bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating the Probability of Ruin for Variable Premiums by Simulation
Authors: Michaud Frédéric
Published: March 2005

There is a duality between the surplus process of classical risk theory and the single-server queue. It follows that the probability of ruin can be retrieved from a single sample path of the waiting time process of the single-server queue. In this paper, premiums are allowed to vary. It has been shown that the stationary distribution of a corresponding storage process is equal to the survival probability (with variable premiums). Thus by simulation of the corresponding storage process, the probability of ruin can be obtained. The special cases where the surplus earns interest and the premiums are charged by layers are considered and illustrated numerically.
A financially Balanced Bonus/Malus System
Authors: Coene Geert , Doray Louis G.
Published: March 2005

The premiums for a bonus-malus system which stays in financial equilibrium over the years are calculated. This is done by minimizing a quadratic function of the difference between the premium for an optimal BMS with an infinite number of classes and the premium for a BMS with a finite number of classes, weighted by the stationary probability of being in a certain class, and by imposing various constraints on the system.
Some Moment Relations for the Hipp approximation
Authors: Dhaene Jan , Sundt Bjørn , De Pril Nelson
Published: March 2005

In the present note we consider the Hipp approximation to the convolution of a finite number of probability distributions on the non-negative integers. It is shown that the moment up to and including order r of the rth order approximation are equal to the corresponding moments of the exact distribution. We also give a relation between the exact and approximated (r + 1)th order moments and indicate how similar relations can be obtained for higher order moments.
A Loglinear Lagrangian Poisson Model
Authors: ter Berg Peter
Published: March 2005

Maximum likelihood estimation is derived for the Lagrangian Poisson distribution for a simple and a loglinear model and illustrated with real data.
On the Hedging Portfolio of Asian Options
Authors: Jacques Michel
Published: March 2005

We give 2 explicit formulae for the hedging portfolio of Asian options. One is based on the usual Lognormal approximation, and the other on an Inverse Gaussian approximation. Both give excellent results as replicating strategies when the parameters of the model are in a reasonable range.
Dependency of Risks and Stop-Loss Order
Authors: Dhaene Jan , Goovaerts Marc J.
Published: March 2005

The correlation order, which is defined as a partial order between bivariate distributions with equal marginals, is shown to be a helpfull tool for deriving results concerning the riskiness of portfolios with pairwise dependencies. Given the distribution functions of the individual risks, it is investigated how changing the dependency assumption influences the stop-loss premiums of such portfolios.
Modified Recursions for a Class of Compound Distributions
Authors: Waldmann Karl-Heinz
Published: March 2005

Recursions are derived for a class of compound distributions having a claim frequency distribution of the well known (a,b)-type. The probability mass function on which the recursions are usually based is replaced by the distribution function in order to obtain increasing iterates. A monotone transformation is suggested to avoid an underflow in the initial stages of the iteration. The faster increase of the transformed iterates is diminished by use of a scaling function. Further, an adaptive weighting depending on the initial value and the increase of the iterates is derived. It enables us to manage an arbitrary large portfolio. Some numerical results are displayed demonstrating the efficiency of the different methods. The computation of the stop-loss premiums using these methods are indicated. Finally, related iteration schemes based on the cumulative distribution function are outlined.
Credibility in the Regression case Revisited (A Late Tribute to Charles A. Hachemeister)
Authors: Bühlmann H. , Gisler A.
Published: March 2005

Many authors have observed that Hachemeisters Regression Model for Credibility – if applied to simple linear regression – leads to unsatisfactory credibility matrices: they typically ‘mix up’ the regression parameters and in particular lead to regression lines that seem ‘out of range’ compared with both individual and collective regression lines. We propose to amend these shortcomings by an appropriate definition of the regression parameters:

–intercept

–slope

Contrary to standard practice the intercept should however not be defined as the value at time zero but as the value of the regression line at the barycenter of time. With these definitions regression parameters which are uncorrected in the collective can be estimated separately by standard one dimensional credibility techniques.

A similar convenient reparametrization can also be achieved in the general regression case. The good choice for the regression parameters is such as to turn the design matrix into an array with orthogonal columns.
The Swiss Re Exposure Curves and the MBBEFD Distribution Class
Authors: Bernegger Stefan
Published: March 2005

A new two-parameter family of analytical functions will be introduced for the modelling of loss distributions and exposure curves. The curve family contains the Maxwell-Boltzmann, the Bose-Einstein and the Fermi-Dirac distributions, which are well known in statistical mechanics. The functions can be used for the modelling of loss distributions on the finite interval [0, 1] as well as on the interval [0, ∞]. The functions defined on the interval [0, 1] are discussed in detail and related to several Swiss Re exposure curves used in practice. The curves can be fitted to the first two moments μ and σ of a loss distribution or to the first moment μ and the total loss probability p.
A Semi-Parametric Predictor of the IBNR Reserve
Authors: Doray Louis G.
Published: March 2005

