bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal levels of nitric oxide are crucial for implantation in mice
Authors: Ota H. , Igarashi S. , Oyama N. , Tanaka T. , Suzuki Y.
Published: November 2003

This study was performed to clarify the critical role of optimal levels of
nitric oxide on fecun-dity in mice during the implantation period. Mature
female pregnant mice were treated with either nitric oxide donor molsidomine
(3, 15, 60 mg kg-1) or nitric oxide synthase inhibitor
NG-nitro-L-arginine methyl ester (L-name; 0.3, 1.5, 6 mg
kg-1) every 12 h, seven times from the night of Day 2 to
Day 5 of gestation. They were killed on Day 14 of gestation. Pregnancy rates
in each group (n = 22) and the number of live or
absorbed fetuses in each mouse was calculated. The pregnancy rates in the
experimental group were reduced in a dose-dependent manner. The rate in the
control group was 100%, whereas those in the 60-mg mol-sidomine and
6-mg L-name groups were 40.9 and 31.8%, respectively. Histological
analysis of uteri on Day 5 of gestation after treatment with 60 mg molsidomine
or 6 mg L-name suggested retarded decidualization of stromal cells or
defective function of predecidualized cells. In conclusion, optimal levels of
nitric oxide are crucial for endometrial function and embryo implantation.
Reproductive cycles of farmed female chital deer (Axis axis)
Authors: Mylrea G. E. , Mulley R. C. , English A. W. , Evans G.
Published: November 2003

Studies were conducted on chital deer hinds (Axis axis)
living in a temperate region to advance the understanding of the patterns of
reproduction of a tropical cervid species. The hinds exhibited regular
patterns of oestrus cyclicity throughout the year as evidenced by
concentrations of serum progesterone mon-itored over a 14-month period, and
detection of behavioural oestrus by vasectomized stags. The mean length of the
oestrous cycle was 18.0 $plusmn; 0.7 days (range, 12–23 days). Profiles
of serum progesterone showed con-centrations of <0.5 ng
mL-1 at the time of oestrus, which rose to a peak (range
1.5–5.0 ng mL-1) about Day 13, and then declined
to low concentrations at the next oestrus. Observations following parturition
showed that the first detected oestrus occurred at a mean (± SEM) time
of 26.9 ± 3.0 days later for seven of nine hinds. The mean length of
the oestrous cycle after the first post-partum oestrus was 16.6 ± 1.0
days (range 7–20 days). The presence of a stag may influence the length
of the post-partum period in chital deer hinds, and hinds in contact with a
stag in this study had a significantly shorter interval from parturition to
first ovu-lation (P<0.01) compared with hinds not in
contact with a stag. By 7 weeks post partum a corpus luteum was detected in
93% of hinds. In comparison only 43% of hinds with no stag
contact had a corpus luteum by 7 weeks post partum. It is suggested that the
tendency towards seasonal calving in the study population may be related more
to male than female factors.
Role of peripheral and central aromatization in the control of gonadotrophin secretion in the male sheep
Authors: Sharma T. P. , Blache D. , Blackberry M. A. , Martin G. B.
Published: November 2003

Both testosterone and its aromatized
metabolite, oestradiol-17b, are known to act centrally on the secretion of
GnRH, but the major site of aromatization is not clear as aromatase activities
are found in numerous tissues including brain and testis. Here, we tested the
importance of central aromatization of testosterone using a non-steroidal
aromatase inhibitor, fadrozole. To distinguish between testicular and
non-testicular sites, five intact and five testosterone-infused castrated rams
(600 g kg –1 per 24 h for 3 days) were given four
injections of fadrozole (i.m; 500 g kg –1 ) at 48,
52, 64 and 68 h relative to the start of testosterone infusion. Control rams
(n = 5) received vehicle only. Fadrozole
treatment decreased plasma oestradiol-17b concentrations and increased the LH
pulse frequency in both intact rams and testosterone-treated castrates,
suggesting that non-testicular sites of aromatization are important in the
control of pulsatile LH secretion. To test the importance of central
aromatization, intact rams (n = 5) were infused
into the third ventricle with vehicle (artificial cerebrospinal fluid) or with
fadrozole (20 and 200 g kg –1 per day). After two
weeks, the same two doses of fadrozole were infused intravenously instead of
intracerebrally. Central infusion of fadro-zole did not affect plasma
oestradiol concentrations but increased LH pulse frequency. Only the highest
dose increased LH pulse frequency when infused intravenously. In conclusion,
central aromatization is involved in the control of pulsatile LH secretion in
male sheep.
The Pattern Recognition Receptor (RAGE) Is a Counterreceptor for Leukocyte Integrins
Authors: Chavakis Triantafyllos , Bierhaus Angelika , Al-Fakhri Nadia , Schneider Darius , Witte Steffen , Linn Thomas , Nagashima Mariko , Morser John , Arnold Bernd , Preissner Klaus T. , Nawroth Peter P.
Published: November 2003

