bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of friction welding conditions on mechanical properties of A5052 aluminium alloy friction welded joint
Authors: Kimura M. , Choji M. , Kusaka M. , Seo K. , Fuji A.
Published: April 2006

The present paper describes the mechanical properties of Al–Mg aluminium alloy (A5052) friction welded joints. Two types of A5052 with different tensile properties were used, namely, H112 base metal with 188 MPa tensile strength and H34 with 259 MPa tensile strength. Similar metal specimens were joined using a continuous drive friction welding machine with an electromagnetic clutch to prevent braking deformation. That is, the joints were welded using the ‘low heat input’ friction welding method developed by the present authors, in which the heat input is lower than in the conventional method. An A5052–H112 joint produced using a friction speed of 27·5 s−1, friction pressure of 30 MPa, friction time of 2·0 s (just after the initial peak torque), and forge pressure of 60 MPa had approximately 95% joint efficiency. It fractured at the welded interface and in the A5052–H112 base metal. To improve the joint efficiency, an A5052–H112 joint was produced at a forge pressure of 75 MPa, which was the same as the yield strength of the A5052–H112 base metal. It had 100% joint efficiency and fractured in the A5052–H112 base metal. In contrast, an A5052–H34 joint was made using a friction speed of 27·5 s−1, friction pressure of 90 MPa, friction time of 0·3 s (just after the initial peak torque), and forge pressure of 180 MPa. It had approximately 93% joint efficiency and fractured in the A5052–H34 base metal. This joint also had a softened region at the welded interface and in the adjacent region. To improve the joint efficiency, an A5052–H34 joint was made at a forge pressure of 260 MPa, which was the same as the ultimate tensile strength of the A5052–H34 base metal. Although this joint had a slightly softened region at its periphery, it had approximately 93% joint efficiency. The failure of the A5052–H34 joint to achieve 100% joint efficiency is due to a slight softening at the periphery and the difference in the anisotropic properties of the A5052–H34 base metal between the longitudinal and radial directions.
Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results
Authors: Lee Margaret T. , Piomelli Sergio , Granger Suzanne , Miller Scott T. , Harkness Shannon , Brambilla Donald J. , Adams Robert J. ,   for the STOP Study Investigators
Published: April 2006

The Stroke Prevention Trial in Sickle Cell Anemia (STOP) was a randomized trial to evaluate whether chronic transfusion could prevent initial stroke in children with sickle-cell anemia at high risk as determined by transcranial Doppler (TCD). The trial demonstrated a large benefit of transfusion and was halted early. After termination of the trial, patients participated in a posttrial follow-up study. More patients in the transfusion group (70%) elected transfusion for primary stroke prevention compared with those on standard care (45%). Six patients with persistently abnormal TCD results developed stroke. A minority with initially abnormal TCD results remained stroke-free without transfusion. Except for lower baseline and follow-up TCD velocities compared with those with stroke, no predictive features of this apparent lower-risk subgroup could be determined. TCD results at last testing in 108 patients that did not have stroke were: normal (44.4%), conditional (26.9%), abnormal (22.2%), and inadequate (6.5%). Patients on transfusion were more likely to have normal TCD results. Transfusion resulted in iron overload and alloimmunization, but no infection. The study provides new information on acceptance rates and long-term effects of transfusion. Persistent TCD elevation signals ongoing stroke risk. Reduction in TCD results over time without transfusion is observed in some patients and requires further study.
Structural basis for platelet collagen responses by the immune-type receptor glycoprotein VI
Authors: Horii Katsunori , Kahn Mark L. , Herr Andrew B.
Published: April 2006

Activation of circulating platelets by exposed vessel wall collagen is a primary step in the pathogenesis of heart attack and stroke, and drugs to block platelet activation have successfully reduced cardiovascular morbidity and mortality. In humans and mice, collagen activation of platelets is mediated by glycoprotein VI (GPVI), a receptor that is homologous to immune receptors but bears little sequence similarity to known matrix protein adhesion receptors. Here we present the crystal structure of the collagen-binding domain of human GPVI and characterize its interaction with a collagen-related peptide. Like related immune receptors, GPVI contains 2 immunoglobulin-like domains arranged in a perpendicular orientation. Significantly, GPVI forms a back-to-back dimer in the crystal, an arrangement that could explain data previously obtained from cell-surface GPVI inhibition studies. Docking algorithms identify 2 parallel grooves on the GPVI dimer surface as collagen-binding sites, and the orientation and spacing of these grooves precisely match the dimensions of an intact collagen fiber. These findings provide a structural basis for the ability of an immunetype receptor to generate signaling responses to collagen and for the development of GPVI inhibitors as new therapies for human cardiovascular disease.
Intravenous administration of activated protein C in Pseudomonas-induced lung injury: impact on lung fluid balance and the inflammatory response
Authors: Robriquet Laurent , Collet François , Tournoys Antoine , Prangère Thierry , Nevière Rémi , Fourrier François , Guery Benoît P
Published: April 2006

Background

Acute lung injury (ALI) induces a coagulation/fibrinolysis imbalance and leads to fibrin deposition. The protein C pathway is an important regulator of the coagulation system and reduces the inflammatory response. The aim of the study was to examine the effects of recombinant human activated protein C (rhAPC) in the early phase of Pseudomonas aeruginosa (Pa)-induced lung injury.

