bluuebunny/crossref_metadata_2025 huggingface dataset:
Major and minor effects of Holocene sea-level rise recorded from microfossils and Ca:Sr ratios in coastal sequences of NW Germany
Authors: Gerdes Gisela , Watermann Frank
Published: May 2003

To study responses of the depositional environments to Holocene sea-level rise, high-resolution analyses of diatoms, foraminifera and Ca:Sr ratios of two boreholes were performed. The diatoms were differentiated according to pelagic and littoral (benthic) lifestyles, and classified following oligohalobous, mesohalobous or polyhalobous attributes. The foraminifera were grouped into brackish-water and euryhaline tidal-flat species. The sedimentary successions include marine and non-marine facies. Marine facies is characteristic of channels and tidal flats. Non-marine facies units include deposits of a low-lying, lagoonary and swampy hinterland, natural and fluvial levees, and finally fen (reed) complexes. In the boreholes studied, polyhalobous marine pelagic diatoms exceed marine facies boundaries and even occur in peat layers. The occurrence of marine allogenes in non-marine strata suggest an origin from minor sea-level undulations. Since the hinterland was a lowland area, it was easily accessible by landward-directed pulses of the sea. Minor sea-level variations were short enough to not change the environment which remained semi-terrestrial. This is different to the transgressive onlaps.
Clinical manifestations of VX poisoning following percutaneous exposure in the domestic white pig
Authors: Chilcott R P , Dalton C H , Hill I , Davidson C M , Blohm K L , Hamilton M G
Published: May 2003

Nerve agents are a class of organophosphorus chemicals that inhibit certain cholinesterase enzymes (ChE). If untreated, percutaneous exposure to nerve agents, such as VX (O-ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothioate) can cause paralysis, apnoea and death. Much of the information concerning the percutaneous absorption and subsequent toxicity of nerve agents has been obtained using various rodent models. However, the most relevant ‘skin model’ is arguably the pig. Therefore, the purpose of this study was to examine the clinical manifestations of VX intoxication in the domestic white pig following a 2 LD50 (120 mg/kg) percutaneous challenge. There was a consistent onset of signs (where present) in each animal: mastication was followed by miosis, salivation, fasciculations and apnoea. Whilst ChE activity did not correlate with the onset of signs, there was a qualitative relationship in that mastication preceded substantial ChE inhibition, miosis lagged behind the linear decrease in acetylcholinesterase (AChE) activity and fasciculations and apnoea occurred after maximum ChE inhibition had been attained (5 / 10% of normal). These observations may be of use for the triage of patients exposed to VX. In comparison with similar studies with GD, VX did not affect glucose utilization. However, VX was similar to GD in that it caused a mild hyperkalaemia and hyperphosphataemia, although the significance of this observation was not clear. There was substantial lateral diffusion of the initial droplet of VX over the application site, indicating that, when decontaminating exposed skin, attention should also be directed to areas peripheral to the original site of exposure.
The Calcium Component of Gonadotropin-Releasing Hormone-Stimulated Luteinizing Hormone Subunit Gene Transcription Is Mediated by Calcium/Calmodulin-Dependent Protein Kinase Type II
Authors: Haisenleder Daniel J. , Ferris Heather A. , Shupnik Margaret A.
Published: May 2003

Calcium influx plays a critical role in GnRH regulation of rat LH subunit gene transcription, but the site(s) of action are undefined. We investigated the potential of GnRH acting through calcium to activate calcium/calmodulin-dependent protein kinase type II (Ca/CaMK II) in mouse gonadotrope-derived LβT2 cells. GnRH stimulated Ca/CaMK II β subunit activity 3-fold 2 min after treatment and returned to control values by 45 min. The Ca/CaMK II response to GnRH was blocked by administration of the Ca/CaMK II-specific inhibitor, KN-93. The calcium channel activator Bay K 8644 stimulated a 3-fold increase in Ca/CaMK II activity, similar to GnRH. Blocking calcium influx with nimodipine or depleting intracellular calcium storage pools with thapsigargin each resulted in a partial suppression of GnRH-induced activation of Ca/CaMK II, and in combination, completely suppressed the Ca/CaMK II response to GnRH. KN-93 and nimodipine also suppressed α-subunit and LHβ promoter responses to GnRH by 40–60%. LHβ promoter constructs containing either proximal or proximal and distal GnRH-responsive regions were sensitive to inhibition. These data show for the first time that Ca/CaMK II activation plays an important role in the transmission of GnRH signals from the plasma membrane to the LH subunit genes.
A Ketogenic Diet Increases Brain Insulin-Like Growth Factor Receptor and Glucose Transporter Gene Expression
Authors: Cheng Clara M. , Kelley Brandon , Wang Jie , Strauss David , Eagles Douglas A. , Bondy Carolyn A.
Published: May 2003