The pattern recognition receptor, RAGE (receptor for advanced glycation endproducts), propagates cellular dysfunction in several inflammatory disorders and diabetes. Here we show that RAGE functions as an endothelial adhesion receptor promoting leukocyte recruitment. In an animal model of thioglycollate-induced acute peritonitis, leukocyte recruitment was significantly impaired in RAGE-deficient mice as opposed to wild-type mice. In diabetic wild-type mice we observed enhanced leukocyte recruitment to the inflamed peritoneum as compared with nondiabetic wild-type mice; this phenomenon was attributed to RAGE as it was abrogated in the presence of soluble RAGE and was absent in diabetic RAGE-deficient mice. In vitro, RAGE-dependent leukocyte adhesion to endothelial cells was mediated by a direct interaction of RAGE with the β2-integrin Mac-1 and, to a lower extent, with p150,95 but not with LFA-1 or with β1-integrins. The RAGE–Mac-1 interaction was augmented by the proinflammatory RAGE-ligand, S100-protein. These results were corroborated by analysis of cells transfected with different heterodimeric β2-integrins, by using RAGE-transfected cells, and by using purified proteins. The RAGE–Mac-1 interaction defines a novel pathway of leukocyte recruitment relevant in inflammatory disorders associated with increased RAGE expression, such as in diabetes, and could provide the basis for the development of novel therapeutic applications.
Memory CD8+ T Cells Provide Innate Immune Protection against Listeria monocytogenes in the Absence of Cognate Antigen
Authors: Berg Rance E. , Crossley Emily , Murray Sean , Forman James
Published: November 2003

Interferon (IFN)-γ plays an important role in the innate immune response against intracellular bacterial pathogens. It is commonly thought that natural killer cells are the primary source of this cytokine that is involved in activating antibacterial effects in infected cells and polarizing CD4+ T cells toward the Th1 subset. However, here we show that both effector and memory CD8+ T cells have the potential to secrete IFN-γ in response to interleukin (IL)-12 and IL-18 in the absence of cognate antigen. We demonstrate that memory CD8+ T cells specific for the ovalbumin protein secrete IFN-γ rapidly after infection with wild-type Listeria monocytogenes (LM). Furthermore, small numbers of ovalbumin-specific, memory CD8+ T cells can reduce spleen and liver bacterial counts in IFN-γ–deficient mice 3 d after LM infection. Up-regulation of the receptors for IL-12 and IL-18 provides a mechanism for the ability of memory CD8+ T cells to respond in this antigen nonspecific manner. Thus, CD8+ T cells play an important role in the innate immune response against intracellular pathogens by rapidly secreting IFN-γ in response to IL-12 and IL-18.
Use of a Small Molecule CCR5 Inhibitor in Macaques to Treat Simian Immunodeficiency Virus Infection or Prevent Simian–Human Immunodeficiency Virus Infection
Authors: Veazey Ronald S. , Klasse Per Johan , Ketas Thomas J. , Reeves Jacqueline D. , Piatak Michael , Kunstman Kevin , Kuhmann Shawn E. , Marx Preston A. , Lifson Jeffrey D. , Dufour Jason , Mefford Megan , Pandrea Ivona , Wolinsky Steven M. , Doms Robert W. , DeMartino Julie A. , Siciliano Salvatore J. , Lyons Kathy , Springer Martin S. , Moore John P.
Published: November 2003

Human immunodeficiency virus type 1 (HIV-1) fuses with cells after sequential interactions between its envelope glycoproteins, CD4 and a coreceptor, usually CC chemokine receptor 5 (CCR5) or CXC receptor 4 (CXCR4). CMPD 167 is a CCR5-specific small molecule with potent antiviral activity in vitro. We show that CMPD 167 caused a rapid and substantial (4–200-fold) decrease in plasma viremia in six rhesus macaques chronically infected with simian immunodeficiency virus (SIV) strains SIVmac251 or SIVB670, but not in an animal infected with the X4 simian–human immunodeficiency virus (SHIV), SHIV-89.6P. In three of the SIV-infected animals, viremia reduction was sustained. In one, there was a rapid, but partial, rebound and in another, there was a rapid and complete rebound. There was a substantial delay (>21 d) between the end of therapy and the onset of full viremia rebound in two animals. We also evaluated whether vaginal administration of gel-formulated CMPD 167 could prevent vaginal transmission of the R5 virus, SHIV-162P4. Complete protection occurred in only 2 of 11 animals, but early viral replication was significantly less in the 11 CMPD 167-recipients than in 9 controls receiving carrier gel. These findings support the development of small molecule CCR5 inhibitors as antiviral therapies, and possibly as components of a topical microbicide to prevent HIV-1 sexual transmission.
Using computer‐based technologies to disseminate business knowledge
Authors: Wongpinunwatana Nitaya
Published: November 2003

The primary objective of this research is to investigate the impact of task complexity on users’ performance in the context of using computer‐based technologies with auditing tasks. A laboratory experiment was performed with 121 undergraduate auditing students. The task complexity is defined in form of structured and unstructured tasks. The dependent variables were accuracy in solving problem and certainty of the correctness of solution. The results suggested that the effect of task complexity on accuracy in solving problems was significant for structured tasks. In addition, the significant effect was also found on certainty of the correctness of solution for structured tasks. The findings suggest the strategy for improving user performance in solving problem and certainty of the correctness of solutions toward a given task by giving users a structured task to perform. In addition, the findings also suggest the need for research on how to benefit from using computer‐based technologies in the context of solving structured task.
Do Peer Groups Matter? Peer Group versus Schooling Effects on Academic Attainment
Authors: Robertson Donald , Symons James
Published: November 2003

This paper estimates an educational production function. Educational attainment is a function of peer group, parental input and schooling. Conventional measures of school quality are not good predictors for academic attainment, once we control for peer group effects; parental qualities also have strong effects on academic attainment. This academic attainment is a then a key determinant of subsequent labour market success, as measured by earnings. The main methodological innovation in this paper is the nomination of a set of instruments, very broad regions of birth, which, as a whole, pass close scrutiny for validity and permit unbiased estimation of the production function.
Self‐enforcing Intergenerational Transfers and the Provision of Education
Authors: Anderberg Dan , Balestrino Alessandro
Published: November 2003

