study tests the intuition that successful aging in men is marked by: 1) impaired feedforward by endogenous LH concentrations (con) of testosterone (Te) secretion (sec); and/or 2) attenuated feedback by unmanipulated Te con of LH sec. The goal was to assess both implicit linkages analytically without disrupting normal pathway coupling. This strategy required: 1) assay of paired LH and Te con sampled every 10 min for 24 h in 13 older (O) (ages 60–78 yr) and 13 young (Y) (ages 18–30 yr) men; 2) deconvolution-based estimation of LH and Te sec rates; 3) lag-specific cross-correlation analyses of the relationships between LH and Te con and sec; and 4) statistical contrasts by age stratum. Salient outcomes were: 1) O and Y men maintain comparable LH con drive of Te sec, viz maximal r = +0.51 and r = +0.52, respectively, at an optimal time lag of 50 min (both P < 0.001 against random LH and Te associations); 2) elderly subjects exhibit reduced Te con inhibition of LH sec [minimal r = −0.008 (O) vs. r = −0.10 (Y), P < 0.01 at a time lag of 40 min]; 3) mean (24-h) LH con do not differ by age; and 4) molar Te/sex hormone-binding globulin con are lower in the elderly than in Y individuals (P < 0.01).

In conclusion, noninvasive analyses predict that attenuation of endogenous Te feedback restraint on the hypothalamo-pituitary unit may be an early biological marker of adaptive changes in the GnRH-LH-Te ensemble axis in the healthy O male.
The Metabolic Syndrome in Obese Postmenopausal Women: Relationship to Body Composition, Visceral Fat, and Inflammation
Authors: You Tongjian , Ryan Alice S. , Nicklas Barbara J.
Published: November 2004

The purpose of this study was to investigate whether aerobic fitness, body composition, body fat distribution, and inflammation are different in obese postmenopausal women with and without the metabolic syndrome (MS), and whether the severity of MS is associated with these characteristics. Fifty-eight women (age, 59 ± 1 yr; body mass index, 33.0 ± 0.6 kg/m2) completed testing of maximal aerobic capacity, body composition (fat mass, lean mass, and percent body fat), body fat distribution (sc and visceral fat areas, and regional adipocyte sizes), and inflammation (C-reactive protein, IL-6, and TNF-α, and their soluble receptors). Lean mass (44.4 ± 0.9 vs. 41.2 ± 0.9 kg; P < 0.05), visceral fat area (180 ± 10 vs. 135 ± 7 cm2; P < 0.001), and plasma soluble TNF receptor 1 (sTNFR1; 860 ± 25 vs. 765 ± 42 pg/ml; P < 0.05) were higher in women with the MS (n = 27) than in those without the MS (n = 31). The number of MS components was directly related to weight, body mass index, fat mass, lean mass, visceral fat area, and plasma sTNFR1. We conclude that obese older women with the MS are characterized by high lean mass, high visceral fat, and elevated sTNFR1, and the severity of the MS is associated with body composition, visceral adiposity, and inflammation.
Decreased Quality of Life in Patients with Acromegaly Despite Long-Term Cure of Growth Hormone Excess
Authors: Biermasz Nienke R. , van Thiel Sjoerd W. , Pereira Alberto M. , Hoftijzer Hendrieke C. , van Hemert Albert M. , Smit Jan W. A. , Romijn Johannes A. , Roelfsema Ferdinand
Published: November 2004

The long-term impact of acromegaly on subjective well-being after treatment of GH excess is unclear. Therefore, we evaluated quality of life by validated questionnaires in a cross-sectional study of 118 successfully treated acromegalic patients. The initial treatment was transsphenoidal surgery in most patients (92%), if necessary followed by radiotherapy or octreotide. All patients were in remission at the time of assessment (GH, <1.9 μg/liter; normal IGF-I for age). General perceived well-being was reduced compared with controls for all subscales (P < 0.001) as measured by the Nottingham Health Profile and the Short Form-36. Acromegalic patients also had lower scores on fatigue (Multidimensional Fatigue Index) and anxiety and depression (Hospital Anxiety and Depression Scale). Radiotherapy was associated with decreased quality of life in all subscales except for the Hospital Anxiety and Depression Scale, and worsened quality of life significantly, according to the fatigue scores. Somatostatin analog treatment was not associated with improved quality of life. Independent predictors of quality of life were age (physical subscales and Nottingham Health Profile), disease duration (social isolation and personal relations), and radiotherapy (physical and fatigue subscales). In conclusion, patients cured after treatment for acromegaly have a persistently decreased quality of life despite long-term biochemical cure of GH excess. Radiotherapy especially is associated with a reduced quality of life.
Choroidal and Skin Metastases from Papillary Thyroid Cancer: Case and a Review of the Literature
Authors: Avram Anca M. , Gielczyk Robert , Su Lyndon , Vine Andrew K. , Sisson James C.
Published: November 2004