Methods

The study was conducted in vivo on a rat model of Pa-induced ALI. Continuous intravenous (IV) rhAPC was administrated simultaneously with intratracheal (IT) Pa. We instilled into the airspaces a 5% bovine albumin solution with 1 μ(Ci of 125 I-albumin and injected IV 1 μ(Ci of 111In-albumin to measure lung liquid clearance (LLC) and endothelial injury. Cytokines levels (TNFα and IL-6) and thrombin-antithrombin (TAT) complexes were measured in blood and bronchoalveolar lavage fluid (BALF) at 4 hours. Four groups were compared: control (CTR), pneumonia (PNP) receiving IT Pa (0.5 ml/kg of 1 × 109 cfu), APC: IV rhAPC (300 μg/kg/h), A-PNP: IT Pa /IV rhAPC.

Results

Alveolar-capillary permeability was increased in the PNP versus the CTR group (0.28 ± 0.08 vs. 0.03 ± 0.01, p < 0.05). IV rhAPC in Pa-induced ALI led to further injury (0.47 ± 0.17 vs. 0.28 ± 0.08, p = 0.2). The LLC was significantly decreased in the A-PNP group compared to PNP group (9.1 ± (4.3% vs. 33.4 ± 2.6%, p < 0.05). The lung wet to dry weight ratio was significantly increased in the PNP group (4.62 ± 0.31) compared to the CTR group (3.87 ± 0.22, p < 0.05). IV rhAPC administration tends to increase this parameter in Pa-induced ALI (5.80 ± 0.66, p = 0.07). These findings were associated with a loss of inflammatory response compartmentalization measured by TNFα and IL-6 systemic levels. TAT complexes in BALF were increased in the A-PNP group (23.17 ± 2.89 ng/ml) compared to the CTR group (0.92 ± 0.17 ng/ml, p < 0.05) and the PNP group (11.06 ± 2.76 ng/ml, p < 0.05).

Conclusion

rhAPC reduces LLC following Pa-induced ALI and may influence pulmonary edema formation. The early massive fibrin formation is probably beneficial in ALI limiting both the extent of injury and permeability disorders.
Expression of S100A8 correlates with inflammatory lung disease in congenic mice deficient of the cystic fibrosis transmembrane conductance regulator
Authors: Tirkos Sam , Newbigging Susan , Nguyen Van , Keet Mary , Ackerley Cameron , Kent Geraldine , Rozmahel Richard F
Published: April 2006

Background

Lung disease in cystic fibrosis (CF) patients is dominated by chronic inflammation with an early and inappropriate influx of neutrophils causing airway destruction. Congenic C57BL/6 CF mice develop lung inflammatory disease similar to that of patients. In contrast, lungs of congenic BALB/c CF mice remain unaffected. The basis of the neutrophil influx to the airways of CF patients and C57BL/6 mice, and its precipitating factor(s) (spontaneous or infection induced) remains unclear.

Methods

The lungs of 20-day old congenic C57BL/6 (before any overt signs of inflammation) and BALB/c CF mouse lines maintained in sterile environments were investigated for distinctions in the neutrophil chemokines S100A8 and S100A9 by quantitative RT-PCR and RNA in situ hybridization, that were then correlated to neutrophil numbers.

Results

The lungs of C57BL/6 CF mice had spontaneous and significant elevation of both neutrophil chemokines S100A8 and S100A9 and a corresponding increase in neutrophils, in the absence of detectable pathogens. In contrast, BALB/c CF mouse lungs maintained under identical conditions, had similar elevations of S100A9 expression and resident neutrophil numbers, but diverged in having normal levels of S100A8.

Conclusion

The results indicate early and spontaneous lung inflammation in CF mice, whose progression corresponds to increased expression of both S100A8 and S100A9, but not S100A9 alone. Moreover, since both C57BL/6 and BALB/c CF lungs were maintained under identical conditions and had similar elevations in S100A9 and neutrophils, the higher S100A8 expression in the former (or suppression in latter) is a result of secondary genetic influences rather than environment or differential infection.
Empirical validation of the S-Score algorithm in the analysis of gene expression data
Authors: Kennedy Richard E , Archer Kellie J , Miles Michael F
Published: April 2006

Background

Current methods of analyzing Affymetrix GeneChip® microarray data require the estimation of probe set expression summaries, followed by application of statistical tests to determine which genes are differentially expressed. The S-Score algorithm described by Zhang and colleagues is an alternative method that allows tests of hypotheses directly from probe level data. It is based on an error model in which the detected signal is proportional to the probe pair signal for highly expressed genes, but approaches a background level (rather than 0) for genes with low levels of expression. This model is used to calculate relative change in probe pair intensities that converts probe signals into multiple measurements with equalized errors, which are summed over a probe set to form the S-Score. Assuming no expression differences between chips, the S-Score follows a standard normal distribution, allowing direct tests of hypotheses to be made. Using spike-in and dilution datasets, we validated the S-Score method against comparisons of gene expression utilizing the more recently developed methods RMA, dChip, and MAS5.

Results

The S-score showed excellent sensitivity and specificity in detecting low-level gene expression changes. Rank ordering of S-Score values more accurately reflected known fold-change values compared to other algorithms.