This paper considers intra‐family financing of human capital under the assumptions that individuals are selfish and binding contracts are not feasible. Cooperation among family members is possible through a family norm (a family ‘social capital’) which prescribes the obligations to be met at each stage in life and sanctions for those who deviate. We characterize the set of self‐enforcing transfers and show that there is a downward bias in the family provision of education. This gives a rationale for public action as a remedy to the lack of commitment between selfish family members.
Inflammatory Blockade Restores Adult Hippocampal Neurogenesis
Authors: Monje Michelle L. , Toda Hiroki , Palmer Theo D.
Published: November 2003

Cranial radiation therapy causes a progressive decline in cognitive function that is linked to impaired neurogenesis. Chronic inflammation accompanies radiation injury, suggesting that inflammatory processes may contribute to neural stem cell dysfunction. Here, we show that neuroinflammation alone inhibits neurogenesis and that inflammatory blockade with indomethacin, a common nonsteroidal anti-inflammatory drug, restores neurogenesis after endotoxin-induced inflammation and augments neurogenesis after cranial irradiation.
HUBBARD-GAP ENGINEERING IN A DOUBLE-HELIX-BASED HIERARCHICAL STRUCTURE
Authors: UGAJIN RYUICHI
Published: November 2003

A Mott–Hubbard gap of interacting electrons has potential application to electronic-material engineering. We investigate how a Mott insulator rises, in particular a Hubbard gap changes, when electrons are confined in a structure with hierarchically organized interactions.
MODELLING INFLATION AS A RANDOM PROCESS
Authors: RAWAL S. , RODGERS G. J.
Published: November 2003

We introduce a model of inflation in which the prices of commodities are inflated by a random process. At each time step a price x is selected with a rate of xα and is inflated by a factor of 1/β where 0<β<1. For α=0, we obtain a general time-dependent solution, where the initial price distribution can be of any form. When α>0, in the long time limit, only the highest price inflates. For α<0, the model exhibits asymptotic scaling behavior. We also consider the effects of a time dependent β, where 0<β(t)<1, for the case α=0. We find that the price distribution approaches a steady state if β(t)-1~0 faster than 1/t.
BUBBLES AND CRASHES: OPTIMISM, TREND EXTRAPOLATION AND PANIC
Authors: WESTERHOFF FRANK
Published: November 2003

The observation that large drawdowns are outliers suggests that a special mechanism may be responsible for large crashes. We develop a simple model with heterogeneous interacting agents which follow technical and fundamental trading rules to determine their orders. Although the chartists are optimistic most of the time, they panic if prices drop sharply. Our main finding is that the selling impact due to a panic attack may be so large that it directly leads to the next panic attack. Such behavior generates temporal correlation in prices, i.e., causes large drawdowns.
QUASI MONTE–CARLO EVALUATION OF SENSITIVITIES OF OPTIONS IN COMMODITY AND ENERGY MARKETS
Authors: BENTH FRED E. , DAHL LARS O. , KARLSEN KENNETH H.
Published: November 2003

In this paper we consider the evaluation of sensitivities of options on spots and forward contracts in commodity and energy markets. We derive different expressions for these sensitivities, based on techniques from the recently introduced Malliavin approach [8, 9]. The Malliavin approach provides representations of the sensitivities in terms of expectations of the payoff and a random variable only depending on the underlying dynamics. We apply Monte–Carlo methods to evaluate such expectations, and to compare with numerical differentiation. We propose to use a refined quasi Monte–Carlo method based on adaptive techniques to reduce variance. Our approach gives a significant improvement of convergence.
A GENERALIZATION OF PRINCIPAL COMPONENT ANALYSIS FOR NON-OBSERVABLE TERM STRUCTURES IN EMERGING MARKETS
Authors: DE ALMEIDA CAIO IBSEN RODRIGUES , DUARTE ANTONIO MARCOS , FERNANDES CRISTIANO AUGUSTO COELHO
Published: November 2003

Principal Component Analysis (PCA) has been traditionally used for identifying the most important factors driving term structures of interest rates movements. Once one maps the term structure dynamics, it can be used in many applications. For instance, portfolio allocation, Asset/Liability models, and risk management, are some of its possible uses. This approach presents very simple implementation algorithm, whenever a time series of the term structure is disposable. Nevertheless, in markets where there is no database for discount bond yields available, this approach cannot be applied. In this article, we exploit properties of an orthogonal decomposition of the term structure to sequentially estimate along time, term structures of interest rates in emerging markets. The methodology, named Legendre Dynamic Model (LDM), consists in building the dynamics of the term structure by using Legendre Polynomials to drive its movements. We propose applying LDM to obtain time series for term structures of interest rates and to study their behavior through the behavior of the Legendre Coefficients levels and first differences properly normalized (Legendre factors). Under the hypothesis of stationarity and serial independence of the Legendre factors, we show that there is asymptotic equivalence between LDM and PCA, concluding that LDM captures PCA as a particular case. As a numerical example, we apply our technique to Brazilian Brady and Global Bond Markets, briefly study the time series characteristics of their term structures, and identify the intensity of the most important basic movements of these term structures.
Emerging Role of the Urotensin II System in Cardiovascular Disease
Authors: Krum Henry , Kompa Andrew , Hannan Ross , Thomas Walter
Published: November 2003

