bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunohistochemical localization of steroidogenic enzymes and comparison with hormone production during follicle development in the pig
Authors: Shores Ellen M. , Hunter Morag G.
Published: November 2003

The steroidogenic enzymes, P450 aromatase
(P450 arom ) and P450 17a-hydroxylase (P450
17a ), were precisely located
within the healthy porcine follicle by immunohistochemistry. Enzyme
distribution was examined throughout follicular development during natural
oestrous cycles (n = 14 gilts) and was compared
with steroid production by healthy whole and theca-only follicles. All
follicles 2 mm or more in diameter were either fixed for immunohistochemistry
(n = 380 of which 197 were assessed as healthy)
or incubated as whole (n = 110) or theca-only
(n = 110) follicles to measure steroidogenesis.
P450 17a was confined to the theca
layer. The number of positive cells and staining intensity increased with
follicle size. P450 arom was consistently detected in
the granulosa layer of follicles measuring 6 mm or more in diameter and those
cells furthest from the antrum were most strongly stained.
P450arom was also detected in the theca layer of these
large follicles. Whole and theca-only follicles produced oestradiol and
androstenedione, and the levels of both hormones increased with follicle size
(P<0.001). Whole follicles produced more oestradiol
(P<0.001), but less androstenedione
(P = 0.01) than theca-only follicles of the same
size. Although granulosa cells contained P450 arom and
synthesized oestradiol, only theca cells contained P450
17a. Theca cells therefore
provided granulosa cells with androgen substrate. In addition, theca cells
possessed P450 arom , making them capable of independent
oestradiol production, which may be required to trigger the LH surge. This
study confirms the vital role of theca cells in follicular steroidogenesis in
the pig.
A Fail-safe Mechanism for Negative Selection of Isotype-switched B Cell Precursors Is Regulated by the Fas/FasL Pathway
Authors: Seagal Jane , Edry Efrat , Keren Zohar , Leider Nira , Benny Ofra , Machluf Marcelle , Melamed Doron
Published: November 2003

In B lymphocytes, immunoglobulin (Ig)M receptors drive development and construction of naive repertoire, whereas IgG receptors promote formation of the memory B cell compartment. This isotype switching process requires appropriate B cell activation and T cell help. In the absence of T cell help, activated B cells undergo Fas-mediated apoptosis, a peripheral mechanism contributing to the establishment of self-tolerance. Using Igμ-deficient μMT mouse model, where B cell development is blocked at pro-B stage, here we show an alternative developmental pathway used by isotype-switched B cell precursors. We find that isotype switching occurs normally in B cell precursors and is T independent. Ongoing isotype switching was found in both normal and μMT B cell development as reflected by detection of IgG1 germline and postswitch transcripts as well as activation-induced cytidine deaminase expression, resulting in the generation of IgG-expressing cells. These isotype-switched B cells are negatively selected by Fas pathway, as blocking the Fas/FasL interaction rescues the development of isotype-switched B cells in vivo and in vitro. Similar to memory B cells, isotype-switched B cells have a marginal zone phenotype. We suggest a novel developmental pathway used by isotype-switched B cell precursors that effectively circumvents peripheral tolerance requirements. This developmental pathway, however, is strictly controlled by Fas/FasL interaction to prevent B cell autoimmunity.
Taxation of e‐commerce in Hong Kong: applying UK and US experience
Authors: Noronha Carlos , Vinten Gerald
Published: November 2003

Due to the rapid growth of electronic commerce worldwide, the traditional approach of taxing business profits in Hong Kong, a source‐based common law jurisdiction, warrants a close review as to its compatibility with such a modern way of doing business. Although the Inland Revenue Department of Hong Kong has issued its views on the taxation of electronic commerce profits as Departmental Interpretation and Practice Note 39, much of the treatment of such profits follow the conventional wisdom of taxing business profits as set in the source‐based rules. This paper reviews the present situation of taxing profits arising from electronic commerce transactions in Hong Kong and compares it with the cases of the UK and the USA. Problems in formulating water‐tight tax law, accounting standards for intangible assets, and coping with cross‐border fraud, indicate that progress may not be straightforward. Issues as to fairness, and the difficulty of taxing such receipts are raised, followed by recommendations.
An assessment of Web accessibility of UK accountancy firms
Authors: Williams Russell , Rattray Rulzion
Published: November 2003

The growth of the Internet and Web offers opportunities to both organisations and individuals. Some of this opportunity is lost to both though if Web site content is not accessible. To date this fact has received little attention. However, as the market matures and legal parameters surrounding discrimination become clearer, the topic of accessibility will take on increasing significance. The purpose of this paper is to contribute to those assessments of Web content accessibility already undertaken, as well as to spread the accessibility word to a wider audience. The study looked at the accessibility of UK‐based accountancy sites utilising the evaluation software Bobby. It found that the accessibility of UK‐based accountancy firms to be relatively poor in comparison to other (mostly US and university and library) surveys.
Are budgets useful? A survey of Malaysian companies
Authors: Nazli Nik Ahmad Nik , Sulaiman Maliah , Alwi Norhayati Mohd.
Published: November 2003

