bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA Replication Origin Interference Increases the Spacing between Initiation Events in Human Cells
Authors: Lebofsky Ronald , Heilig Roland , Sonnleitner Max , Weissenbach Jean , Bensimon Aaron
Published: September 2006

Mammalian DNA replication origins localize to sites that range from base pairs to tens of kilobases. A regular distribution of initiations in individual cell cycles suggests that only a limited number of these numerous potential start sites are converted into activated origins. Origin interference can silence redundant origins; however, it is currently unknown whether interference participates in spacing functional human initiation events. By using a novel hybridization strategy, genomic Morse code, on single combed DNA molecules from primary keratinocytes, we report the initiation sites present on 1.5 Mb of human chromosome 14q11.2. We confirm that initiation zones are widespread in human cells, map to intergenic regions, and contain sequence motifs found at other mammalian initiation zones. Origins used per cell cycle are less abundant than the potential sites of initiation, and their limited use increases the spacing between initiation events. Between-zone interference decreases in proportion to the distance from the active origin, whereas within-zone interference is 100% efficient. These results identify a hierarchical organization of origin activity in human cells. Functional origins govern the probability that nearby origins will fire in the context of multiple potential start sites of DNA replication, and this is mediated by origin interference.
TIF1 Activates the Intra-S-Phase Checkpoint Response in the Diploid Micronucleus and Amitotic Polyploid Macronucleus ofTetrahymena
Authors: Yakisich J. Sebastian , Sandoval Pamela Y. , Morrison Tara L. , Kapler Geoffrey M.
Published: September 2006

The ribosomal DNA origin binding protein Tif1p regulates the timing of rDNA replication and is required globally for proper S-phase progression and division of the Tetrahymena thermophila macronucleus. Here, we show that Tif1p safeguards chromosomes from DNA damage in the mitotic micronucleus and amitotic macronucleus. TIF1p localization is dynamically regulated as it moves into the micro- and macronucleus during the respective S phases. TIF1 disruption mutants are hypersensitive to hydroxyurea and methylmethanesulfonate, inducers of DNA damage and intra-S-phase checkpoint arrest in all examined eukaryotes. TIF1 mutants incur double-strand breaks in the absence of exogenous genotoxic stress, destabilizing all five micronuclear chromosomes. Wild-type Tetrahymena elicits an intra-S-phase checkpoint response that is induced by hydroxyurea and suppressed by caffeine, an inhibitor of the apical checkpoint kinase ATR/MEC1. In contrast, hydroxyurea-challenged TIF1 mutants fail to arrest in S phase or exhibit caffeine-sensitive Rad51 overexpression, indicating the involvement of TIF1 in checkpoint activation. Although aberrant micro- and macronuclear division occurs in TIF1 mutants and caffeine-treated wild-type cells, TIF1p bears no similarity to ATR or its substrates. We propose that TIF1 and ATR function in the same epistatic pathway to regulate checkpoint responses in the diploid mitotic micronucleus and polyploid amitotic macronucleus.
Rendezvin: An Essential Gene Encoding Independent, Differentially Secreted Egg Proteins That Organize the Fertilization Envelope Proteome after Self-Association
Authors: Wong Julian L. , Wessel Gary M.
Published: September 2006

Preventing polyspermy during animal fertilization relies on modifications to the egg's extracellular matrix. On fertilization in sea urchins, the contents of cortical granules are secreted and rapidly assemble into the egg's extracellular vitelline layer, forming the fertilization envelope, a proteinaceous structure that protects the zygote from subsequent sperm. Here, we document rendezvin, a gene whose transcript is differentially spliced to yield proteins destined for either cortical granules or the vitelline layer. These distinctly trafficked variants reunite after cortical granule secretion at fertilization. Together, they help coordinate assembly of the functional fertilization envelope, whose proteome is now defined in full.
Support vector machines for prediction of dihedral angle regions
Authors: Zimmermann Olav , Hansmann Ulrich H. E.
Published: September 2006

Motivation: Most secondary structure prediction programs target only alpha helix and beta sheet structures and summarize all other structures in the random coil pseudo class. However, such an assignment often ignores existing local ordering in so-called random coil regions. Signatures for such ordering are distinct dihedral angle pattern. For this reason, we propose as an alternative approach to predict directly dihedral regions for each residue as this leads to a higher amount of structural information.

Results: We propose a multi-step support vector machine (SVM) procedure, dihedral prediction (DHPRED), to predict the dihedral angle state of residues from sequence. Trained on 20 000 residues our approach leads to dihedral region predictions, that in regions without alpha helices or beta sheets is higher than those from secondary structure prediction programs.

Availability: DHPRED has been implemented as a web service, which academic researchers can access from our webpage

Contact:  u.hansmann@fz-juelich.de
CAPS: coevolution analysis using protein sequences
Authors: Fares Mario A. , McNally David
Published: September 2006

Summary: Coevolution Analysis using Protein Sequences (CAPS) is a PERL based software that identifies co-evolution between amino acid sites. Blosum-corrected amino acid distances are used to identify amino acid co-variation. The phylogenetic sequence relationships are used to remove the phylogenetic and stochastic dependencies between sites. The 3D protein structure is used to identify the nature of the dependencies between co-evolving amino acid sites. Friendly interpretable output files are generated.

Availability: CAPS version 1 is available at . Distribution versions for Linux/Unix, Mac OS X and Windows operating systems are available, including manual and example files.