Urotensin II is a potent 11-amino-acid vasoconstrictor peptide. The discovery of its endogenous receptor has led to renewed interest in its role in human cardiovascular physiology and pathophysiology. The cardiovascular actions of urotensin II are complex and include direct effects on the vasculature, systemic hemodynamic effects and effects on the myocardium, including actions on contractility, myocyte hypertrophy and extracellular matrix deposition. Plasma levels of urotensin have been found to be elevated in patients with chronic heart failure, diabetes mellitus and chronic renal disease. These elevations raise the possibility that urotensin II might be involved in the pathogenesis and/or progression of these disease states. Highly selective urotensin II antagonists have been developed, which should help to definitively clarify the role of urotensin II in these and other conditions.
Ich-Erleben, Synästhesie und Gefühl: Zur Bedeutung von Gefühlszuständen für die Einheit des Bewusstseins1
Authors: Emrich Hinderk M.
Published: November 2003

Jungs Auffassung vom Ich als ein Komplex von Vorstellungen, der das Zentrum des Bewusstseinsfeldes aufmacht, wird in Beziehung zu kognitionspsychologischen und neuropsychologischen Befunden und Überlegungen zum Phänomen der Synästhesie untersucht.
Anmerkungen zu V. Hansen: «Empfinden als kollektive Hilfsfunktion – Ein anderer Aspekt der Typologie»
Authors: Wilke H.-J.
Published: November 2003

Leider besteht für diesen Artikel keine Zusammenfassung. Als Einstieg stellen wir den Textanfang zur Verfügung. So wichtig es mir scheint, nach langer Zeit wieder eine Arbeit zur Typologie der Analytischen Psychologie [Hansen, 2002] zu finden, so gross ist mein Unbehagen mit dieser Form des Umganges, zu der sich der Autor scheinbar durch J. Hillman und P. Schellenbaum veranlasst fühlte, obwohl Schellenbaum sich vermutlich bewusst und absichtlich nicht «ausdrücklich auf Jungsche typologische Terminologie» bezieht, wie Hansen auf Seite 290 im 6. Absatz schreibt, aber «die gleichen Begriffe verwendet», obwohl es sich dann doch wohl nur um den gleichen Wortgebrauch handelt, wenn Jungs Inhaltsbestimmung nicht gelten soll und keine neue Inhaltsdefinition gegeben wäre.
Observations of Mating, Birthing and Parental Behaviour in Three Subspecies of Slender Loris (Loris tardigradus and Loris lydekkerianus ) in India and Sri Lanka
Authors: Nekaris K.A.I.
Published: November 2003

Studies of the life history parameters of slender lorises in captivity have led to conflicting results regarding gestation length, birth seasonality, interspecies variation in litter size and the degree of parental care given to offspring. During the course of field studies of Loris lydekkerianus lydekkerianus, L. l. nordicus and L. tardigradus tardigradus, data were collected on these life history variables, as well as on behaviours relating to mating. All 3 taxa displayed courtship behaviour involving the pursuit of a female by multiple males. Mating corresponded closely with captive observations, with a period of prolonged single intromissions lasting 3–11 min. One gestation period of 163 days was calculated for L. l. lydekkerianus. Births for all 3 taxa were distributed throughout the year, and males were seenmating throughout the year. All 3 taxa gave birth to singletons and twins; no subspecific pattern in litter size was evident. Females carried infants for the first 4 weeks of life and were regularly attended by males, which groomed both the mother and her offspring. After infants had been parked, female L. l. lydekkerianus and L. l. nordicus rarely returned before dawn, though males visited and played with infants. Female L. t. tardigradus maintained proximity with their infants, whilst males were not observed in proximity to infants during the night. All 3 taxa slept in social groups. High-energy milk, in combination with male care, may aid in the potentially high reproductive output of 4 infants per year.
Human Uterine Epithelial RL95-2 Cells Reorganize Their Cytoplasmic Architecture with Respect to Rho Protein and F-Actin in Response to Trophoblast Binding
Authors: Heneweer Carola , Adelmann Holger G. , Kruse Lars Hendric , Denker Hans-Werner , Thie Michael
Published: November 2003

Embryo implantation is initiated by interaction of trophoblast with uterine epithelium via the apical cell poles of both partners. Using spheroids of human trophoblastoid JAR cells and monolayers of human uterine epithelial RL95-2 cells to simulate this initial interaction, we previously demonstrated that formation of stable cell-to-cell bonds depends on actin cytoskeleton (F-actin) and small GTPases of the Rho family, most likely RhoA. In this study, we determined the apical as well as the basal distribution of these proteins by fluorescence confocal microscopy before and after binding of JAR spheroids. We focussed on changes in cytoplasmic organization with respect to apicobasal polarity of RL95-2 cells. Before binding of spheroids, significantly higher fluorescence signals of RhoA [37 ± 6 grey scale values (gsv)] and of F-actin (41 ± 3 gsv) were found in the basal region of RL95-2 cells as compared to the apical pole (RhoA: 24 ± 3 gsv, F-actin: 28 ± 2 gsv). After binding of JAR spheroids, this apicobasal asymmetry was inverted (RhoA: 55 ± 10 gsv apical vs. 25 ± 3 gsv basal; F-actin: 108 ± 17 gsv apical vs. 57 ± 7 gsv basal). Inactivation of Rho GTPases in RL95-2 cells by Clostridium difficile toxin A leads to a loss of their apical adhesion competence, as previously published. Here, we observed a uniform distribution of RhoA and F-actin between apical and basal region rather than an asymmetric one in toxin A-treated cells. These data suggest that activation of Rho GTPases and coordinated rearrangement of F-actin within uterine epithelial cells in response to trophoblast binding are part of a generalized structural and functional reorganization of the cytoplasm. This involves not only the immediate contact zone (apical) but also the opposite (basal) cell pole and may be a critical element of uterine epithelial reactions during transition between trophoblast adhesion and transmigration.
Conceptus Polarity and Cell-Zona Adhesion during Early Cleavage (Fertilized Tubal Egg to 8-Cell Stage) in the Marsupial Sminthopsis macroura
Authors: Kress Annetrudi , Selwood Lynne
Published: November 2003