This study examines if budgets are still used in Malaysian companies. There are two divergent views on the usefulness of budgets. Proponents of budgets argue that they are still relevant and useful. Meanwhile, critics claim that budgets are obsolete. The study uses the instrument developed by Druryet al.. Results are compared to those of Guildinget al. The results show that budgeting practices in Malaysia are similar to those in the UK and New Zealand. There are only three major differences. First, Malaysian managers appear to feel that a participative approach to budgeting may encourage budget padding. Second, a much higher percentage of respondents compared to the Guildinget al.’s study, agree that top management should evaluate performance mainly on ability to achieve budgetary goals. Finally, companies in Malaysia appear to use flexible budgets more than those in the UK and New Zealand.
Modelling Political Instability and Economic Performance: Israeli Investment during the Intifada
Authors: Fielding David
Published: November 2003

I construct a model of investment in Israel that incorporates both standard economic factors and indicators of political instability and unrest. The model is used to estimate both the extent to which the Intifada has depressed Israeli investment in different kinds of capital good, and the size of the corresponding ‘peace dividend’.
General and relationship‐specific models of social cognition: explaining the overlap and discrepancies
Authors: Humfress Harriet , O'Connor Thomas G. , Slaughter Jeremy , Target Mary , Fonagy Peter
Published: November 2003

Background: This study examined the degree of overlap and sources of discrepancies between two alternative models of social cognition in early adolescence, a general model based on ‘theory of mind’ and a relationship‐specific model rooted in attachment theory.

Methods: We administered newly developed, age‐appropriate measures of advanced theory of mind or ‘mentalising’ and child–parent attachment, indexed by the coherence of children's narratives about attachment relationships, to a sample of 70 early adolescents (mean age 12.6 years).

Results: The central findings were that, as expected, there was significant overlap between the mentalising and attachment indices of social cognition (r(70)=.35, p < .01). The overlap was not significantly mediated by verbal ability or general measures of parenting. There were also substantial discrepancies in children's performance on these measures that were conceptually interesting and statistically reliable. Specifically, adolescent reports of parenting discriminated between measures of mentalising and attachment coherence. In addition, those children who exhibited a less coherent model of attachment than was predicted from performance on a mentalising task were more likely to be rated as exhibiting a ‘Dismissing/Avoidant’ style in the attachment interview.

Conclusions: Findings support a connection between mentalising and attachment in early adolescence, and further suggest that social cognitive processes may be context and relationship‐specific.
SELECTION OF STATES AND FLUCTUATION UNDER THE FIRST ORDER PHASE TRANSITIONS
Authors: LEV BOHDAN , YOKOYAMA HIROSHI
Published: November 2003

A unified approach is proposed which provides both microscopic and phenomenological description of the first-order phase transition accompanied by the formation of thermodynamically stable bubbles of the new phase. A procedure is proposed for selecting the probable states whose contribution in the thermodynamic behavior of the system is dominant. This technique makes it possible to take into account fluctuation of any scales and to obtain a closed expression for the parameters of the new phase formation, in particular its dimensions, lifetime and time of relaxation towards a thermodynamically stable state. The feasibility of experimental observation the parameters dependence of the new phase bubble on the governing quantities is discussed.
IMPURITY AND SUPPORT EFFECTS ON SURFACE COMPOSITION AND CO+NO REACTIONS OVER Pt–Rh/CeO2 NANOPARTICLES: A COMPARATIVE STUDY
Authors: KHANRA BADAL C. , DE SARKAR ABIR
Published: November 2003

A Monte Carlo simulation technique has been used to investigate the effect of sulphur impurity and ceria support on the surface composition and catalytic activity of Pt–Rh /ceria nanocatalysts. For temperatures in the range of 400–1300 K the surface Pt concentration decreases with increase in sulphur coverage. The Pt concentration at the base of the nanocatalyst in contact with the support increases with metal-support interaction. However, for weak metal-support interaction (Vms<-0.01 eV ) the surface Pt concentration slightly increases with metal-support interaction. Overall, sulphur is found to influence the surface composition much more strongly than the metal-support interaction. The MC-simulated surface composition results have been used to study the energetics of the CO+NO reactions over Pt–Rh/CeO 2 catalysts. It is found that the CO 2 formation rate decreases with increase in sulphur coverage and marginally increases with metal-support interaction up to Vms=-0.01 eV . All the results qualitatively agree with the experimental results.
EVALUATION OF THE ACTIVATION ENERGY OF LOCAL DYNAMICS IN SOME POLYISOPRENE-C7D8 SOLUTIONS
Authors: TODICA M. , SUCIU I.
Published: November 2003

The activation energy of the local dynamics of the polymeric segments is calculated from the spin–lattice relaxation time, measured by NMR method. A new algorithm of analysis of the experimental data is proposed in order to increase the accuracy of the evaluation of this parameter. This method was applied for some polyisoprene- C 7 D 8 solutions and for the molten polyisoprene.
RELATIVISTIC QUANTUM FIELD THEORY FOR CONDENSED SYSTEMS (II): RENORMALIZATION PROCEDURE
Authors: MATSUURA HIROYUKI
Published: November 2003

