bluuebunny/crossref_metadata_2025 huggingface dataset:
XBRL awareness in auditing: a sleeping giant?
Authors: Pinsker Robert
Published: November 2003

EXtensible Business Reporting Language (XBRL) is a revolutionary digital language that “tags” information for business reporting since it represents a universal standard for global business reporting. XBRL usage has a significant impact on auditors – both external and internal and is seen as a tool to implement the American Institute of Certified Public Accountants’ (AICPA) new reporting model. The model calls for real‐time, or continuous, reporting of company information. In order to do so reliably, continuous assurance on the data would need to be performed by external auditors. XBRL General Ledger (GL) is a taxonomy incorporating all ledger functions into XBRL. Thus, company information that typically takes days to create could be available in real‐time, anywhere in the world. This article reports on an XBRL survey conducted using accountants and auditors. Results indicate many accountants and auditors have low (if any) knowledge or experience with XBRL and do not perceive the intended benefits XBRL usage provides.
Audit of accounting program on oral communications apprehension: a comparative study among accounting students
Authors: Aly Ibrahim M. , Islam Majidul
Published: November 2003

Business research identified communications apprehension as a problem for improving communication skills. Research has indicated that communication skills are very important to employers in hiring and promotion decisions. This study provides empirical evidence as to whether the accounting program has contributed toward lowering the level of communications apprehension on two groups of accounting students: those who are entering the program and others who are exiting the program. Findings show that there is no significant difference between the level of communications apprehension between the groups when they entered the program and the time when they exited the program, raising a question of the potency of the accounting program in alleviating the communications apprehension of accounting students. Some remedial measures have been suggested.
SUPERCONDUCTING COHERENT STATES FOR AN EXTENDED HUBBARD MODEL
Authors: MADOURI F. , HASSOUNI Y. , EL BAZ M.
Published: November 2003

An extended Hubbard model with phonons is considered. q-coherent states relative to the superconducting quantum symmetry of the model are constructed and their properties studied. It is shown that they can have energy expectation lower than eigenstates constructed via conventional processes and that they exhibit ODLRO.
FIELD THEORY OF ANISOTROPIC QUANTUM HALL GAS: METROLOGY AND A NOVEL QUANTUM HALL REGIME
Authors: ISHIKAWA K. , AOYAMA T. , ISHIZUKA Y. , MAEDA N.
Published: November 2003

The von Neumann lattice representation is a convenient representation for studying several intriguing physics of quantum Hall systems. In this formalism, electrons are mapped to lattice fermions. A topological invariant expression of the Hall conductance is derived and is used for the proof of the integer quantum Hall effect in the realistic situation. Anisotropic quantum Hall gas is investigated based on the Hartree–Fock approximation in the same formalism. Thermodynamic properties, transport properties, and unusual response under external modulations are found. Implications for the integer quantum Hall effect in the finite systems are also studied and a new quantum Hall regime with non-zero longitudinal resistance is shown to exist.
OPTIMAL PORTFOLIOS WITH DEFAULTABLE SECURITIES A FIRM VALUE APPROACH
Authors: KORN RALF , KRAFT HOLGER
Published: November 2003

Credit risk is an important issue of current research in finance. While there is a lot of work on modeling credit risk, there is only a few works on continuous-time portfolio optimization with defaultable securities. In this paper we solve investment problems with defaultable bonds and stocks. We assume that credit risk is modeled by a firm value model.
Dinos, Zauberer und Engel –Konstellation des kollektiven Unbewussten und/oder Modetrends?1
Authors: Riedel Ingrid
Published: November 2003

Jungs Theorie von der Dynamik des kollektiven Unbewussten besagt, dass sich im kollektiven Unbewussten einer Gesellschaft jeweils das belebt und konstelliert, was dem kollektiven Bewusstsein zu der Zeit am meisten fehlt: Das gehäufte Auftreten von Dinosauriern in den Fantasien, Träumen und anderweitigen Produktionen des kollektiven Unbewussten in den vergangenen Jahren, die anhaltende Faszination durch Engel und neuerdings durch das «göttliche Kind», das auch in der Harry-Potter-Gestalt erkennbar ist, lässt auf bestimmte Konstellationen von Archetypen schliessen, die sich kompensatorisch zum gegenwärtigen kollektiven Bewusstsein entfalten. Der Beitrag plädiert für ein Wahrnehmen solcher Konstellationen und ihrer heilsamen kompensatorischen Wirkung, auch angesichts sogenannter Modetrends.
Costs and Potential Benefits of Parental Care in the Nocturnal Fat-Tailed Dwarf Lemur (Cheirogaleus medius)
Authors: Fietz Joanna , Dausmann Kathrin H.
Published: November 2003

Parental care should evolve only if fitness benefits exceed fitness costs. In Cheirogaleus medius, a small nocturnal lemur of western Madagascar, we found the peculiar situation of considerable parental care by both sexes, combined with an extremely high rate of extra-pair young (EPY). In this paper, we try to elucidate the costs and benefits of parental care in C. medius, and we discuss hypotheses as to why males might actively participate in raising young, especially with regard to the high rate of EPY. The study was carried out in the dry deciduous forest of western Madagascar between 1996 and 2001. The most important components of parental care in C. medius are babysitting and guarding of the young. Observational data suggest that thermoregulatory demands during the first days after birth and defence from predators may be the driving factors selecting for this infant care behaviour. The reproducing individuals of both sexes incur considerable energetic costs by this behaviour, resulting in reduced fat stores and body condition in comparison to non-reproducing individuals. The reason why males also care for EPY remains elusive. We propose that males might not be able to detect individual relatedness and that they would jeopardise the survival of their own young if they gave no parental care. Alternatively, they might gain advantages other than direct fitness from raising EPY, for example if caring behaviour increases their chances in further reproduction, or if EPY are fathered by close kin.
Predation Experiments on Infant Spectral Tarsiers (Tarsius spectrum)
Authors: Gursky Sharon
Published: November 2003