This study outlines the ultrastructural changes that occur in Sminthopsis macroura tubal zygotes to the 8-cell stage in relation to observations of development in vitro, oocyte polarity and cell-zona adhesion. The extremely polarized mature oocytes and zygotes have nuclear material at one pole and accumulated vesicular bodies at the other. The first division is associated with extrusion of vesicular bodies and some cytoplasm as a membrane-bound yolk mass into the perivitelline space. Early cleavage is accompanied by the appearance of an extensive, highly structured extracellular matrix (ECM) comprised of amorphous substance, granules and filaments. At the 2- and 4-cell stage the decrease in density of the ECM in the vicinity of the blastomeres may facilitate cell-zona contact. At the 8-cell stage, discharge of vesicular bodies, which mostly appear to be empty, may contribute to the ECM by increasing the area of plasma membrane for synthesis of a hyaluronan-like ECM. As in other marsupials, the precedence of cell-zona adhesion over cell-cell contacts prevents morula formation. The earliest cell-zona contacts appear when microvilli contact the zona in the uterine zygote 12–16 h after uterine entry and continue at later stages. This early contact is possible because of the absence of a dense subzonal ECM in this species. Between late zygote and late 4-cell stage the cytoplasm also contains, beside a large amount of vesicular bodies, demarcated areas where smooth endoplasmic reticulum encloses mitochondria, vesicles, granular material and fibrillar arrays. The latter develop in the late zygote stage and are found outside demarcated areas as well, often closely surrounding large vesicles, probably helping vesicle extrusion. A putative germ plasm was identified at the 4-cell stage.
Types of Programmed Cell Death: Two Variants Expressed by Neonatal Murine Hepatocytes
Authors: Sasaki K. , Sonoda Y. , Kumano I. , Suda M.
Published: November 2003

Neonatal livers examined with the terminal transferase-mediated dUTP nick end labeling (TUNEL) method contained numerous positive cells. Although the majority of dying cells are either hematopoietic cells including erythroids and granulocytes or macrophages, a few hepatocytes were also positive. As for the ultrastructural features of these dying hepatocytes, two different types, type I and II, could be identified. The early features of type I appeared in the cytoplasm, which was characterized by dilated rough endoplasmic reticulum, and the cell fragments displayed a round, foamy appearance. Type II was characterized by nuclear compaction and margination of heterochromatin resulting in the formation of sharply circumscribed masses, followed by the condensation of the cytoplasm. The cell death of type I, characterized by the formation of massive vacuolization of the endoplasmic reticulum, corresponds to cytoplasmic type degeneration or nonapoptotic death, while that of type II corresponds to nuclear type cell death or classical apoptotic death. In the two types of programmed cell death, the incidence of nonapoptotic cell death was much higher than that of classical apoptosis in neonatal murine hepatocytes.
Solitary Chemosensory Cells in Mammals?
Authors: Sbarbati A. , Osculati F.
Published: November 2003

In fish, solitary chemosensory cells (SCCs) occur in the oropharynx, gills and skin and have often been found in association with taste buds. Among amphibia, a diffuse chemosensory system has been described on the ventral skin of toads, and a structural resemblance of SCCs to taste bud cells has been reported in frogs. Putative solitary chemoreceptors have been described in mammals too, at specific sites in the digestive or respiratory apparatus. In newborn rodents, a specific set of SCCs (composed of elements positive for α-gustducin, a marker of chemosensory cells) is associated with the gustatory epithelium. In conclusion, the available data suggest that a SCC system is not restricted to fish but is present in amphibia and mammals as well. At our present level of knowledge, establishing a precise homology between different species is difficult. However, the data from mammals and amphibia fully confirm previous findings in fish, and the use of chemical markers to study the diffuse chemosensory systems of vertebrates seems promising.
Pre- and Postweaning Iron Deficiency Alters Myelination in Sprague-Dawley Rats
Authors: Beard John L. , Wiesinger Jason A. , Connor James R.
Published: November 2003

Iron deficiency in early life is associated with hypomyelination; however, the role which iron plays in myelinogenesis is not clearly established. In this study, we examined the effect of preweaning [postnatal days (PND) 4–14 and PND 4–21] and postweaning (PND 21–63) iron deficiency on hindbrain 2′,3′-cyclic nucleotide 3′-phosphohydrolase (CNPase) activity (marker of oligodendrocyte metabolic activity) and myelin basic protein (MBP) concentrations. Both CNPase activity and concentrations in the cerebrum and hindbrain were significantly lower in pre- and postweaning iron-deficient rats. Similarly, MBP concentrations were also reduced (25–35%) in all three groups of iron-deficient animals. Iron-deficient animals also had significant alterations in the fatty acid composition of individual phospholipids within the hindbrain as well as changes in cytochrome oxidase activities. These studies show that postnatal iron deficiency, for as little as 10 days, can significantly alter the production of myelin and oligodendrocyte functioning. Importantly, postweaning iron deficiency was still associated with a decrease in CNPase activity and MBP concentrations despite occurring well past a likely key sensitive period of peak myelinogenesis at PND 8–12. This suggests that iron deficiency in later life, as well as during early postnatal growth, can effect the production and maintenance of myelin.
Estrogen Induces de novo Progesterone Synthesis in Astrocytes
Authors: Sinchak Kevin , Mills Richard H. , Tao Leslie , LaPolt Philip , Lu John K.H. , Micevych Paul
Published: November 2003