A ketogenic diet suppresses seizure activity in children and in juvenile rats. To investigate whether alteration in brain IGF activity could be involved in the beneficial effects of the ketogenic diet, we examined the effects of this diet on IGF system gene expression in the rat brain. Juvenile rats were fed one of three different diets for 7 d: ad libitum standard rat chow (AL-Std), calorie-restricted standard chow (CR-Std), or a calorie-restricted ketogenic diet (CR-Ket). The calorie-restricted diets contained 90% of the rats’ calculated energy requirements. The AL-Std diet group increased in weight, whereas the two CR groups merely maintained their weight during the 7-d diet. Glucose levels were significantly reduced in both CR groups compared with the AL-Std group, but only the CR-Ket group developed ketonemia. IGF1 mRNA levels were reduced by 30–50% in most brain regions in both CR groups. IGF1 receptor (IGF1R) mRNA levels were decreased in the CR-Std group but were increased in the CR-Ket diet group. Brain IGF binding protein (IGFBP)-2 and -5 mRNA levels were not altered by diet, but IGFBP-3 mRNA levels were markedly increased by the ketogenic diet while not altered by calorie restriction alone. Brain glucose transporter expression was also investigated in this study. Glucose transporter (GLUT) 4 mRNA levels were quite low and not appreciably altered by the different diets. Parenchymal GLUT1 mRNA levels were increased by the CR-Ket diet, but endothelial GLUT1 mRNA levels were not affected. Neuronal GLUT3 expression was decreased with the CR-Std diet and increased with the CR-Ket diet, in parallel with the IGF1R pattern. These observations reveal divergent effects of dietary caloric content and macronutrient composition on brain IGF system and GLUT expression. In addition, the data may be consistent with a role for enhanced IGF1R and GLUT expression in ketogenic diet-induced seizure suppression.
Microarray and Suppression Subtractive Hybridization Analyses of Gene Expression in Pheochromocytoma Cells Reveal Pleiotropic Effects of Pituitary Adenylate Cyclase-Activating Polypeptide on Cell Proliferation, Survival, and Adhesion
Authors: Grumolato Luca , Elkahloun Abdel G. , Ghzili Hafida , Alexandre David , Coulouarn Cédric , Yon Laurent , Salier Jean-Philippe , Eiden Lee E. , Fournier Alain , Vaudry Hubert , Anouar Youssef
Published: May 2003

Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts trophic effects on several neuronal, neuroendocrine, and endocrine cells. To gain insight into the pattern of the transcriptional modifications induced by PACAP during cell differentiation, we studied the effects of this neuropeptide on rat pheochromocytoma PC12 cells. We first analyzed the transcriptome of PC12 cells in comparison to that of terminally differentiated rat adrenomedullary chromaffin cells, using a high-density microarray, to identify genes associated with the proliferative phenotype that are possible targets of PACAP during differentiation of sympathoadrenal normal and tumoral cells. We then studied global gene expression in PC12 cells after 48 h of exposure to PACAP, using both cDNA microarray and suppression subtractive hybridization technologies. These complementary approaches resulted in the identification of 75 up-regulated and 70 down-regulated genes in PACAP-treated PC12 cells. Among the genes whose expression is modified in differentiated cells, a vast majority are involved in cell proliferation, survival, and adhesion/motility. Expression changes of most of these genes have been associated with progression of several neoplasms. A kinetic study of the effects of PACAP on some of the identified genes showed that the neuropeptide likely exerts early as well as late actions to achieve the gene expression program necessary for cell differentiation. In conclusion, the results of the present study underscore the pleiotropic role of PACAP in cell differentiation and provide important information on novel targets that could mediate the effects of this neuropeptide in normal and tumoral neuroendocrine cells.
Committing Embryonic Stem Cells to Differentiate into Thyrocyte-Like Cells in Vitro
Authors: Lin Reigh-Yi , Kubo Atsushi , Keller Gordon M. , Davies Terry F.
Published: May 2003

The derivation of thyrocyte-like cells in culture is of importance in the basic study of early thyroid embryogenesis and the generation of an unlimited clinical source of thyrocytes for genetic manipulation and cell transplantation. We have established an experimental system, which shows that 6-d-old embryoid bodies (EBs) differentiated from mouse embryonic stem (ES) cells expressed a set of genes traditionally associated with thyroid cells. The genes analyzed included the thyroid transcription factor PAX8, the Na+/I− symporter, thyroperoxidase, thyroglobulin, and the TSH receptor (TSHR). Immunofluorescent analysis demonstrated the presence of TSHR-positive cells as outgrowths from 8-d-old EBs cultured on chamber slides. Accordingly, this area of cells also expressed PAX8 and another thyroid transcription factor TTF2. Of importance, TSH, the main regulator of the thyroid gland, was necessary to maintain the expression of PAX8 and TSHR genes during EB differentiation. Furthermore, thyroid-specific function, such as cAMP generation by TSH, was maintained in this model. Together, these results suggested that the developmental program associated with thyrocyte development is recapitulated in the ES/EB model system. The differentiation of mouse ES cells into thyrocyte-like cells provides a powerful model for the study of thyrocyte developmental diseases associated with this lineage and contributes to the development of thyroid hormone-secreting cell lines.
Cytochrome P450 Genes Are Differentially Expressed in Female and Male Hepatocyte Retinoid X Receptor α-Deficient Mice
Authors: Cai Yan , Dai Tiane , Ao Yan , Konishi Tamiko , Chuang Kuang-Hsiang , Lue Yanhe , Chang Chawnshang , Wan Yu-Jui Yvonne
Published: May 2003