In this paper, I investigate how mother and infant spectral tarsiers, Tarsius spectrum, respond to the presence of potential predators. I conducted this study at Tangkoko Nature Reserve in Sulawesi, Indonesia, from June to November 1999. I exposed 2 infants to 3 types of potential predators (large models of birds of prey, large rubber snakes and the vocalizations of large birds of prey) for a total of 18 nights. Infants moved a greater distance from their parked location when exposed to rubber snakes (1.8 m) compared to nights when they were not exposed to potential predators (0.23 m). On the other hand, when large bird of prey models were placed near the parked infant, the infant did not move from its parked locale (0.05 m). Parked infants repeatedly gave alarm calls in response to the presentation of all potential predator types. When an infant produced an alarm call following the presentation of a potential predator, the mother responded with her own alarm call approximately 88% of the time. However, when an infant produced an inappropriate alarm call, the mother responded with her own alarm call only 19% of the time. These results suggest that spectral tarsier infants use alarm calls to ask questions about the things they encounter in their environment. Infants and mothers both produced a twittering alarm call in response to the bird of prey models, whereas they both produced a harsh loud call 3 times in rapid succession in response to the presence of the rubber snakes.
Sex Differences in the Behavior and the Social Interactions of Immature Galago senegalensis braccatus
Authors: Nash Leanne T.
Published: November 2003

There is little detailed documentation of immature behavior, especially mother-offspring interactions, for nocturnal prosimians, and few studies have examined sex differences in mother-offspring interactions. This study compares the behavior of captive-born Galago senegalensis braccatus, the Senegal galago, from 1 to 20 weeks of age for 3–5 females and 4–6 males. The subjects lived in social groups, onfa reversed light cycle. Three 10-min focal samples were taken each week, for each subject, during each of the 6 most active hours of the waking cycle (night). Locally weighted regression scatterplot smoothing analysis was used to test for sex differences in behavior. There were no sex differences in most forms of mother-offspring contact, including nursing, control of proximity with the mother or grooming. Females were more active than males in the rate of solitary acrobatic play and, only after the age of weaning, in locomotion. Altogether, these observations suggest that the sexes might not present more energetic ''costs’ to mothers. There were tendencies for female immatures to play with the mother more than male immatures did, and a tendency for the males to investigate the cage more than the females. Male and female immatures groomed non-mother group mates in equivalent amounts. Since males are likely the dispersing sex in galagos, these differences might be reflective of later dispersal patterns. However, comparisons are needed with a female dispersal species (e.g. chimpanzees) to test this hypothesis. Alternative hypotheses concerning the ''cost’ and/or ''value’ of sons versus daughters need to be explored.
Infant Response to Mother Call Patterns in Otolemur garnettii
Authors: Becker Michelle , Buder Eugene , Bakeman Roger , Price Melissa , Ward Jeannette
Published: November 2003

Garnett’s greater bushbaby infants vocalize in apparent response to their mother’s contact calls. However, it remains unclear whether specific vocal or behavioral patterns by a mother elicit this vocal response. We video-recorded the behaviors and vocalizations of 4 individual mother-infant groups (mother with twins), analyzed vocalizations via spectrography and documented behaviors of mothers and infants. Initial analyses of all groups revealed that short growls and short growl bouts (or chains), but not long growls, emitted by mothers, were followed by infant clicks within 5 s. Further statistical examination of 1 mother-infant group revealed that an infant’s vocal response is conditional on the sequencing of the mother’s short growls and somewhat conditional on the mother’s behavior before or after the short growls.
Contractile Regulatory Proteins Tropomyosin and Troponin-T as Indicators of the Modulatory Role of Retinoic Acid
Authors: Vélez C. , Aránega A.E. , Marchal J.A. , Prados J. , Melguizo C. , Carrillo E. , Boulaiz H. , Madeddu R. , Sánchez-Montesinos I. , Aránega A.
Published: November 2003

Retinoic acid (RA), the active metabolite of vitamin A, plays a significant role in regulating cardiac form and function throughout the life of the organism. Both cardiac morphogenesis and myocardial differentiation are affected by alterations in RA homeostasis. In order to test the effect of all-trans RA and 13-cis RA on cardiomyocyte differentiation, we studied the level and the subcellular compartmentalization of α-tropomyosin and troponin-T proteins in cultures of chick embryo cardiomyocytes obtained from Hamburger and Hamilton’s (HH) stage 22, 32 and 40 embryos. The retinoids increased the levels of α-tropomyosin and troponin-T in the cytoplasmic and cytoskeletal fractions of cells at all three stages of development. The greatest increases in α-tropomyosin occurred in the cytoplasmic fraction in HH22 cells cultured for 24 h with all-trans RA or 13-cis RA, whereas the greatest increases in troponin-T were found in the cytoplasmic fraction of HH32 cells exposed to retinoids for 24 h. In cultures treated for 48 h with retinoids, the levels of α-tropomyosin and troponin-T showed significant increases in the cytoplasmic compartment of cells treated in HH32-with respect to the control values. These findings are further evidence that RA plays a modulating role in the formation and reorganization of sarcomeric proteins during the process of cardiomyocyte maturation.
Comparative Histology of the Laminar Bone between Young Calves and Foals
Authors: Mori R. , Kodaka T. , Sano T. , Yamagishi N. , Asari M. , Naito Y.
Published: November 2003