The brain is an established target for peripheral steroids, but also expresses steroidogenic enzymes and is capable of de novo ‘sex’ steroid synthesis (neurosteroidogenesis) independent of peripheral steroidogenic organs. In adrenalectomized and ovariectomized rats that do not have peripheral sources of steroids, estrogen treatment increased progesterone levels specifically in the hypothalamus, indicating that estrogen stimulates progesterone neurosteroidogenesis. Recent studies have demonstrated that specific cell types preferentially secrete specific steroids, and that astrocytes are the primary progesterone synthesizing cells in the nervous system. We hypothesized that estrogen could directly induce de novo synthesis of progesterone in astrocytes. To determine whether estrogen stimulates progesterone synthesis in astrocytes, astrocyte-enriched cultures were grown to confluence, then grown for an additional 48 h in an estrogen- and phenol-free Dulbecco’s Modified Eagle Medium (DMEM) and then treated with either 17β-estradiol or steroid-free media. After culturing for 48 h in steroid-free, phenol red-free DMEM, low levels of progesterone were detected in the media, whereas progesterone levels were significantly increased in the media of astrocytes cultured in DMEM with 17β-estradiol (10–7–10–4M). To determine whether estrogen regulated the mRNA expression of progesterone synthetic enzymes, P-450 side-chain cleavage and 3β-hydroxysteroid dehydrogenase, control and 17β-estradiol-treated astrocytes were harvested and prepared for Northern and slot blot analysis. Expression levels of enzyme mRNAs were very low and 17β-estradiol did not significantly increase mRNA levels of either steroidogenic enzyme. These results suggest that estrogen directly stimulated the de novo synthesis of neuroprogesterone in astrocytes, and demonstrate the potential for estrogen to regulate reproductive physiology and behavior through the paracrine actions of astrocyte-derived progesterone.
Brain Malformations Caused by Retroviral Vector-Mediated Gene Transfer of Hippocampal Cholinergic Neurostimulating Peptide Precursor Protein into the CNS via Embryonic Mice Ventricles
Authors: Matsukawa N. , Ikenaka K. , Nanmoku K. , Yuasa H. , Hattori M. , Kawano M. , Nakazawa H. , Fujimori O. , Ueda R. , Ojika K.
Published: November 2003

Hippocampal cholinergic neurostimulating peptide precursor protein (HCNP-pp) is a unique multifunctional protein, being not only the precursor of HCNP, which promotes the phenotype development of septo-hippocampal cholinergic neurons, but also the binding protein of phosphatidylethanolamine, ATP, Raf-1 kinase (known as ‘Raf-1 kinase inhibitory factor’ in peripheral organs), and serine protease. We obtained a high-titer retroviral vector harboring HCNP-pp cDNA by the use of a modified packaging cell line and centrifugation, and by injecting it into embryonic mouse ventricles, we investigated the function of its gene product within the central nervous system (CNS). We found that efficient transduction into hippocampal pyramidal neurons can be achieved by injecting the vector into embryonic brain ventricles on embryonic day 14 (E14). Three days after receiving the intraventricular injection of the high-titer HCNP-pp retrovirus vector on E14, the tissues around the ventricles showed an overexpression of HCNP-pp. This was accompanied by a reduced amount of activated MEK and Erk (as analyzed by histochemical and Western blot methods), suggesting that HCNP-pp also regulates the MAP-kinase cascade within the CNS. Surprisingly, mouse brains that received the HCNP-pp retroviral vector showed massive malformation of the hippocampus and cerebellum when examined 30 days after birth. This shows that strictly regulated HCNP-pp gene expression is necessary for the normal development of the mouse brain, and that the moderate overexpression achieved by retroviral vector-mediated gene transfer is sufficient to cause severe abnormality of entire brain structures.
Association between Brain Natriuretic Peptide and Extracellular Water in Hemodialysis Patients
Authors: Fagugli Riccardo Maria , Palumbo Barbara , Ricciardi Daniela , Pasini Paolo , Santirosi Paola , Vecchi Luigi , Pasticci Franca , Palumbo Renato
Published: November 2003

Background: Brain natriuretic peptide (BNP) is a hormone released by the left ventricle (LV) as a consequence of pressure or volume load. BNP increases in left ventricle hypertrophy (LVH), LV dysfunction, and it can also predict cardiovascular mortality in the general population as well as those undergoing hemodialysis (HD). We investigated the association between BNP and volume load in HD patients. Methods: We studied 32 HD patients (60 ± 17.1 years) treated thrice-weekly for at least 6 months. Exclusion criteria were: LV dysfunction, atrial fibrillation, malnutrition. Blood chemistries and BNP were determined on mid-week HD day. Blood pressure (BP) and cardiac diameters were determined on mid-week inter-HD day by using 24-hour ambulatory blood pressure monitoring and echocardiography. Bioimpedance was performed after HD and extracellular water (ECW%), calculated as a percentage of total body water, was considered as the index of volume load. Results: Patients were divided into quartiles of 8 patients depending on the BNP value: 1st qtl BNP ≤45.5 pg/ml (28.4 ± 10.9 pg/ml), 2nd qtl BNP > 45.5 pg/ml and ≤99.1 pg/ml (60.9 ± 15.8 pg/ml), 3rd qtl BNP > 99.1 pg/ml and ≤231.8 pg/ml (160.5 ± 51.8 pg/ml), 4th qtl BNP > 231.8 pg/ml (664.8 ± 576.6 pg/ml). No inter-quartile differences were reported in age, HD age, body mass index spKt/V, or blood chemistries. As expected patients in the 4th BNP quartile showed the highest values of 24-hour pulse pressure (PP) and LV mass index (LVMi). The study of body composition revealed significant differences in ECW%, which was higher in the 4th quartile when compared to the others (4th q: 50 ± 9.6%, vs 1st q. 40.1 ± 2.4%, 2nd q. 41.9 ± 5%, 3rd q. 42.8 ± 6.9%). Using multiple stepwise linear regression where BNP was the dependent variable, and PP and ECW% the independent variables, only ECW% maintained statistical significance as a predictor of BNP levels (PP: Beta = 0.86, p = 0.58; ECW%: Beta = 0.64, p < 0.001 p < 0.001). Conclusions: Few studies have investigated the relationship between plasma BNP and volume load, and direct evidence is lacking. We used bioimpedance and the determination of ECW% to assess volume state in HD patients finding an association between BNP and ECW. The increased synthesis and release of BNP from the LV in HD patients appear to be mainly related to volume stress rather than to pressure load.
Renal and Vascular Nitric Oxide System in Reduced Renal Mass Saline Hypertension
Authors: Arranz Cristina , Tomat Analía , Fellet Andrea , García Julia , Balaszczuk Ana María , de los Angeles Costa María
Published: November 2003

