bluuebunny/crossref_metadata_2025 huggingface dataset:
Neo-epitopes are required for immunogenicity of the La/SS-B nuclear antigen in the context of late apoptotic cells
Authors: Pan Z-J , Davis K , Maier S , Bachmann M P , Kim-Howard X R , Keech C , Gordon T P , McCluskey J , Farris A D
Published: December 2005

Mechanisms responsible for the induction of anti-nuclear autoantibodies (ANA) following exposure of the immune system to an excess of apoptotic cells are incompletely understood. In this study, the immunogenicity of late apoptotic cells expressing heterologous or syngeneic forms of La/SS-B was investigated following subcutaneous administration to A/J mice, a non-autoimmune strain in which the La antigenic system is well understood. Immunization of A/J mice with late apoptotic thymocytes taken from mice transgenic (Tg) for the human La (hLa) nuclear antigen resulted in the production of IgG ANA specific for human and mouse forms of La in the absence of foreign adjuvants. Preparations of phenotypically healthy cells expressing heterologous hLa were also immunogenic. However, hLa Tg late apoptotic cells accelerated and enhanced the apparent heterologous healthy cell-induced anti-La humoral response, while non-Tg late apoptotic cells did not. Subcutaneous administration of late apoptotic cells was insufficient to break existing tolerance to the hLa antigen in hLa Tg mice or to the endogenous mouse La (mLa) antigen in A/J mice immunized with syngeneic thymocytes, indicating a requirement for the presence of heterologous epitopes for anti-La ANA production. Lymph node dendritic cells (DC) but not B cells isolated from non-Tg mice injected with hLa Tg late apoptotic cells presented immunodominant T helper cell epitopes of hLa. These studies support a model in which the generation of neo-T cell epitopes is required for loss of tolerance to nuclear proteins after exposure of the healthy immune system to an excess of cells in late stages of apoptosis.
Kinetics of preβ1 HDL and αHDL in type II diabetic patients
Authors: Chétiveaux M. , Lalanne F. , Lambert G. , Zair Y. , Ouguerram K. , Krempf M.
Published: December 2005

Background  The aim of this study was to analyze the recycling of high density lipoprotein (HDL) in six type II diabetic patients compared with six control subjects by endogenous labelling of apolipoprotein A‐I (Apo A‐I) with stable isotope Apo A.

Materials and methods  The ‐I–HDL kinetics were performed by infusion of (5·5·5‐2H3)‐leucine for 14 h. The preβ1 and αHDL were separated by gel filtration fast protein liquid chromatrography system (FPLC). Kinetics of isotopic enrichment of Apo A‐I were analyzed with a multi‐compartmental model software (SAAM II, SAAM Institute, Seattle, WA).

Results  Plasma Apo A‐I concentration was decreased in patients with type II diabetes as a result of a decrease in Apo A‐I‐αHDL (P < 0·05). Diabetic patients were also characterized by an increased relative contribution of Apo A‐I in preβ1 HDL (18·3 ± 2·8% vs 11·9 ± 3·7%, P < 0·01). The synthetic rate of preβ1 HDL was slightly increased in diabetic patients compared with control (NS) and an increase of recycling rate of α to preβ1 HDL was observed (11·67 ± 3·14 d−1 vs 7·09 ± 4·51 d−1, P < 0·05). The clearance rate of Apo A‐I was higher in diabetic patients (P < 0·05 for Apo A‐I‐preβ1 HDL and P < 0·005 for Apo A‐I‐αHDL).

Conclusion  This study suggests that the usual increase in preβ1 HDL in type II diabetic patients is mainly related to an increased conversion rate of α to preβ1 HDL.
Antisense c‐myc fragments induce normal differentiation cycles in HL‐60 cells
Authors: Chen J. P. , Chen L. , Leek J. , Lin C.
Published: December 2005

Background  We have investigated the potential for using antisense technology as a means of delivering treatment for acute myeloblastic leukaemia (FAB‐M2) by gene therapy.

Materials and methods  A test recombinant adenovirus vector was constructed containing human c‐myc antisense fragments to study the effects of altering c‐myc overexpression in the human HL‐60 cell line. Control vector contained the human LacZ gene. Transfection efficiency in HL‐60 cells was determined using control vector in the presence of protamine sulphate and multiplicity of infection of 100. Morphological and mechanistic changes were assessed using immunohistochemical analysis, flow cytometry and reverse transcription‐polymerase chain reaction.

Results  Transfection efficiency of control vector was 79·8% and morphological differences were observed after 72 h in culture. The rate of proliferation of HL‐60 cells infected with test vector was inhibited by 73% compared with control following 6 days in culture. Normal terminal differentiation leading to apoptosis was only evident in test vector infected cells. Peak apoptosis (34·7%) was detected at day 6 and cell cycle arrest at days 2, 4 and 6. Expression of c‐fos protein was significantly increased in test vector treated cells with a noticeable down‐regulation of c‐myc expression.