To study the functional role of retinoid X receptor α (RXRα) in hepatocytes, hepatocyte RXRα-deficient mice have been established. Characterization has been performed on male mice. In this paper, we show that the expression of CYP450 genes is differentially expressed in male and female hepatocyte RXRα-deficient mice; male mice have reduced expression of cytochrome P450 (CYP) CYP4A, CYP3A, and CYP2B mRNAs, but females do not exhibit such phenotypes. To examine the hormonal effects on this sexual dimorphic phenotype, male and female mice were subjected to 17β-estradiol and 5α-dihydrotestosterone (DHT) treatment, respectively, and then the expression of the CYP450 genes was studied. Estradiol had no effect on protecting the hepatocyte RXRα-deficient mice from reduced expression of the CYP450 genes. In contrast, DHT induced hepatocyte RXRα-deficient female mice, but not wild-type female mice, to have the reduced expression of CYP450 mRNAs. In addition, castration prevented the mutant male mice from exhibiting reduced expression of CYP450 mRNAs. wild-type and mutant mouse livers from both genders express androgen receptors (ARs). By transient transfection, DHT-AR could inhibit RXRα-mediated transcription. Furthermore, by transfection and coimmunoprecipitation, RXR can interact with AR in vivo. These data suggest that testosterone has a negative impact on retinoid signaling when the level of RXRα is low, which may in turn reduce the expression of the CYP450 genes.
Prostate Hyperplasia in a Transgenic Mouse with Prostate-Specific Expression of Prolactin
Authors: Kindblom Jon , Dillner Karin , Sahlin Lena , Robertson Fiona , Ormandy Christopher , Törnell Jan , Wennbo Håkan
Published: May 2003

Prolactin (PRL) is one of several polypeptide factors known to exert trophic effects on the prostate. We have previously reported a dramatic prostate enlargement with concurrent chronic hyperprolactinemia and elevated serum androgen levels in a PRL transgenic mouse (Mt-PRL) with ubiquitous expression of the transgene. To address the role of local PRL action in the prostate, a new transgenic mouse model (Pb-PRL) was generated using the prostate-specific rat probasin (Pb) minimal promoter to drive expression of the rat PRL gene. Pb-PRL transgenic males developed a significant enlargement of both the dorsolateral and ventral prostate lobes evident from 10 wk of age and increasing with age. Expression of the transgene was restricted to the prostate and detected from 4 wk of age. Low levels of transgenic rat PRL were detectable in the serum of adult Pb-PRL animals. Serum androgen levels were normal. The Pb-PRL prostate displayed significant stromal hyperplasia, ductal dilation, and focal areas of epithelial dysplasia. Quantitative analysis of prostatic tissue cellularity demonstrated a marked increase in the stromal to epithelial ratio in all lobes of Mt-PRL and Pb-PRL transgenic prostates compared with controls. Microdissections demonstrated an increased ductal morphogenesis in dorsolateral and ventral prostate lobes of Mt-PRL prostate vs. Pb-PRL and controls. In conclusion, this study indicates the ability of PRL to promote, directly or indirectly, ductal morphogenesis in the developing prostate and further to induce abnormal growth primarily of the stroma in the adult gland in a setting of normal androgen levels.
Thyroid Hormone Enhances Aggrecanase-2/ADAM-TS5 Expression and Proteoglycan Degradation in Growth Plate Cartilage
Authors: Makihira Seicho , Yan Weiqun , Murakami Hiroshi , Furukawa Masae , Kawai Toshihisa , Nikawa Hiroki , Yoshida Eri , Hamada Taizo , Okada Yasunori , Kato Yukio
Published: May 2003

Effects of thyroid hormone on proteoglycan degradation in various regions of cartilage were investigated. In propylthiouracil-treated rats with hypothyroidism, proteoglycan degradation in epiphyseal cartilage during endochondral ossification was markedly suppressed. However, injections of T4 reversed this effect of propylthiouracil on proteoglycan degradation. In pig growth plate explants, T3 also induced breakdown of proteoglycan. T3 increased the release of aggrecan monomer and core protein from the explants into the medium. Accordingly, the level of aggrecan monomer remaining in the tissue decreased after T3 treatment, and the monomer lost hyaluronic acid-binding capacity, suggesting that the cleavage site is in the interglobular domain. The aggrecan fragment released from the T3-exposed explants underwent cleavage at Glu373-Ala374, the major aggrecanase-cleavage site. The stimulation of proteoglycan degradation by T3 was less prominent in resting cartilage explants than in growth plate explants and was barely detectable in articular cartilage explants. Using rabbit growth plate chondrocyte cultures, we explored proteases that may be involved in T3-induced aggrecan degradation and found that T3 enhanced the expression of aggrecanase-2/ADAM-TS5 (a disintegrin and a metalloproteinase domain with thrombospondin type I domains) mRNA, whereas we could not detect any enhancement of stromelysin, gelatinase, or collagenase activities or any aggrecanase-1/ADAM-TS4 mRNA expression. We also found that the aggrecanse-2 mRNA level, but not aggrecanase-1, increased at the hypertrophic stage during endochondral ossification. These findings suggest that aggrecanse-2/ADAM-TS5 is involved in aggrecan breakdown during endochondral ossification, and that thyroid hormone stimulates the aggrecan breakdown partly via the enhancement of aggrecanase-2/ADAM-TS5.
Overexpression of Glutamic Acid Decarboxylase-67 (GAD-67) in Gonadotropin-Releasing Hormone Neurons Disrupts Migratory Fate and Female Reproductive Function in Mice
Authors: Heger Sabine , Seney Marianne , Bless Elizabeth , Schwarting Gerald A. , Bilger Marie , Mungenast Alison , Ojeda Sergio R. , Tobet Stuart A.
Published: May 2003