We develop a semi-parametric predictor of the IBNR reserve in a macro-model when the claim amount for a certain accident and development year can be expressed in a loglinear form composed of a deterministic part and a random error. We need to make assumptions only on the first two moments of the error, without any specified parametric assumption on its distribution. We give its properties, present its advantages and compare the estimates obtained with various predictors of the IBNR reserve, parametric and non-parametric, using a data set.
Discussion of the Danish Data on Large Fire Insurance Losses
Authors: Resnick Sidney I.
Published: March 2005

Alexander McNeil's (1996) study of the Danish data on large fire insurance losses provides an excellent example of the use of extreme value theory in an important application context. We point out how several alternate statistical techniques and plotting devices can buttress McNeil's conclusions and provide flexible tools for other studies.
Fair Pricing of Life Insurance Participating Policies with a Minimum Interest Rate Guaranteed
Authors: Bacinello Anna Rita
Published: March 2005

In this paper we analyse, in a contingent-claims framework, one of the most common life insurance policies sold in Italy during the last two decades. The policy, of the endowment type, is initially priced as a standard one, given a mortality table and a technical interest rate. Subsequently, at the end of each policy year, the insurance company grants a bonus, which is credited to the mathematical reserve and depends on the performance of a special investment portfolio. More precisely, this bonus is determined in such a way that the total interest rate credited to the insured equals a given percentage (participation level) of the annual return on the reference portfolio and anyway does not fall below the technical rate (minimum interest rate guaranteed, henceforth). Moreover, if the contract is paid by periodical premiums, it is usually stated that the annual premium is adjusted at the same rate of the bonus, and thus the benefit is also adjusted in the same measure. In such policy the variables controlled by the insurance company (control-variables, henceforth) are the technical rate, the participation level and, in some sense, the riskiness of the reference portfolio measured by its volatility. However, as it is intuitive, not all sets of values for these variables give rise to a fair contract, i.e. to a contract priced consistently with the usual assumptions on financial markets and, in particular, with no-arbitrage. We derive then necessary and sufficient conditions under which each control-variable is determined by a fair pricing of the contract, given the remaining two ones.
Empirical Issues in Value-at-Risk
Authors: Bams Dennis , Wielhouwer Jacco L.
Published: March 2005

For the purpose of Value-at-Risk (VaR) analysis, a model for the return distribution is important because it describes the potential behavior of a financial security in the future. What is primarily, is the behavior in the tail of the distribution since VaR analysis deals with extreme market situations. We analyze the extension of the normal distribution function to allow for fatter tails and for time-varying volatility. Equally important to the distribution function are the associated parameter values. We argue that parameter uncertainty leads to uncertainty in the reported VaR estimates. There is a tradeoff between more complex tail-behavior and this uncertainty. The “best estimate”-VaR should be adjusted to take account of the uncertainty in the VaR. Finally, we consider the VaR forecast for a portfolio of securities. We propose a method to treat the modeling in a univariate, rather than a multivariate, framework. Such a choice allows us to reduce parameter uncertainty and to model directly the relevant variable.
Allowance for the Age of Claims in Bonus-Malus Systems
Authors: Pinquet Jean , Guillén Montserrat , Bolancé Catalina
Published: March 2005

The purpose of the paper is to use the age of claims in the prediction of risks. A dynamic random effects model on longitudinal count data is presented, and estimated on the portfolio of a major Spanish insurance company. The estimated autocorrelation coefficients of stationary random effects are decreasing. A consequence is that the predictive ability of a claim decreases with the lag between the period of risk prediction and the period of occurrence. There is a wide gap between the long term properties of actuarial and real-world experience rating schemes. This gap can be partly filled if the age of claims is taken into account in the actuarial model.
A Note on Ruin in a Two State Markov Model
Authors: Wagner Christian
Published: March 2005

We are dealing with the ruin probability and the expected ruin time in a two state Markov model where the premium is the reciprocal of an integer and the initial surplus is a multiple of the premium.
Sentinel Node Biopsy as Staging Tool in a Multimodality Treatment Approach to Cancer of the Oral Cavity and the Oropharynx
Authors: Kovács Adorján F. , Landes Constantin A. , Hamscho Nadja , Risse Jörn H. , Berner Uwe , Menzel Christian
Published: April 2005

OBJECTIVES:

Feasibility of sentinel lymph node (SLN) biopsy in head and neck cancer as a staging tool embedded in a multimodality regimen including neoadjuvant intraarterial chemotherapy.

STUDY DESIGN AND SETTING:

39 patients with oral and anterior oropharyngeal cancer classified N0 by [18F]FDG‐PET underwent SLN scintigraphy. Selective SLN biopsy without elective neck dissection (ND) was performed, immediately followed by radical resection of the primary tumor. Histopathology included step‐serial sections and immunocyto‐chemistry.

RESULTS:

Lymphoscintigraphy detected 104 spots. In 15 patients there was bilateral drainage. 114 SLN were excised due to additional intraoperative discrimination. 95% of visualised SLN could be removed. Histology was positive in 3 patients (8%), all underwent ND which yielded another positive node in 2 cases. Median observation time was 30 months. Two patients (5%) had a neck relapse in combination with a second primary.

CONCLUSIONS:

SLN biopsy as only surgical staging tool seems to be feasible.