Conclusion

The S-score method, utilizing probe level data directly, offers significant advantages over comparisons using only probe set expression summaries.
Application of a sensitive collection heuristic for very large protein families: Evolutionary relationship between adipose triglyceride lipase (ATGL) and classic mammalian lipases
Authors: Schneider Georg , Neuberger Georg , Wildpaner Michael , Tian Sun , Berezovsky Igor , Eisenhaber Frank
Published: April 2006

Background

Manually finding subtle yet statistically significant links to distantly related homologues becomes practically impossible for very populated protein families due to the sheer number of similarity searches to be invoked and analyzed. The unclear evolutionary relationship between classical mammalian lipases and the recently discovered human adipose triglyceride lipase (ATGL; a patatin family member) is an exemplary case for such a problem.

Results

We describe an unsupervised, sensitive sequence segment collection heuristic suitable for assembling very large protein families. It is based on fan-like expanding, iterative database searches. To prevent inclusion of unrelated hits, additional criteria are introduced: minimal alignment length and overlap with starting sequence segments, finding starting sequences in reciprocal searches, automated filtering for compositional bias and repetitive patterns. This heuristic was implemented as FAMILYSEARCHER in the ANNIE sequence analysis environment and applied to search for protein links between the classical lipase family and the patatin-like group.

Conclusion

The FAMILYSEARCHER is an efficient tool for tracing distant evolutionary relationships involving large protein families. Although classical lipases and ATGL have no obvious sequence similarity and differ with regard to fold and catalytic mechanism, homology links detected with FAMILYSEARCHER show that they are evolutionarily related. The conserved sequence parts can be narrowed down to an ancestral core module consisting of three β-strands, one α-helix and a turn containing the typical nucleophilic serine. Moreover, this ancestral module also appears in numerous enzymes with various substrate specificities, but that critically rely on nucleophilic attack mechanisms.
Smad7 and protein phosphatase 1α are critical determinants in the duration of TGF-β/ALK1 signaling in endothelial cells
Authors: Valdimarsdottir Gudrun , Goumans Marie-José , Itoh Fumiko , Itoh Susumu , Heldin Carl-Henrik , Dijke Peter ten
Published: April 2006

Background

In endothelial cells (EC), transforming growth factor-β (TGF-β) can bind to and transduce signals through ALK1 and ALK5. The TGF-β/ALK5 and TGF-β/ALK1 pathways have opposite effects on EC behaviour. Besides differential receptor binding, the duration of TGF-β signaling is an important specificity determinant for signaling responses. TGF-β/ALK1-induced Smad1/5 phosphorylation in ECs occurs transiently.

Results

The temporal activation of TGF-β-induced Smad1/5 phosphorylation in ECs was found to be affected by de novo protein synthesis, and ALK1 and Smad5 expression levels determined signal strength of TGF-β/ALK1 signaling pathway. Smad7 and protein phosphatase 1α (PP1α) mRNA expression levels were found to be specifically upregulated by TGF-β/ALK1. Ectopic expression of Smad7 or PP1α potently inhibited TGF-β/ALK1-induced Smad1/5 phosphorylation in ECs. Conversely, siRNA-mediated knockdown of Smad7 or PP1α enhanced TGF-β/ALK1-induced signaling responses. PP1α interacted with ALK1 and this association was further potentiated by Smad7. Dephosphorylation of the ALK1, immunoprecipitated from cell lysates, was attenuated by a specific PP1 inhibitor.

Conclusion

Our results suggest that upon its induction by the TGF-β/ALK1 pathway, Smad7 may recruit PP1α to ALK1, and thereby control TGF-β/ALK1-induced Smad1/5 phosphorylation.
Bacterial repetitive extragenic palindromic sequences are DNA targets for Insertion Sequence elements
Authors: Tobes Raquel , Pareja Eduardo
Published: April 2006

Background

Mobile elements are involved in genomic rearrangements and virulence acquisition, and hence, are important elements in bacterial genome evolution. The insertion of some specific Insertion Sequences had been associated with repetitive extragenic palindromic (REP) elements. Considering that there are a sufficient number of available genomes with described REPs, and exploiting the advantage of the traceability of transposition events in genomes, we decided to exhaustively analyze the relationship between REP sequences and mobile elements.

Results

This global multigenome study highlights the importance of repetitive extragenic palindromic elements as target sequences for transposases. The study is based on the analysis of the DNA regions surrounding the 981 instances of Insertion Sequence elements with respect to the positioning of REP sequences in the 19 available annotated microbial genomes corresponding to species of bacteria with reported REP sequences. This analysis has allowed the detection of the specific insertion into REP sequences for ISPsy8 in Pseudomonas syringae DC3000, ISPa11 in P. aeruginosa PA01, ISPpu9 and ISPpu10 in P. putida KT2440, and ISRm22 and ISRm19 in Sinorhizobium meliloti 1021 genome. Preference for insertion in extragenic spaces with REP sequences has also been detected for ISPsy7 in P. syringae DC3000, ISRm5 in S. meliloti and ISNm1106 in Neisseria meningitidis MC58 and Z2491 genomes. Probably, the association with REP elements that we have detected analyzing genomes is only the tip of the iceberg, and this association could be even more frequent in natural isolates.