Laminar bone or primary plexiform tissue, not Haversian bone, shows an alternative concentric pattern of laminar-bone units or plates around the bone marrow periphery of long bones, although the laminar bone is gradually replaced by osteons during the growth period. One laminar-bone unit is constructed with a hypercalcified line in the center, woven bone on both sides of the line, and lamellar bone with laminated appositional lines. Such a laminar bone showing a homogeneous calcification has been reported in young calves and some young large animals, but it has not been reported in foals although a previous report proposed that the bone structure was distinguishable from plexiform tissue. In this study, we compared young calves with foals by backscattered electron imaging mainly of transverse ground sections of mid-diaphysis. Foals had many hypercalcified lines arranged concentrically around the bone marrow periphery, which were similar to those of young calves. However, rows of cylindrical osteon-like structures with Haversian canal-like canals running along the long-bone axis were arranged between the concentric hypercalcified lines. Each Haversian canal-like structure was enclosed with laminated appositional rings of lamellar bone deposited on the woven bone. In the developing period, the bone units containing the concentric hypercalcified lines were basically equal to the laminar-bone units. The osteon-like structures or ‘pseudo-osteons’ were gradually replaced by ‘true osteons’ during the growth period. The blood vessels in the Haversian canal-like canals of foals ran along the long-bone axis, whereas the blood vessels in the concentrically prolonged bone cavities of young calves ran transversely to obliquely against the long-bone axis. Thus, the long-bone cortex of foals showing an alternative concentric pattern of a row of the osteon-like structures arranged between the hypercalcified lines will be histologically classified into a variety of laminar bone caused by the different arrangement of blood vessels. Such a laminar bone may have a biomechanical structure against physical stress, especially the modified laminar bone of foals with osteon-like structures, when compared with the typical concentric laminar bone of young calves and also Haversian bone possessing variously calcified numerous osteons caused by bone remodeling.
Neuronal Nitric Oxide Synthase Modulation of Dorsal Horn Neuronal Responses in the Rat: A Developmental Study
Authors: Urch C.E. , Dickenson A.H.
Published: November 2003

Nitric oxide (NO) is a diffusible chemical messenger functionally linked to N-methyl-D-aspartate (NMDA) receptor activity and has been shown to be involved in modulating numerous pathways in the central nervous system. In order to investigate the role of the neuronal NO synthase type I (nNOS)/NO system in the postnatal development of dorsal horn nociceptive pathways in rats, the specific nNOS inhibitor 7-nitroindazole sodium salt (7-NI) and the non-specific NOS inhibitor nitro-L-arginine methyl ester (L-NAME) were applied spinally at postnatal days (P) 14, 21, 28 and >56 (adult) and their effects on neuronal responses were compared. In response to a train of 16 noxious electrical stimuli, the wide dynamic range neurones in the deep dorsal horn showed a dose-dependent inhibition of C-fibre-evoked response, post-discharge and windup to both 7-NI and L-NAME. No difference between any age group was observed with either agent on these responses. However, the effect of both 7-NI and L-NAME on the primary evoked response, a measure of the events occurring pre-synaptic and intrinsic to the neurone recorded, was significantly different between the P14 and older age groups. nNOS is known to be expressed later in postnatal development than the NMDA receptor and from the results presented here, it is fully mature and functional from P14 onwards. The subtle differences in attenuation of the primary evoked response at P14 compared with older ages may reflect the immaturity of the dorsal horn and in particular the incomplete development of intrinsic and descending inhibitory controls.
Brain Bioenergetics and Cognitive Ability
Authors: Rae Caroline , Scott Richard B. , Lee Martin , Simpson Judy M. , Hines Nicola , Paul Caroline , Anderson Mike , Karmiloff-Smith Annette , Styles Peter , Radda George K.
Published: November 2003

We obtained 31P magnetic resonance spectra from the brains in vivo of 101 males (range 6–72 years). In addition, cognitive test data were obtained from 42 boys (6–13 years) and from 26 adult males (22–56 years) of this test group. Significant correlations were observed in both adults and children between various inorganic phosphate (Pi)-containing 31P peak ratios [e.g. Pi/adenosine triphosphate (ATP)] and (predominantly verbal) cognitive tasks. No change in the Pi/ATP ratio was observed across the age range studied. Brain pH was shown to decrease significantly with age in a relationship best described by a decaying exponential. This indicated that brain pH does not stabilize at adult values until at least the late teens. We explored the possibility of a relationship between brain pH and neuronal density. In particular, we noted that our previous observation of a relationship between pH and IQ in children was not readily detected in the adult populations, whereas phosphorus metabolite ratios (in particular, those containing Pi) were found to correlate with (predominantly verbal) cognitive task performance in both adults and children. We assessed how these observations may be interpreted in the context of a metabolic vs. histological debate.
Prenatal and Postnatal Contents of Amino Acid Neurotransmitters in Mouse Parietal Cortex
Authors: Benítez-Diaz Pedro , Miranda-Contreras Leticia , Mendoza-Briceño Rosa Virginia , Peña-Contreras Zulma , Palacios-Prü Ernesto
Published: November 2003