We proposed Atomic Schwinger–Dyson method (ASD method) in previous paper, which was a nonperturbative and relativistic quantum field theory for a finite baryon density. We think it is important to show the significance of renormarization in order to get real physical predictions. Moreover, the real value of physical mass, electric charge and wave function are completely different from those of the non-renormalized electron and photon in mean field theory, since there are many of the particle-antiparticle creations and annihilations, particle-hole excitation, and Pauli blocking, which give an effect on bare mass, electric charge, polarization of vacuum, and self-energy. In this paper, we shows that ASD method is renormalizable theory, and that photon condensation of ASD method gave rise to Coulomb's potential and the mass shift of electron. The interacting photon and electron fields, which have physical mass and electric charge, are expressed as generalized free field equations by using the mass shift and the self-energy of those particles. We obtain the expression of an exact solution of these particles on the basis of the Green functional method.
A New Emerging Risk Factor for Cardiovascular Disease: Apo(a) Polymorphism
Authors: Gazzaruso Carmine , Fratino Pietro , Garzaniti Adriana
Published: November 2003

Apolipoprotein(a) [apo(a)], the specific apolipoprotein of lipoprotein(a), is characterized by a high degree of genetic polymorphism. Recent studies have shown that apo(a) polymorphism may represent a powerful independent cardiovascular risk factor. Indeed, an association between apo(a) polymorphism and coronary artery disease (CAD) has been documented both in the general population and among subjects at high cardiovascular disease risk, such as hypertensive, uremic, hypercholesterolemic, and diabetic patients. In addition, apo(a) polymorphism seems to correlate well with age of onset and severity of CAD. Nevertheless, at present, some problems prohibit the utilization of apo(a) polymorphism in clinical practice. Indeed, apo(a) phenotyping methods are not standardized, and there is not a cutoff of apo(a) polymorphism for clinical purposes. Moreover, large prospective studies should confirm the predictive value of apo(a) polymorphism for CAD. When the above problems are solved, apo(a) polymorphism could be a reliable tool to discriminate subjects with genetic predisposition to CAD among people with a family history of CAD and among patients with diseases representing a high cardiovascular risk, such as hypercholesterolemia, hypertension, diabetes, and uremia.
Mating System in Mouse Lemurs: Theories and Facts, Using Analysis of Paternity
Authors: Andrès Marjorie , Solignac Michel , Perret Martine
Published: November 2003

Among nocturnal Malagasy prosimians, the grey mouse lemur (Microcebus murinus) is considered a solitary species which has a promiscuous mating system. Indirect indicators, such as the lack of sexual dimorphism, the overlapping of male and female home ranges with each other, the synchronism of seasonal oestrus and the high relative testes size of males, support the presence of sperm competition. In captivity, an intense sexual precopulatory competition develops among males, leading to the emergence of a dominant male who fathers the majority of the litters. Although multiple mating did occur, the dominant male achieved the majority of the matings on the first day of oestrus. A ‘mate-guarding’ behaviour, exhibited by the dominant male, was observed in 11 groups out of 15, on only the first day of the vaginal opening and was significantly more often directed towards younger females. Females also played an important role in sexual competition among males, since their presence enhances the aggressive interactions between males. Difference in aggressive behaviours of females, in response to male sexual solicitations, suggests female mate choice. Compared with data from wild animals, it may be hypothesised that alternative mating strategies can be used by male grey mouse lemurs to enhance their reproductive success, depending on the availability and distribution of receptive females.
Ontogeny of Soluble and Particulate Prolyl Endopeptidase Activity in Several Areas of the Rat Brain and in the Pituitary Gland
Authors: Agirregoitia Naiara , Irazusta Amaia , Ruiz Fátima , Irazusta Jon , Gil Javier
Published: November 2003

We have analyzed the activity of prolyl endopeptidase (PEP) in several areas of the rat brain (brain cortex, striatum, brain stem, cerebellum and hypothalamus) and in the pituitary gland during ontogeny. In all of these areas, we observed a reduction in PEP activity during development. However, the temporal profile of these alterations was found to be area specific and differences in the ontogeny of the soluble and particulate forms of PEP were observed. Thus, by postnatal day 20 (PD20), soluble PEP activity had began to decrease in the brain cortex and striatum, whereas decreased soluble PEP activity was observed earlier, at PD15, in the brain stem and cerebellum. Changes in the particulate fraction were even more pronounced. Senescence was associated with decreased soluble PEP activity in the striatum, but in contrast, particulate PEP activity was found to be increased in the senescent brain stem. The present results indicate that alterations in the levels of activity of PEP may represent an important event in the development and aging of the central nervous system.
Differential Expression of Two Cell Adhesion Molecules, Ephrin-A5 and Integrin α6, during Cranial Neurulation in the Chick Embryo
Authors: Colas Jean-François , Schoenwolf Gary C.
Published: November 2003

The formation of the neural tube (neurulation) depends on the physical properties of the cells and tissues both inside and outside the neural plate. One such important physical property is cell adhesion. Theoretical and biological evidence support a role for cell adhesion in neurulation, but few specific cell adhesion molecules have been identified during this process. Ephrin-A5 and integrin α6 are two of the known genes encoding cell adhesion molecules that are likely to be directly involved in neurulation because neural tube defects result when they are knocked out in mice. Yet it remains unclear how they can act on the cell and tissue behaviors of neurulation, because their domains of expression in neurulating tissues have not been reported. We report here the detailed pattern of expression of these two cell adhesion molecules in the chick embryo throughout the stages of neurulation at the mRNA and protein level. We show that ephrin-A5 and integrin α6 are differentially expressed in the ectoderm, outside and inside the neural plate, respectively, and that they are both restricted to neurulation at cranial (brain) levels. We discuss the potential contribution of this differential expression to the cell adhesion mechanisms involved in cranial neurulation and anencephaly.
Vascular Protective Effects of Dihydropyridine Calcium Antagonists
Authors: Berkels Reinhard , Taubert Dirk , Rosenkranz Anke , Rösen Renate
Published: November 2003