Conclusions  These data suggest that transfection of a human HL‐60 cell line with vector containing c‐myc antisense fragments could inhibit proliferation, but induce differentiation and apoptosis. Thus, we believe that further study of this construct is warranted as a potential gene therapy reagent for treatment of acute myeloblastic leukaemia.
Smad3‐null mice lack interstitial cells of Cajal in the colonic wall
Authors: Vetuschi A. , Sferra R. , Latella G. , D’Angelo A. , Catitti V. , Zanninelli G. , Con Tinenza M. A. , Gaudio E.
Published: December 2005

Background  Transforming growth factor‐β (TGF‐β)/Smad's signalling pathway plays a pivotal role in organogenesis, oncogenesis, inflammation, repair and fibrosis. The aim of this study was to evaluate the morphology of muscle layers and the density and distribution of interstitial cells of Cajal (ICC) in the colon of Smad3 knockout mice.

Materials and methods  Eighteen Smad3 wild‐type mice and 12 null mice were sacrificed at age 4 months and the colons were collected for histology (Haematoxilin‐Eosin, Masson thrichrome and Gomori silver staining), morphometry and immunohistochemistry (IHC) analysis. For IHC we used the c‐Kit, α‐smooth muscle actine (α‐SMA), vimentin, desmin and neuronal cocktail (S‐100, NSE, neurofilament 200) antibodies.

Results  When sacrificed, 40% of the null mice showed different degrees of colon dilatation when compared with the wild‐type. Histological and morphometric evaluation revealed a significant reduction in muscle layer thickness of the colon in all the null mice when compared with the wild‐type. Immunohistochemistry evaluation showed a marked reduction, or even absence, of c‐Kit immunoreactivity, which identifies ICC, in the colon of all the null mice, compared with the wild‐type.

Conclusions  Smad3 null mice showed a marked reduction, or even absence, of ICC in the colon together with a concomitant reduction of intestinal smooth muscle layer thickness. This data could account for the colonic dilation observed in approximately 40% of the Smad3 null mice. Alteration of intestinal smooth muscle layers and ICC could also be involved in the resistance of the Smad3 null mice to develop colonic fibrosis.
Dealing with the family: CD147 interactions with cyclophilins
Authors: Yurchenko Vyacheslav , Constant Stephanie , Bukrinsky Michael
Published: December 2005

CD147 is a widely expressed plasma membrane protein that has been implicated in a variety of physiological and pathological activities. It is best known for its ability to function as extracellular matrix metalloproteinase inducer (hence the other name for this protein, EMMPRIN), but has also been shown to regulate lymphocyte responsiveness, monocarboxylate transporter expression and spermatogenesis. These functions reflect multiple interacting partners of CD147. Recently, interaction of CD147 with proteins of the cyclophilin family has been demonstrated and activity of CD147 as a signalling receptor to extarcellular cyclophilins A and B has been shown. Given that extracellular cyclophilins are potent chemotactic agents for various immune cells, further studies of the role of cyclophilin–CD147 interaction in inflammation followed. They demonstrated that agents targeting CD147 or cyclophilin had a significant anti‐inflammatory effect in animal models of acute or chronic lung diseases and rheumatoid arthritis. Here, we review the current knowledge about interactions between CD147 and cyclophilins.
Development of polycystic ovary syndrome: involvement of genetic and environmental factors
Authors: FRANKS STEPHEN , MCCARTHY MARK I , HARDY KATE
Published: December 2005

We have recently proposed that polycystic ovary syndrome (PCOS) has its origin in fetal life. This hypothesis is based on data from animal models (rhesus monkey or sheep that have been exposed prenatally to high doses of androgen) and is supported by clinical studies. It is suggested that, in human females, exposure to excess androgen, at any stage from fetal development of the ovary to the onset of puberty, leads to many of the characteristic features of PCOS, including abnormalities of luteinizing hormone secretion and insulin resistance. It is likely that, in humans with PCOS, the development of the PCOS phenotype results primarily from a genetic predisposition for the fetal ovary to hypersecrete androgen. At present, it is unclear whether the maternal environment directly influences the development of PCOS in the offspring. Maternal androgen excess is unlikely to affect the fetus, because the placenta presents an effective barrier, but metabolic disturbances during pregnancy could affect development of the syndrome in the fetus. In postnatal life, the natural history of PCOS can be further modified by factors affecting insulin secretion and/or action, most importantly, nutrition. We now have evidence for a disorder of early follicular development in the polycystic ovary that is consistent with an increased population of primordial follicles in the fetal ovary. It remains to be determined whether this phenomenon is the cause or the effect of increased exposure to androgen within the ovary. PCOS is the commonest endocrine disorder in women. It is not only a very prevalent cause of anovulatory infertility, menstrual disturbances and hirsutism, but it is also a major risk factor for the development of type 2 diabetes mellitus in later life. The aetiology of the syndrome remains uncertain but there is increasing evidence for a genetic basis. PCOS very often becomes clinically manifest during adolescence with maturation of the hypothalamic‐pituitary‐ovarian axis but the genesis of the syndrome may be during very early development – perhaps even in utero. In this review, this hypothesis is explored in the light of clinical, biochemical and genetic research.
Dispersal‐related life‐history trade‐offs in a butterfly metapopulation
Authors: HANSKI ILKKA , SAASTAMOINEN MARJO , OVASKAINEN OTSO
Published: December 2005