Contact: faresm@tcd.ie
Cerebral Vascular and Metabolic Effects of Fentanyl and Midazolam in Young and Aged Rats
Authors: Baughman Verna L. , Hoffman William E. , Albrecht Ronald F. , Miletich David J.
Published: September 2006

Cerebral blood flow (CBF) and cerebral oxygen consumption (CMRO2) were measured, and electroencephalogram (EEG) was recorded in young (6-month-old) and aged (28-month-old) rats during ventilation with 70% N2O/30% O2 and following fentanyl or midazolam administration. Cerebral blood flow (CBF) was measured with radioactive microspheres, and cerebral oxygen consumption (CMRO2) was calculated from the arterial-sagittal sinus oxygen content difference and CBF measurements. Fentanyl at the highest dose used (200 µg/kg and 400 µg • kg−1 • h−1) depressed the EEG and decreased CBF 49% and CMRO2 39% in young rats, whereas in old rats, this fentanyl dose decreased CBF 37% and CMRO2 34%, both significantly less than in young rats (P < 0.05). Midazolam at the highest dose used (5.75 mg/kg) also depressed EEG in both age groups, and decreased CBF 51% and CMRO2 38% in young rats. This depression was significantly less than the 62% decrease in CBF and 59% decrease in CMRO2 produced by midazolam in old rats (P < 0.05). These results indicate that aging attenuates the cerebrovascular and cerebral metabolic depression produced by fentanyl, but potentiates the same effects produced by midazolam. The enhanced cerebral metabolic depression produced by midazolam in the aged is similar to that seen with phenobarbital, and suggests a similar action of these drugs at the central GABA-benzodiazepine-barbiturate receptor complex.
Combinatorial Domain Hunting: An effective approach for the identification of soluble protein domains adaptable to high‐throughput applications
Authors: Reich Stefanie , Puckey Loretto H. , Cheetham Caroline L. , Harris Richard , Ali Ammar A.E. , Bhattacharyya Uma , Maclagan Kate , Powell Keith A. , Prodromou Chrisostomos , Pearl Laurence H. , Driscoll Paul C. , Savva Renos
Published: September 2006

Exploitation of potential new targets for drug and vaccine development has an absolute requirement for multimilligram quantities of soluble protein. While recombinant expression of full‐length proteins is frequently problematic, high‐yield soluble expression of functional subconstructs is an effective alternative, so long as appropriate termini can be identified. Bioinformatics localizes domains, but doesn't predict boundaries with sufficient accuracy, so that subconstructs are typically found by trial and error. Combinatorial Domain Hunting (CDH) is a technology for discovering soluble, highly expressed constructs of target proteins. CDH combines unbiased, finely sampled gene‐fragment libraries, with a screening protocol that provides “holistic” readout of solubility and yield for thousands of protein fragments. CDH is free of the “passenger solubilization” and out‐of‐frame translational start artifacts of fusion‐protein systems, and hits are ready for scale‐up expression. As a proof of principle, we applied CDH to p85α, successfully identifying soluble and highly expressed constructs encapsulating all the known globular domains, and immediately suitable for downstream applications.
Elucidation of the mechanism of the regulatory function of the Ig1 module of the fibroblast growth factor receptor 1
Authors: Kiselyov Vladislav V. , Kochoyan Arthur , Poulsen Flemming M. , Bock Elisabeth , Berezin Vladimir
Published: September 2006

The extracellular part of the fibroblast growth factor (FGF) receptor (FGFR) consists of up to three Ig modules (Ig1–Ig3), in which the Ig2 and Ig3 modules determine affinity and specificity for FGF and heparin. The FGFR isoforms lacking the Ig1 module have higher affinity for FGF and heparin than the triple Ig‐module isoforms, suggesting that the Ig1 module is involved in the regulation of the FGFR–ligand interaction. We show here by surface plasmon resonance and NMR analyses that the Ig1 module binds to the Ig2 module, and identify by NMR the binding sites involved in the Ig1–Ig2 interaction. The identified binding site in the Ig2 module was found to be in the area of the FGF–Ig2 and Ig2–heparin contact sites, thus providing direct structural evidence that the Ig1 module functions as a competitive autoinhibitor of the FGFR–ligand interaction. Furthermore, the Ig1 binding site of the Ig2 module overlaps the Ig2–Ig2 contact site. This suggests that the function of the Ig1 module is not only regulation of the FGFR–ligand binding affinity but also prevention of spontaneous FGFR dimerization (through a direct Ig2–Ig2 interaction) in the absence of FGF.
Trapping the tetrahedral intermediate in the alkaline phosphatase reaction by substitution of the active site serine with threonine
Authors: Wang Jie , Kantrowitz Evan R.
Published: September 2006

We report here the construction of a mutant version of Escherichia coli alkaline phosphatase (AP) in which the active site Ser was replaced by Thr (S102T), in order to investigate whether the enzyme can utilize Thr as the nucleophile and whether the rates of the critical steps in the mechanism are altered by the substitution. The mutant AP with Thr at position 102 exhibited an ∼4000‐fold decrease in k cat along with a small decrease in K m. The decrease in catalytic efficiency of ∼2000‐fold was a much smaller drop than that observed when Ala or Gly were substituted at position 102. The mechanism by which Thr can substitute for Ser in AP was further investigated by determining the X‐ray structure of the S102T enzyme in the presence of the Pi (S102T_Pi), and after soaking the crystals with substrate (S102T_sub). In the S102T_Pi structure, the Pi was coordinated differently with its position shifted by 1.3 Å compared to the structure of the wild‐type enzyme in the presence of Pi. In the S102T_sub structure, a covalent Thr‐Pi intermediate was observed, instead of the expected bound substrate. The stereochemistry of the phosphorus in the S102T_sub structure was inverted compared to the stereochemistry in the wild‐type structure, as would be expected after the first step of a double in‐line displacement mechanism. We conclude that the S102T mutation resulted in a shift in the rate‐determining step in the mechanism allowing us to trap the covalent intermediate of the reaction in the crystal.
Engineered zinc‐binding sites confirm proximity and orientation of transmembrane helices I and III in the human serotonin transporter
Authors: White Kellie J. , Kiser Philip D. , Nichols David E. , Barker Eric L.
Published: September 2006