This study documents the variation in the amino acid neurotransmitter contents during mouse parietal cortex development, from embryonic day 13 (E13) until young adulthood, between postnatal day 21 (P21) and P30. Taurine, an inhibitory neurotransmitter and neuromodulator, is the most abundant neurotransmitter in the developing neocortex, whereas, at the adult stage, glutamate is the more prominent neurotransmitter playing an excitatory role, and GABA is the major inhibitory neurotransmitter. During the proliferative stage of neurogenesis in the mouse cerebral cortex, between E13 and E17, relatively high levels of glutamate, aspartate, taurine and glycine were detected, consistent with a possible trophic influence of these neurotransmitters during cortical development prior to synaptogenesis. Between E17 and E19, a significant decline in the contents of these neurotransmitters was observed, consistent with earlier reports of cell death in the ventricular and subventricular zones during this stage of development. During the perinatal period, a progressive increment in glutamate level was seen between E21 and P5, and then the values remained constant until the second postnatal week. Glutamate also decreased by about 25% between P11 and P15, on the other hand, aspartate diminished by about 20% between P7 and P9. These results were consistent with previous reports of histogenetic cell death during the first 2 postnatal weeks in mouse neocortex. GABA increased from the embryonic period until young adulthood, in contrast, the glycine content decreased; thus, in the adult parietal cortex, the GABA content was about 2.6-fold higher than that of glycine. During the first postnatal week, the concentrations of glutamate and GABA showed significant increments between P0 and P5, while those of aspartate and glycine remained constant. During this period, amino acids are predominantly excitatory and the cerebral cortex is vulnerable to epileptiform activity; the significant increment in taurine content between P0 and P3 suggests a neuroprotective action of taurine against excitotoxicity. At P15, coinciding with the period of maximum cortical synaptogenesis, significant increments in GABA and glycine contents were observed which could be related to the maturation of inhibitory synaptic transmission. At the young adult stage, there was a rise in the levels of both excitatory neurotransmitters, glutamate and aspartate, and a significant reduction in the contents of all three inhibitory neurotransmitters, GABA, glycine and taurine.
Therapeutic Drug Monitoring of the HIV/AIDS Drugs Abacavir, Zidovudine, Efavirenz, Nevirapine, Indinavir, Lopinavir, and Nelfinavir
Authors: Donnerer J. , Kronawetter M. , Kapper A. , Haas I. , Kessler H.H.
Published: November 2003

Combination therapy with antiretroviral drugs is used for the treatment of patients infected with the human immunodeficiency virus. To achieve optimal drug concentrations for viral suppression and avoidance of drug toxicity, monitoring of drug levels has been considered essential. We set up an analytical procedure for monitoring the plasma concentrations of a total of seven drugs: abacavir, zidovudine, efavirenz, nevirapine, indinavir, lopinavir, and nelfinavir. The plasma samples were liquid/liquid extracted and subjected to high-performance liquid chromatography (HPLC) analysis. The compounds were monitored by ultraviolet detection: indinavir, lopinavir, and nelfinavir at 215 nm; efavirenz at 254 nm, and abacavir, zidovudine, and nevirapine at 266 nm. Two different extraction procedures and two different HPLC eluents on a C8 reversed-phase HPLC column were used to monitor all seven compounds. Under steady state conditions, the plasma concentrations of antiviral drugs in 175 patients were correlated with the time after the last dosing to define the peak or trough levels. Due to the short plasma elimination half-life of abacavir and zidovudine, only peak levels could be determined for these compounds, whereas both peak and trough levels could be assessed for the other compounds because of a longer plasma elimination half-life. The mean peak concentrations (µg/ml) were 0.69 for abacavir and 0.57 for zidovudine; the mean peak/trough concentrations (µg/ml) were 2.07/1.32 for efavirenz, 2.43/2.23 for nevirapine, 5.48/1.08 for indinavir, 4.69/3.51 for lopinavir, and 3.54/1.45 for nelfinavir. The described analytical method offers a broad-spectrum monitoring of plasma levels of antiretroviral drugs.
Characterization of Micro-Fibers at the Interface between the Renal Collecting Duct Ampulla and the Cap Condensate
Authors: Schumacher K. , Strehl R. , Minuth W.W.
Published: November 2003

The development of renal histo-architecture substantially depends on the three-dimensional extension of the collecting duct (CD) ampulla, since under its influence, nephron induction takes place in the surrounding mesenchyme. Recently, micro-fibers were detected by soybean agglutinin (SBA), which line from the basal aspect of each CD ampulla through the mesenchyme towards the organ capsule in embryonic kidney. Their unique distribution suggests that they may play an important role in the control of CD ampulla growth and in forming the renal stem cell niche. A profound analysis of interstitial proteins between the CD ampulla and the nephrogenic mesenchyme is lacking. Consequently, the goal of the current investigation was to colocalize the micro-fibers detected by SBA with interstitial proteins. For this reason a detailed cell biological analysis of extracellular molecules at this site was carried out. Double labeling showed that the micro-fibers do not correspond to known collagens and other extracellular matrix molecules such as agrin, versican or MMP-9. In addition, it could be demonstrated that the micro-fibers do not contain epithelial or mesenchymal cell elements. Furthermore, two-dimensional electrophoresis with subsequent Western blotting yielded two different amino acid sequences (1: GHYADPTSPR; 2: NNGCCSSDYHA) obtained from SBA-labeled protein spots. Both amino acid sequences could not be assigned to known rodent proteins. The findings suggest that the SBA-labeled micro-fibers represent a new type of extracellular structure between the CD ampulla, the mesenchyme and the organ capsule.
Identification of Oilseed Rape (Brassica napus) Pollen Profilin as a Cross-Reactive Allergen
Authors: Focke Margarete , Hemmer W. , Valenta R. , Jarisch R.
Published: November 2003