Dihydropyridine calcium antagonists play an important role in the treatment of hypertension and angina pectoris. They lower blood pressure by a well-characterized mechanism of blocking L-type calcium channels in smooth muscle cells. Additionally, there is growing evidence that dihydropyridines also modulate endothelial functions by other mechanisms, since macrovascular endothelial cells do not express L-type calcium channels. A number of studies have demonstrated that dihydropyridine calcium antagonists enhance bioavailability of endothelial nitric oxide (NO). Endothelium-derived NO plays a pivotal role in the regulation of vasorelaxation, leukocyte adhesion and platelet aggregation and an impaired NO release is associated with the genesis and progression of atherosclerotic diseases. This review summarizes results from experimental findings that dihydropyridine calcium antagonists increase endothelial NO formation as well as studies which demonstrate these effects in vivo both in animals and humans. Moreover, the influence of dihydropyridine calcium antagonists on the progression of atherosclerosis is discussed. These pleiotropic effects of dihydropyridine calcium antagonists may underlie or contribute to antiatherosclerotic effects of this substance class.
Highly Active Antiretroviral Therapy and the Cardiovascular System: The Heart of the Matter
Authors: Barbaro Giuseppe
Published: November 2003

Highly active antiretroviral therapy (HAART) has prolonged many patients’ lives, but many cardiac sequelae of HIV are not affected by HAART and continue to develop even with treatment. In addition, HAART itself causes in a high proportion of patients a metabolic syndrome, characterized by lipodystrophy/lipoatrophy, dyslipidemia and insulin resistance that may be associated with an increase in coronary artery disease and stroke. Careful cardiovascular evaluation in the course of HIV disease can identify cardiac complications early enough to treat. All HIV-infected patients are candidates for antiretroviral therapy and patients already under treatment should undergo an assessment that includes the evaluation of the cardiovascular risk according to the available guidelines.
Methylenedioxymethamphetamine (MDMA, ‘Ecstasy‘) Serves as a Robust Positive Reinforcer in a Rat Runway Procedure
Authors: Wakonigg Gudrun , Sturm Katja , Saria Alois , Zernig Gerald
Published: November 2003

Although ‘ecstasy’ (3,4-methylenedioxymethamphetamine, MDMA) is, after marijuana, the second most prevalent illegal drug of abuse in European adolescents, animal experimental evidence of MDMA’s reinforcing effect has remained scarce, particularly in the rodent model, raising questions about the robustness of MDMA’s reinforcing effect under controlled laboratory conditions. In the present rat runway study, Sprague-Dawley and Long-Evans rats were given the opportunity to run for intravenous injections of saline or MDMA (1 mg/kg). MDMA significantly decreased runtimes in both rat strains. Thus, MDMA’s positive reinforcing effect can be demonstrated not only across rat strains but also across operant conditioning paradigms. These findings should reassure the drug abuse research community that the investigation of MDMA’s reinforcing effect in the inexpensive and widely used rodent model is indeed feasible.
Effect of the Antidepressant Desipramine on Cytosolic Ca2+ Movement and Proliferation in Human Osteosarcoma Cells
Authors: Jan Chung-Ren , Lu Yih-Chau , Tseng Li-Ling , Jiann Bang-Ping , Chang Hong-Tai , Wang Jue-Long , Chen Wei-Chuan , Huang Jong-Khing
Published: November 2003

In human osteosarcoma MG63 cells, the effect of desipramine, an antidepressant, on intracellular Ca2+ concentration ([Ca2+]i) was measured by using fura-2. Desipramine (>10 µmol/l) caused a rapid and sustained rise of [Ca2+]i in a concentration-dependent manner (EC50 = 200 µmol/l). Desipramine-induced [Ca2+]i rise was prevented by 80% by removal of extracellular Ca2+ but was not altered by voltage-gated Ca2+ channel blockers. In Ca2+-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum (ER) Ca2+-ATPase, caused a monophasic [Ca2+]i rise, after which the increasing effect of desipramine on [Ca2+]i was abolished; also, pretreatment with desipramine partly reduced thapsigargin-induced [Ca2+]i increase. U73122, an inhibitor of phospholipase C, did not affect desipramine-induced [Ca2+]i rise. Overnight incubation with 10 µmol/l desipramine did not alter cell proliferation, but killed 32 and 89% of cells at concentrations of 100 and 200 µmol/l, respectively. These findings suggest that desipramine rapidly increases [Ca2+]i in osteoblasts by stimulating both extracellular Ca2+ influx and intracellular Ca2+ release, and is cytotoxic at high concentrations.
Pharmacological Effects of Darifenacin on Human Isolated Urinary Bladder
Authors: Miyamae Koichi , Yoshida Masaki , Murakami Shigetaka , Iwashita Hitoshi , Ohtani Masayuki , Masunaga Koichi , Ueda Shoichi
Published: November 2003