The human serotonin transporter (hSERT) regulates neurotransmission by removing released serotonin (5‐HT) from the synapse. Previous studies identified residues in SERT transmembrane helices (TMHs) I and III as interaction sites for substrates and antagonists. Despite an abundance of data supporting a 12‐TMH topology, the arrangement of the TMHs in SERT and other biogenic amine transporters remains undetermined. A high‐resolution structure of a bacterial leucine transporter that demonstrates homology with SERT has been reported, thus providing the basis for the development of a SERT model. Zn2+‐binding sites have been utilized in transporters and receptors to define experimentally TMH proximity. Focusing on residues near the extracellular ends of hSERT TMHs I and III, we engineered potential Zn2+‐binding sites between V102 or W103 (TMH I) and I179–L184 (TMH III). Residues were mutated to either histidine or cysteine. TMH I/III double mutants were constructed from functional TMH I mutants, and Zn2+ sensitivity was assessed. Dose‐response assays suggest an approximately twofold increase in sensitivity to Zn2+ inhibition at the hSERT V102C/M180C and approximately fourfold at the V102C/I179C mutant compared to the hSERT V102C single mutant. We propose that the increased sensitivity to Zn2+ confirms the proximity and the orientation of TMHs I and III in the membrane. Homology modeling of the proposed Zn2+‐binding sites using the coordinates of the Aquifex aeolicus leucine transporter structure provided a structural basis for interpreting the results and developing conclusions.
Effect of CD34+ cell dose on hematopoietic reconstitution and outcome in 508 patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation
Authors: Klaus Jens , Herrmann Doris , Breitkreutz Iris , Hegenbart Ute , Mazitschek Uta , Egerer Gerlinde , Cremer Friedrich W. , Lowenthal Ray M. , Huesing Johannes , Fruehauf Stefan , Moehler Thomas , Ho Anthony D. , Goldschmidt Hartmut
Published: September 2006

Background: We analyzed the hematopoietic reconstitution and outcome of 508 patients with multiple myeloma (MM) with respect to the number of CD34+ cells reinfused at our center. Patients and methods: Each cohort of 390 patients (unselected CD34+ cell transplant) and 118 patients (CD34+ selected transplant) was divided into four subgroups. Among the 390 transplantations, 86 patients received a high dose (HD−) of ≥6.50 × 106 unselected CD34+ cells/kg, 116 patients a low dose (LD−) of <3.00 × 106 CD34+ cells/kg. Among the patients treated with CD34+ selected PBSC, 34 received ≥6.50 × 106 CD34+ cells/kg (HD+) and 16 <3.00 × 106 CD34+ cells/kg (LD+). Results: HD− patients experienced a reduced median time to leukocyte (13 d vs. 14 d) (P < 0.001) and platelet reconstitution >20 × 109/L (10 d vs. 12 d) (P < 0.001). Similarly, HD+ showed a reduced median time to leukocyte (12 d vs. 15 d) (P < 0.001) and platelet recovery >20 × 109/L (10 d vs. 11 d) (P = 0.058). CD34+ cell‐dose was significant for long‐term platelet recovery at day 360 (unselected transplant P = 0.015, selected transplant P = 0.023). Number of transplanted CD34+ cells had no significant impact on transplant related mortality, overall survival or CR/PR rates within 100 d. In terms of supportive care the differences of high‐/low‐dose grafts were minimal. Conclusions: These results confirm that high doses of CD34+ PBSC shorten hematopoietic reconstitution and reduce hospitalization. Nevertheless secure engraftment results from transplantation of 2.00–3.00 × 106 CD34+ cells/kg. As 60% of our pretreated patients are able to collect ≥5.00 × 106 CD34+ cells/kg within a single leukapheresis, division into two or more freezing bags allows safe tandem transplantation in the majority of MM patients.
Appraisal of current vitamin K dosing algorithms for the reversal of over‐anticoagulation with warfarin: the need for a more tailored dosing regimen
Authors: Sconce Elizabeth A. , Kamali Farhad
Published: September 2006