Recent studies on butterflies have documented apparent evolutionary changes in dispersal rate in response to climate change and habitat change. These studies often assume a trade‐off between dispersal rate (or flight capacity) and reproduction, which is the rule in wing‐dimorphic species but might not occur equally in wing‐monomorphic species such as butterflies.

To investigate the relationship between dispersal rate and fecundity in the Glanville fritillary butterflyMelitaea cinxiawe recorded lifetime individual movements, matings, ovipositions, and maximal life span in a large (32 × 26 m) population cage in the field. Experimental material was obtained from 20 newly established and 20 old local populations within a large metapopulation in the Åland Islands in Finland.

Females of the Glanville fritillary from newly established populations are known to be more dispersive in the field, and in the cage they showed significantly greater mobility, mated earlier, and laid more egg clutches than females from old populations. The dispersive females from new populations exhibited no reduced lifetime fecundity in the cage, but they had a shorter maximal life span than old‐population females.

These results challenge the dispersal–fecundity trade‐off for nonmigratory butterflies but instead suggest a physiological trade‐off between high metabolic performance and reduced maximal life span. High metabolic performance may explain high rates of dispersal and oviposition in early life.

In fragmented landscapes, an ecological trade‐off exists between being more dispersive and hence spending more time in the landscape matrix vs. having more time for reproduction in the habitat. We estimate with a dispersal model parameterized for the Glanville fritillary that the lifetime egg production is 4% smaller on average in the more dispersive butterflies in a representative landscape, with much variation depending on landscape structure in the neighbourhood of the natal patch, from −26 to 45% in the landscape analysed in this paper.
Grasshopper ontogeny in relation to time constraints: adaptive divergence and stasis
Authors: BERNER DANIEL , BLANCKENHORN WOLF U.
Published: December 2005

Life history theory generally predicts a trade‐off between short juvenile development and large adult size, assuming invariant growth rates within species. This pivotal assumption has been explicitly tested in few organisms.

We studied ontogeny in 13 populations of Omocestus viridulus grasshoppers under common garden conditions. High‐altitude populations, facing short growing seasons and thus seasonal time constraints, were found to grow at a similar rate to low altitude conspecifics.

Instead, high‐altitude grasshoppers evolved faster development, and the correlated change in body size led to an altitudinal size cline mediating a trade‐off with female fecundity.

An additional juvenile stage occurred in low‐ but not high‐altitude females. This difference is probably due to the evolution of lowered critical size thresholds in high‐altitude grasshoppers to accelerate development.

We found a strikingly lower growth rate in males than females that we interpret as the outcome of concurrent selection for protandry and small male size.

Within populations, large individuals developed faster than small individuals, suggesting within‐population genetic variation in growth rates.

We provide evidence that different time constraints (seasonal, protandry selection) can lead to different evolutionary responses in intrinsic growth, and that correlations among ontogenetic traits within populations cannot generally be used to predict life history adaptation among populations. Moreover, our study illustrates that comparisons of ontogenetic patterns can shed light on the developmental basis underlying phenotypic evolution.
Isolation by distance and gene flow in the Eurasian badger (Meles meles) at both a local and broad scale
Authors: POPE L. C. , DOMINGO‐ROURA X. , ERVEN K. , BURKE T.
Published: December 2005

Eurasian badgers,Meles meles, have been shown to possess limited genetic population structure within Europe; however, field studies have detected high levels of philopatry, which are expected to increase population structure. Population structure will be a consequence of both contemporary dispersal and historical processes, each of which is expected to be evident at a different scale. Therefore, to gain a greater understanding of gene flow in the badger, we examined microsatellite diversity both among and within badger populations, focusing on populations from the British Isles and western Europe. We found that while populations differed in their allelic diversity, the British Isles displayed a similar degree of diversity to the rest of western Europe. The lower genetic diversity occurring in Ireland, Norway and Scotland was more likely to have resulted from founder effects rather than contemporary population density. While there was significant population structure (FST = 0.19), divergence among populations was generally well explained by geographic distance (P < 0.0001) across the entire range studied of more than 3000 km. Transient effects from the Pleistocene appear to have been replaced by a strong pattern of genetic isolation by distance across western Europe, suggestive of colonization from a single refugium. Analysis of individuals within British populations through Mantel tests and spatial autocorrelation demonstrated that there was significant local population structure across 3–30 km, confirming that dispersal is indeed restricted. The isolation by distance observed among badger populations across western Europe is likely to be a consequence of this restricted local dispersal.
Geographic patterns of microsatellite variation inBoechera stricta, a close relative ofArabidopsis
Authors: SONG BAO‐HUA , CLAUSS MARIA J. , PEPPER ALAN , MITCHELL‐OLDS THOMAS
Published: December 2005