Darifenacin [(S)-2--2,2-diphenylacetamide] is a novel antimuscarinic drug currently undergoing phase III trials for the treatment of overactive bladder. We investigated the functional antagonist potency of darifenacin, and the antimuscarinic drugs propiverine, oxybutynin and atropine, on human detrusor smooth muscle. Urinary bladder specimens were obtained from 20 patients who underwent total cystectomy for malignant bladder tumor. Using an organ-bath technique, the effects of the compounds on carbachol-, KCl-, CaCl2- or electrical field stimulation (EFS)-induced contractions of the tissues were evaluated. The order of antagonist potency (pA2 values) at the muscarinic M3 receptors was: darifenacin (9.34) > atropine (9.26) > oxybutynin (7.74) > propiverine (7.68). Darifenacin and atropine, at concentrations up to 10–6 mol/l, did not inhibit the KCl- and CaCl2-induced contractions (concentrations 80 and 5 mmol/l, respectively), while propiverine and oxybutynin (10–5 mol/l) significantly inhibited these contractions. Pretreatment with darifenacin (10–9–10–6 mol/l), propiverine (10–8– 10–5 mol/l), oxybutynin (10–8–10–5 mol/l) and atropine (10–9–10–6 mol/l) significantly inhibited maximum EFS-induced contractions. Darifenacin inhibited contractions of human detrusor smooth muscle only through its antimuscarinic action, while propiverine and oxybutynin had both antimuscarinic and Ca2+ channel antagonist actions. These findings indicate that darifenacin is a potent antagonist at the M3 receptor and support its use as a treatment for overactive bladder.
Effect of High Glucose on Nitric Oxide Production and Endothelial Nitric Oxide Synthase Protein Expression in Human Glomerular Endothelial Cells
Authors: Hoshiyama Mari , Li Bing , Yao Jian , Harada Takashi , Morioka Tetsuo , Oite Takashi
Published: November 2003

Background: Hyperglycemia directly contributes to the development of diabetic nephropathy. Nitric oxide (NO), a potent endothelium-derived vasodilator, has been suggested to participate in the regulation of renal blood flow, glomerular filtration rate, and mesangial matrix accumulation. Human vascular endothelial cells are known to exhibit functional heterogeneity, this prompted us to do the first study of NO bioavailability in human glomerular endothelial cells (HGECs), in response to high glucose exposure. Methods: NO release was examined by detecting nitrite generation by the Griess assay in HGECs exposed to control-level (5.5 mM) and high-level (15, 30 and 60 mM) glucose solutions at various time periods (24, 48 and 72 h) in the presence or absence of L-arginine (1 mM), or superoxide dismutase (SOD) (250 U/ml). In addition, we evaluated the effect of glucose on the expression of endothelial nitric oxide synthase (eNOS) in HGECs by Western blotting. Results: Final levels of nitrite generated in HGECs were reduced significantly, in a time- and concentration-dependent manner, after high glucose exposure. However, Western blot analysis revealed that eNOS protein expression was significantly upregulated at 12 h after exposure to high glucose concentrations (30 mM), reaching a peak at 48 h (twofold increase over baseline levels). The inhibitory effect of high glucose on NO production was restored by the addition of SOD. Addition of L-arginine (1 mM) to external media also reversed the inhibitory effect of high glucose on NO production of HGECs as well. Conclusions: The present study demonstrated that high glucose increased eNOS protein expression, but decreased NO release finally. Decreased NO bioavailability seems to be associated with overproduction of superoxide and L-arginine deficiency. These findings provide an important clue in clarifying the molecular basis of the mechanisms by which elevated glucose leads to an imbalance between NO and superoxide, resulting in impaired endothelial function. In addition, restoration of NO function by both administration of L-arginine and adequate intake of antioxidants suggests a potential supportive treatment for patients with diabetic nephropathy.
Regulation of Blood Pressure by Dopamine Receptors
Authors: Jose Pedro A. , Eisner Gilbert M. , Felder Robin A.
Published: November 2003

Dopamine is an important regulator of blood pressure. Its actions on renal hemodynamics, epithelial transport and humoral agents such as aldosterone, catecholamines, endothelin, prolactin, pro-opiomelanocortin, renin and vasopressin place it in central homeostatic position for regulation of extracellular fluid volume and blood pressure. Dopamine also modulates fluid and sodium intake via actions in the central nervous system and gastrointestinal tract, and by regulation of cardiovascular centers that control the functions of the heart, arteries and veins. Abnormalities in dopamine production and receptor function accompany a high percentage of human essential hypertension and several forms of rodent genetic hypertension. Some dopamine receptor genes and their regulators are in loci linked to hypertension in humans and in rodents. Furthermore, single nucleotide polymorphisms (SNPs) of genes that regulate dopamine receptors, alone or via the interaction with SNPs of genes that regulate the renin-angiotensin system, are associated with human essential hypertension. Each of the five dopamine receptor subtypes (D1, D2, D3, D4 and D5) participates in the regulation of blood pressure by mechanisms specific for the subtype. Some receptors (D2 and D5) influence the central and/or peripheral nervous system; others influence epithelial transport and regulate the secretion and receptors of several humoral agents (e.g., the D1, D3 and D4 receptors interact with the renin-angiotensin system). Modifications of the usual actions of the receptor can produce blood pressure changes. In addition, abnormal functioning of these dopamine receptor subtypes impairs their antioxidant function.
Choosing Not to Dialyse: Evaluation of Planned Non-Dialytic Management in a Cohort of Patients with End-Stage Renal Failure
Authors: Smith Carolyn , Da Silva-Gane Maria , Chandna Shahid , Warwicker Paul , Greenwood Roger , Farrington Ken
Published: November 2003