Abstract:  Warfarin is the most commonly prescribed oral anticoagulant in the UK for the treatment and prevention of thromboembolic disorders. Vitamin K administration is an effective way of reversing excessive anticoagulation. Over‐anticoagulated patients present with a wide range of international normalized ratio (INR) values and may respond differently to a fixed dose of vitamin K. Current dosing algorithms for vitamin K administration in the non‐urgent treatment of over‐anticoagulation do not take this variability in response into account. Consequently, over a third of over‐anticoagulated patients still remain outside their target INR 24 h after treatment. Such patients are therefore prone to either haemorrhage (if the patient is still over‐anticoagulated) or thromboembolism (if the INR reversal is over‐corrected). A number of factors such as patient age, body weight, co‐morbidity, frailty, warfarin daily dose and CYP2C9 and VKORC1 polymorphism could affect response to vitamin K and thus the rate and extent of INR reversal. There is a need for a more individualized approach to the reversal of over‐anticoagulation in asymptomatic or mildly haemorrhagic patients in order to improve the safety of warfarin therapy.
Cancer specific Mucin‐1 glycoforms are expressed on multiple myeloma
Authors: Cloosen Silvie , Gratama JanWillem , Van Leeuwen Ellen B. M. , Senden‐Gijsbers Birgit L. M. G. , Oving Ellis B. H. , Von Mensdorff‐Pouilly Silvia , Tarp Mads A. , Mandel Ulla , Clausen Henrik , Germeraad Wilfred T. V. , Bos Gerard M. J.
Published: September 2006

Present therapies cannot cure the large majority of patients with multiple myeloma (MM) and therefore new treatment strategies are imperative. This study analysed the different glycosylation profiles of Mucin‐1 (MUC1) on MM and acute myeloid leukaemia (AML) cells using a series of anti‐MUC1 antibodies. Seventy‐three per cent of the MM patients had plasma cells that expressed the fully glycosylated forms of MUC1. In contrast to controls, normal bone marrow cells and AML cells, the differentiation‐dependent and cancer‐associated glycoforms of MUC1 were present on 59% and 36% MM tumour cells respectively. This indicated that aberrantly glycosylated MUC1 is a potential immunotherapeutic target in MM patients.
Reduced myocarditis following Coxsackievirus infection in cellular FLICE inhibitory protein – long form‐transgenic mice
Authors: Huber Sally , Dohrman Austin , Sartini Danielle , Budd Ralph C.
Published: September 2006

Cellular FLICE inhibitory protein – long form (c‐FLIPL) is a caspase‐defective homologue of caspase‐8 that blocks apoptosis by death receptors. c‐FLIPL expression in T cells can also augment activation of the mitogen‐activated protein kinase, extracellular signal‐related kinase, as well as nuclear factor‐κB. This contributes to increased production of interleukin‐2 and CD25, resulting in hyperproliferation of T cells from c‐FLIPL‐transgenic mice. c‐FLIP also heterodimerizes with and activates caspase‐8, resulting in increased death of T cells and a selection of a T helper 2 cytokine profile. The effects of c‐FLIP on cytolytic function of CD8+ T cells have not been examined previously. We studied the cytolytic capacity of T cells from c‐FLIPL‐transgenic mice using an antigen‐specific system, as well as the consequences during a viral immune response to Coxsackievirus B3 (CVB3). The increased T‐cell receptor (TCR) signalling due to c‐FLIP did not alter the cytolytic machinery but did reduce cytotoxicity because of decreased surface expression of TCR and CD8. It also produced a Tc2 cytokine profile. These effects of c‐FLIP collectively served to diminish the severity of CVB3‐induced myocarditis.
Population trends of farmland birds in Sweden and England: similar trends but different patterns of agricultural intensification
Authors: WRETENBERG JOHAN , LINDSTRÖM ÅKE , SVENSSON SÖREN , THIERFELDER TOMAS , PÄRT TOMAS
Published: September 2006

Studies, mainly from the UK, show that many farmland birds have declined as a result of recent agricultural intensification. We tested this idea by analysing farmland bird population trends in Sweden, a country displaying less dramatic agricultural changes and less intensive agriculture. Specifically we investigated whether (i) farmland specialists have declined more than generalists, (ii) population declines in Sweden are less marked than in England and (iii) Swedish population trends are associated with changes in the amount of autumn‐sown crops, and inputs of pesticides and fertilizers.

Data on population trends for 21 farmland bird species collected from the Swedish Breeding Bird Survey 1976–2001 were analysed in relation to agricultural changes in Sweden.

Fifteen (71%) farmland bird species declined significantly in number (P < 0·05) over the 26 years. Farmland specialists displayed a significantly stronger average decline (55%) as a group than farmland generalists (7%). For seven species the declines were significantly steeper between 1976 and 1988 than between 1988 and 2001.

Farmland bird populations have declined at least as much in Sweden as in England. Several specialist species displayed similar temporal patterns in population change in both countries.

The area of autumn‐sown crops has remained stable in Sweden, whereas use of pesticides and fertilizers has declined. There are no clear associations between these factors and observed farmland bird population declines.

The similarities in bird population trends in Sweden and England, despite large differences in patterns of agricultural change in Sweden and England, may be explained by: (i) common wintering grounds, (ii) similar negative effects of agricultural intensification (England) and intensification/abandonment (Sweden) and (iii) a simultaneous loss of landscape heterogeneity.

Synthesis and applications. Farmland birds in Sweden have declined by at least as much as in England, despite clear differences between the two countries in the degree of agricultural intensification over the last 30 years. We suggest that the marked declines in Swedish populations are caused by (i) the dual negative effects of intensification and abandonment of farmland at breeding grounds, and (ii) Swedish populations partly sharing wintering grounds with English populations. We conclude that agri‐environmental schemes need to be flexible enough to address the negative effects both of intensification and the abandonment of farming. In addition, our results emphasize that farmland bird conservation is an issue without country borders.
Biological Flora of the British Isles: Pteridium aquilinum (L.) Kuhn
Authors: MARRS R. H. , WATT A. S.
Published: September 2006

This account reviews information on all aspects of the biology of bracken Pteridium (mainly aquilinum ssp. aquilinum) that are relevant to understanding its ecological characteristics and behaviour. The main topics are presented within the standard framework of the Biological Flora of the British Isles: distribution, habitat, communities, responses to biotic factors, responses to environment, structure and physiology, phenology, reproductive characters, herbivores and disease, history, and conservation.