SIGNIFICANCE:

Method promises reduction of elective ND and morbidity in N0 patients.
Effects of Genioglossal Muscle Advancement on Speech: An Acoustic Study of Vowel Sounds
Authors: Vähätalo Kimmo , Laaksonen Juha‐Pertti , Tamminen Henna , Aaltonen Olli , Happonen Risto‐Pekka
Published: April 2005

OBJECTIVE:

The effects of the genioglossal muscle advancement on phonetic quality of speech were studied analyzing the acoustic features of vowel sounds.

STUDY DESIGN AND SETTING:

The study group consisted of 5 men suffering from partial upper airway obstruction during sleep. To prevent tongue base collapse, genioglossal muscle advancement was made with chin osteotomy without hyoid myotomy and suspension. The speech material consisted of 8 vowels produced in sentence context repeated 10 times before the operation, and 10 days and 6 weeks after the operation. The acoustic features of vowels were analyzed.

RESULTS:

The operation had no significant effects on vowel quality. Only for 2 of the subjects the pitches changed systematically due to the operation.

CONCLUSION:

According to the acoustic analysis, genioglossal muscle advancement with chin osteotomy has no effects on vowel production. Some short‐term changes were observed, but these changes were highly individual.

SIGNIFICANCE:

The operation seems to have no potential to change vowel production.
A Hystopathological Study of Thyroarytenoid Muscle Invasion in Early (T1) Glottic Carcinoma
Authors: Kocatürk Sinan , Han Ünsal , Yilmazer D. , Onal Binnur , Erkam Ünsal
Published: April 2005

PATIENTS AND METHODS:

Surgical specimens belonging to 16 patients who underwent partial laryngectomy for T1 glottic cancer were subjected to detailed histopathologic examination; 11 of the patients were staged as T1a while 5 were staged as T1b.

RESULTS:

It was detected that in 11 patients the tumor was confined to the mucosal or submucosal connective layer, and in 5 (31.2%) cases, the tumor invaded the thyroarytenoid (TA) muscle. In cases involving the one‐third anterior part of the vocal cords and the anterior commissure, a 50% (4/8) TA muscle invasion was detected.

DISCUSSION AND CONCLUSION:

Our finding TA muscle invasion at the rate of 31.2% in our 16 case series clinically staged as T1 revealed that deep invasion did not always impair the vocal cord mobility. Observing TA muscle invasion at the rate of 50% in cases involving the one‐third anterior part of the vocal cord and the anterior commissure suggested that TA muscle invasion in the anterior part did not significantly impair mobility.
Long‐Term Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) in Patients with Chronic Tinnitus
Authors: Kleinjung Tobias , Eichhammer Peter , Langguth Berthold , Jacob Peter , Marienhagen Joerg , Hajak Goeran , Wolf Stephan R. , Strutz Juergen
Published: April 2005

OBJECTIVES:

The pathophysiologic mechanisms of idiopathic tinnitus remain unclear. Recent studies demonstrated focal brain activation in the auditory cortex of patients with chronic tinnitus. Low‐frequency repetitive transcranial magnetic stimulation (rTMS) is able to reduce cortical hyperexcitability.

STUDY DESIGN:

Fusing of the individual PET‐scan with the structural MRI‐scan (T1, MPRAGE) allowed us to identify exactly the area of increased metabolic activity in the auditory cortex of patients with chronic tinnitus. With the use of a neuronavigational system, this target area was exactly stimulated by the figure 8‐shaped magnetic coil. In a prospective study, rTMS (110% motor threshold; 1 Hz; 2000 stimuli/day over 5 days) was performed using a placebo controlled cross‐over design. Patients were blinded regarding the stimulus condition. For the sham stimulation a specific sham‐coil system was used. Fourteen patients were followed for 6 months. Treatment outcome was assessed with a specific tinnitus questionnaire (Goebel and Hiller).

SETTING:

Tertiary referral medical center.

RESULTS:

Increased metabolic activation in the auditory cortex was verified in all patients. After 5 days of verum rTMS, a highly significant improvement of the tinnitus score was found whereas the sham treatment did not show any significant changes. The treatment outcome after 6 months still demonstrated significant reduction of tinnitus score.

CONCLUSION:

These preliminary results demonstrate that neuronavigated rTMS offers new possibilities in the understanding and treatment of chronic tinnitus.
Stratigraphic evidence for anthropogenically induced coastal environmental change from Oaxaca, Mexico
Authors: Goman Michelle , Joyce Arthur , Mueller Raymond
Published: April 2005