Conclusion

Our findings characterize REP elements as hot spots for transposition and reinforce the relationship between REP sequences and genomic plasticity mediated by mobile elements. In addition, this study defines a subset of REP-recognizer transposases with high target selectivity that can be useful in the development of new tools for genome manipulation.
Similarities in the immunoglobulin response and VH gene usage in rhesus monkeys and humans exposed to porcine hepatocytes
Authors: Zahorsky-Reeves Joanne L , Gregory Clare R , Cramer Donald V , Patanwala Insiyyah Y , Kyles Andrew E , Borie Dominic C , Kearns-Jonker Mary K
Published: April 2006

Background

The use of porcine cells and organs as a source of xenografts for human patients would vastly increase the donor pool; however, both humans and Old World primates vigorously reject pig tissues due to xenoantibodies that react with the polysaccharide galactose α (1,3) galactose (αGal) present on the surface of many porcine cells. We previously examined the xenoantibody response in patients exposed to porcine hepatocytes via treatment(s) with bioartficial liver devices (BALs), composed of porcine cells in a support matrix. We determined that xenoantibodies in BAL-treated patients are predominantly directed at porcine αGal carbohydrate epitopes, and are encoded by a small number of germline heavy chain variable region (VH) immunoglobulin genes. The studies described in this manuscript were designed to identify whether the xenoantibody responses and the IgVHgenes encoding antibodies to porcine hepatocytes in non-human primates used as preclinical models are similar to those in humans. Adult non-immunosuppressed rhesus monkeys (Macaca mulatta) were injected intra-portally with porcine hepatocytes or heterotopically transplanted with a porcine liver lobe. Peripheral blood leukocytes and serum were obtained prior to and at multiple time points after exposure, and the immune response was characterized, using ELISA to evaluate the levels and specificities of circulating xenoantibodies, and the production of cDNA libraries to determine the genes used by B cells to encode those antibodies.

Results

Xenoantibodies produced following exposure to isolated hepatocytes and solid organ liver grafts were predominantly encoded by genes in the VH3 family, with a minor contribution from the VH4 family. Immunoglobulin heavy-chain gene (VH) cDNA library screening and gene sequencing of IgM libraries identified the genes as most closely-related to the IGHV3-11 and IGHV4-59 germline progenitors. One of the genes most similar to IGHV3-11, VH3-11cyno, has not been previously identified, and encodes xenoantibodies at later time points post-transplant. Sequencing of IgG clones revealed increased usage of the monkey germline progenitor most similar to human IGHV3-11 and the onset of mutations.

Conclusion

The small number of IGVHgenes encoding xenoantibodies to porcine hepatocytes in non-human primates and humans is highly conserved. Rhesus monkeys are an appropriate preclinical model for testing novel reagents such as those developed using structure-based drug design to target and deplete antibodies to porcine xenografts.
Detection of human and rodent 5-HT3Breceptor subunits by anti-peptide polyclonal antibodies
Authors: Reeves David C , Lummis Sarah CR
Published: April 2006

Background

The 5-HT3 receptor is a member of a neurotransmitter-gated ion channel family which includes nicotinic acetylcholine, GABAA, and glycine receptors. While antibodies specific for the 5-HT3A receptor subunit are plentiful, and have revealed a wealth of structural and functional information, few antisera exist for the detection of 5-HT3B receptor subunits. Here we describe the generation and characterisation of a rabbit polyclonal antiserum that specifically recognises 5-HT3B receptor subunits

Results

Immunization of a rabbit with a 20-mer peptide, corresponding to the N-terminus of the human 5-HT3B receptor subunit, generated serum with polyclonal antibodies from which an IgG fraction was purified, yielding pAb77. The antibodies were shown to label 5-HT3B receptor subunits in transfected human embryonic kidney cells and rodent tissues using Western blots. Immunocytochemistry using pAb77 on these cells showed that 5-HT3B receptor subunits do not reach the plasma membrane in the absence of 5-HT3A receptor subunits. Immunohistochemical analysis of rat brain sections showed pAb77 immunoreactivity in distinct populations of cells in the hippocampus.

Conclusion

We have demonstrated that pAb77 antibodies specifically label native and recombinant 5-HT3B receptor subunits with high affinity and specificity. The antibody was shown to be useful for the determination of both receptor trafficking and also mapping 5-HT3B receptor subunit expression in the CNS.
Reproducibility of the STARD checklist: an instrument to assess the quality of reporting of diagnostic accuracy studies
Authors: Smidt Nynke , Rutjes Anne WS , van der Windt Daniëlle AWM , Ostelo Raymond WJG , Bossuyt Patrick M , Reitsma Johannes B , Bouter Lex M , de Vet Henrica CW
Published: April 2006

Background

In January 2003, STAndards for the Reporting of Diagnostic accuracy studies (STARD) were published in a number of journals, to improve the quality of reporting in diagnostic accuracy studies. We designed a study to investigate the inter-assessment reproducibility, and intra- and inter-observer reproducibility of the items in the STARD statement.

Methods

Thirty-two diagnostic accuracy studies published in 2000 in medical journals with an impact factor of at least 4 were included. Two reviewers independently evaluated the quality of reporting of these studies using the 25 items of the STARD statement. A consensus evaluation was obtained by discussing and resolving disagreements between reviewers. Almost two years later, the same studies were evaluated by the same reviewers. For each item, percentages agreement and Cohen's kappa between first and second consensus assessments (inter-assessment) were calculated. Intraclass Correlation coefficients (ICC) were calculated to evaluate its reliability.