Pteridium is a complex genus comprising a number of species, subspecies and varieties. The treatment here is based on a recent revision that incorporates both morphological and molecular data, and is related to its geographical distribution.

Pteridium is thought to be a woodland genus, but it can grow in the open. It is cosmopolitan and occurs on all continents except Antarctica. It responds to human disturbance and is often found in open spaces after forest clearance and cultivation. In some situations it can be a troublesome weed, causing problems for land managers. Moreover, its abundance and distribution in Britain are predicted to increase as a result of global climate change.

Pteridium aquilinum ssp. aquilinum, the most common taxon in the British Isles, occurs in many plant communities, and it is apparently limited by frost and waterlogging. Its abundance has probably increased in the relatively recent past as a result of changing land management, and this increase impinges on plant communities with a high conservation interest. The changed land management reflects changing use of agricultural land and also a reduction in the use of Pteridium as a resource. Accordingly, in many places Pteridium is viewed as a weed and management is needed to control it and restore more desirable vegetation. These management techniques are summarized.
The impact of gender on survival amongst patients with implantable cardioverter defibrillators for primary prevention against sudden cardiac death
Authors: HENYAN N. N. , WHITE C. M. , GILLESPIE E. L. , SMITH K. , COLEMAN C. I. , KLUGER J.
Published: September 2006

Background.  Implantable cardioverter defibrillators (ICDs) are a life‐saving therapy for many patients with cardiovascular disease at increased risk of fatal dysrhythmias. As men comprise the majority of the study population (67–92%) in clinical trials, the benefit to women is unknown. We performed a meta‐analysis of primary prevention trials to evaluate the impact of ICDs in men and women on death from any cause.

Methods.  Included trials met the following criteria: (i) randomized controlled trials versus standard of care, (ii) ICD used as primary prevention in a well‐described protocol and (iii) data provided on risk of death from any cause for both male and female patients.

Results.  Five clinical trials were included in this meta‐analysis. The risk of death from any cause was significantly reduced by 26% in male patients who received ICD therapy compared to control, hazard ratio (HR) 0.74 (95% CI 0.60–0.91) but not amongst female patients, HR 0.81 (95% CI 0.60–1.09). As the COMPANION trial evaluated the combination of biventricular pacemaker with ICD therapy we conducted a separate analysis without the inclusion of this study. Male patients receiving ICD therapy demonstrated a similar 24% reduction in risk of death from any cause, HR 0.76 (95% CI 0.58–0.99) whilst female patients demonstrated a reduction of only 12%, HR 0.88 (95% CI 0.63–1.22).

Conclusions.  Unlike their male counterparts, females did not significantly benefit from ICD therapy and without concurrent biventricular pacing, appear only to achieve a nonsignificant 12% reduction in risk of death.
Antigen mimicry, epitope spreading and the pathogenesis of pemphigus
Authors: Tchernev G. , Orfanos C. E.
Published: September 2006

The molecular and cellular pathogenesis of pemphigus remains unclear. However, the integrity of intraepidermal and dermoepidermal adhesion appears to be of special importance, and the presence of antibodies directed against desmosomal plaque proteins can provoke pemphigus‐like pathologies. Antibodies reactive with various tissue antigens have been detected in pemphigus‐like skin conditions. Two major factors determining the occurrence of different pemphigus subforms are antigen mimicry and epitope spreading, as these two phenomena underpin antibody generation in response to different antigens. This multiplicity of target antigens and antibody responses may lead to diagnostic problems early in the disease and may also explain the apparent transformation of one disease subform into another as time progresses.
Stress Response of Campylobacter spp. and its Role in Food Processing
Authors: Alter T. , Scherer K.
Published: September 2006

In many temperate countries Campylobacter spp. are the most common bacterial causes of human infectious intestinal disease. Yet the aetiology of this infection has only partly been described. A majority of human campylobacteriosis cases are associated with food of animal origin. Despite being very sensitive to environmental stressors Campylobacter spp. are able to persist in the food chain and can pose a threat to the consumer. In this review, the survival potential and stress response of Campylobacter spp. in food will be summarized and the importance of food preservation technologies will be discussed.
Outbreak of Tuberculosis Caused by Mycobacterium caprae in a Zoological Garden
Authors: Pate M. , ŠVara T. , Gombač M. , Paller T. , ŽOlnir‐Dovč M. , Emeršič I. , Prodinger W. M. , Bartoš M. , Zdovc I. , Krt B. , Pavlik I. , Cvetnić Ž. , Pogačnik M. , Ocepek M.
Published: September 2006

In the autumn of 2004, tuberculosis caused by Mycobacterium caprae occurred in a zoo in Slovenia. A dromedary camel (Camelus dromedarius) was killed after a history of progressive emaciation. Necropsy findings indicated disseminated tuberculosis, which was confirmed by cultivation of M. caprae. Consequently, a tuberculin skin test was performed in all epidemiologically linked animals and another dromedary camel and six bison (Bison bison) were positive and killed. Mycobacterium caprae was isolated from two bison while M. scrofulaceum and Mycobacterium spp. were found in two other bison, respectively. The second dromedary camel was found to be negative for mycobacteria under both microscopic and culture tests. The isolates were investigated with commercial identification kits, IS6110 PCR, IS6110 restriction fragment length polymorphism analysis, spoligotyping and mycobacterial interspersed repetitive units typing. Genotyping results revealed that the dromedary camel and the two bison were infected by the same M. caprae.
Management consensus of inflammatory bowel disease for the Asia–Pacific region
Authors: Ouyang Qin , Tandon Rakesh , Goh K L , Pan Guo‐Zong , Fock K M , Fiocchi Claudio , Lam S K , Xiao Shu‐Dong
Published: September 2006