Previous interdisciplinary paleoenvironmental and archaeological research along the Río Verde Valley of Oaxaca, Mexico, showed that Holocene erosion in the highland valleys of the upper drainage basin triggered geomorphic changes in the river's coastal floodplain. This article uses stratigraphic data from sediment cores extracted from Laguna Pastoría, an estuary in the lower Río Verde Valley, to examine changes in coastal geomorphology potentially triggered by highland erosion. Coastal lagoon sediments contain a stratigraphically and chronologically distinct record of major hurricane strikes during late Holocene times. Three distinct storm facies are identified from sediment cores obtained from Laguna Pastoría, which indicate that profound coastal environmental changes occurred within the region and are correlated with increased sediment supplied from highland erosion. TheChione/Laevicardiumfacies was deposited in an open bay while theMytella/barnacle facies and sand facies were deposited in an enclosed lagoon following bay barrier formation. We argue that highland erosion triggered major geomorphic changes in the lowlands including bay barrier formation by ∼2500 cal yr B.P. These environmental changes may have had significant effects on human populations in the region. The lagoon stratigraphy further indicates an increase in mid–late Holocene hurricane activity, possibly caused by increased El Niño frequencies.
A checkpoint control linking meiotic S phase and recombination initiation in fission yeast
Authors: Tonami Yuko , Murakami Hiroshi , Shirahige Katsuhiko , Nakanishi Makoto
Published: April 2005

During meiosis, high levels of recombination initiated by DNA double-strand breaks (DSBs) occur only after DNA replication. However, how DSB formation is coupled to DNA replication is unknown. We examined several DNA replication proteins for a role in this coupling in
Schizosaccharomyces pombe
, and we show that ribonucleotide reductase, the rate-limiting enzyme of deoxyribonucleotide synthesis and the target of the DNA synthesis inhibitor hydroxyurea (HU) is indirectly required for DSB formation linked to DNA replication. However, in cells in which the function of the DNA-replication-checkpoint proteins Rad1p, Rad3p, Rad9p, Rad17p, Rad26p, Hus1p, or Cds1p was compromised, DSB formation occurred at similar frequencies in the absence or presence of HU. The DSBs in the HU-treated mutant cells occurred at normal sites and were associated with recombination. In addition, Cdc2p is apparently not involved in this process. We propose that the sequence of meiotic S phase and initiation of recombination is coordinated by DNA-replication-checkpoint proteins.
Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin
Authors: Tate Sarah K. , Depondt Chantal , Sisodiya Sanjay M. , Cavalleri Gianpiero L. , Schorge Stephanie , Soranzo Nicole , Thom Maria , Sen Arjune , Shorvon Simon D. , Sander Josemir W. , Wood Nicholas W. , Goldstein David B.
Published: April 2005

Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final “maintenance” dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the α-subunit of the sodium channel, encoded by theSCNfamily of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism inCYP2C9is highly associated with the maximum dose of phenytoin (P= 0.0066). We also show that an intronic polymorphism in theSCN1Agene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P= 0.0051 andP= 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5′ splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication.
Replication checkpoint kinase Cds1 regulates Mus81 to preserve genome integrity during replication stress
Authors: Kai Mihoko , Boddy Michael N. , Russell Paul , Wang Teresa S.-F.
Published: April 2005

The replication checkpoint kinase Cds1 preserves genome integrity by stabilizing stalled replication forks. Cds1 targets substrates through its FHA domain. The Cds1 FHA domain interacts with Mus81, a subunit of the Mus81-Eme1 structure-specific endonuclease. We report here that Mus81 and Rhp51 are required for generating deletion mutations in fission yeast replication mutants that experience replication stress. A mutation in the Mus81 FHA-binding motif eliminates its Cds1-binding and Cds1-dependent phosphorylation. Furthermore, this mutation exacerbates the deletion mutator phenotype of a replication mutant, and induces a hyper-recombination phenotype in hydroxyurea-treated cells. In unperturbed cells, Mus81 associates with chromatin throughout S phase. In replication mutants grown at semipermissive temperature, Mus81 undergoes minor Cds1-dependent phosphorylation, remains chromatin-associated, generates deletion mutations, and maintains cell growth. Upon S-phase arrest by acute hydroxyurea treatment, Mus81 is not required for cell viability but is essential for recovery from replication fork collapse. Moreover, Mus81 undergoes extensive Cds1-dependent phosphorylation and dissociates from chromatin in hydroxyurea-arrested cells, thereby preventing it from cleaving stalled replication forks that could lead to fork breakage and chromosomal rearrangement. These results provide novel insights into how Cds1 regulates Mus81 accordingly when cells experience different replication stress to preserve genome integrity.
Cloning and Characterization of MicroRNAs from Rice
Authors: Sunkar Ramanjulu , Girke Thomas , Jain Pradeep Kumar , Zhu Jian-Kang
Published: April 2005

MicroRNAs (miRNAs) are a growing family of small noncoding RNAs that downregulate gene expression in a sequence-specific manner. The identification of the entire set of miRNAs from a model organism is a critical step toward understanding miRNA-guided gene regulation. Rice (Oryza sativa) and Arabidopsis thaliana, two plant model species with fully sequenced genomes, are representatives of monocotyledonous and dicotyledonous flowering plants, respectively. Thus far, experimental identification of miRNAs in plants has been confined to Arabidopsis. Computational analysis based on conservation with known miRNAs from Arabidopsis has predicted 20 families of miRNAs in rice. To identify miRNAs that are difficult to predict in silico or not conserved in Arabidopsis, we generated three cDNA libraries of small RNAs from rice shoot, root, and inflorescence tissues. We identified 35 miRNAs, of which 14 are new, and these define 13 new families. Thirteen of the new miRNAs are not conserved in Arabidopsis. Four of the new miRNAs are conserved in related monocot species but not in Arabidopsis, which suggests that these may have evolved after the divergence of monocots and dicots. The remaining nine new miRNAs appear to be absent in the known sequences of other plant species. Most of the rice miRNAs are expressed ubiquitously in all tissues examined, whereas a few display tissue-specific expression. We predicted 46 genes as targets of the new rice miRNAs: 16 of these predicted targets encode transcription factors, and other target genes appear to play roles in diverse physiological processes. Four target genes have been experimentally verified by detection of miRNA-mediated mRNA cleavage. Our identification of new miRNAs in rice suggests that these miRNAs may have evolved independently in rice or been lost in other species.
ELECTRON MICROSCOPY IN THE CATALYSIS OF ALKANE OXIDATION, ENVIRONMENTAL CONTROL, AND ALTERNATIVE ENERGY SOURCES
Authors: Gai Pratibha L. , Calvino Jose J.
Published: April 2005