The genusBoecherais a widespread North American group with great potential for studies of ecology and evolution:Boecherais closely related toArabidopsisand exhibits different ecological and reproductive strategies.Boechera stricta(previouslyArabis drummondii) is a morphologically and genetically well‐defined, perennial crucifer species. Fifteen natural populations of diploid individuals from the Rocky Mountains were analysed using 21 microsatellite loci. In accordance with our expectation for this predominately inbreeding species, a highFISvalue (0.89) was observed. Furthermore, populations ofB. strictawere highly differentiated, as indicated byFST = 0.56. Three clusters were identified usingstructure— the majority of populations belonged to either the Northern or Southern cluster. Together, the north–south partitioning and evenness of genetic variation across the two clusters suggested multiple refugia for this perennial herb in the Rocky Mountains. Pleistocene glaciation, together with the topographically and climatologically heterogeneous cordillera, has profoundly influenced the genetic architecture ofB. stricta. Genetic population structure was also influenced by relatively recent genome admixture at two levels: within species (involving individuals from the Northern and Southern clusters) and between species (with the hybridization ofB. strictaandBoechera holboellii). This complexity of population structure at presumably neutral microsatellite loci located throughout the genome inB. strictaprovides a baseline against which to test whether functional genetic variation is undergoing local adaptive evolution throughout the natural species range.
Polymorphism of visual pigment genes in the muriqui (Primates, Atelidae)
Authors: TALEBI M. G. , POPE T. R. , VOGEL E. R. , NEITZ M. , DOMINY N. J.
Published: December 2005

Colour vision varies within the family Atelidae (Primates, Platyrrhini), which consists of four genera with the following cladistic relationship: {Alouatta[Ateles(LagothrixandBrachyteles)]}. Spider monkeys (Ateles) and woolly monkeys (Lagothrix) are characteristic of platyrrhine monkeys in possessing a colour vision polymorphism. The polymorphism results from allelic variation of the single‐locus middle‐to‐long wavelength (M/L) cone opsin gene on the X‐chromosome. The presence in the population of alleles coding for different M/L photopigments results in a variety of colour vision phenotypes. Such a polymorphism is absent in howling monkeys (Alouatta), which, alone among platyrrhines, acquired uniform trichromatic vision similar to that of Old World monkeys, apes, and humans through opsin gene duplication. Dietary and morphological similarities between howling monkeys and muriquis (Brachyteles) raise the possibility that the two genera share a similar form of colour vision, uniform trichromacy. Yet parsimony predicts that the colour vision ofBrachyteleswill resemble the polymorphism present inLagothrixandAteles. Here we test this assumption. We obtained DNA from the blood or faeces of 18 muriquis and sequenced exons 3 and 5 of the M/L opsin gene. Our results affirm the existence of a single M/L cone opsin gene in the genusBrachyteles. We detected three alleles with predicted λmaxvalues of 530, 550, and 562 nm. Two females were heterozygous and are thus predicted to have different types of M/L cone pigment. We discuss the implication of this result towards understanding the evolutionary ecology of trichromatic vision.
Possible role of nitric oxide in visceral hypersensitivity in patients with irritable bowel syndrome
Authors: Kuiken S. D. , Klooker T. K. , Tytgat G. N. , Lei A. , Boeckxstaens G. E.
Published: December 2005

Abstract  Background:  Visceral hypersensitivity is a consistent finding in a considerable proportion of patients with irritable bowel syndrome (IBS), and may provide a physiological basis for the development of IBS symptoms. In this study, we aimed to confirm the hypothesis that nitric oxide (NO) is involved in maintaining visceral hypersensitivity in IBS. Ten healthy volunteers (HV) and 12 IBS patients with documented hypersensitivity to rectal distension underwent a rectal barostat study. The effect of placebo and the specific NO synthase inhibitor NG‐monomethyl‐l‐arginine (l‐NMMA) on resting volume, rectal sensitivity to distension and rectal compliance was evaluated in a double‐blind, randomized, cross‐over fashion. NG‐monomethyl‐l‐arginine did not alter resting volumes in HV or IBS patients. In HV, l‐NMMA did not alter rectal sensory thresholds compared to placebo (45 ± 3 and 46 ± 3 mmHg, respectively). In contrast, l‐NMMA significantly increased the threshold for discomfort/pain in IBS patients (placebo: 18 ± 2, l‐NMMA: 21 ± 3 mmHg, P < 0.05). Rectal compliance was not affected by l‐NMMA. Although NO does not seem to play a major role in normal rectal sensation or tone, we provide evidence that NO may be involved in the pathophysiology of visceral hypersensitivity in IBS.
A multimodal laser Doppler and endosonographic distension device for studying mechanosensation and mucosal blood flow in the oesophagus
Authors: Hoff D. A. L. , Gregersen H. , Odegaard S. , Nesje L. B. , Oevreboe K. , Hausken T. , Gilja O. H. , Matre K. , Hatlebakk J. G.
Published: December 2005