γ-Aminobutyric acid (GABA) inhibits the embryonic migration of GnRH neurons and regulates hypothalamic GnRH release. A subset of GnRH neurons expresses GABA along their migratory route in the nasal compartment before entering the brain, suggesting that GABA produced by GnRH neurons may help regulate the migratory process. To examine this hypothesis and the possibility that persistence of GABA production by GnRH neurons may affect subsequent reproductive function, we generated transgenic mice in which the expression of glutamic acid decarboxylase-67 (GAD-67), a key enzyme in GABA synthesis, is targeted to GnRH neurons under the control of the GnRH gene promoter. On embryonic d 15, when GnRH neurons are still migrating, the transgenic animals had more GnRH neurons in aberrant locations in the cerebral cortex and fewer neurons reaching the hypothalamic-preoptic region, whereas migration into the brain was not affected. Hypothalamic GnRH content in mutant mice was low during the first week of postnatal life, increasing to normal values during infantile development (second week after birth) in the presence of increased pulsatile GnRH release. Consistent with these changes, serum LH and FSH levels were also elevated. Gonadotropin release returned to normal values by the time steroid negative feedback became established (fourth week of life). Ovariectomy at this time demonstrated an enhanced gonadotropin response in transgenic animals. Although the onset of puberty, as assessed by the age at vaginal opening and first ovulation, was not affected in the mutant mice, estrous cyclicity and adult reproductive capacity were disrupted. Mutant mice had reduced litter sizes, increased time intervals between deliveries of litters, and a shorter reproductive life span. Thus, GABA produced within GnRH neurons does not delay GnRH neuronal migration, but instead serves as a developmental cue that increases the positional diversity of these neurons within the basal forebrain. In addition, the results suggest that the timely termination of GABA production within the GnRH neuronal network is a prerequisite for normal reproductive function. The possibility arises that similar abnormalities in GABA homeostasis may contribute to syndromes of hypothalamic amenorrhea/oligomenorrhea in humans.
Glucosamine Induces Resistance to Insulin-Like Growth Factor I (IGF-I) and Insulin in Hep G2 Cell Cultures: Biological Significance of IGF-I/Insulin Hybrid Receptors
Authors: Sakai K. , Clemmons D. R.
Published: May 2003

IGF-I stimulates insulin-like actions directly through its receptor, and it also enhances sensitivity to insulin-mediated effects in vivo. These studies were undertaken to analyze the role of IGF-I, insulin, and insulin/IGF-I hybrid receptors (HRs) in mediating IGF-I and insulin signaling in cells that had been made insulin-resistant by treatment with glucosamine. Human HepG2 cells, which express IGF-I receptors, insulin receptors (IRs), and IGF-I/insulin HRs, were exposed to 20 mm glucosamine; and the effects of IGF-I and insulin in stimulating glycogen synthesis were determined. An overnight exposure to glucosamine markedly attenuated the effects of insulin and IGF-I in stimulating glycogen synthesis. To determine which receptors were mediating this effect, the ability of insulin and IGF-I to stimulate phosphorylation of their respective receptors was analyzed. An 18-h exposure to glucosamine (20 mm) caused a 75% reduction in the ability of IGF-I to phosphorylate its receptor but no change in receptor abundance. Glucosamine also caused a major reduction in insulin-stimulated receptor phosphorylation, although, unlike IGF-I, there was also a 50% reduction in IR abundance. Exposure to glucosamine also resulted in a reduction in the ability of IGF-I or insulin to stimulate phosphorylation of insulin IGF-I/HRs. The combination of insulin plus IGF-I was a more potent stimulus of HR phosphorylation than either agent alone, and this combination was also more potent in partially reversing the inhibitory effect of glucosamine. Taken together, these findings indicate that glucosamine induces a loss of sensitivity to stimulation of insulin, IGF-I, or HR tyrosine kinase activity by insulin or IGF-I. Although insulin is able to partially reverse the effect of glucosamine on IR phosphorylation, it has a very minimal effect on glucosamine-induced inhibition of HR phosphorylation. However, the combination of IGF-I and insulin induces a major increase in HR phosphorylation, even in the presence of glucosamine, suggesting that it is improving the sensitivity of the HR to insulin activation.
Expression and Characterization of the Extracellular Ca2+-Sensing Receptor in Melanotrope Cells of Xenopus laevis
Authors: van den Hurk M. J. J. , Ouwens D. T. W. M. , Scheenen W. J. J. M. , Limburg V. , Gellekink H. , Bai M. , Roubos E. W. , Jenks B. G.
Published: May 2003

The extracellular Ca2+-sensing receptor (CaR) is expressed in many different organs in various species, ranging from mammals to fish. In some of these organs, this G protein-coupled receptor is involved in the control of systemic Ca2+ homeostasis, whereas in other organs its role is unclear (e.g. in the pituitary gland). We have characterized the CaR in the neuroendocrine melanotrope cell of the intermediate pituitary lobe of the South African clawed toad Xenopus laevis. First, the presence of CaR mRNA was demonstrated by RT-PCR and in situ hybridization. Then it was shown that activation of the CaR by an elevated extracellular Ca2+ concentration and different CaR-activators, including l-phenylalanine and spermine, stimulates both Ca2+ oscillations and secretion from the melanotrope. Furthermore, it was revealed that activation of the receptor stimulates Ca2+ oscillations through opening of voltage-operated Ca2+ channels in the plasma membrane of the melanotropes. Finally, it was shown that the CaR activator l-phenylalanine could induce the biosynthesis of proopiomelanocortin in the intermediate lobe. Thus, in this study it is demonstrated that the CaR is present and functional in a defined cell type of the pituitary gland, the amphibian melanotrope cell.
High Levels of Intrauterine Corticotropin-Releasing Hormone, Urocortin, Tryptase, and Interleukin-8 in Spontaneous Abortions
Authors: Madhappan Bhuvaneshwari , Kempuraj Duraisamy , Christodoulou Spyridon , Tsapikidis Stavros , Boucher William , Karagiannis Vasilis , Athanassiou Achilles , Theoharides Theoharis C.
Published: May 2003