▪ Abstract  The key role of electron microscopy in understanding and creating advanced catalyst materials and processes in selective alkane oxidation, environmental control, and alternative energy sources is reviewed. In many technological processes, catalysts are increasingly nanoscale heterogeneous materials. With growing regulatory guidelines requiring efficient and environmentally compatible catalytic processes, it is crucial to have a fundamental understanding of the catalyst nanostructure and modes of operation under reaction conditions to design novel catalysts and processes. The review highlights the pioneering development and applications of atomic resolution in situ-environmental transmission electron microscopy (ETEM) for probing dynamic catalysis directly at the atomic level, high-resolution electron microscopy, and analytical spectroscopic methods in the development of alkane catalyzation, environmental protection, and new energy sources.
Paracrine mitogenic effect of human endothelial progenitor cells: role of interleukin-8
Authors: He Tongrong , Peterson Timothy E. , Katusic Zvonimir S.
Published: April 2005

Endothelial progenitor cells (EPCs) play an important role in repair of vascular injury and neovascularization. Molecular mechanisms underlying vascular effects of EPCs are not fully understood. The present study was designed to test the hypothesis that human EPCs exert a strong paracrine mitogenic effect on mature endothelial cells. Levels of interleukin-8 (IL-8) were significantly higher in conditioned medium (CM) collected from EPCs than in CM derived from mature endothelial cells [umbilical vein endothelial cells (HUVECs) and coronary artery endothelial cells (CAECs)]. CM of EPCs stimulated proliferation of HUVECs and CAECs. This mitogenic effect was partially inhibited by IL-8-neutralizing antibody. In contrast, CM of HUVECs and CAECs had a weak or no mitogenic effect on mature endothelial cells. Our results demonstrate significantly higher levels of IL-8 secretion by human EPCs than by mature endothelial cells. IL-8 appears to be an important mediator of the paracrine mitogenic effect of EPCs.
HIV-1 Tat protein-induced VCAM-1 expression in human pulmonary artery endothelial cells and its signaling
Authors: Liu Kai , Chi David S. , Li Chuanfu , Hall H. Kenton , Milhorn Denise M. , Krishnaswamy Guha
Published: April 2005

Expression of cell adhesion molecule in endothelial cells upon activation by human immunodeficiency virus (HIV) infection is associated with the development of atherosclerotic vasculopathy. We postulated that induction of vascular cell adhesion molecule-1 (VCAM-1) by HIV-1 Tat protein in endothelial cells might represent an early event that could culminate in inflammatory cell recruitment and vascular injury. We determined the role of HIV-1 Tat protein in VCAM-1 expression in human pulmonary artery endothelial cells (HPAEC). HIV-1 Tat protein treatment significantly increased cell-surface expression of VCAM-1 in HPAEC. Consistently, mRNA expression of VCAM-1 was also increased by HIV-1 Tat protein as measured by RT-PCR. HIV-1 Tat protein-induced VCAM-1 expression was abolished by the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) and the p38 MAPK inhibitor SB-203580. Furthermore, HIV-1 Tat protein enhanced DNA binding activity of NF-κB, facilitated nuclear translocation of NF-κB subunit p65, and increased production of reactive oxygen species (ROS). Similarly to VCAM-1 expression, HIV-1 Tat protein-induced NF-κB activation and ROS generation were abrogated by PDTC and SB-203580. These data indicate that HIV-1 Tat protein is able to induce VCAM-1 expression in HPAEC, which may represent a pivotal early molecular event in HIV-induced vascular/pulmonary injury. These data also suggest that the molecular mechanism underlying the HIV-1 Tat protein-induced VCAM-1 expression may involve ROS generation, p38 MAPK activation, and NF-κB translocation, which are the characteristics of pulmonary endothelial cell activation.
E. colivirulence factor hemolysin induces neutrophil apoptosis and necrosis/lysis in vitro and necrosis/lysis and lung injury in a rat pneumonia model
Authors: Russo Thomas A. , Davidson Bruce A. , Genagon Stacy A. , Warholic Natalie M. , MacDonald Ulrike , Pawlicki Patrick D. , Beanan Janet M. , Olson Ruth , Holm Bruce A. , Knight Paul R
Published: April 2005