Abstract  We describe the development of a multimodal device combining bag distension, manometry, high frequency intraluminal ultrasound, laser Doppler flowmetry and symptom registration. Bench tests showed that the different modalities did not influence each other. During bag distension we obtained high quality images of the oesophageal wall for computing biomechanical parameters, and laser Doppler signals showing variation in mucosal perfusion. We conclude that the principle of measurement is sound and that the device can provide a basis for further studies.
Is there a role of food allergy in irritable bowel syndrome and functional dyspepsia? A systematic review
Authors: Park M‐i. , Camilleri M.
Published: December 2005

Abstract  A significant proportion of adults believe they suffer from food allergy, and 20–65% of patients with irritable bowel syndrome (IBS) attribute their symptoms to something in food that activates an abnormal response. This systematic review evaluates the role of food allergy in aetiology and management of these disorders. Activation of gastrointestinal mucosal immune system may be one of the causative factors in the pathogenesis of functional dyspepsia and IBS. This activation may result from effects of bacterial infection or other luminal factors including commensal microbial flora and food antigens. Some studies have reported on the role of food allergy in IBS; only one epidemiological study on functional dyspepsia and food allergy has been published. The mechanism by which food activates mucosal immune system is uncertain, but food specific IgE and IgG4 appeared to mediate the hypersensitivity reaction in a subgroup of IBS patients. Exclusion diets based on skin prick test, RAST for IgE or IgG4, hypoallergic diet and clinical trials with oral disodium cromoglycate have been conducted, and some success has been reported in a subset of IBS patients. Further well‐controlled studies are needed to establish whether food allergy plays a role in the pathophysiology of functional dyspepsia and IBS.
Resistance of wheat to septoria tritici blotch (Mycosphaerella graminicola) and associations with plant ideotype and the 1BL−1RS translocation
Authors: Arraiano L. S. , Brading P. A. , Dedryver F. , Brown J. K. M.
Published: December 2005

Septoria tritici blotch (STB) is a major disease of wheat, reaching epidemic proportions in many parts of the world. In several studies, taller, later‐maturing cultivars have had lower disease levels. This study was undertaken to investigate the genetic associations of natural field infection by STB with disease‐escape mechanisms related to heading date and height components, mainly leaf spacing, in a population where height and maturity are not controlled by major genes. In field trials of a single seed‐descent population of a cross between two nonsemi‐dwarf cultivars, Apollo (with strong partial resistance to STB) and Thésée (susceptible), conducted over 3 years, there was a negative correlation between STB and heading date. There was no correlation between STB and distance from stem base to leaf 2; and there was an unexpected positive correlation between STB and distance from flag leaf to leaf 2, which contradicted the so‐called ‘ladder effect’ postulated in STB epidemiology. No effect was detected of the presence of the 1BL−1RS translocation on STB levels. The largest single contributor to variation in STB levels was genetic variation between the progeny lines, and the narrow‐sense heritability was 42%. These results suggest that breeders can select for STB resistance alongside optimal stature within the range of height which is adaptive in a particular environment.
Stress and Substance P but not the Substance P‐metabolite SP5‐11 trigger murine abortion by augmenting TNF‐α levels at the feto–maternal interface
Authors: Fest S. , Zenclussen A. C. , Joachim R. , Hagen E. , Demuth H.‐U. , Hoffmann T.
Published: December 2005

In a well‐established murine abortion model, stress is thought to trigger fetal rejection by inducing a proinflammatory immune response via substance P (SP), being tumour necrosis factor (TNF)‐α‐producing CD8+ T cells involved. Interestingly, the SP metabolite SP5‐11 also binds to SP receptors and mediates SP‐like effects on immune cells at sites of inflammation. No data were available regarding the effects of SP5‐11 on pregnancy outcome in the CBA/J × DBA/2J abortion‐prone combination. We investigated the influence of SP5‐11 in contrast to stress or SP on the abortion rate and the cytokine production by lymphocytes as well as on the levels of CD8+ T cells. Stress and SP boosted the abortion rate and increased the percentage of type 1 [TNF‐α, interferon‐γ, interleukin (IL)‐12] and type 2 (IL‐4 and IL‐10) cytokine‐producing lymphocytes in blood and decidua, predominantly CD8+ T cells. Interestingly, SP5‐11 did not significantly affect the abortion rate or cytokine production in the decidua, while increasing the Th1 and Th2 cytokine production systemically. Our data suggest that stress and SP induce abortion by augmenting the local levels of TNF‐α, which seems therefore to be a potent trigger of miscarriage. On the contrary, the SP metabolite SP5‐11 only affects the systemic cytokine production without boosting the abortion rate in this experimental model.
Location of Major Histocompatibility Complex Class II Molecules in Rafts on Dendritic Cells Enhances the Efficiency of T‐Cell Activation and Proliferation
Authors: Eren E. , Yates J. , Cwynarski K. , Preston S. , Dong R. , Germain C. , Lechler R. , Huby R. , Ritter M. , Lombardi G.
Published: December 2005