Results

The overall inter-assessment agreement for all items of the STARD statement was 85% (Cohen's kappa 0.70) and varied from 63% to 100% for individual items. The largest differences between the two assessments were found for the reporting of the rationale of the reference standard (kappa 0.37), number of included participants that underwent tests (kappa 0.28), distribution of the severity of the disease (kappa 0.23), a cross tabulation of the results of the index test by the results of the reference standard (kappa 0.33) and how indeterminate results, missing data and outliers were handled (kappa 0.25). Within and between reviewers, also large differences were observed for these items. The inter-assessment reliability of the STARD checklist was satisfactory (ICC = 0.79 [95% CI: 0.62 to 0.89]).

Conclusion

Although the overall reproducibility of the quality of reporting on diagnostic accuracy studies using the STARD statement was found to be good, substantial disagreements were found for specific items. These disagreements were not so much caused by differences in interpretation of the items by the reviewers but rather by difficulties in assessing the reporting of these items due to lack of clarity within the articles. Including a flow diagram in all reports on diagnostic accuracy studies would be very helpful in reducing confusion between readers and among reviewers.
How good is probabilistic record linkage to reconstruct reproductive histories? Results from the Aberdeen children of the 1950s study
Authors: Nitsch Dorothea , Morton Susan , DeStavola Bianca L , Clark Heather , Leon David A
Published: April 2006

Background

Probabilistic record linkage is widely used in epidemiology, but studies of its validity are rare. Our aim was to validate its use to identify births to a cohort of women, being drawn from a large cohort of people born in Scotland in the early 1950s.

Methods

The Children of the 1950s cohort includes 5868 females born in Aberdeen 1950–56 who were in primary schools in the city in 1962. In 2001 a postal questionnaire was sent to the cohort members resident in the UK requesting information on offspring. Probabilistic record linkage (based on surname, maiden name, initials, date of birth and postcode) was used to link the females in the cohort to birth records held by the Scottish Maternity Record System (SMR 2).

Results

We attempted to mail a total of 5540 women; 3752 (68%) returned a completed questionnaire. Of these 86% reported having had at least one birth. Linkage to SMR 2 was attempted for 5634 women, one or more maternity records were found for 3743. There were 2604 women who reported at least one birth in the questionnaire and who were linked to one or more SMR 2 records. When judged against the questionnaire information, the linkage correctly identified 4930 births and missed 601 others. These mostly occurred outside of Scotland (147) or prior to full coverage by SMR 2 (454). There were 134 births incorrectly linked to SMR 2.

Conclusion

Probabilistic record linkage to routine maternity records applied to population-based cohort, using name, date of birth and place of residence, can have high specificity, and as such may be reliably used in epidemiological research.
Serious infections in children: an incidence study in family practice
Authors: Van den Bruel Ann , Bartholomeeusen Stefaan , Aertgeerts Bert , Truyers Carla , Buntinx Frank
Published: April 2006

Background

Information on the incidence of serious infections in children in general practice is scarce. However, estimates on the incidence of disease are important for several reasons, for example to assess the burden of disease or as a basis of diagnostic research. We therefore estimated the incidence of serious infections in general practice in Belgium.

Methods

Intego is a morbidity registration network, in which 51 general practitioners continuously register all diagnoses and additional data in their electronic medical records. Serious infections were defined as pneumonia, sepsis, meningitis, pyelonephritis and osteomyelitis. Incidences are calculated for the period of 1998 to 2002, per 1000 patients in the yearly contact group, which is the group of patients that consulted their GP at least once that year, and in the practice population, which is the estimated true population of that practice.

Results

The incidence of all infectious diseases peaks in children between 0 and 4 years, with 1731 infections per 1000 children per year in the yearly contact group. Incidence drops with increasing age: 972 infections per 1000 children per year in children between 5 and 9 years old, and 732 in children between 10 and 14 years old. The same decline in incidence is observed in the subgroup of serious infections: 21 infections per 1000 children per year in children between 0 and 4 years, 12 in children between 5 and 9 years and 5 in children between 10 and 14 years. The results for the estimated practice population are respectively 17, 9 and 4 serious infections per 1000 children per year.

Conclusion

In contrast to the total incidence of acute infections, serious infections are rare, around 1% per year. Children younger than 4 years old have the highest risk for serious infections, and incidences of some infections are different for boys and girls.
Contribution of main causes of death to social inequalities in mortality in the whole population of Scania, Sweden
Authors: Rosvall Maria , Chaix Basile , Lynch John , Lindström Martin , Merlo Juan
Published: April 2006

Background

To more efficiently reduce social inequalities in mortality, it is important to establish which causes of death contribute the most to socioeconomic mortality differentials. Few studies have investigated which diseases contribute to existing socioeconomic mortality differences in specific age groups and none were in samples of the whole population, where selection bias is minimized. The aim of the present study was to determine which causes of death contribute the most to social inequalities in mortality in each age group in the whole population of Scania, Sweden.

Methods

Data from LOMAS (Longitudinal Multilevel Analysis in Skåne) were used to estimate 12-year follow-up mortality rates across levels of socioeconomic position (SEP) and workforce participation in 975,938 men and women aged 0 to 80 years, during 1991–2002.