Stress induces CRH secretion that activates hypothalamic-pituitary-adrenal axis and is also abortogenic. In addition to hypothalamus, CRH and its analog urocortin (Ucn) are also secreted locally outside the brain where they activate mast cells leading to inflammation; however, the level of CRH and Ucn or mast cell mediators has not been examined in products of conception (POC). CRH and Ucn were measured by enzyme immunoassay, tryptase by fluoroenzyme immunoassay, and IL-8 by ELISA in POC of 7-9 wk gestation from Caucasian women; they were divided into group I with elective abortions (n = 4), group II with one spontaneous abortion (n = 12), and group III with at least two spontaneous abortions (n = 7). CRH, Ucn, tryptase, and IL-8 levels were higher (P < 0.05) in group III (8683 ± 1201 pg/g, 7961 ± 1499 pg/g, 1553 ± 572 ng/g, and 8317 ± 1874 pg/g, respectively) than group II (2561 ± 314 pg/g, 2349 ± 394 pg/g, 403 ± 97 ng/g, and 3199 ± 449 pg/g, respectively) and group I (163 ± 162 pg/g, 328 ± 327 pg/g, 72 ± 31 ng/g, and 3681 ± 931 pg/g, respectively). Immunostaining of POC showed significantly more tryptase in group III women. High POC levels of CRH and Ucn under stress in habitual spontaneous abortions may activate uterine mast cells to secrete abortogenic tryptase and IL-8.
Minireview: Overview of the Renin-Angiotensin System—An Endocrine and Paracrine System
Authors: Lavoie Julie L. , Sigmund Curt D.
Published: May 2003

Since the discovery of renin as a pressor substance in 1898, the renin-angiotensin (RAS) system has been extensively studied because it remains a prime candidate as a causative factor in the development and maintenance of hypertension. Indeed, some of the properties of the physiologically active component of the RAS, angiotensin II, include vasoconstriction, regulation of renal sodium and water absorption, and increasing thirst. Initially, its affect on blood pressure was thought to be mediated primarily through the classical endocrine pathway; that is, the generation of blood-borne angiotensin with actions in target tissues. More recently, however, it has become appreciated that a local autocrine or paracrine RAS may exist in a number of tissues, and that these may also play a significant role in regulating blood pressure. Some of the difficulties in studying tissue RAS stem from the limitations of pharmacology in not differentiating between RAS products made systemically from those synthesized locally. However, the development of transgenic animals with highly specific promoters to target the RAS to specific tissues provided important tools to dissect these systems. Thus, this minireview will discuss recent advances in understanding the relationship between endocrine and paracrine (tissue) RAS using transgenic models.
Minireview: Primary Aldosteronism—Changing Concepts in Diagnosis and Treatment
Authors: Young William F.
Published: May 2003

Primary aldosteronism affects 5–13% of patients with hypertension. Patients with hypertension and hypokalemia and most patients with treatment-resistant hypertension should undergo screening for primary aldosteronism with a plasma aldosterone concentration to plasma renin activity ratio. A high plasma aldosterone concentration to plasma renin activity ratio is a positive screening test result, a finding that warrants confirmatory testing. For those patients that want to pursue a surgical cure, the accurate distinction between the subtypes (unilateral vs. bilateral adrenal disease) of primary aldosteronism is a critical step. The subtype evaluation may require one or more tests, the first of which is imaging the adrenal glands with computed tomography, followed by selective use of adrenal venous sampling. Because of the deleterious cardiovascular effects of aldosterone, normalization of circulating aldosterone or aldosterone receptor blockade should be part of the management plan for all patients with primary aldosteronism. Unilateral laparoscopic adrenalectomy is an excellent treatment option for patients with unilateral aldosterone-producing adenoma. Bilateral idiopathic hyperaldosteronism should be treated medically. In addition, aldosterone-producing adenoma patients may be treated medically if the medical treatment includes mineralocorticoid receptor blockade.
Asymptotic shape in a continuum growth model
Authors: Deijfen Maria
Published: May 2003

A continuum growth model is introduced. The state at time t, St, is a subset of
ℝd and consists of a connected union of randomly sized Euclidean balls, which emerge from outbursts at their centre points. An outburst occurs somewhere in St after an exponentially distributed time with expected value
|St|-1 and the location of the outburst is uniformly distributed over St. The main result is that, if the distribution of the radii of the outburst balls has bounded support, then St grows linearly and St/t has a nonrandom shape as t → ∞. Due to rotational invariance the asymptotic shape must be a Euclidean ball.
Inhomogeneous spatial point processes by location-dependent scaling
Authors: Hahn Ute , Jensen Eva B. Vedel , van Lieshout Marie-Colette , Nielsen Linda Stougaard
Published: May 2003

A new class of models for inhomogeneous spatial point processes is introduced. These locally scaled point processes are modifications of homogeneous template point processes, having the property that regions with different intensities differ only by a scale factor. This is achieved by replacing volume measures used in the density with locally scaled analogues defined by a location-dependent scaling function. The new approach is particularly appealing for modelling inhomogeneous Markov point processes. Distance-interaction and shot noise weighted Markov point processes are discussed in detail. It is shown that the locally scaled versions are again Markov and that locally the Papangelou conditional intensity of the new process behaves like that of a global scaling of the homogeneous process. Approximations are suggested that simplify calculation of the density, for example, in simulation. For sequential point processes, an alternative and simpler definition of local scaling is proposed.
Local convergence of the Boolean shell model towards the thick Poisson hyperplane process in the Euclidean space
Authors: Michel Julien , Paroux Katy
Published: May 2003