The existence of major histocompatibility complex (MHC) class II molecules in lipid rafts has been described in dendritic cells (DC); however, the importance of rafts in T‐cell activation has not been clarified. In this study, the distribution of the lipid raft components (CD59 and GM1 ganglioside) in human monocyte‐derived DC was investigated. DC had an even distribution of these components at the cell surface. In addition, raft‐associated GM1 ganglioside colocalized with cross‐linked MHC class II. This implies coaggregation of raft components with these MHC molecules, which may be important in the interaction between T cells and antigen‐presenting cells. In studies carried out to investigate the effect of the DC : T‐cell interaction on raft distribution, we found a clustering of the lipid raft component CD59 on DC at the synaptic interface, with associated activation of the interacting T cell. In an antigen‐specific response between DC and CD4+ T‐cell clones, disruption of lipid rafts resulted in inhibition of both CD59 clustering and T‐cell activation. This was most pronounced when limiting amounts of cognate peptide were used. Together, these data demonstrate the association of MHC class II with lipid rafts during DC : T‐cell interaction and suggest an important role for DC lipid rafts in T‐cell activation.
Immunosuppressive Activity of the Immunophilin‐binding Drug Sanglifehrin A in Human Whole Blood: Potent Inhibition of Interleukin‐6 Produced by Lymphocytes and Monocytes
Authors: Härtel C. , Iblher P. , Puzik A. , Wortmeier K. , Ebel B. , Schultz C. , Müller‐Steinhardt M.
Published: December 2005

The novel immunosuppressant Sanglifehrin A (SFA) is an immunophilin‐binding metabolite with a yet unidentified mechanism of action. Several reports demonstrated the effects of SFA on proliferation and cytokine production of purified T cells with in part different results. However, less is known about the impact of SFA on the regulation of innate immune responses. We used a whole blood assay to investigate the impact of SFA on monocyte responses and T‐lymphocyte activity/proliferation upon lipopolysaccharide (LPS) stimulation and anti‐CD3/anti‐CD28 costimulation, respectively. SFA was found to inhibit interleukin (IL)‐2 protein expression of T lymphocytes. Whereas IL‐2 mRNA expression was significantly reduced after 4 h of costimulation, the mRNA expression of IL‐4 and IL‐6 but not tumour necrosis factor (TNF)‐α was inhibited by SFA both after 4 and 24 h of costimulation. The production of IL‐2 and IL‐6 protein in T lymphocytes was even strongly affected by SFA than the mRNA expression of the respective cytokine. Unlike other immunophilin‐binding immunosuppressants, SFA also inhibited LPS‐induced IL‐6 and TNF‐α mRNA and protein expression. At the single cell level, SFA was demonstrated to block the intracellular production of IL‐6 in CD14+ monocytes but not the expression of other proinflammatory cytokines such as IL‐8 and TNF‐α. On the basis of these data, we propose that SFA may have a significant effect on the initiation and direction of immune responses. Considering the pleiotropic role of bioactive IL‐6 production at the interface of innate and acquired immunity in a variety of disease conditions, it was found that these novel aspects of the unique immunosuppressive action could strongly impact on future clinical application of SFA.
IgE‐receptor Activation of Mast Cells Regulates Phosphorylation and Expression of Forkhead and Bcl‐2 Family Members
Authors: Alfredsson J. , Möller C. , Nilsson G.
Published: December 2005

Activation of the high‐affinity IgE‐receptor, Fc?RI, expressed on mast cells can result in either enhanced survival or apoptosis depending on the circumstances. In this study, we have analysed signalling pathways involved in the regulation of mast cell survival and apoptosis. Fc?RI cross‐linking induces phosphorylation of Akt and its downstream target forkhead transcription factors. In addition, Bad, GSK‐3β and IκB‐α also become phosphorylated. A1, a prosurvival Bcl‐2 homologue transcriptionally controlled by NFκB transcription factors, is upregulated upon Fc?RI activation. These events have prosurvival effects on the mast cells. Moreover, Fc?RI activation upregulates the levels of the proapoptotic protein Bim and induces a rapid, but transient, phosphorylation of Bim. Thus, Fc?RI activation of mast cells leads to both prosurvival and proapoptotic signalling events where the outcome most likely depends on the balance between these signals.
CD8+ T‐Cell Tolerance can be Broken by an Adenoviral Vaccine While CD4+ T‐Cell Tolerance is Broken by Additional Co‐administration of a Toll‐Like Receptor Ligand
Authors: Salucci V. , Mennuni C. , Calvaruso F. , Cerino R. , Neuner P. , Ciliberto G. , La Monica N. , Scarselli E.
Published: December 2005