A patient with widely metastatic papillary thyroid cancer who had been previously treated with 131I and external beam radiation presented with purple nodular lesions on his face and scalp. On biopsy, the nodules were papillary carcinoma with cells that stained for thyroglobulin. Subsequently he developed decreased left eye visual acuity, and fundoscopy revealed lesions typical of choroidal metastases. Dermal and choroidal metastases of papillary thyroid carcinoma are both rare. However, the significance of these clinical manifestations may be overlooked and ignored unless the diagnosis is considered. New skin nodules or visual acuity decline in a patient with papillary thyroid cancer may represent manifestations of distant metastatic disease and should prompt thorough evaluation with dermatological examination and fundoscopy. Choroidal and skin metastases have almost always occurred in patients with advanced disease, but initial presentation with these lesions is possible, and in such instances a thorough search for additional sites of metastatic disease is recommended. Occasionally such metastases may respond to 131I therapy or external beam radiation.
Intrafamilial Variability of the Deafness and Goiter Phenotype in Pendred Syndrome Caused by a T416P Mutation in the SLC26A4 Gene
Authors: Napiontek Ulrike , Borck Guntram , Müller-Forell Wiebke , Pfarr Nicole , Bohnert Andrea , Keilmann Annerose , Pohlenz Joachim
Published: November 2004

Pendred syndrome (PS) is the most common cause of syndromic deafness, accounting for more than 5% of all autosomal-recessive hearing loss cases. It is characterized by bilateral sensorineural hearing loss and by goiter with or without hypothyroidism. Mutations in the SLC26A4 gene cause both classical PS and deafness associated with an enlarged vestibular aqueduct without goiter.

To investigate a possible genotype-phenotype correlation in PS, we performed a detailed clinical and genetic study in three adult German sibs with typical PS caused by a common homozygous SLC26A4 mutation, T416P. An audiological long-term follow-up of 23 yr showed that the mutation T416P is associated with a distinct type of hearing loss in each of the three sibs: moderate-to-profound progressive deafness, profound nonprogressive deafness, and a milder but more rapidly progressing form. We show that these phenotypic differences are not caused by either different degrees of inner ear malformations or sequence variations in the GJB2/connexin 26 gene.

Because the thyroid phenotype was also highly variable within the family, with thyroid sizes ranging from normal to large goiters requiring thyroidectomy, this study leads to the conclusion that other environmental and/or genetic factors have an impact on the PS phenotype.
Identification of Target Genes Involved in the Antiproliferative Effect of Glucocorticoids Reveals a Role for Nuclear Factor-κB Repression
Authors: Bladh Lars-Göran , Lidén Johan , Pazirandeh Ahmad , Rafter Ingalill , Dahlman-Wright Karin , Nilsson Stefan , Okret Sam
Published: November 2004

Glucocorticoid hormones (GCs) exert an antiproliferative effect on most cells. However, the molecular mechanism is still largely unclear. We investigated the antiproliferative mechanism by GCs in human embryonic kidney 293 cells with stably introduced glucocorticoid receptor (GR) mutants that discriminate between cross-talk with nuclear factor-κB (NF-κB) and activator protein-1 signaling, transactivation and transrepression, and antiproliferative vs. non-antiproliferative responses. Using the GR mutants, we here demonstrate a correlation between repression of NF-κB signaling and antiproliferative response. Gene expression profiling of endogenous genes in cells containing mutant GRs identified a limited number of genes that correlated with the antiproliferative response. This included a GC-mediated up-regulation of the NF-κB-inhibitory protein IκBα, in line with repression of NF-κB signaling being important in the GC-mediated antiproliferative response. Interestingly, the GC-stimulated expression of IκBα was a direct effect despite the inability of the GR mutant to transactivate through a GC-responsive element. Selective expression of IκBα in human embryonic kidney 293 cells resulted in a decreased percentage of cells in the S/G2/M phase and impaired cell proliferation. These results demonstrate that GC-mediated inhibition of NF-κB is an important mechanism in the antiproliferative response to GCs.
Rumen metabolites serve ticks to exploit large mammals
Authors: Donzé Gérard , McMahon Conor , Guerin Patrick M.
Published: November 2004