At the present there are no large‐scale epidemiologic data on inflammatory bowel disease (IBD) in the Asia–Pacific region, but several studies have shown an increased incidence and prevalence of IBD in this region. Compared to the West, there appears to exist a time lag phenomenon. With regard to the two main forms of IBD, ulcerative colitis (UC) is more prevalent than Crohn's disease (CD). In addition to geographic differences, ethnic differences have been observed in the multiracial Asian countries. Moreover, the genetic backgrounds are different in the Asian compared to Western patients. For instance, NOD2/CARD15 variants have not been found in Asian CD patients. In general, the clinical course of IBD seems to be less severe in the Asia–Pacific region than in Western countries. Diagnosis of IBD in this region poses special problems. The lack of a gold standard for the diagnosis of IBD, and the existence of a variety of infectious enterocolitis with similar manifestations to those of IBD make the differential diagnosis particularly difficult. So far, Western diagnostic criteria have been introduced for the diagnosis of IBD. A stepwise approach to exclude non‐IBD enterocolitis also must be introduced, and a definite diagnosis must include typical histological features. In some patients, follow up and therapeutic trials might be necessary to obtain a definitive diagnosis. A better understanding of the pathogenesis of IBD will allow the development of better diagnostic markers. The management of IBD also poses some special problems in the Asia–Pacific Region. There is often a delay in using proper medications for IBD, and alternative local remedies are still widely used. With a combination of Western guidelines and regional experiences, similar principles can be used for induction and maintenance of remission. A stepwise selection of medications is advocated depending on the extent, activity and severity of the disease. Comprehensive and individualized approaches are suggested for different IBD patients. Deeper understanding of disease pathogenesis and the unique characteristics of IBD in the Asia–Pacific region, combined with reasonable and practical guidelines for drug management and the future use of biological agents would improve the therapeutic outlook of IBD in this region.
Methylation of Ras association domain family protein 1, isoform A correlated with proliferation and drug resistance in hepatocellular carcinoma cell line SMMC‐7721
Authors: Zhao Qiang‐Zi , Dou Ke‐Feng
Published: September 2006

Background:  It has been proposed that aberrant DNA methylation can alter cancer's response to therapeutic agents. The purpose of the present study was to investigate the relationship between Ras association domain family protein 1, isoform A (RASSF1A) and drug resistance or growth of hepatocellular carcinoma cell line SMMC‐7721.

Methods:  Methylation status of RASSF1A from genomic gene of SMMC‐7721 was determined with methylation‐specific polymerase chain reaction and was further verified by demethylation treatment with 5‐aza‐2′‐deoxycytidine. Wild‐type RASSF1A cDNA was introduced into SMMC‐7721; chemosensitivity to cisplatin, mitomycin and fluorouracil were analyzed using 3‐[4, 5‐dimethylthiazol‐2‐yl]‐2, 5‐diphenyltetrazolium bromide assay. Growth of cells was detected by colony formation assay and xenograft model.

Results:  RASSF1A was inactivated in SMMC‐7721 cell line through epigenetic hypermethylation, and reintroduction of RASSF1A was markedly able to reduce the resistance to some anticancer drugs and inhibit the growth of cancer cells either in vitro or in vivo.

Conclusion:  These results correlate methylation status of RASSF1A with biological profiles of SMMC‐7721 and thus, associate methylation with cancer therapy. RASSF1A may be useful to predict treatment response and help to develop novel treatment strategies for clinical treatment of hepatocellular carcinoma.
DURABILITY OF AUTOGENOUS VEIN AND POLYTETRAFLUOROETHYLENE BYPASS GRAFTS TO THE CAROTID ARTERIES
Authors: Huilgol Ravi L. , Young Jane , Lemech Lubomyr , Stephen Michael S. , May James , Harris John P. , White Geoffrey H.
Published: September 2006

Background:  Bypass for extra‐cranial arterial disease is infrequently carried out. We reviewed our experience to determine the outcome of carotid artery grafting using either an autogenous vein or polytetrafluoroethylene (PTFE).

Methods:  Details of patients were recorded prospectively as part of a vascular surgical registry. Patients identified from the registry as having carotid artery bypass procedures were classified according to the type of conduit used. Comparison was made between patients with autogenous vein and PTFE grafts.

Results:  Between 1978 and 2002, 24 patients (13 men and 11 women) mean age 60.0 ± 13.4 years (range, 20–81 years) underwent 28 bypass procedures (three were bilateral and one was a reoperation). Symptomatic carotid disease was the clinical indication in 20 of 28 procedures (71.4%). Pathological indications included advanced atherosclerosis of the carotid arteries (15), past radiotherapy (4), failed stenting (3), resection of carotid body tumour (2), trauma (1), reoperation on a failed graft (1), carotid aneurysm (1) and iatrogenic carotid occlusion (1). An autogenous vein was used in 16, PTFE in 11 and autogenous artery in 1 of the patients. Using the Kaplan–Meier method, the overall patient cumulative 5‐year survival was 84% and cumulative 5‐year stroke‐free survival was 93%. The combined perioperative stroke and mortality rate was 7.1%. Two patients had transient ischaemic attacks (7.1%), one had cranial nerve palsies (3.6%) and one required reoperation for bleeding (3.6%). Five‐year cumulative graft primary patency using the Kaplan–Meier method was 74% for PTFE grafts and 92% for autogenous vein grafts (P = 0.37).