T‐cell tolerance to tumor antigens is a considerable challenge to cancer immunotherapy. The existence of a murine model transgenic for human carcinoembryonic antigen (CEA) allows CEA vaccination efficacy to be studied in a physiologically tolerant context. Immunization of CEA‐transgenic mice with an adenoviral vector coding for CEA induced a significant CD8+ T‐cell response specific to CEA but failed to induce CEA‐specific CD4+ T cells and antibodies. To overcome CD4+ T‐cell tolerance, we explored the effect of adjuvants inducing in vivo dendritic cell maturation. Two different Toll‐like receptor ligands, monophosphoryl lipid A (MPL) and CpG motif‐containing oligodeoxynucleotides (CpG‐ODN), were tested. CD4+‐mediated IFN‐γ production was induced in the CEA‐transgenic mice only when the genetic immunization was performed in the presence of these adjuvants. Moreover, CpG‐ODN had a greater effect than MPL in inducing CD4+ T‐cell response and enabling anti‐CEA antibody production.
Pleistocene speleothems of Mallorca: implications for palaeoclimate and carbonate diagenesis in mixing zones
Authors: CSOMA ANITA É. , GOLDSTEIN ROBERT H. , POMAR LUIS
Published: December 2005

The Pleistocene speleothems of Sa Bassa Blanca cave, Mallorca, are excellent indicators of palaeoclimate variations, and are samples that allow evaluation of the products and processes of mixing‐zone diagenesis in an open‐water cave system. Integrated stratigraphic, petrographic and geochemical data from a horizontal core of speleothem identified two main origins for speleothem precipitates: meteoric‐marine mixing zone and meteoric‐vadose zone. Mixing‐zone precipitates formed at and just below the water–air interface of cave pools during interglacial times, when the cave was flooded as a result of highstand sea‐level. Mixing‐zone precipitates include bladed and dendritic high‐Mg calcite, microporous‐bladed calcite with variable Mg content, and acicular aragonite; their presence suggests that calcium‐carbonate cementation is significant in the studied mixing‐zone system. Fluid inclusion salinities, δ13C and δ18O compositions of the mixing‐zone precipitates suggest that mixing ratio was not the primary control on whether precipitation or dissolution occurred, rather, the proximity to the water table and degassing of CO2 at the interface, were the major controls on precipitation. Thus, simple two‐end‐member mixing models may apply only in mixing zones well below the water table. Meteoric‐vadose speleothems include calcite and high‐Mg calcite with columnar and bladed morphologies. Vadose speleothems precipitated during glacial stages when sea level was lower than present. Progressive increase in δ13C and δ18O of the vadose speleothems resulted from cooling temperatures and more positive seawater δ18O associated with glacial buildup. Such covariation could be considered as a valid alternative to models predicting invariant δ18O and highly variable δ13C in meteoric calcite. Glacio‐eustatic oscillations of sea‐level are recorded as alternating vadose and mixing‐zone speleothems. Short‐term climatic variations are recorded as alternating aragonite and calcite speleothems precipitated in the mixing zone. Fluid‐inclusion and stable‐isotope data suggest that aragonite, as opposed to calcite, precipitated during times of reduced meteoric recharge.
Chronic alcoholism and esophageal motor activity: A 24‐h ambulatory manometry study
Authors: FERDINANDIS TG HIMANI , DISSANAYAKE ASOKA S , DE SILVA H JANAKA
Published: December 2005

Background:  Stationary esophageal manometry has shown esophageal motor abnormalities in patients with chronic alcoholism. The abnormalities identified in different studies are not consistent. Twenty‐four hour ambulatory esophageal manometry enables monitoring of esophageal motor activity under a variety of physiological conditions and gives a more complete assessment.

Method:  Twenty‐four hour ambulatory esophageal manometry and pH‐metry were performed using a combined pH and pressure catheter. Subjects with chronic alcoholism with no other illness and not in withdrawal were studied with age‐ and sex‐matched healthy controls. Autonomic nerve functions tests were performed in all subjects.

Results:  Twenty‐three chronic alcoholic subjects and 12 control subjects completed the study. The median ethanol consumption was 95 g/day (range 75 −175 g/day) for 12 years (range 5–30 years) among alcoholic subjects. Eight alcoholic subjects had heartburn and regurgitation but none had dysphagia. Ten (43%) alcoholic subjects had autonomic neuropathy and four (17%) had increased gastroesophageal acid reflux. Lower esophageal sphincter hypertension was observed in alcoholic subjects with autonomic neuropathy. Esophageal body motility parameters (i.e. frequency, duration, amplitude and percentage of peristaltic waves) were not significantly different between alcoholic subjects and controls.