In this article we prove local convergence for a Boolean model of shells conditioned by the noncovering of the origin towards the thick hyperplane Poisson process in the Euclidean space. The existing results of Hall as well as the convergence theorems proved by Paroux or Molchanov concerned the zero-width process and the connected component of the unfilled region of the origin. Our results deal with the convergence in any given window of the space, with the earlier results of Paroux and Molchanov as a corollary.
An almost sure result for path lengths in binary search trees
Authors: Dekking F. M. , Meester L. E.
Published: May 2003

This paper studies path lengths in random binary search trees under the random permutation model. It is known that the total path length, when properly normalized, converges almost surely to a nondegenerate random variable Z. The limit distribution is commonly referred to as the ‘quicksort distribution’. For the class 𝒜m of finite binary trees with at most m nodes we partition the external nodes of the binary search tree according to the largest tree that each external node belongs to. Thus, the external path length is divided into parts, each part associated with a tree in 𝒜m. We show that the vector of these path lengths, after normalization, converges almost surely to a constant vector times Z.
Symmetric fixed points of a smoothing transformation
Authors: Caliebe Amke
Published: May 2003

LetT= (T1,T2,…) be a sequence of real random variables with ∑j=1∞1|Tj|>0< ∞ almost surely. We consider the following equation for distributions μ:W≅ ∑j=1∞TjWj, whereW,W1,W2,… have distribution μ andT,W1,W2,… are independent. We show that the representation of general solutions is a mixture of certain infinitely divisible distributions. This result can be applied to investigate the existence of symmetric solutions forTj≥ 0: essentially under the condition that E ∑j=1∞Tj2log+Tj2< ∞, the existence of nontrivial symmetric solutions is exactly determined, revealing a connection with the existence of positive solutions of a related fixed-point equation. Furthermore, we derive results about a special class of canonical symmetric solutions including statements about Lebesgue density and moments.
Overshoots over curved boundaries
Authors: Doney R. A. , Griffin P. S.
Published: May 2003

We consider the asymptotic behaviour of a random walk when it exits from a symmetric region of the form {(x, n) :|x| ≤ rnb} as r → ∞. In order to be sure that this actually occurs, we treat only the case where the power b lies in the interval [0,½), and we further assume a condition that prevents the probability of exiting at either boundary tending to 0. Under these restrictions we establish necessary and sufficient conditions for the pth moment of the overshoot to be O(rq), and for the overshoot to be tight, as r → ∞.
Discrete-time singularly perturbed Markov chains: aggregation, occupation measures, and switching diffusion limit
Authors: Yin G. , Zhang Q. , Badowski G.
Published: May 2003

This work is devoted to asymptotic properties of singularly perturbed Markov chains in discrete time. The motivation stems from applications in discrete-time control and optimization problems, manufacturing and production planning, stochastic networks, and communication systems, in which finite-state Markov chains are used to model large-scale and complex systems. To reduce the complexity of the underlying system, the states in each recurrent class are aggregated into a single state. Although the aggregated process may not be Markovian, its continuous-time interpolation converges to a continuous-time Markov chain whose generator is a function determined by the invariant measures of the recurrent states. Sequences of occupation measures are defined. A mean square estimate on a sequence of unscaled occupation measures is obtained. Furthermore, it is proved that a suitably scaled sequence of occupation measures converges to a switching diffusion.
Energy cascades as branching processes with emphasis on Neveu's approach to Derrida's random energy model
Authors: Huillet Thierry
Published: May 2003

Continuous-space-time branching processes (CSBP) are investigated in order to model random energy cascades. CSBPs are based on spectrally positive Lévy processes and, as such, are characterized by their corresponding Laplace exponents. Special emphasis is put on the CSBPs of Feller, Lamperti and Neveu and on their Poisson point process representations. The Neveu model (either supercritical or subcritical) is of particular interest in physics for its connection with the random energy model of Derrida, as revisited by Ruelle. Exploiting some connections between the partition functions of energy and the Poisson-Dirichlet distributions of Pitman and Yor, some information on the zero-temperature limit is extracted. Finally, for the subcritical versions of the three models, we compute the distribution of some of their interesting features: extinction time and probability, area under the profile (total energy) and width (maximal energy).
Frailty models based on Lévy processes
Authors: Gjessing Håkon K. , Aalen Odd O. , Hjort Nils Lid
Published: May 2003

Generalizing the standard frailty models of survival analysis, we propose to model frailty as a weighted Lévy process. Hence, the frailty of an individual is not a fixed quantity, but develops over time. Formulae for the population hazard and survival functions are derived. The power variance function Lévy process is a prominent example. In many cases, notably for compound Poisson processes, quasi-stationary distributions of survivors may arise. Quasi-stationarity implies limiting population hazard rates that are constant, in spite of the continual increase of the individual hazards. A brief discussion is given of the biological relevance of this finding.
On stability of queueing networks with job deadlines
Authors: Ward Amy R. , Bambos Nicholas
Published: May 2003

In this paper, we consider a single-server queue with stationary input, where each job joining the queue has an associated deadline. The deadline is a time constraint on job sojourn time and may be finite or infinite. If the job does not complete service before its deadline expires, it abandons the queue and the partial service it may have received up to that point is wasted. When the queue operates under a first-come-first served discipline, we establish conditions under which the actual workload process—that is, the work the server eventually processes—is unstable, weakly stable, and strongly stable. An interesting phenomenon observed is that in a nontrivial portion of the parameter space, the queue is weakly stable, but not strongly stable. We also indicate how our results apply to other nonidling service disciplines. We finally extend the results for a single node to acyclic (feed-forward) networks of queues with either per-queue or network-wide deadlines.
On exact and large deviation approximation for the distribution of the longest run in a sequence of two-state Markov dependent trials
Authors: Fu James C. , Wang Liqun , Lou W. Y. Wendy
Published: May 2003