Objectives: To study factors influencing the recommendation for palliative (non-dialytic) treatment in patients approaching end-stage renal failure and to study the subsequent outcome in patients choosing not to dialyse. Design: Cohort study of patients approaching end-stage renal failure who underwent multidisciplinary assessment and counselling about treatment options. Recruitment was over 54 months, and follow-up ranged from 3 to 57 months. Groups were defined on the basis of the therapy option recommended (palliative or renal replacement therapy). Setting: Renal unit in a district general hospital serving a population of about 1.15 million people. Subjects: 321 patients, mean age ± SD 61.5 ± 15.4 years (range: 16–92), 57% male, 30% diabetic. Main Outcome Measures: Survival, place of death (hospital or community). Results: Renal replacement therapy was recommended in 258 patients and palliative therapy in 63 (19.6%). By logistic regression analysis, patients recommended for palliative therapy were more functionally impaired (modified Karnofsky scale), older and more likely to have diabetes. The comorbidity severity score was not an independent predictor. Thirty-four patients eventually died during palliative treatment, 26 of whom died of renal failure. Ten patients recommended for palliative treatment opted for and were treated by dialysis. Median survival after dialysis initiation in these patients (8.3 months) was not significantly longer than survival beyond the putative date of dialysis initiation in palliatively treated patients (6.3 months). 65% of deaths occurring in dialysed patients took place in hospital compared with 27% in palliatively treated patients (p = 0.001). Conclusions: In high-risk, highly dependent patients with renal failure, the decision to dialyse or not has little impact on survival. Dialysis in such patients risks unnecessary medicalisation of death.
Toll-Like Receptor-Mediated Activation of Mast Cells: Implications for Allergic Disease?
Authors: Marshall Jean S. , McCurdy Jeffrey D. , Olynych Tim
Published: November 2003

Toll-like receptors have a critical role in innate immunity and host defence. However their role in allergic disease has not been studied in great detail. The presence of these receptors on mast cells opens up new possibilities concerning the role of Toll-like receptors in the pathogenesis of asthma and atopic dermatitis. The current review examines the biology of Toll-like receptors expressed on mast cells. In particular, mast cell expression of Toll-like receptors and the diverse responses observed following Toll-like receptor-mediated activation are considered. Several pathogens such as Staphylococcus aureus and respiratory syncytial virus are known to contribute to the development or maintenance of allergic disease and also express potent activators of the Toll-like receptor pathways. The importance of such interactions and the full role of pathogens in chronic allergic disease remain to be elucidated. The unusual ability of Toll-like receptor 2 activators to selectively induce leukotriene production by mast cells opens up new possibilities concerning mechanisms of disease exacerbation during infection.
Pathomechanisms in Celiac Disease
Authors: Dieterich Walburga , Esslinger Birgit , Schuppan Detlef
Published: November 2003

Celiac disease is a complex autoimmune disease which is characterized by a strong genetic association (HLA-DQ2 or -DQ8), gluten as nutritional etiological factor, and the enzyme tissue transglutaminase as endomysial autoantigen. Patients develop highly predictive IgA autoantibodies to tTG. Certain gluten peptides are presented by the disease-associated HLA-DQ2/DQ8 molecules leading to stimulation of gluten-specific T cells. This immune response which is driven in the lamina propria causes the mucosal transformation characteristic for celiac disease. Increased intestinal expression of tTG in patients with CD appears to play an important role in the pathogenesis of CD. Thus, modification of gluten peptides by tTG, especially deamidation of certain glutamine residues, can enhance their binding to HLA-DQ2 or -DQ8 and potentiate T cell stimulation. Furthermore, tTG-catalyzed cross-linking and consequent haptenization of gluten with extracellular matrix proteins allows for storage and extended availability of gluten in the mucosa. New therapeutic approaches aim at proteolytic destruction of immunodominant gliadin peptides that are resistant to intestinal enzymes by bacterial prolyl endopeptidases, the inhibition of tTG activity with highly specific enzyme inhibitors or at HLA-DQ2/DQ8 blocking peptide analogues.
A New Glycoprotein Allergen/Antigen with the Protease Activity from Aspergillus fumigatus
Authors: Nigam Shailly , Ghosh P.C. , Sarma P. Usha
Published: November 2003

Background:Aspergillus fumigatus is an opportunistic fungus causing allergic and invasive aspergillosis in humans and animals. It secretes an array of complex biologically active glycoprotein antigens and allergens. It is important to identify and characterize probable potential virulent factors playing a major role in the pathogenesis of aspergillosis. Methods: Using protein purification techniques (lectin affinity chromatography, gel filtration, electroelution and high-pressure liquid chromatography), a major antigen/allergen with a molecular weight of 56 kD (gp56) from A. fumigatus was purified to homogeneity. The protein was characterized by immunoblot, ELISA and protease assays. The N-terminal amino acid sequencing was performed. Results: The gp56 protein showed a single band on silver staining and isoelectric focussing. The protein to carbohydrate ratio was 1.5:1 and gp56 gave a protein band at a molecular weight of 34 kD on enzymatic deglycosylation. It also exhibited IgG and IgE immunobinding with antibodies present in sera of allergic bronchopulmonary aspergillosis patients. The gp56 exhibited protease activity and N-terminal seven-amino acid sequence showed homology with fungal serine proteases. Conclusions: The gp56 protein by virtue of its proteolytic activity could be one of the virulent factors of A. fumigatus involved in establishing infection in the host along with other factors.
Cytokine Synthesis in Occupational Allergy to Caddisflies in Hydroelectric Plant Workers
Authors: Warrington R.J. , Whitman C. , McPhillips Warrington S.
Published: November 2003