Conclusion:  Carotid artery bypass is a safe and a useful treatment option for complex extra‐cranial arterial disease. Either PTFE or autogenous veins may be used as conduits.
CONCEPTS OF TRANSTIBIAL AMPUTATION: BURGESS TECHNIQUE VERSUS MODIFIED BRÜCKNER PROCEDURE
Authors: Stahel Philip F. , Oberholzer Andreas , Morgan Steven J. , Heyde Christoph E.
Published: September 2006

The technique of a long posterior myocutaneous flap described by Ernest M. Burgess in the late 1960s is one of the most frequent procedures for below‐knee amputations worldwide. To account for some potential problems associated with this procedure in patients with occlusive arterial disease, Lutz Brückner developed a modified amputation technique for transtibial amputation in the 1980s. Although this new standardized procedure has been widely used in Germany, it is not well known outside central Europe, secondary to its lack of description in English published work. In this review article, we describe a comparison of the technical aspects of the Burgess procedure with the modified Brückner technique for transtibial amputations. In addition, the charts of 69 consecutive patients with end‐stage occlusive arterial disease undergoing below‐knee amputation by either of the two standardized procedures (Burgess, n = 29; Brückner, n = 40) were reviewed. The clinical results of the two procedures are reported and compared. Review of the German published work suggests that the two techniques for transtibial amputation in patients with occlusive arterial disease appear to have similar results. This is further supported by data from our own 10‐year experience with 69 patients undergoing below‐knee amputation by either of the two standardized procedures. This suggests that the Brückner technique is at least equivalent to the Burgess procedure with regard to the clinical outcome in patients with occlusive arterial disease. The potential advantages of the standardized modified Brückner procedure compared with the ‘classical’ Burgess technique for transtibial amputation remain to be assessed in prospective multicentre trials.
LOWER EXTREMITY VENOUS CHANGES IN PNEUMOPERITONEUM DURING LAPAROSCOPIC SURGERY
Authors: Güleç Bülent , ÖNer Köksal , Yigitler Cengizhan , Kocaoğlu Murat , Aydin Yüksel , Sağlam Mutlu
Published: September 2006

Background:  The effect of pneumoperitoneum on veins of the lower limbs related to the intra‐abdominal working pressures during laparoscopic cholecystectomy has not been thoroughly investigated. We tested the hypothesis that working pressures do not affect the venous haemodynamics in the lower limbs.

Methods:  The cross‐sectional area and peak flow rates of femoral and saphenous veins in the right groin were measured in 60 patients divided into two groups according to the intra‐abdominal working pressures (11 vs 14 mmHg). All measurements were carried out preoperatively and at predetermined periods during and after laparoscopic cholecystectomy by colour Doppler ultrasonography. One‐way anova and χ2 test were used for the analysis of demographic data. For the repeated measures, anova and Student’s t‐test were used for statistical analysis. The probabilities less than 0.05 were accepted as statistically significant.

Results:  The cross‐sectional area of the veins increased, whereas the peak flow rate in veins decreased during pneumoperitoneum. Comparing the peak flow rate in the saphenous vein at the third intraoperative measurement, there is statistically significant difference between the two groups (P < 0.05).

Conclusion:  The degree of intra‐abdominal pressure affects the haemodynamics of the peripheral veins. Pneumoperitoneum during laparoscopy causes stasis in the peripheral veins. It is reasonable to use routine prophylaxis for deep vein thrombosis, in the light of these findings.
SPECIALIST SURGICAL TRAINING IN PAPUA NEW GUINEA: THE OUTCOMES AFTER 10 YEARS
Authors: Kevau Ikau , Watters David A. K.
Published: September 2006

Surgical training commenced in 1975, the year that Papua New Guinea (PNG) gained independence. The training involves a 4‐year programme leading to a Master of Medicine (MMed), awarded by the University of Papua New Guinea. In the past 30 years just over 50 general surgeons have graduated. There have also been 9 graduates in the area of ear nose and throat, 10 in ophthalmology and 2 in oral surgery. The subspecialization of general surgeons began in 1994 with four trainees, two orthopaedic, one head and neck and one urological. The model used was to develop specialist skills over 2–3 years only qualified (MMed) general surgeons so that their ability to carry out general surgical procedures and work in a remote hospital was not lost. The different specialties required different balances of in‐country and out‐of‐country training depending on the local ability to provide training in PNG. An important sponsor has been the PNG National Department of Health, which has funded the training posts by using existing general surgical positions and covering the loss of manpower while surgeons are training overseas, sometimes for up to 2 years. Medical education and tertiary health service projects, funded by Aus‐Aid, have also contributed significantly to the teaching and training. These projects have provided visiting specialists to teach and hospital attachments for national surgeons to train in Australasia. Various individual surgeons and their specialist societies in Australasia have also provided invaluable support. Three surgeons have been recipients of the Rowan Nicks scholarship. Twelve surgeons have been awarded a specialist diploma and a further five are in training. The posting of national specialist surgeons to Port Moresby has resulted in all modules of the General surgery MMed programme being taught by Papua New Guineans, which would have been hard to imagine back in 1993. The MMed is now a sustainable programme and can be provided without external support. National surgeons carry out a wide range of specialist procedures, formerly carried out only by visiting teams. They are also able to make outreach visits within PNG and specialist visits to neighbouring Pacific Island countries.
From terrestrial to aquatic habitats and back again — molecular insights into the evolution and phylogeny of Hydrophiloidea (Coleoptera) using multigene analyses
Authors: Bernhard Detlef , Schmidt Claudia , Korte Anja , Fritzsch Guido , Beutel Rolf Georg
Published: September 2006