Consider a sequence of outcomes from Markov dependent two-state (success-failure) trials. In this paper, the exact distributions are derived for three longest-run statistics: the longest failure run, longest success run, and the maximum of the two. The method of finite Markov chain imbedding is used to obtain these exact distributions, and their bounds and large deviation approximation are also studied. Numerical comparisons among the exact distributions, bounds, and approximations are provided to illustrate the theoretical results. With some modifications, we show that the results can be easily extended to Markov dependent multistate trials.
Precise large deviations for the prospective-loss process
Authors: Ng Kai W. , Tang Qihe , Yan Jiaan , Yang Hailiang
Published: May 2003

In this paper, we propose a customer-arrival-based insurance risk model, in which customers' potential claims are described as independent and identically distributed heavy-tailed random variables and premiums are the same for each policy. We obtain some precise large deviation results for the prospective-loss process under a mild assumption on the random index (in our case, the customer-arrival process), which is much weaker than that in the literature.
An exponential functional of random walks
Authors: Szabados Tamás , Székely Balázs
Published: May 2003

The aim of this paper is to investigate discrete approximations of the exponential functional of Brownian motion (which plays an important role in Asian options of financial mathematics) with the help of simple, symmetric random walks. In some applications the discrete model could be even more natural than the continuous one. The properties of the discrete exponential functional are rather different from the continuous one: typically its distribution is singular with respect to Lebesgue measure, all of its positive integer moments are finite and they characterize the distribution. On the other hand, using suitable random walk approximations to Brownian motion, the resulting discrete exponential functionals converge almost surely to the exponential functional of Brownian motion; hence their limit distribution is the same as in the continuous case, namely that of the reciprocal of a gamma random variable, and so is absolutely continuous with respect to Lebesgue measure. In this way, we also give a new and elementary proof of an earlier result by Dufresne and Yor.
Solution of jump parameter systems of differential and difference equations with semi-Markov coefficients
Authors: Shmerling Efraim , Hochberg Kenneth J.
Published: May 2003

We study linear jump parameter systems of differential and difference equations whose coefficients depend on the state of a semi-Markov process. We derive systems of equations for the first two moments of the random solutions of these jump parameter systems, and illustrate how moment equations can be used in examining their asymptotic stability.
Haplotypes: the joint distribution of alleles at linked loci
Authors: Fearnhead Paul
Published: May 2003

We prove a result concerning the joint distribution of alleles at linked loci on a chromosome drawn from the population at stationarity. For a neutral locus, the allele is a draw from the stationary distribution of the mutation process. Furthermore, this allele is independent of the alleles at different loci on any chromosomes in the population.
Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry of Dextran and Dextrin Derivatives
Authors: Bashir Sajid , Derrick Peter J. , Critchley Peter , Gates Paul J. , Staunton James
Published: May 2003

Application of matrix-assisted laser desorption/ionization (MALDI) to the analysis of dextran and dextrin derivatives, specifically glucose saccharides, by time-of-flight (TOF) mass spectrometry is reported. MALDI-TOF analysis was carried out on alpha-, beta-and gamma-cyclodextrin, two O-methylated beta-cyclodextrins of differing degrees of substitution (DS) and dextrans (a linear glucose saccharide), as pure and doped solutions and as mixtures of two or more of these analytes. Doping was carried out with trace amounts of inorganic salts. The purpose of the analysis of the cyclodextrins was to determine whether they would form inclusion complexes with the various added cations, or whether less specific cation addition/exchange was occurring either prior to desorption or in the gas phase.
Mass-Selected Resonance-Enhanced Multiphoton Ionisation Spectra of Laser-Desorbed Molecules for Environmental Analysis: 16 Representative Polycyclic Aromatic Compounds
Authors: Rink Jörg E. , Boesl Ulrich
Published: May 2003

Mass-selected gas-phase UV spectra of laser-desorbed molecules at room temperature have been measured via resonance-enhanced multiphoton ionisation (REMPI) and time-of-flight mass selection. The wavelength range of 260 to 320 nm is optimal for detection of polycyclic aromatic hydrocarbons (PAHs) using REMPI-mass spectrometry. A new laser desorption/laser ionisation source has been used which features a compact size and thermal equilibrium of the desorbed molecules. 16 PAHs have been investigated which have been selected by the US Environmental Protection Agency (EPA). These 16 EPA-PAHs are commonly used world-wide to characterise the PAH-load of environmental samples.
Structural Characterisation by Both Positive- and Negative-Ion Electrospray Mass Spectrometry of Partially Methyl-Esterified Oligogalacturonides Purified by Semi-Preparative High-Performance Anion-Exchange Chromatography
Authors: Quéméner Bernard , Désiré Cédric , Lahaye Marc , Debrauwer Laurent , Negroni Luc
Published: May 2003