Background: Workers in hydroelectric plants appear to be readily sensitized to caddisfly allergens. This sensitization probably occurs de novo from occupational exposure. In some workers, sensitization occurs on a non-atopic background. Cytokine synthesis of IFN-γ, IL-5 and IL-13 in atopic and non-atopic caddisfly-allergic workers was examined to determine if responses were similar or different. Methods: Peripheral blood mononuclear cells were isolated from atopic caddisfly-allergic workers, non-atopic caddisfly-allergic workers and non-atopic caddisfly-exposed but non-allergic workers. Stimulation with caddisfly antigens was carried out and synthesis of IFN-γ, IL-5 and IL-13 was determined by sandwich ELISA. Results: Both caddisfly-allergic and non-allergic subjects responded to stimulation with caddisfly extract. The response in non-atopic caddisfly-non-allergic subjects was TH1 predominant, while that in atopic caddisfly-allergic subjects was TH2 predominant. The response in non-atopic caddisfly-allergic subjects was between that of the atopic caddisfly-allergic workers and the non-atopic caddisfly-non-allergic workers and the trend was to a TH2 response. Work-related symptoms were similarly intermediate between the atopic caddisfly-allergic and non-atopic caddisfly-non-allergic group. Differences were significant for IFN-γ/IL-5 ratios but not IFN-γ/IL-13 ratios for atopic and non-atopic caddisfly-allergic individuals, compared to non-atopic caddisfly-non-allergic workers. However, a linear relationship existed between IFN-γ synthesis and IL-5 and IL-13 synthesis in non-atopic caddisfly-allergic workers but not in atopic caddisfly-allergic subjects. Conclusions: Caddisfly allergy in hydroelectric workers may be a useful model for the development of allergy to a previously unencountered allergen, and points to some interesting differences between atopic and non-atopic subjects who become sensitized to environmental allergens.
The Interleukin-13 Production by Peripheral Blood T Cells from Atopic Dermatitis Patients Does Not Require CD2 Costimulation
Authors: Simon Dagmar , von Gunten Stephan , Borelli Siegfried , Braathen Lasse R. , Simon Hans-Uwe
Published: November 2003

Background: Although allergic mechanisms appear to be important, the pathogenesis of both extrinsic and intrinsic forms of atopic dermatitis (AD) is unknown. Methods: We compared the cytokine production of peripheral blood mononuclear cells of extrinsic AD (EAD) and intrinsic AD (IAD) patients and normal control individuals after stimulation with anti-CD3 and/or anti-CD28 monoclonal antibodies (mAbs) in the presence or absence of anti-CD2-blocking mAb. The cytokine production was measured by immunoassays in supernatants of 24-hour cultures. Results: EAD patients showed a decreased capacity to synthesize interferon gamma and granulocyte-macrophage colony-stimulating factor upon anti-CD3 mAb stimulation as compared with IAD patients. Both EAD and IAD patients demonstrated an increased production of interleukin (IL)-5 and IL-13. As expected, interferon gamma, granulocyte-macrophage colony-stimulating factor, and IL-5 levels were reduced in the presence of anti-CD2-blocking mAbs. CD28 costimulation restored the release in cultures with anti-CD2 mAbs added, suggesting that CD2 and CD28 have redundant functions in T cell activation and subsequent cytokine production. Strikingly, the IL-13 production was not blocked by anti-CD2 mAbs and also not increased by agonistic anti-CD28 mAb, in particular within the EAD patient group. Conclusion: The signalling pathway initiated by the T cell receptor complex leading to increased IL-13 production in AD patients appears to be highly sensitive and is largely independent on CD2 costimulatory signals.
Correlation between T-Cell and Mast Cell Activity in Patients with Chronic Urticaria
Authors: Hidvégi Bernadett , Nagy Eszter , Szabó Teréz , Temesvári Erzsébet , Marschalkó Márta , Kárpáti Sarolta , Horváth Attila , Gergely Péter
Published: November 2003