Background: Major allergens of oilseed rape (OSR) pollen with molecular weights of 6/8, 14 and between 27 and 69 kD have been described. The aim of the present study was to further characterize the 14-kD allergen. Methods: The 14-kD protein was purified from OSR pollen extracts by poly-(L-proline) (PLP)-Sepharose affinity chromatography and characterized immunologically by means of allergic patients’ IgE antibodies, profilin-specific rabbit antisera, Western blot and ELISA inhibition using recombinant birch profilin (rBet v 2), and skin prick testing. Results: By PLP affinity chromatography, OSR pollen profilin was purified as a single protein of 14.5 kD and further identified as a profilin by three polyclonal rabbit antisera raised against ragweed and tobacco pollen profilin and the C-terminus of birch profilin. IgE binding of a human serum pool (n = 15) and four profilin-reactive sera to nitrocellulose-blotted OSR profilin was completely inhibited by 1 µg/ml rBet v 2 (birch profilin). Reciprocal ELISA inhibition using increasing concentrations of rBet v 2 and purified OSR profilin, respectively, showed that rBet v 2 strongly inhibits antibody binding to OSR profilin, whereas almost 100 times the amount of OSR profilin was needed to inhibit IgE binding to rBet v 2. Skin prick tests were positive (wheal ≧3 mm) with 5 µg/ml rBet v 2 in all three patients tested, and with OSR profilin in two patients at a concentration of 50 µg/ml. Conclusions: OSR pollen profilin shares IgE and IgG epitopes with Bet v 2 and other plant profilins and may represent a potentially relevant allergen for profilin-sensitized patients.
How Accurate and Safe Is the Diagnosis of Hazelnut Allergy by Means of Commercial Skin Prick Test Reagents?
Authors: Akkerdaas Jaap H. , Wensing Marjolein , Knulst André C. , Krebitz Monika , Breiteneder Heimo , de Vries Sacco , Penninks André H. , Aalberse Rob C. , Hefle Sue L. , van Ree Ronald
Published: November 2003

Background: Allergy to tree nuts, like hazelnuts, ranks among the most frequently observed food allergies. These allergies can start at early childhood and are, in contrast to other food allergies, not always outgrown by the patient. Tree nut allergy is frequently associated with severe reactions. Diagnosis partially relies on in vivo testing by means of a skin prick test (SPT) using commercially available SPT reagents. Methods: Protein and allergen composition of nine commercial SPT solutions was evaluated using standard protein detection methods and specific immunoassays for measurement of five individual allergens. Diagnostic performance was assessed by SPT in 30 hazelnut-allergic subjects, of which 15 were provocation proven. Results: Protein concentrations ranged from 0.2–14 mg/ml. SDS-PAGE/silver staining revealed clear differences in protein composition. The major allergen Cor a 1 was present in all extracts but concentrations differed up to a factor 50. An allergen associated with severe symptoms, Cor a 8 (lipid transfer protein), was not detected on immunoblot in three products, and concentrations varied by more than a factor 100 as was shown by RAST inhibition. Similar observations were made for profilin, thaumatin-like protein and a not fully characterized 38-kD allergen. Ratios of individual allergens were variable among the nine extracts. SPT showed significant difference, and 6/30 patients displayed false-negative results using 3/9 products. Conclusion: Variability in the composition of products for the diagnosis of hazelnut allergy is extreme. Sometimes, allergens implicated in severe anaphylaxis are not detected by immunoblotting. These shortcomings in standardisation and quality control can potentially cause a false-negative diagnosis in subjects at risk of severe reactions to hazelnuts.
Family-Based Association Analysis with Tightly Linked Markers
Authors: Knapp Michael , Becker Tim
Published: November 2003

Refining genomic regions which have been identified by linkage analysis to contain a disease susceptibility locus has proven to be a challenging task. Detecting association between the disease and a genetic marker can significantly narrow down the candidate region. Since an adequate sample of families is already available from the genome scan, family-based association tests may be used to search for association. The use of haplotypes consisting of tightly linked markers can be more powerful for detecting association than the use of individual markers. An extension of the transmission/disequilibrium test to allow the simultaneous analysis of more than one marker locus is complicated by ambiguity of phase in some families of the sample. The present paper shows that a recently proposed method for the analysis of nuclear families with a single affected child can be viewed as a special application of a more general principle. This observation justifies several modifications, potentially increasing the power, as well as an extension of the method to allow the analysis of general nuclear families. Finally, the problem of missing parental genotypes is discussed.
A New Powerful Non-Parametric Two-Stage Approach for Testing Multiple Phenotypes in Family-Based Association Studies
Authors: Lange Christoph , Lyon Helen , DeMeo Dawn , Raby Benjamin , Silverman Edwin K. , Weiss Scott T.
Published: November 2003