Enteric gram-negative bacilli, such as Escherichia coli are the most common cause of nosocomial pneumonia. In this study a wild-type extraintestinal pathogenic strain of E. coli (ExPEC)(CP9) and isogenic derivatives deficient in hemolysin (Hly) and cytotoxic necrotizing factor (CNF) were assessed in vitro and in a rat model of gram-negative pneumonia to test the hypothesis that these virulence factors induce neutrophil apoptosis and/or necrosis/lysis. As ascertained by in vitro caspase-3/7 and LDH activities and neutrophil morphology, Hly mediated neutrophil apoptosis at lower E. coli titers (1 × 105–6cfu) and necrosis/lysis at higher titers (≥1 × 107cfu). Data suggest that CNF promotes apoptosis but not necrosis or lysis. We also demonstrate that annexin V/7-amino-actinomycin D staining was an unreliable assessment of apoptosis using live E. coli. The use of caspase-3/7 and LDH activities and neutrophil morphology supported the notion that necrosis, not apoptosis, was the primary mechanism by which neutrophils were affected in our in vivo gram-negative pneumonia model using live E. coli. In addition, in vivo studies demonstrated that Hly mediates lung injury. Neutrophil necrosis was not observed when animals were challenged with purified lipopolysaccharide, demonstrating the importance of using live bacteria. These findings establish that Hly contributes to ExPEC virulence by mediating neutrophil toxicity, with necrosis/lysis being the dominant effect of Hly on neutrophils in vivo and by lung injury. Whether Hly-mediated lung injury is due to neutrophil necrosis, a direct effect of Hly, or both is unclear.
Conflict Processes between Youth Groups in a Norwegian City: Polarisation and Revenge
Authors: Bjørgo Tore
Published: April 2005

This study analyses the dynamics of conflict between two youth scenes in the Norwegian city of Kristiansand, commonly described as 'the neo-Nazis', and their counterparts, referred to as 'the anti-racists' or 'the Valla Gang'. The 'neo-Nazis' regularly committed acts of violence against other youths belonging to the multi-ethnic youth scene. As such, many of these incidents could clearly be described as acts of racist violence or hate crime. However, through interviews with 50 participants from both sides it became clear that the acts of violence were part of a more complex set of conflict dynamics between youth groups. This involved processes of polarisation within and between the local youth scenes as well as cycles of generalised revenge based on widely shared notions of 'one for all and all for one'. Youth groups and individual actors switched between political identities and gang identities depending on the situation, and conflicts that initially had nothing to do with racism or anti-racism could easily become politicised. Based on an understanding of the conflict processes, several points of intervention could be identified. Several of the interventions gave positive outcomes.
Super paramagnetic clustering of protein sequences
Authors: Tetko Igor V , Facius Axel , Ruepp Andreas , Mewes Hans-Werner
Published: April 2005

Background

Detection of sequence homologues represents a challenging task that is important for the discovery of protein families and the reliable application of automatic annotation methods. The presence of domains in protein families of diverse function, inhomogeneity and different sizes of protein families create considerable difficulties for the application of published clustering methods.

Results

Our work analyses the Super Paramagnetic Clustering (SPC) and its extension, global SPC (gSPC) algorithm. These algorithms cluster input data based on a method that is analogous to the treatment of an inhomogeneous ferromagnet in physics. For the SwissProt and SCOP databases we show that the gSPC improves the specificity and sensitivity of clustering over the original SPC and Markov Cluster algorithm (TRIBE-MCL) up to 30%. The three algorithms provided similar results for the MIPS FunCat 1.3 annotation of four bacterial genomes, Bacillus subtilis, Helicobacter pylori, Listeria innocua and Listeria monocytogenes. However, the gSPC covered about 12% more sequences compared to the other methods. The SPC algorithm was programmed in house using C++ and it is available at http://mips.gsf.de/proj/spc. The FunCat annotation is available at http://mips.gsf.de.

Conclusion

The gSPC calculated to a higher accuracy or covered a larger number of sequences than the TRIBE-MCL algorithm. Thus it is a useful approach for automatic detection of protein families and unsupervised annotation of full genomes.
Bayesian coestimation of phylogeny and sequence alignment
Authors: Lunter Gerton , Miklós István , Drummond Alexei , Jensen Jens Ledet , Hein Jotun
Published: April 2005

Background

Two central problems in computational biology are the determination of the alignment and phylogeny of a set of biological sequences. The traditional approach to this problem is to first build a multiple alignment of these sequences, followed by a phylogenetic reconstruction step based on this multiple alignment. However, alignment and phylogenetic inference are fundamentally interdependent, and ignoring this fact leads to biased and overconfident estimations. Whether the main interest be in sequence alignment or phylogeny, a major goal of computational biology is the co-estimation of both.