Background: The presence of autoantibodies reacting with the high affinity IgE receptor (FcΕRIα) usually indicates a more severe form of chronic urticaria (CU). Previously, we showed an increased lymphocyte reactivity in CU patients; however, the relation between enhanced cellular immunity and the presence of anti-FcΕRIα-specific autoantibodies has not been investigated. Methods: Cellular and humoral immune reactivity of 50 CU patients and 28 healthy controls was studied.Serum sIL-2R, neopterin, and tryptase levels were measured to assess T-cell, monocyte/macrophage and mast cell activity, respectively. Helicobacter pylori (HP)-specific IgG antibody, and IgE levels were also tested. Anti-FcΕRIα-specific autoantibody was determined by Western blotting. In vivo histamine-releasing activity of patients’ sera was assessed by the autologous serum skin test (AST). Results: 17/50 CU patients, who both had IgG-type anti-FcΕRIα-antibodies by Western blotting and a positive AST response, were classified as autoimmune CU. All patients with CU had significantly higher serum sIL-2R and tryptase levels than healthy controls (p = 0.000257, p = 0.000166, respectively), indicating T-cell and mast cell activation. Patients with higher sIL-2R levels also had higher tryptase levels; the strongest correlation was shown in the autoimmune subgroup of patients (ρ = 0.688, p = 0.002). There was a tendency towards higher tryptase levels in the autoimmune subgroup, as compared to the nonautoimmune CU patients. While the serum IgE was significantly lower in autoimmune than in nonautoimmune CU (p = 0.000836), there was no significant difference in their sIL-2R, neopterin and HP-specific IgG antibody levels. CU patients with a positive AST response (38/50) had significantly higher tryptase levels (p = 0.0107) when compared to the negative skin test group. Conclusions: The significant correlation between sIL-2R and tryptase levels in patients with CU indicates that T cell activation is proportional to mast cell degranulation in these patients. The increased level of tryptase in autoimmune CU may suggest more severe disease.
Bayesian Spatial Modeling of Haplotype Associations
Authors: Thomas Duncan C. , Stram Daniel O. , Conti David , Molitor John , Marjoram Paul
Published: November 2003

We review methods for relating the risk of disease to a collection of single nucleotide polymorphisms (SNPs) within a small region. Association studies using case-control designs with unrelated individuals could be used either to test for a direct effect of a candidate gene and characterize the responsible variant(s), or to fine map an unknown gene by exploiting the pattern of linkage disequilibrium (LD). We consider a flexible class of logistic penetrance models based on haplotypes and compare them with an alternative formulation based on unphased multilocus genotypes. The likelihood for haplotype-based models requires summation over all possible haplotype assignments consistent with the observed genotype data, and can be fitted using either Expectation-Maximization (E-M) or Markov chain Monte Carlo (MCMC) methods. Subtleties involving ascertainment correction for case-control studies are discussed. There has been great interest in methods for LD mapping based on the coalescent or ancestral recombination graphs as well as methods based on haplotype sharing, both of which we review briefly. Because of their computational complexity, we propose some alternative empirical modeling approaches using techniques borrowed from the Bayesian spatial statistics literature. Here, space is interpreted in terms of a distance metric describing the similarity of any pair of haplotypes to each other, and hence their presumed common ancestry. Specifically, we discuss the conditional autoregressive model and two spatial clustering models: Potts and Voronoi. We conclude with a discussion of the implications of these methods for modeling cryptic relatedness, haplotype blocks, and haplotype tagging SNPs, and suggest a Bayesian framework for the HapMap project.
Data Adaptive Interim Modification of Sample Sizes for Candidate-Gene Association Studies
Authors: Scherag André , Müller Hans-Helge , Dempfle Astrid , Hebebrand Johannes , Schäfer Helmut
Published: November 2003

Objectives: The use of conventional Transmission/Disequilibrium tests in the analysis of candidate-gene association studies requires the precise and complete pre-specification of the total number of trios to be sampled to obtain sufficient power at a certain significance level (type I error risk). In most of these studies, very little information about the genetic effect size will be available beforehand and thus it will be difficult to calculate a reasonable sample size. One would therefore wish to reassess the sample size during the course of a study. Method: We propose an adaptive group sequential procedure which allows for both early stopping of the study with rejection of the null hypothesis (H₀) and for recalculation of the sample size based on interim effect size estimates when H₀ cannot be rejected. The applicability of the method which was developed by Müller and Schäfer [Biometrics 2001;57:886–891] in a clinical context is demonstrated by a numerical example. Monte Carlo simulations are performed comparing the adaptive procedure with a fixed sample and a conventional group sequential design. Results: The main advantage of the adaptive procedure is its flexibility to allow for design changes in order to achieve a stabilized power characteristic while controlling the overall type I error and using the information already collected. Conclusions: Given these advantages, the procedure is a promising alternative to traditional designs.
The Ubiquitous Nature of Epistasis in Determining Susceptibility to Common Human Diseases
Authors: Moore Jason H.
Published: November 2003

There is increasing awareness that epistasis or gene-gene interaction plays a role in susceptibility to common human diseases. In this paper, we formulate a working hypothesis that epistasis is a ubiquitous component of the genetic architecture of common human diseases and that complex interactions are more important than the independent main effects of any one susceptibility gene. This working hypothesis is based on several bodies of evidence. First, the idea that epistasis is important is not new. In fact, the recognition that deviations from Mendelian ratios are due to interactions between genes has been around for nearly 100 years. Second, the ubiquity of biomolecular interactions in gene regulation and biochemical and metabolic systems suggest that relationship between DNA sequence variations and clinical endpoints is likely to involve gene-gene interactions. Third, positive results from studies of single polymorphisms typically do not replicate across independent samples. This is true for both linkage and association studies. Fourth, gene-gene interactions are commonly found when properly investigated. We review each of these points and then review an analytical strategy called multifactor dimensionality reduction for detecting epistasis. We end with ideas of how hypotheses about biological epistasis can be generated from statistical evidence using biochemical systems models. If this working hypothesis is true, it suggests that we need a research strategy for identifying common disease susceptibility genes that embraces, rather than ignores, the complexity of the genotype to phenotype relationship.