We introduce a new powerful nonparametric testing strategy for family-based association studies in which multiple quantitative traits are recorded and the phenotype with the strongest genetic component is not known prior to the analysis. In the first stage, using a population-based test based on the generalized estimating equation approach, we test all recorded phenotypes for association with the marker locus without biasing the nominal significance level of the later family-based analysis. In the second stage the phenotype with the smallest p value is selected and tested by a family-based association test for association with the marker locus. This strategy is robust against population admixture and stratification and does not require any adjustment for multiple testing. We demonstrate the advantages of this testing strategy over standard methodology in a simulation study. The practical importance of our testing strategy is illustrated by applications to the Childhood Asthma Management Program asthma data sets.
Detecting Disease Associations due to Linkage Disequilibrium Using Haplotype Tags: A Class of Tests and the Determinants of Statistical Power
Authors: Chapman Juliet M. , Cooper Jason D. , Todd John A. , Clayton David G.
Published: November 2003

In the ‘indirect’ method of detecting genetic associations between a trait and a DNA variant, we type several markers in a gene or chromosome region of linkage disequilibrium. If there is association between markers and the trait, we presume the existence of one or more causal polymorphisms in the region. In order to obtain a sufficiently dense set of markers it will almost always be necessary to use single nucleotide polymorphisms (SNPs). Although there is an emerging literature on methods for choosing an optimal set of ‘haplotype tag SNPs’ (htSNPs) to detect association between a genetic region and a trait, less attention has been given to the problem of how such studies should be analysed when completed, and how the initial data which was used to select the htSNPs should be incorporated into the analysis. This paper discusses this problem for both population – and family-based association studies. The role of the R2 measure of association between a causal locus and various methods of scoring of marker haplotypes is highlighted. In most cases, the simplest method of scoring (locus coding), which does not require phase resolution, is shown generally to be more powerful than scoring methods that include haplotype information. A new ‘multi-locus TDT’ is also proposed.
The Identity by Descent Process along the Chromosome
Authors: Cannings Chris
Published: November 2003

The probabilities of the various possible identity by descent (IBD) states at a locus captures all the genealogical information for that locus for the set of individuals under consideration. Here we study the stochastic process of the IBD state as one moves across the genome of a set of individuals. In general it is no longer sufficient to specify the IBD state, one needs to increase the state space if one is to maintain the Markov property, as has been discussed by for instance McPeak and Sun [Am J Hum Genet 2000;66:1076–1094] and Browning and Browning [Theor Popul Biol 2002;62:1–8]. This paper discusses a general method of deriving the transition matrix for that Markov chain iteratively from one time point to a subsequent one. This method allows a considerable reduction in the size of the state space needed. The basic recursion is set out here and the application is illustrated by two specific examples.
Haplotype Frequency Estimation in the Presence of Genotyping Errors
Authors: Zou Guohua , Zhao Hongyu
Published: November 2003

Several statistical methods have been proposed to estimate haplotype frequencies, either based on unrelated individuals or based on families. These estimates may yield insights on population genetics as well as associations between candidate regions and disease of interest. One limitation of the existing methods is that all these methods make the implicit assumption that there are no genotyping errors. However, genotyping errors are unavoidable in practice. Numerous methods have been developed to incorporate genotyping errors in genetic studies, but none to date have addressed the issues of haplotype inference in the presence of genotyping errors. In this article, we develop statistical methods for haplotype inference incorporating genotyping errors. We describe how our methods can be applied to analyze unrelated individuals as well as nuclear families. Our simulation results show that the proposed methods perform well in the presence of genotyping errors.
Genetic Susceptibility for Lung Cancer: Interactions with Gender and Smoking History and Impact on Early Detection Policies
Authors: Gorlova Olga Y. , Amos Christopher , Henschke Claudia , Lei Lei , Spitz Margaret , Wei Qingyi , Wu Xifeng , Kimmel Marek
Published: November 2003

Objectives: To identify a subgroup of former, current and never smokers (males and females) at high risk for developing lung cancer, based on their genetic susceptibility profiles, to estimate their lifetime probabilities of the disease, and to assess the potential mortality reduction that could be achieved by screening the high-risk group. Methods: Case-control data (764 cases and 677 matched controls), on two assays of DNA damage and repair (mutagen susceptibility and DNA repair capacity, DRC) in different smoking categories were used to obtain estimates of susceptibility using the formula of total probability. The estimates were inserted into a model of lung cancer natural history and detection by screening to assess mortality reduction due to screening of high-risk individuals. Results: The high-risk group was defined as that 12.5% of the population who were above the third quartile for bleomycin sensitivity and below the median for DRC. High-risk male current, former, and never smokers had lifetime probabilities for developing lung cancer of 38, 21, and 5%, respectively. Females had lower probabilities to develop lung cancer: 15, 8, and 1.5% for high-risk current, former, and never smokers, respectively. Screening of high-risk smokers (12.5% of all smokers) reduced overall mortality by 7% compared to 30% reduction if all smokers were screened. Analogous results were obtained for former and never smokers. Conclusions: Genetic susceptibility constitutes an important factor in the selection of a high-risk group for early lung cancer detection.
Blinded End Point Adjudication in the ‘Danish Multicenter Randomized Study on Fibrinolytic Therapy versus Acute Coronary Angioplasty in Acute Myocardial Infarction’ (DANAMI-2 Trial)
Authors: Vejlstrup Niels , Clemmensen Peter , Steinmetz Ebbe , Krusell Lars Romer , Hansen Knud Nørregaard , Christiansen Ib , Hansen Peter Riis , Andersen Henning Rud
Published: November 2003