Results

The results generally showed increasing absolute mortality differences between those holding manual and non-manual occupations with increasing age, while there were inverted u-shaped associations when using relative inequality measures. Cardiovascular diseases (CVD) contributed to 52% of the male socioeconomic difference in overall mortality, cancer to 18%, external causes to 4% and psychiatric disorders to 3%. The corresponding contributions in women were 55%, 21%, 2% and 3%. Additionally, those outside the workforce (i.e., students, housewives, disability pensioners, and the unemployed) showed a strongly increased risk of future mortality in all age groups compared to those inside the workforce. Even though coronary heart disease (CHD) played a major contributing role to the mortality differences seen, stroke and other types of cardiovascular diseases also made substantial contributions. Furthermore, while the most common types of cancers made substantial contributions to the socioeconomic mortality differences, in some age groups more than half of the differences in cancer mortality could be attributed to rarer cancers.

Conclusion

CHD made a major contribution to the socioeconomic differences in overall mortality. However, there were also important contributions from diseases with less well understood mechanistic links with SEP such as stroke and less-common cancers. Thus, an increased understanding of the mechanisms connecting SEP with more rare causes of disease might be important to be able to more successfully intervene on socioeconomic differences in health.
Structural proteomics of minimal organisms: Conservation of protein fold usage and evolutionary implications
Authors: Chandonia John-Marc , Kim Sung-Hou
Published: April 2006

Background

Determining the complete repertoire of protein structures for all soluble, globular proteins in a single organism has been one of the major goals of several structural genomics projects in recent years.

Results

We report that this goal has nearly been reached for several "minimal organisms" – parasites or symbionts with reduced genomes – for which over 95% of the soluble, globular proteins may now be assigned folds, overall 3-D backbone structures. We analyze the structures of these proteins as they relate to cellular functions, and compare conservation of fold usage between functional categories. We also compare patterns in the conservation of folds among minimal organisms and those observed between minimal organisms and other bacteria.

Conclusion

We find that proteins performing essential cellular functions closely related to transcription and translation exhibit a higher degree of conservation in fold usage than proteins in other functional categories. Folds related to transcription and translation functional categories were also overrepresented in minimal organisms compared to other bacteria.
Human dignity in the Nazi era: implications for contemporary bioethics
Authors: O'Mathúna Dónal P
Published: April 2006

Background

The justification for Nazi programs involving involuntary euthanasia, forced sterilisation, eugenics and human experimentation were strongly influenced by views about human dignity. The historical development of these views should be examined today because discussions of human worth and value are integral to medical ethics and bioethics. We should learn lessons from how human dignity came to be so distorted to avoid repetition of similar distortions.

Discussion

Social Darwinism was foremost amongst the philosophies impacting views of human dignity in the decades leading up to Nazi power in Germany. Charles Darwin's evolutionary theory was quickly applied to human beings and social structure. The term 'survival of the fittest' was coined and seen to be applicable to humans.

Belief in the inherent dignity of all humans was rejected by social Darwinists. Influential authors of the day proclaimed that an individual's worth and value were to be determined functionally and materialistically. The popularity of such views ideologically prepared German doctors and nurses to accept Nazi social policies promoting survival of only the fittest humans.

A historical survey reveals five general presuppositions that strongly impacted medical ethics in the Nazi era. These same five beliefs are being promoted in different ways in contemporary bioethical discourse. Ethical controversies surrounding human embryos revolve around determinations of their moral status. Economic pressures force individuals and societies to examine whether some people's lives are no longer worth living. Human dignity is again being seen as a relative trait found in certain humans, not something inherent. These views strongly impact what is taken to be acceptable within medical ethics.

Five beliefs central to social Darwinism will be examined in light of their influence on current discussions in medical ethics and bioethics.

Acceptance of these during the Nazi era proved destructive to many humans. Their widespread acceptance today would similarly lead to much human death and suffering. A different ethic in needed which views human dignity as inherent to all human individuals.
Demand of elderly people for residential care: an exploratory study
Authors: van Bilsen PMA , Hamers JPH , Groot W , Spreeuwenberg C
Published: April 2006

Background

Because of the rapid aging population, the demand for residential care exceeds availability. This paper presents the results of a study that focuses on the demand of elderly people for residential care and determinants (elderly people's personal characteristics, needs and resources) that are associated with this demand. Furthermore, the accuracy of the waiting list as a reflection of this demand has been examined.

Methods

67 elderly people waiting for admission into a home for the elderly, are subjected to semi-structured interviews. The data are analyzed by using multivariate statistics.

Results

Elderly people who indicate that they would refuse an offer of admission into a home for the elderly feel healthier (p = 0.02), have greater self-care agency (p = 0.02) and perceive less necessity of admission (p < 0.01), compared to those who would accept such an offer. Especially the inability to manage everyday activities and the lack of a social network are highly associated with the elderly people's demand for residential care. Furthermore, it is evident that waiting lists for homes for the elderly do not accurately reflect the demand for residential care, since 35% of the elderly people on a waiting list did not actually experience an immediate demand for residential care and stated that they would not accept an offer of admission. Quite a lot of respondents just registered out of a sense of precaution; a strategic decision dictated by current shortages in care provision and a vulnerable health status.