The off-line coupling of high-performance anion-exchange chromatography (HPAEC) to electrospray ionisation/ion trap mass spectrometry (ESI-ITMS) is described. The Dionex carbohydrate membrane desalter (CMD) has been assessed as an on-line chromatographic desalting system to remove the high sodium concentration necessary for the HPAEC separation of partially methyl-esterified oligogalacturonides. The developed HPAEC configuration proved to be suitable for indirect coupling with ESI-ITMS. This paper provides some interesting features of positive- and negative-ion multistage tandem mass spectrometry (MSn) analysis of these acidic oligosaccharides. The spectra acquired in both negative- and positive-ion modes show characteristic fragment ions resulting from glycosidic bond and cross-ring cleavages. Some new mass spectrometric fragmentation routes are also described. The positive-ion mode gave more complex spectra but was as informative as the negative-ion mode. ESI-ITMS was revealed to be, as previously reported from direct use on an unseparated enzymatic digest, a powerful sequencing technique for the determination of linkage type and the methyl ester distribution of partially methyl-esterified oligogalacturonides. Moreover, unlike matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-ToF MS), it gives valuable information on the elution behaviour of these oligomers in relation to their structure, namely the HPAEC co-elution of isomeric structures.
Derivatization in Mass Spectrometry—1. Silylation
Authors: Halket John M. , Zaikin Vladimir G.
Published: May 2003

This is the first of a series of reviews on the application of derivatization in mass spectrometry. A description is given of advances in silylation as a powerful tool used for increasing the volatility, thermal and thermo-catalytic stability, and chromatographic mobility of polar and unstable organic compounds. In addition to chemical aspects of silylation, mass spectral properties of silyl derivatives useful for structure determination and quantitation of various organic and biologically-active compounds, mainly by GC/MS, are described. Practically all tested and widely used silylating agents are described. The role of comprehensive libraries containing reference mass spectra for various silyl derivatives and search systems in structure determination is emphasized. Applications of silylation for particular analyses are summarised.
Atmospheric Pressure Matrix-Assisted Laser Desorption/Ionisation Ion Trap Mass Spectrometry of Synthetic Polymers: A Comparison with Vacuum Matrix-Assisted Laser Desorption/Ionisation Time-of-Flight Mass Spectrometry
Authors: Creaser Colin S. , Reynolds James C. , Hoteling Andrew J. , Nichols William F. , Owens Kevin G.
Published: May 2003

Atmospheric pressure matrix-assisted laser desorption/ionisation quadrupole ion trap (AP-MALDI/QIT) mass spectrometry has been investigated for the analysis of polyethylene glycol (PEG 1500) and a hyperbranched polymer (polyglycidol) in the presence of alkali–metal salts. Mass spectra of PEG 1500 obtained at atmospheric pressure showed dimetallated matrix/analyte adducts, in addition to the expected alkali–metal/PEG ions, for all matrix/alkali–metal salt combinations. The relative intensities of the desorbed ions were dependent on the matrix, the alkali–metal salt added to aid cationisation and the ion trap interface conditions [capillary temperature, in-source collisionally-induced dissociation (CID)]. These data indicate that the adducts are rapidly stabilised by collisional cooling enabling them to be transferred into the ion trap. Experiments using identical sample preparation conditions were carried out on a vacuum MALDI time-of-flight (ToF) mass spectrometer. In all cases, vacuum MALDI-ToF spectra showed only alkali–metal/PEG ions and no matrix/analyte adducts. The tandem mass spectrometry (MS/MS) capability of the ion trap has been demonstrated for a lithiated polyglycol yielding a rich fragment-ion spectrum. Analysis of the hyperbranched polymer polyglycidol by AP-MALDI/QIT reveals the characteristic ion series for these polymers as also observed under vacuum MALDI-ToF conditions.
Atmospheric Pressure Electrospray Ionization Mass Spectra of Glucose and 2-Fluorodeoxyglucose for Quantitative Analysis of 2-Fluorodeoxyglucose by High-Performance Liquid Chromatography
Authors: Macášek F. , Brúder P. , Patakyová A. , Búriová E.
Published: May 2003

2-Fluoro-2-deoxy-d-glucose (FDG) labeled by fluorine-18 is the most widely used radiopharmaceutical for positron emission tomography (PET). For high-performance liquid chromatography (HPLC)/MS assay and quality control, the mass spectra of FDG and glucose (Glc) in organic + water solutions were studied by flow injection analysis (FIA) and in a chromatographic eluate. In acetonitrile (MeCN) + 0.025% ammonium formate (NH4HCO2) solvent (80: 20), electrospray ionisation (ESI) of glucose-FDG provides M.NH4+ and 2M.Na+ (M = Glc or FDG) as the most intense positive ions. Formation of the latter ions and also of M.MeCN.Na+ and 2MeCN.Na+ is typical of the presence of NaCl in the ESI inlet. The positive ions include heavier ions corresponding to the impurities separated by HPLC and also to the cross-ring fragmentation of complexes (2FDG. aMeCN–X)L, where a = 0 or 1, L is either Na+ or NH4+ and X is a fragmented pyranose or anhydropyranose residue. The second most abundant Glc negative ion is m/z = 359 which was interpreted as (2Glc–H+)−. The negative-ion spectrum of FDG has dominating lines due to FDG.HCO2− ions at m/z 227 and also (2FDG–H+)− at m/z 363. The m/z 363 signal is suppressed in the presence of NaCl at a molar ratio of 4:1 to NH4HCO2, while the ions at m/z 217 and 219, i.e. FDG.Cl−, become three times more intense than FDG.HCO2−. The latter ion appears to be most suitable as an analytical signal for chemical analysis of FDG at m/z 226 and 227. Limits of FDG quantitation ( LOQ) of 19 ng and 21 ng were found for the 200+ and 227− ion signals, respectively, and are wholly adequate for verification of total FDG content in radiopharmaceuticals.