The phylogenetic relationships within Hydrophiloidea have been a matter of controversial discussion for many years and the supposedly repeated changes between aquatic and terrestrial lifestyles are not well understood. In order to address these issues we used an extensive molecular data set comprising sequences from six nuclear and mitochondrial genes. The analyses accomplished with the entire data set resulted in largely congruent tree topologies concerning the main branches, independent from the analytical procedures. However, only Bayesian analyses yielded sufficient high posterior probabilities, whereas bootstrap support values for most nodes were generally low. Our results are only partially congruent with hypotheses based on morphological analyses. Spercheidae were placed as the sister group of the remaining hydrophiloid subgroups. Hydrophiloidea excluding Spercheidae split into two clades: the ‘helophorid lineage’ comprising the small groups Epimetopidae, Hydrochidae, Georissidae and Helophoridae, and the largest family, Hydrophilidae. Within Hydrophilidae, Hydrophilinae do not form a monophylum. The predominantly terrestrial Sphaeridiinae were placed as a subordinate clade within this subfamily. Furthermore, our data suggest a single origin of the aquatic lifestyle in Hydrophiloidea, with numerous secondary changes to terrestrial habits and tertiary changes to aquatic habitats within Sphaeridiinae.
A mitogenomic study on the phylogenetic position of snakes
Authors: Douglas Desirée A. , Janke Axel , Arnason Ulfur
Published: September 2006

Phylogenetic relationships of squamates (lizards, amphisbaenians and snakes) have received considerable attention, although no consensus has been reached concerning some basal divergences. This paper focuses on the Serpentes (snakes), whose phylogenetic position within the Squamata remains uncertain despite a number of morphological and molecular studies. Some mitogenomic studies have suggested a sister‐group relationship between snakes and varanid lizards, while other studies have identified snakes and lizards as sister groups. However, recent studies using nuclear data have presented a different scenario, with snakes being more closely related to anguimorph and iguanian lizards. In this mitogenomic study we have examined the above hypotheses with the inclusion of amphisbaenians, one gekkotan and one acrodont lizard, taxa not represented in previous mitogenomic studies. To this end we have also extended the representation of snakes by sequencing five additional snake genomes: two scolecophidians (Ramphotyphlops australisandTyphlops mirus) two henophidians (Eunectes notaeusandBoa constrictor) and one caenophidian (Elaphe guttata). The phylogenetic analysis recovered snakes and amphisbaenians as sister groups, thereby differing from previous hypotheses. In addition to a discussion on previous morphological and molecular studies in light of the results presented here, the current study also provides some details regarding features of the new snake mitochondrial genomes described.
Lévy Copulas: Dynamics and Transforms of Upsilon Type
Authors: BARNDORFF‐NIELSEN OLE E. , LINDNER ALEXANDER M.
Published: September 2006

Abstract.  Lévy processes and infinitely divisible distributions are increasingly defined in terms of their Lévy measure. In order to describe the dependence structure of a multivariate Lévy measure, Tankov (2003) introduced Lévy copulas on . (For an extension to ℝm, see Kallsen & Tankov, 2006.) Together with the marginal Lévy measures they completely describe multivariate Lévy measures on . In this article we show that any such Lévy copula defines itself a Lévy measure with one‐stable margins, in a canonical way. A limit theorem is obtained, characterizing convergence of Lévy measures with the aid of Lévy copulas. Homogeneous Lévy copulas are considered in detail. They correspond to Lévy processes which have a time‐constant Lévy copula, and a complete description of homogeneous Lévy copulas is obtained. A general scheme to construct multivariate distributions having special properties is outlined, for distributions with prescribed margins having the same properties. This makes use of Lévy copulas and of certain mappings of Upsilon type. The construction is then exemplified for distributions in the Goldie–Steutel–Bondesson class, the Thorin class and for self‐decomposable distributions.
Ancient and early modern mortality: experience and understanding1
Authors: WOODS ROBERT
Published: September 2006

This article discusses the various problems associated with the derivation of mortality measures for ancient Greece and Rome. It outlines two new sets of high mortality model life tables that describe the experiences of such populations more effectively than existing models. The issue of ‘demographic borrowing’ is also considered, particularly the use of early modern Europe and East Asia as sources for analogies, together with the ways in which the mortality component of historical demographic regimes has been represented and interpreted.
Changing wage structure and education in Vietnam, 1992–98
Authors: Liu Amy Y. C.
Published: September 2006

This paper examines the changes in relative earnings of workers with different education levels in Vietnam. Using a simple demand‐and‐supply framework developed by Katz and Murphy (1992), it was found that an increase in the relative demand for better‐educated male workers in particular appears to play an important role in explaining the earnings differentials between workers of different education groups. Education reform to better suit the needs of the post‐reform emerging market, on‐the‐job training for workers and equal access to education are some policy options that hold the key to reducing wage inequality between different education groups.