Results

We developed a fully Bayesian Markov chain Monte Carlo method for coestimating phylogeny and sequence alignment, under the Thorne-Kishino-Felsenstein model of substitution and single nucleotide insertion-deletion (indel) events. In our earlier work, we introduced a novel and efficient algorithm, termed the "indel peeling algorithm", which includes indels as phylogenetically informative evolutionary events, and resembles Felsenstein's peeling algorithm for substitutions on a phylogenetic tree. For a fixed alignment, our extension analytically integrates out both substitution and indel events within a proper statistical model, without the need for data augmentation at internal tree nodes, allowing for efficient sampling of tree topologies and edge lengths. To additionally sample multiple alignments, we here introduce an efficient partial Metropolized independence sampler for alignments, and combine these two algorithms into a fully Bayesian co-estimation procedure for the alignment and phylogeny problem.

Our approach results in estimates for the posterior distribution of evolutionary rate parameters, for the maximum a-posteriori (MAP) phylogenetic tree, and for the posterior decoding alignment. Estimates for the evolutionary tree and multiple alignment are augmented with confidence estimates for each node height and alignment column. Our results indicate that the patterns in reliability broadly correspond to structural features of the proteins, and thus provides biologically meaningful information which is not existent in the usual point-estimate of the alignment. Our methods can handle input data of moderate size (10–20 protein sequences, each 100–200 bp), which we analyzed overnight on a standard 2 GHz personal computer.

Conclusion

Joint analysis of multiple sequence alignment, evolutionary trees and additional evolutionary parameters can be now done within a single coherent statistical framework.
Investigation of the potentiation of the analgesic effects of fentanyl by ketamine in humans: a double-blinded, randomised, placebo controlled, crossover study of experimental pain[ISRCTN83088383]
Authors: Tucker Adam P , Kim Yong Ik , Nadeson Raymond , Goodchild Colin S
Published: April 2005

Background

Despite preclinical evidence suggesting a synergistic interaction between ketamine and opioids promoting analgesia, several clinical trials have not identified dosing regimens capable of eliciting a benefit in the co-administration of ketamine with opioids.

Methods

Ten healthy volunteers participated in a double blinded, randomised, placebo controlled, crossover laboratory study in order to determine whether a low dose of ketamine potentiated the antinociceptive effect of fentanyl without causing an increase in sedative effects. A battery of tests was used to assess both nociception and sedation including electrical current, pressure, thermal stimuli, psychometric tests, and both subjective and objective scores of sedation. Target controlled infusions of the study drugs were used. Ketamine and fentanyl were administered alone and in combination in a double-blinded randomised crossover design. Saline was used as the control, and propofol was used to validate the tests of sedation. Cardiovascular and respiratory parameters were also assessed.

Results

The electrical current pain threshold dose response curve of fentanyl combined with ketamine was markedly steeper than the dose response curve of fentanyl alone. While a ketamine serum concentration of 30 ng/ml did not result in a change in electrical pain threshold when administered alone, when it was added to fentanyl, the combination resulted in greater increase in pain threshold than that of fentanyl administered alone. When nociception was assessed using heat and pressure stimuli, ketamine did not potentiate the anti-nociceptive effect of fentanyl. There was no difference between the sedative effect of fentanyl and fentanyl in combination with ketamine as assessed by both subjective and objective measures of sedation. Cardiovascular and respiratory parameters were unaffected by the study drugs at the doses given.

Conclusion

A serum concentration of ketamine that did not alter indices of sedation potentiated the antinociceptive effect of fentanyl. This potentiation of antinociception occurred without an increase in sedation suggesting that low steady doses of ketamine (30–120 ng/ml) might be combined with μ opioid agonists to improve their analgesic effect in a clinical setting. (296 words)
Statistically significant dependence of the Xaa-Pro peptide bond conformation on secondary structure and amino acid sequence
Authors: Pahlke Doreen , Freund Christian , Leitner Dietmar , Labudde Dirk
Published: April 2005

Background

A reliable prediction of the Xaa-Pro peptide bond conformation would be a useful tool for many protein structure calculation methods. We have analyzed the Protein Data Bank and show that the combined use of sequential and structural information has a predictive value for the assessment of the cis versus trans peptide bond conformation of Xaa-Pro within proteins. For the analysis of the data sets different statistical methods such as the calculation of the Chou-Fasman parameters and occurrence matrices were used. Furthermore we analyzed the relationship between the relative solvent accessibility and the relative occurrence of prolines in the cis and in the trans conformation.

Results

One of the main results of the statistical investigations is the ranking of the secondary structure and sequence information with respect to the prediction of the Xaa-Pro peptide bond conformation. We observed a significant impact of secondary structure information on the occurrence of the Xaa-Pro peptide bond conformation, while the sequence information of amino acids neighboring proline is of little predictive value for the conformation of this bond.

Conclusion

In this work, we present an extensive analysis of the occurrence of the cis and trans proline conformation in proteins. Based on the data set, we derived patterns and rules for a possible prediction of the proline conformation. Upon adoption of the Chou-Fasman parameters, we are able to derive statistically relevant correlations between the secondary structure of amino acid fragments and the Xaa-Pro peptide bond conformation.
Transient increase of ATP as a response to temperature up-shift in Escherichia coli
Authors: Soini Jaakko , Falschlehner Christina , Mayer Christina , Böhm Daniela , Weinel Stefan , Panula Johanna , Vasala Antti , Neubauer Peter
Published: April 2005

Background

Escherichia coli induces the heat shock response to a temperature up-shift which is connected to the synthesis of a characteristic set of proteins, including ATP dependent chaperones and proteases. Therefore the balance of the nucleotide pool is important for the adaptation and continuous function of the cell. Whereas it has been observed in eukaryotic cells, that the ATP level immediately decreased after the temperature shift, no data are available for E. coli about the adenosine nucleotide levels during the narrow time range of minutes after a temperature up-shift.