Background: Reduction in renal mass is associated with several structural and functional adaptations including compensatory renal growth and hemodynamic changes. The mediators of the renal hemodynamic adaptations have not been definitively identified. Several investigators have postulated that nitric oxide (NO) is involved this physiological mechanisms. The purpose of this study was to evaluate the role of vascular and renal NO pathway in the model of subtotal nephrectomy-salt load hypertension. Materials and Methods: Wistar rats with 75% renal mass reduction (RMR) and saline load were studied during 4 weeks. Weekly, indirect systolic blood pressure (SBP) were measured. One week after nephrectomy, animals were divided in two groups, hypertensive (SBP > 140 mm Hg) and normotensive (SBP < 140 mm Hg). Urinary excretion of nitrates and nitrites (NOx), urinary chemioluminiscence levels and NOS activity in the left kidney and in the thoracic aorta artery were determined at the fourth week after subtotal nephrectomy. Results: Urinary excretion of sodium was higher in normotensive rats than hypertensive rats and in both groups this parameter was higher than in sham rats. NOx excretion and NOS activity in the different nephron segments were higher in normotensive rats than in the hypertensive ones. In contrast, NOS activity in aorta sections and urinary chemiluminescence levels in hypertensive animals were enhanced compared with normotensive rats. These parameters were higher in both groups of nephrectomized rats than in sham ones. Conclusion: This study provides evidence to support the fact that the activation of the renal NO system is an important mechanism whereby the remnant kidney regulates sodium and water balance, contributing to control the arterial blood pressure in the renal mass reduction and saline load model.
Tuning of Innate Immunity and Polarized Responses by Decoy Receptors
Authors: Mantovani Alberto , Bonecchi Raffaella , Martinez Fernando O. , Galliera Emanuela , Perrier Patrick , Allavena Paola , Locati Massimo
Published: November 2003

After the identification of the interleukin (IL)-1 type II receptor as the prototype, decoy receptors have been identified for a number of members of the IL-1/IL-18, TNF, IL-10 and IL-13 receptor families. Moreover, the silent receptor D6 is a promiscuous decoy and scavenger receptor of inflammatory chemokines. The IL-1 decoy receptor is regulated by pro- and anti-inflammatory signals and its levels may serve as a readout of the activation of anti-inflammatory pathways, for instance by glucocorticoid hormones. Decoy receptors represent a strategy to tune inflammatory and polarized adaptive responses.
Analysis of Highly Expressed Genes in Monocytes from Atopic Dermatitis Patients
Authors: Nagata Naoko , Oshida Tadahilo , Yoshida Ning Lu , Yuyama Noriko , Sugita Yuji , Tsujimoto Gozoh , Katsunuma Toshio , Akasawa Akira , Saito Hirohisa
Published: November 2003

Background: Monocytes, macrophages, and antigen-presenting cells (APCs) are key effectors of both innate and acquired immune responses. Such cells have been implicated in the pathogenesis of some inflammatory diseases. Differential gene expression in CD14-positive cells from patients with atopic dermatitis (AD) was studied using real-time quantitative RT-PCR to measure transcription levels of selected genes. Methods: PBMCs were prepared by Ficoll gradient separation from 30 AD patients (the anti-mite-specific IgE RAST score: 0.75 to >100 UA/ml) and 10 healthy adult individuals (the RAST score: <0.34–0.37 UA/ml) and CD14-positive cells were selected. A total of 64 genes was selected for study from groups of genes with different molecular function. Results: Genes involved in MHC class I antigen presentation, such as β2-microglobulin, subunits of an immunoproteasome and ATP-binding cassette transporter TAP2 were expressed at higher levels in the AD patients than in the healthy controls. The genes for Toll-like receptors, CD36 and IFNγ receptor were also upregulated in the AD patients. These genes are involved in MHC class I antigen presentation, recognition of bacterial pathogens and apoptotic cells. Conclusions: The upregulation of genes suggests that circulating monocytes in AD patients may be primed to differentiate into effector cells by conditions associated with AD. The upregulation of genes may prove to be a useful marker for AD.
Potential Action of IL-4 and IL-13 as Fibrogenic Factors on Lung Fibroblasts in vitro
Authors: Saito Akira , Okazaki Hitoshi , Sugawara Isamu , Yamamoto Kazuhiko , Takizawa Hajime
Published: November 2003