Background: Allocation concealment in trials that compare interventional procedures with medical therapy is impossible. Bias introduced by the investigators when end points are adjudicated is a methodological problem in such trials. Objective: To develop and test a novel method of blinded end point adjudication in open trials. Method: In the DANAMI-2 trial, a randomised open trial comparing primary angioplasty to fibrinolytic treatment of acute myocardial infarction, end points were evaluated by an independent end point committee (EPC). The cardiologists who presented the clinical end point data to the EPC were asked not to disclose any information on the randomised treatment, in order for the EPC to pass a truly blinded end point adjudication. The EPC categorised their evaluation of each end point as evaluated blinded or evaluated not blinded. Results: Blinded end point adjudication was possible in 84% of cases. All deaths reported by local investigators were confirmed by the EPC. Local investigators reported 78 cases of reinfarction and 31 (40%) of these events were rejected by the EPC, whereas the EPC discovered 35 unreported cases of reinfarction. Thirty-one strokes were reported by local investigators of which 2 (6%) were rejected by the EPC which, however, included 2 previously unreported strokes. A total of 383 cases of bleeding were reported of which 115 (30%) were rejected, whereas the EPC included 16 another cases of unreported bleedings. Blinded end point adjudication therefore contributed significantly to the final number of end points. Conclusion: Blinded end point adjudication is feasible in open randomised trials and is likely to reduce bias.
Effects of the Oral Direct Thrombin Inhibitor Ximelagatran on P-Selectin Expression and Thrombin Generation in Atrial Fibrillation
Authors: Wolzt Michael , Boström Stig L. , Svensson Mia , Wåhlander Karin , Grind Margaretha , Sarich Troy C.
Published: November 2003

This study investigated the pharmacodynamic effects of the oral direct thrombin inhibitor ximelagatran on platelet activation and thrombin generation in patients with nonvalvular atrial fibrillation. Using an open, group-matched study design, the effects of ximelagatran (36 mg twice daily for 5 days) were studied in 12 patients with permanent nonvalvular atrial fibrillation and in 12 healthy controls. After ximelagatran for 5 days, elevated platelet P-selectin expression in atrial fibrillation patients was lowered to that during coumarin treatment or in controls but had no effect in control subjects. Using the endogenous thrombin potential as a marker, ximelagatran decreased and delayed thrombin generation in both groups. In conclusion, direct thrombin inhibition with ximelagatran reduced elevated platelet P-selectin expression and inhibited thrombin generation.
Vascular Bed Specific Alterations in Coagulation and Fibrinolytic Parameters in Young Women following Myocardial Infarction, Lacunar Cerebral Infarction and Deep Vein Thrombosis
Authors: Salobir Barbara , Šabovič Mišo , Peternel Polona , Stegnar Mojca
Published: November 2003

The possible existence of distinctive, vascular bed specific alterations of coagulation and fibrinolytic parameters associated with three different types of thrombosis was investigated in young women (n = 68, <45 years at onset of the event) following myocardial infarction (MI) (n = 22), lacunar cerebral infarction (LACI) (n = 16), idiopathic deep vein thrombosis (VT) (n = 14) and venous thrombosis due to oral contraceptive use (n = 16) in the stable period after the acute thrombotic event. Coagulation and fibrinolytic parameters, as well as classical metabolic variables, were measured and compared with 52 age-matched, healthy controls. In MI women we observed elevated tissue type plasminogen activator (t-PA) antigen levels, which correlated significantly with parameters of the plurimetabolic syndrome. In LACI women we found elevated fibrinogen, which correlated with D-dimer, systolic blood pressure, smoking, and sedimentation rate. Prolonged euglobulin clot lysis time, elevated t-PA antigen, PAI-1 antigen and activity, which all correlated with parameters of the plurimetabolic syndrome, were found in women with idiopathic VT, who were also clearly obese but not in women in whom oral contraceptives were the triggering factor for VT. Our results showed not parallel, but different profiles of alterations in fibrinolytic and coagulation parameters in line with the prediction of a vascular bed specific thrombosis process.
Leukocyte CD15 Expression and Platelet Activation in the Coronary Sinus after Coronary Intervention
Authors: Rauch Ursula , Wolff Ursula Maria , Schultheiss Heinz-Peter , Schwimmbeck Peter Lothar
Published: November 2003

Markers associated with coronary restenosis must be identified to develop therapeutic strategies for improving the clinical outcome. We studied whether adhesion proteins on leukocytes and platelets from coronary sinus blood were associated with restenosis after coronary intervention in patients with stable coronary artery disease. Adhesion proteins on platelets and leukocytes were measured by flow cytometry. Pre- and postinterventional leukocyte CD15 expression was significantly higher in patients with restenosis than in those without it. Increased leukocyte CD15 expression during the intervention may contribute to coronary restenosis. Inhibition of leukocyte adhesion may be useful for the prevention of restenosis.
Effect of Endothelin Blockade on Early Cardiovascular Remodeling in the One-Clip-Two-Kidney Hypertension of the Rat
Authors: Saam Tobias , Ehmke Heimo , Haas Christian , Ritz Eberhard , Amann Kerstin
Published: November 2003