Conclusion

The results contribute to the understanding of waiting lists and the demand for residential care. It became apparent that not everybody who asks for admission into a home for the elderly, really needed it. The importance of elderly people's resources like social networks and the ability to manage everyday activities in relation to the demand for care became clear. These findings are important because they indicate that resources also play a role in predicting elderly people's demand and as a result can guide the development and the (re)design of adequate health care services.
The chemopreventive properties of chlorogenic acid reveal a potential new role for the microsomal glucose-6-phosphate translocase in brain tumor progression
Authors: Belkaid Anissa , Currie Jean-Christophe , Desgagnés Julie , Annabi Borhane
Published: April 2006

Background

Chlorogenic acid (CHL), the most potent functional inhibitor of the microsomal glucose-6-phosphate translocase (G6PT), is thought to possess cancer chemopreventive properties. It is not known, however, whether any G6PT functions are involved in tumorigenesis. We investigated the effects of CHL and the potential role of G6PT in regulating the invasive phenotype of brain tumor-derived glioma cells.

Results

RT-PCR was used to show that, among the adult and pediatric brain tumor-derived cells tested, U-87 glioma cells expressed the highest levels of G6PT mRNA. U-87 cells lacked the microsomal catalytic subunit glucose-6-phosphatase (G6Pase)-α but expressed G6Pase-β which, when coupled to G6PT, allows G6P hydrolysis into glucose to occur in non-glyconeogenic tissues such as brain. CHL inhibited U-87 cell migration and matrix metalloproteinase (MMP)-2 secretion, two prerequisites for tumor cell invasion. Moreover, CHL also inhibited cell migration induced by sphingosine-1-phosphate (S1P), a potent mitogen for glioblastoma multiform cells, as well as the rapid, S1P-induced extracellular signal-regulated protein kinase phosphorylation potentially mediated through intracellular calcium mobilization, suggesting that G6PT may also perform crucial functions in regulating intracellular signalling. Overexpression of the recombinant G6PT protein induced U-87 glioma cell migration that was, in turn, antagonized by CHL. MMP-2 secretion was also inhibited by the adenosine triphosphate (ATP)-depleting agents 2-deoxyglucose and 5-thioglucose, a mechanism that may inhibit ATP-mediated calcium sequestration by G6PT.

Conclusion

We illustrate a new G6PT function in glioma cells that could regulate the intracellular signalling and invasive phenotype of brain tumor cells, and that can be targeted by the anticancer properties of CHL.
Induction of apoptosis with tobacco smoke and related products in A549 lung epithelial cells in vitro
Authors: Ramage Lindsay , Jones Amanda C , Whelan Clifford J
Published: April 2006

Background

This study has investigated the ability of tobacco smoke, and ingredients of tobacco smoke, to induce apoptosis in the airway epithelial cell line A549.

Method

A549 cells were treated with 80 μg/ml Tobacco smoke condensate (TSC), 10 mM Nicotine, 10 μM paraldehyde, 10 μM hydrogen peroxide, 1 μM Taxol®(Paclitaxel), 100%, 50% and 25% cigarette smoke extract (CSE). Following 4–48 h incubation apoptosis was measured morphologically following staining of cells with DAPI. TUNEL staining was also used to assess DNA damage after 24 and 48 h incubation. In addition, loss of mitochondrial cytochrome C and activation of Bax-α, early events in the apoptotic process, were measured after 4 h of incubation.

Results

Incubation of A549 cells with vehicle, Taxol, TSC, nicotine, paraldehyde, hydrogen peroxide and CSE caused a time-dependent detachment of the cells from the flask between 6 and 48 h. DAPI staining revealed that the cells remaining adhered to the flask appeared healthy whereas some of those that had detached appeared to be either apoptotic or indeterminate. Treatment with Taxol, TSC, nicotine, paraldehyde, hydrogen peroxide and CSE caused a significant increase in the number of apoptotic cells. Similarly, treatment with Taxol, TSC, nicotine, hydrogen peroxide and CSE caused a significant increase in the number of apoptotic cells among the cells that had detached from the culture plate. After 4 h of incubation, Taxol, TSC, hydrogen peroxide and CSE caused a significant reduction in mitochondrial cytochrome C and an increase in cytosolic cytochrome C. At the same time point, hydrogen peroxide and CSE significantly increased the concentration of Bax-α in the mitochondria.

Conclusion

Tobacco smoke initiates apoptosis in A549 airway epithelial cells as a result of mitochondrial damage and that this results in a cell detachment and full apoptosis. This effect appears to result from factors in tobacco smoke other than nicotine and may result from free radical activity. However, additional stable factors may also be involved since the free radical content of TSC is likely to be low.
Effects of anti-inflammatory [1, 2, 4]triazolo[4, 3-a] [1, 8]naphthyridine derivatives on human stimulated PMN and endothelial cells: an in vitro study
Authors: Dianzani Chiara , Collino Massimo , Gallicchio Margherita , Di Braccio Mario , Roma Giorgio , Fantozzi Roberto
Published: April 2006

Background

[1, 2, 4] triazolo [4, 3-a][1, 8]naphthyridine derivatives (including NF161 and NF177) were tested for anti-inflammatory, analgesic and antipyretic properties and for their effects on spontaneous locomotor activity in mice and acute gastrolesivity in rats. Both NF161 and NF177 appeared to be anti-inflammatory and analgesic agents without toxic effects or acute gastrolesivity, but NF161 showed stronger anti-inflammatory activity, whereas NF177 was more active as analgesic.

Methods

An EIA kit was used to investigate the ability of NF161 and NF177 to affect prostaglandin E2(PGE2) and prostacyclin (PGI2) production by human umbilical vascular endothelial cells (HUVEC).