Background: Asthma is characterized by chronic inflammation of the airway with the presence of Th2 cytokines. Airway remodeling in asthma is closely related to clinical manifestations. Lung myofibroblasts play a critical role in the airway remodeling and Th2 cytokines may modulate their behavior. We examined the effect of two major Th2 cytokines, IL-4 and IL-13, on differentiation of lung fibroblasts to myofibroblasts. We hypothesized that these cytokines would stimulate fibroblast proliferation in association with decreased prostaglandin E2 (PGE2). Methods: Lung fibroblasts were incubated with IL-4 and IL-13 with or without Th1 cytokine interferon-γ (IFN-γ) in vitro. Differentiation of lung fibroblasts to myofibroblasts was characterized by the expression of α-smooth muscle actin (α-SMA) as well as a morphological and immunohistochemical analysis. Fibroblast proliferation stimulated by IL-4 and IL-13 was assessed with the MTT assay. We also investigated the effect of these cytokines on cyclooxygenase (COX) gene expression and PGE2 production. Results: IL-4 and IL-13 increased α-SMA expression and myofibroblastic differentiation. This effect was attenuated by IFN-γ and dexamethasone failed to have an influence on differentiation. IL-4 and IL-13 stimulated fibroblast proliferation. These cytokines downregulated the expression of both COX-1 and COX-2 genes and decreased the production of PGE2. Conclusions: IL-4 and IL-13 induce differentiation of fibroblasts to myofibroblasts and this response is attenuated by IFN-γ. IL-4 and IL-13 stimulate fibroblast proliferation and this effect is at least partly due to suppressed COX gene expressions and subsequently decreased PGE2 production. These findings suggest that IL-4 and IL-13 directly act on lung fibroblast to induce a fibrogenic response.
Association of Genetic Traits to Estimated Haplotypes from SNP Genotypes Using EM Algorithm and Markov Chain Monte Carlo Techniques
Authors: Rohde K. , Fürst R.
Published: November 2003

In order to find association of genetic traits to some haplotypes from closely spaced multilocus phase-unknown genotypes we use a three-stage approach. Haplotype frequencies and the most likely haplotype pair for each individual are estimated from random samples of individual or small (nuclear) family genotypes via an EM algorithm. If the most likely haplotype pair configuration of the whole sample outweighs the less likely ones, we may consider the estimated haplotypes as alleles of a multi-allelic marker and carry out the conventional statistics, TDT or ANOVA for quantitative traits. If the most likely haplotype pair configuration and the less likely ones do not differ much in their weight, we sample the TDT or ANOVA statistic over all haplotype pair configurations using the Metropolis-Hastings algorithm. Applications of our method to simulated data as well as real data are given.
Group Sequential Study Designs in Genetic-Epidemiological Case-Control Studies
Authors: König Inke R. , Ziegler Andreas
Published: November 2003

Objective: In past years, the focus of genetic-epidemiological studies has shifted to analyzing complex diseases. Here, single genes often contribute only little to the manifestation of traits so that many probands have to be included in a study to reliably detect small effects. To reduce the number of required phenotypings and genotypings and thus facilitate analyzing complex traits, sequential study designs can be applied. Methods: For sequential analyses of complex diseases in association studies, we compare the procedure by Sobell et al. (Am J Med Genet 1993;48:28–35) with the adaptation of formal group sequential study designs by Pampallona and Tsiatis (J Stat Plan Inf 1994;42:19–35). Error rates and average sample sizes are investigated by Monte-Carlo simulations. Results: Formal sequential designs have a higher power regardless of underlying genetic effects. In addition, compared with conventional designs with fixed samples, average sample sizes are reduced considerably; under the null hypothesis of no association, up to 50% of the required sample size can be spared. Conclusions: To increase the efficiency of genetic-epidemiological case-control studies, we recommend using formal group sequential study designs. The tremendous savings in average sample sizes are expected to affect both cost and time spent on large-scale studies.
Positional Identification of Microdeletions with Genetic Markers
Authors: Amos Christopher I. , Shete Sanjay , Chen Jianfang , Yu Robert K.
Published: November 2003

The positional identification of genetic factors for both simple and complex diseases is difficult. There is increasing evidence that small deletions are a fairly common cause for many genetic diseases and some complex diseases. To date, no statistical basis has been available for the identification of microdeletions in family studies. Here, we present an approach to the identification of novel microdeletions for parent-affected offspring trios. We present several different approaches that can be applied to identify microdeletions and also evaluate the statistical behavior of one of these methods in simulated data. The results show that for the study of single nucleotide polymorphisms, the error rate has an approximately linear effect in decreasing the ability to identify microdeletions. On the other hand, heterogeneity of causation, with only some families showing a microdeletion had a more severe influence upon the ability to identify de novo microdeletions.
Genome Sharing in Large Pedigrees: Multiple Imputation of ibd for Linkage Detection
Authors: Thompson Elizabeth , Basu Saonli
Published: November 2003

Our objective is the development of robust methods for assessment of evidence for linkage of loci affecting a complex trait to a marker linkage group, using data on extended pedigrees. Using Markov chain Monte Carlo (MCMC) methods, it is possible to sample realizations from the distribution of gene identity by descent (ibd) patterns on a pedigree, conditional on observed data YM at multiple marker loci. Measures of gene ibdW which capture joint genome sharing in extended pedigrees often have unknown and highly skewed distributions, particularly when conditioned on marker data. MCMC provides a direct estimate of the distribution of such measures. Let W be the ibd measure from data YM, and W* the ibd measure from pseudo-data Y*M simulated with the same data availability and genetic marker model as the true data YM, but in the absence of linkage. Then measures of the difference in distributions of W and W* provide evidence for linkage. This approach extracts more information from the data YM than either comparison to the pedigree prior distribution of W or use of statistics that are expectations of W given the data YM. A small example is presented.