Background: In models of hypertension and of renal failure, pharmacological blockade of the ETA receptor has been shown to cause some inconsistent lowering of blood pressure (BP) and lesser left ventricular hypertrophy (LVH). The effects of ETA receptor blockade (ETA-RB) on vascular remodeling and their potential relation to BP lowering, have not been clarified. Design: The experimental study in male Sprague-Dawley rats was designed to compare four experimental groups: (1) sham-operated controls (sham); (2) untreated rats with one-clip-two-kidney (1C-2K) renovascular hypertension; (3) 1C-2K rats treated with the ACE inhibitor (ACE-i) trandolapril (0.3 mg/kg b.w./day), and (4) 1C-2K rats treated with the ETA-RB LU-135252 (50 mg/kg b.w./day). BP was measured weekly by tail plethysmography. After 3 weeks, animals were sacrificed and cardiac, aortic and mesenteric artery morphology was evaluated using morphometric and stereological techniques. Results: Systolic BP was significantly higher in 1C-2K rats compared to sham. BP was not significantly affected by ETA-RB, but was significantly lowered by the ACE-i. Despite no significant change in BP, ETA-RB treatment led to a significantly less volume density of the cardiac interstitium (sham 1.40 ± 0.18, 1C-2K 2.66 ± 0.56, 1C-2K + ACE-i 1.88 ± 0.38, 1C-2K + ETA-RB 2.15 ± 0.37%). In contrast, ETA-RB had no significant effect on left ventricular/body weight ratio (sham 2.85 ± 0.26, 1C-2K 2.96 ± 0.33, 1C-2K + ACE-i 2.54 ± 0.22 and 1C-2K + ETA-RB 3.15 ± 0.44 mg/g) or on wall thickness of intramyocardial arteries. Conclusions: The ETA-RB LU-135252 ameliorated the development of myocardial fibrosis in a short-term hyperreninemic normal salt model of experimental hypertension nearly as effectively as an ACE-i. This effect of LU-135252 is independent of systemic BP. In contrast to findings in other models, ETA receptor blockade had no significant effect on LVH or vascular remodeling. Only the ACE-i but not the ETA-RB prevented structural changes of small intramyocardial arteries and of the aorta.
Androgen-Dependent Expression of c-jun and c-fos in Human Non-Transformed Epithelial Prostatic Cells: Association with Cell Proliferation
Authors: Brum Ilma S. , Morsch Débora M. , Pozzobon Adriane , Boeri Valderes A. , Geib Guilherme , Spritzer Poli Mara
Published: November 2003

Objective: To assess the effect of dihydrotestosterone (DHT) on the gene expression of c-fos and c-jun and on the proliferation of human non-transformed epithelial prostatic (HNTEP) cells. Methods: Cell proliferation (MTT) and c-fos and c-jun mRNA expression (RT-PCR) were determined in cells treated with DHT (10–8, 10–10, and 10–13M) or with control medium. Results: DHT 10–13 M had a significant stimulatory effect on cell proliferation (p < 0.05) and c-fos and c-jun gene expression when compared to cells treated with higher concentrations of this hormone (10–10 and 10–8M) or with the control group. Conclusions: Our data demonstrate that the increase in c-fos and c-jun expression and cell growth in HNTEP cells is maximal with the lowest DHT concentration (10–13M). These proto-oncogenes may play a role in the control of hormone responsiveness and cell proliferation in HNTEP cells.
Effects of Different Sex Hormones on Male Rabbit Urodynamics: An Experimental Study
Authors: Celayir Sinan
Published: November 2003

Background: The effects of different sex hormones on urodynamics in female rabbits have been investigated previously. Estrogen induces an increase in bladder capacity and compliance, whereas testosterone and progesterone reduced bladder capacity and compliance. Objective: The aim of this study was to investigate the effects of sex hormones on bladder urodynamics in male rabbits. Methods: 5 groups were set up for the study: group I, low midline laparotomy (LML) + 0.9% NaCl; group II, LML + testosterone; group III, LML + bilateral orchiectomy (BO) + testosterone; group IV, LML + BO + progesterone, and group V, LML + BO + estrogen. Baseline urodynamic records and blood sex hormone levels were measured. In the follow-up all rabbits from each group underwent urodynamics 5, 10 and 30 days after injection. Estrogen, progesterone and testosterone levels were also measured during the follow-up period. For statistical verification Mann-Whitney U and Kruskal-Wallis χ2 tests were used. Results:Hormone levels: Testosterone levels were found to be increased in groups II and III 5 and 10 days after the injection. Testosterone declined thereafter and returned to baseline levels on day 30. In groups IV and V progesterone and estrogen levels increased after the injection and returned to baseline levels on day 30. Urodynamics: In groups II and III testosterone increased the bladder capacity and compliance on days 5 and 10. In these groups, capacity and compliance decreased thereafter and returned to the baseline levels on day 30. These urodynamic findings correlated with the alterations in blood testosterone levels. In groups I and IV no changes were observed in bladder capacity and compliance. In group V capacity and compliance were found to be increased on day 5 after the injection and returned to baseline levels on day 30. The changes in bladder capacity were found to be statistically significant in groups II, III and V. Conclusion: In this study, after the injection of testosterone, bladder capacity and compliance increased with high blood testosterone levels in male rabbits. The most interesting finding was observed in the estrogen group, questioning the role of estrogens in males. These findings allow us to reconsider the role of sex hormones in bladder functions.