Hard ticks spend most of their life isolated from passing vertebrates but require a blood meal to proceed to the next life stage (larva, nymph or adult). These opportunist ectoparasites must be capable of anticipating signals that render suitable hosts apparent. Large ungulates that tolerate a high ectoparasite burden are the favoured hosts of adult hard ticks. Ruminants, comprising the majority of ungulate species, must regularly eruct gases from the foregut to relieve excess pressure and maintain a chemical equilibrium. Through eructations from individuals, and particularly herds,ruminants inadvertently signal their presence to hard ticks. Here, we report that all adult hard tick species we tested are attracted to cud and demonstrate that these acarines possess olfactory receptor cells for the carboxylic acid, phenol and indole end-products of the rumen bioreactor. Compounds from each of these classes of volatiles attract ticks on their own,and mixtures of these volatiles based on rumen composition also attract. Appetence for rumen metabolites represents a fundamental resource-tracking adaptation by hard ticks for large roaming mammals.
Dragonfly flight: free-flight and tethered flow visualizations reveal a diverse array of unsteady lift-generating mechanisms, controlled primarilyviaangle of attack
Authors: Thomas Adrian L. R. , Taylor Graham K. , Srygley Robert B. , Nudds Robert L. , Bomphrey Richard J.
Published: November 2004

Here we show, by qualitative free- and tethered-flight flow visualization,that dragonflies fly by using unsteady aerodynamic mechanisms to generate high-lift, leading-edge vortices. In normal free flight, dragonflies use counterstroking kinematics, with a leading-edge vortex (LEV) on the forewing downstroke, attached flow on the forewing upstroke, and attached flow on the hindwing throughout. Accelerating dragonflies switch to in-phase wing-beats with highly separated downstroke flows, with a single LEV attached across both the fore- and hindwings. We use smoke visualizations to distinguish between the three simplest local analytical solutions of the Navier–Stokes equations yielding flow separation resulting in a LEV. The LEV is an open U-shaped separation, continuous across the thorax, running parallel to the wing leading edge and inflecting at the tips to form wingtip vortices. Air spirals in to a free-slip critical point over the centreline as the LEV grows. Spanwise flow is not a dominant feature of the flow field – spanwise flows sometimes run from wingtip to centreline, or vice versa –depending on the degree of sideslip. LEV formation always coincides with rapid increases in angle of attack, and the smoke visualizations clearly show the formation of LEVs whenever a rapid increase in angle of attack occurs. There is no discrete starting vortex. Instead, a shear layer forms behind the trailing edge whenever the wing is at a non-zero angle of attack, and rolls up, under Kelvin–Helmholtz instability, into a series of transverse vortices with circulation of opposite sign to the circulation around the wing and LEV. The flow fields produced by dragonflies differ qualitatively from those published for mechanical models of dragonflies, fruitflies and hawkmoths, which preclude natural wing interactions. However, controlled parametric experiments show that, provided the Strouhal number is appropriate and the natural interaction between left and right wings can occur, even a simple plunging plate can reproduce the detailed features of the flow seen in dragonflies. In our models, and in dragonflies, it appears that stability of the LEV is achieved by a general mechanism whereby flapping kinematics are configured so that a LEV would be expected to form naturally over the wing and remain attached for the duration of the stroke. However, the actual formation and shedding of the LEV is controlled by wing angle of attack, which dragonflies can vary through both extremes, from zero up to a range that leads to immediate flow separation at any time during a wing stroke.
Variation of crustacean hyperglycemic hormone (cHH) level in the eyestalk and haemolymph of the shrimpPalaemon elegansfollowing stress
Authors: Lorenzon Simonetta , Edomi Paolo , Giulianini Piero G. , Mettulio Romina , Ferrero Enrico A.
Published: November 2004