The compounds' effects on the production of reactive oxygen species (ROS) by human polymorphonuclear cells (PMNs) were studied in anin vitrocell model, evaluating inhibition of superoxide anion (O2-.) production induced byN-formylmethionyl-leucyl-phenylalanine (FMLP). Their effects on PMN adhesion to HUVEC were also investigated; they were incubated with PMNs and endothelial cells (EC) and challenged by stimuli including Platelet Activating Factor (PAF), FMLP, Phorbol Myristate Acetate (PMA), Tumor Necrosis Factor-α (TNF-α) and Interleukin-1β (IL-1β). Adhesion was quantitated by computerized micro-imaging fluorescence analysis.

Results

Neither compounds modified PGE2or PGI2production induced by IL-1α.

O2-.production and myeloperoxidase release from PMNs stimulated by FMLP was inhibited in a dose- but not time-dependent manner by both [1, 8]naphthyridine derivatives, NF161 being statistically more active than NF177 (P < 0.01).

The compounds inhibited adhesion evoked by the pro-inflammatory stimuli PAF, FMLP, TNF-α and IL-1β in a concentration-dependent manner in the 10-6–10-4M range, being more active when PAF was used as stimulus and inactive when cells were challenged by PMA. Both compounds acted both on PMN and HUVEC.

Conclusion

Considering the interesting anti-inflammatory effects of these compounds inin vivomodels and the absence of acute gastrolesivity, the study improved knowledge of anti-inflammatory properties of NF161 and NF177, also demonstrating their potentialin vitro, through inhibition of O2-.production, myeloperoxidase release and PMN adhesion to HUVEC. Negative results on PG production suggest a cyclooxygenase (COX)-independent mechanism.
Role of HOXA7 to HOXA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina)
Authors: Burel Agnès , Mouchel Thomas , Odent Sylvie , Tiker Filiz , Knebelmann Bertrand , Pellerin Isabelle , Guerrier Daniel
Published: April 2006

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome refers to the congenital absence or severe hypoplasia of the female genital tract, often described as uterovaginal aplasia which is the prime feature of the syndrome. It is the second cause of primary amenorrhea after gonadal dysgenesis and occurs in ~1 in 4500 women. Aetiology of this syndrome remains poorly understood. Frequent association of other malformations with the MRKH syndrome, involving kidneys, skeleton and ears, suggests the involvement of major developmental genes such as those of the HOX family. Indeed mammalian HOX genes are well known for their crucial role during embryogenesis, particularly in axial skeleton, hindbrain and limb development. More recently, their involvement in organogenesis has been demonstrated notably during urogenital differentiation. Although null mutations of HOX genes in animal models do not lead to MRKH-like phenotypes, dominant mutations in their coding sequences or aberrant expression due to mutated regulatory regions could well account for it. Sequence analysis of coding regions of HOX candidate genes and of PBX1, a likely HOX cofactor during Müllerian duct differentiation and kidney morphogenesis, did not reveal any mutation in patients showing various forms of MRKH syndrome. This tends to show that HOX genes are not involved in MRKH syndrome. However it does not exclude that other mechanisms leading to HOX dysfunction may account for the syndrome.
Psychometric properties of two measures of psychological well-being in adult growth hormone deficiency
Authors: McMillan Carolyn V , Bradley Clare , Gibney James , Russell-Jones David L , Sönksen Peter H
Published: April 2006

Background

Psychometric properties of two measures of psychological well-being were evaluated for adults with growth hormone deficiency (GHD): the General Well-being Index, (GWBI) – British version of the Psychological General Well-being Index, and the 12-item Well-being Questionnaire (W-BQ12).

Methods

Reliability, structure and other aspects of validity were investigated in a cross-sectional study of 157 adults with treated or untreated GHD, and sensitivity to change in a randomised placebo-controlled study of three months' growth hormone (GH) withdrawal from 12 of 21 GH-treated adults.

Results

Very high completion rates were evidence that both questionnaires were acceptable to respondents. Factor analyses did not indicate the existence of useful GWBI subscales, but confirmed the validity of calculating a GWBI Total score. However, very high internal consistency reliability (Cronbach's alpha = 0.96, N = 152), probably indicated some item redundancy in the 22-item GWBI. On the other hand, factor analyses confirmed the validity of the three W-BQ12 subscales of Negative Well-being, Energy, and Positive Well-being, each having excellent internal reliability (alphas of 0.86, 0.86 and 0.88, respectively, N from 152 to 154). There was no sign of item redundancy in the highly acceptable Cronbach's alpha of 0.93 (N = 148) for the whole W-BQ12 scale. Whilst neither questionnaire found significant differences between GH-treated and non-GH-treated patients, there were correlations (for GH-treated patients) with duration of GH treatment for GWBI Total (r = -0.36, p = 0.001, N = 85), W-BQ12 Total (r = 0.35, p = 0.001, N = 88) and for all W-BQ12 subscales: thus the longer the duration of GH treatment (ranging from 0.5 to 10 years), the better the well-being. Both questionnaires found that men had significantly better overall well-being than women. The W-BQ12 was more sensitive to change than the GWBI in the GH-Withdrawal study. A significant between-group difference in change in W-BQ12 Energy scores was found [t(18) = 3.25, p = 0.004, 2-tailed]: patients withdrawn from GH had reduced energy at end-point. The GWBI found no significant change.

Conclusion

The W-BQ12 is recommended in preference to the GWBI to measure well-being in adult GHD: it is considerably shorter, has three useful subscales, and has greater sensitivity to change.