Results

The current study shows that a temperature up-shift is followed by a very fast significant transient increase of the cellular ATP concentration within the first minutes. This increase is connected to a longer lasting elevation of the cellular respiration and glucose uptake. Also the mRNA level of typical heat shock genes increases within only one minute after the heat-shock.

Conclusion

The presented data prove the very fast response of E. coli to a heat-shock and that the initial response includes the increase of the ATP pool which is important to fulfil the need of the cell for new syntheses, as well as for the function of chaperones and proteases.
Clinical evaluation of autoantibodies to a novel PM/Scl peptide antigen
Authors: Mahler Michael , Raijmakers Reinout , Dähnrich Cornelia , Blüthner Martin , Fritzler Marvin J
Published: April 2005

Anti-PM/Scl antibodies represent a specific serological marker for a subset of patients with scleroderma (Scl) and polymyositis (PM), and especially with the PM/Scl overlap syndrome (PM/Scl). Anti-PM/Scl reactivity is found in 24% of PM/Scl patients and is found in 3–10% of Scl and PM patients. The PM/Scl autoantigen complex comprises 11–16 different polypeptides. Many of those proteins can serve as targets of the anti-PM/Scl B-cell response, but most frequently the PM/Scl-100 and PM/Scl-75 polypeptides are targeted. In the present study we investigated the clinical relevance of a major alpha helical PM/Scl-100 epitope (PM1-α) using a newly developed peptide-based immunoassay and compared the immunological properties of this peptide with native and recombinant PM/Scl antigens. In a technical comparison, we showed that an ELISA based on the PM1-α peptide is more sensitive than common techniques to detect anti-PM/Scl antibodies such as immunoblot, indirect immunofluorescence on HEp-2 cells and ELISA with recombinant PM/Scl polypeptides. We found no statistical evidence of a positive association between anti-PM1-α and other antibodies, with the exception of known PM/Scl components. In our cohort a negative correlation could be found with anti-Scl-70 (topoisomerase I), anti-Jo-1 (histidyl tRNA synthetase) and anti-centromere proteins. In a multicenter evaluation we demonstrated that the PM1-α peptide represents a sensitive and reliable substrate for the detection of a subclass of anti-PM/Scl antibodies. In total, 22/40 (55%) PM/Scl patients, 27/205 (13.2%) Scl patients and 3/40 (7.5%) PM patients, but only 5/288 (1.7%) unrelated controls, tested positive for the anti-PM1-α peptide antibodies. These data indicate that anti-PM1-α antibodies appear to be exclusively present in sera from PM/Scl patients, from Scl patients and, to a lesser extent, from PM patients. The anti-PM1-α ELISA thus offers a new serological marker to diagnose and discriminate different systemic autoimmune disorders.
Dynamic magnetic resonance of the wrist in psoriatic arthritis reveals imaging patterns similar to those of rheumatoid arthritis
Authors: Cimmino Marco A , Parodi Massimiliano , Innocenti Stefania , Succio Giulia , Banderali Simone , Silvestri Enzo , Garlaschi Giacomo
Published: April 2005

This dynamic magnetic resonance imaging (MRI) study is concerned with a prospective evaluation of wrist synovitis in patients with psoriatic arthritis (PsA) in comparison with patients with rheumatoid arthritis (RA) and healthy controls. Fifteen consecutive patients with PsA, 49 consecutive patients with RA, 30 RA patients matched for disease severity with those with PsA, and 8 healthy controls were studied. MRI was performed with a low-field (0.2T), extremity-dedicated machine. After an intravenous bolus injection of gadolinium-diethylenetriaminepentaacetic acid, 20 consecutive fast spin-echo axial images of the wrist were obtained every 18 s. The enhancement ratio was calculated both as rate of early enhancement (REE), which shows the slope of the curve of contrast uptake per second during the first 55 s, and as relative enhancement (RE), which indicates the steady state of enhancement. The REE was 1.0 ± 0.6 in patients with PsA, 1.6 ± 0.7 in consecutive patients with RA, and 0.1 ± 0.1 in controls (p <0.001). The RE was 87.1 ± 39.2 in patients with PsA, 125.8 ± 48.0 in consecutive RA patients, and 15.5 ± 19.2 in controls (p <0.001). However, the same figures in matched RA patients were 1.3 ± 0.7 and 107.3 ± 48.2, respectively (not significant in comparison with PsA). Rheumatoid-like PsA and oligoarticular PsA did not differ from each other in terms of synovial enhancement. Dynamic MRI shows the same pattern of synovitis in patients with PsA and RA when the two groups are matched for disease severity. This technique cannot be used to differentiate PsA from RA. However, REE and RE were significantly higher in PsA than in normal controls, with only one instance of overlap between values found for the two groups.