This study investigates (by means of bioassays and ELISA using an antibody against recombinant cHH) the variation of cHH levels in the eyestalks and haemolymph of Palaemon elegans (Decapoda, Caridea) following exposure to various stresses (heavy metals and lipopolysaccharide), and correlates them with the variation in amount and time course of blood glucose. The dose-relationship between exposure to copper and quick release of cHH from the eyestalk into haemolymph was confirmed by variation of blood glucose with a dose-related hyperglycaemia, that peaked 2 h after immersion in contaminated seawater. Animals exposed to a sublethal concentration of mercury showed the same dose relation between toxicant, release of cHH from the eyestalk,increment of circulating hormone level and subsequent hyperglycaemia as observed for copper contamination. It is of note that although the highest lethal mercury concentration induced the release of cHH from the eyestalk into the haemolymph, it was not followed by a significant variation of blood glucose. Step doses of a bacterial contaminant [such as lipopolysaccharide(LPS) from E. coli injected into shrimps] confirmed the dose-relationship and convergent chain of events that bring about hyperglycaemia. These are the first data that relate the release of cHH from the eyestalk, the circulating hormone level and the consequent glycaemic response to stress. Moreover, they confirm the dose-related pathway that leads to variation of blood glucose as a quantitative biomarker of environmental quality, even at sublethal toxicant concentrations.
The effect of advance ratio on the aerodynamics of revolving wings
Authors: Dickson William B. , Dickinson Michael H.
Published: November 2004

Recent studies have demonstrated that a quasi-steady model closely matches the instantaneous force produced by an insect wing during hovering flight. It is not clear, however, if such methods extend to forward flight. In this study we use a dynamically scaled robotic model of the fruit fly Drosophila melanogaster to investigate the forces produced by a wing revolving at constant angular velocity while simultaneously translating at velocities appropriate for forward flight. Because the forward and angular velocities were constant wing inertia was negligible, and the measured forces can be attributed to fluid dynamic phenomena. The combined forward and revolving motions of the wing produce a time-dependent free-stream velocity profile,which suggests that added mass forces make a contribution to the measured forces. We find that the forces due added mass make a small, but measurable,component of the total force and are in excellent agreement with theoretical values. Lift and drag coefficients are calculated from the force traces after subtracting the contributions due to added mass. The lift and drag coefficients, for fixed angle of attack, are not constant for non-zero advance ratios, but rather vary in magnitude throughout the stroke. This observation implies that modifications of the quasi-steady model are required in order to predict accurately the instantaneous forces produced during forward flight. We show that the dependence of the lift and drag coefficients upon advance ratio and stroke position can be characterized effectively in terms of the tip velocity ratio – the ratio of the chordwise components of flow velocity at the wing tip due to translation and revolution. On this basis we develop a modified quasi-steady model that can account for the varying magnitudes of the lift and drag coefficients. Our model may also resolve discrepancies in past measurements of wing performance based on translational and revolving motion.
Infrasound initiates directional fast-start escape responses in juvenile roachRutilus rutilus
Authors: Karlsen Hans E. , Piddington Robert W. , Enger Per S. , Sand Olav
Published: November 2004

Acoustic stimuli within the sonic range are effective triggers of C-type escape behaviours in fish. We have previously shown that fish have an acute sensitivity to infrasound also, with acceleration thresholds in the range of 10–5 m s–2. In addition, infrasound at high intensities around 10–2 m s–2 elicits strong and sustained avoidance responses in several fish species. In the present study, the possible triggering of C-escapes by infrasonic single-cycle vibrations was examined in juvenile roach Rutilus rutilus. The fish were accelerated in a controlled and quantifiable manner using a swing system. The applied stimuli simulated essential components of the accelerations that a small fish would encounter in the hydrodynamic flow field produced by a predatory fish. Typical C- and S-type escape responses were induced by accelerations within the infrasonic range with a threshold of 0.023 m s–2 for an initial acceleration at 6.7 Hz. Response trajectories were on average in the same direction as the initial acceleration. Unexpectedly, startle behaviours mainly occurred in the trailing half of the test chamber, in which the fish were subjected to linear acceleration in combination with compression, i.e. the expected stimuli produced by an approaching predator. Very few responses were observed in the leading half of the test chamber, where the fish were subjected to acceleration and rarefaction, i.e. the stimuli expected from a suction type of predator. We conclude that particle acceleration is essential for the directionality of the startle response to infrasound, and that the response is triggered by the synergistic effects of acceleration and compression.