Conclusions:  Results of ambulatory esophageal manometry on subjects with chronic alcoholism seem to indicate that long‐term ethanol intake has no major effects on esophageal motor activity other than lower esophageal sphincter hypertension among those with alcoholic autonomic neuropathy.
Effectiveness of chemical biliary duct embolization for chemical hepatectomy
Authors: LI FU‐YU , CHENG JING‐QIU , LI NING , HE SHENG , ZHANG MING‐MING , DONG JIA‐HONG , JIANG LI‐SHENG , CHENG NAN‐SHENG
Published: December 2005

Background and Aims:  The high recurrence of hepatolithiasis and high operative trauma of hepatectomy necessitate new therapeutic approaches. Thus, this study was designed to (i) investigate the effectiveness of chemical biliary duct embolization (CBDE) for chemical hepatectomy; and (ii) to determine the mechanism of CBDE.

Methods:  The median biliary ducts in rats were injected with phenol or absolute ethanol alone, or in conjunction with cyanoacrylate. The effectiveness of CBDE for chemical hepatectomy was assessed by investigating histology, in situ hybridization for Fas and transforming growth factor (TGF)‐β1, immunohistochemistry for α‐smooth muscle actin, and reverse transcription‐polymerase chain reaction (RT‐PCR) for procollagen I mRNA.

Results:  Histologically, phenol or absolute ethanol plus cyanoacrylate could embolize the targeted bile duct and promote hepatic fibrosis and atrophy in the embolized lobe better than using phenol or ethanol alone. In addition, CBDE accelerated hepatocellular apoptosis via up‐regulation of Fas, thereby resulting in the death of hepatocytes, which were replaced by proliferative bile ductules and collagen. Importantly, the hepatocytes disappeared completely in the periphery of the embolized lobe, thus achieving the desired effects of chemical hepatectomy. Further investigation indicated that CBDE initiated progressive fibrogenic processes of chemical hepatectomy via up‐regulation of TGF‐β1, which greatly enhanced the synthesis of collagen. Indeed, higher levels of TGF‐β1 and procollagen I mRNA were observed in the phenol embolization group than in any other group.

Conclusion:  Chemical biliary duct embolization, especially using phenol plus cyanoacrylate, might achieve the effects of chemical hepatectomy.
Non‐invasive multislice computed tomography coronary angiography for imaging coronary arteries, stents and bypass grafts
Authors: Soon K. H. , Kelly A.‐M. , Cox N. , Chaitowitz I. , Bell K. W. , Lim Y. L.
Published: December 2005

Multislice computed tomography (MSCT) is evolving rapidly and available data suggest that MSCT coronary angiography may be a reliable and accurate non‐invasive imaging modality of coronary arteries. Current generations of MSCT scanners have high sensitivity and specificity for diagnosing native coronary artery disease and coronary bypass graft occlusion. The performance of MSCT in the evaluation of stent patency is still being assessed. In comparison with conventional selective coronary angiography (SCA), MSCT is non‐invasive, cheaper and it has the advantages of imaging plaque compositions as well as assessment of luminal patency. Nevertheless, the role of MSCT in the management of coronary artery disease is yet to be fully defined.
Using a clinical pathway and education to reduce inappropriate prescribing of enoxaparin in patients with acute coronary syndromes: a controlled study
Authors: Buckmaster N. D. , Heazlewood V. , Scott I. A. , Jones M. , Haerer W. , Hillier K.
Published: December 2005

Aims: To evaluate efficacy of a pathway‐based quality improvement intervention on appropriate prescribing of the low molecular weight heparin, enoxaparin, in patients with varying risk categories of acute coronary syndrome (ACS).

Methods: Rates of enoxaparin use retrospectively evaluated before and after pathway implementation at an intervention hospital were compared to concurrent control patients at a control hospital; both were community hospitals in south‐east Queensland. The study population was a group of randomly selected patients (n = 439) admitted to study hospitals with a discharge diagnosis of chest pain, angina, or myocardial infarction, and stratified into high, intermediate, low‐risk ACS or non‐cardiac chest pain: 146 intervention patients (September–November 2003), 147 historical controls (August–December 2001) at the intervention hospital; 146 concurrent controls (September–November 2003) at the control hospital. Interventions were active implementation of a user‐modified clinical pathway coupled with an iterative education programme to medical staff versus passive distribution of a similar pathway without user modification or targeted education. Outcome measures were rates of appropriate enoxaparin use in high‐risk ACS patients and rates of inappropriate use in intermediate and low‐risk patients.

Results: Appropriate use of enoxaparin in high‐risk ACS patients was above 90% in all patient groups. Inappropriate use of enoxaparin was significantly reduced as a result of pathway use in intermediate risk (9% intervention patients vs 75% historical controls vs 45% concurrent controls) and low‐risk patients (9% vs 62% vs 41%; P < 0.001 for all comparisons). Pathway use was associated with a 3.5‐fold (95% CI: 1.3–9.1; P = 0.012) increase in appropriate use of enoxaparin across all patient groups.

Conclusion: Active implementation of an acute chest pain pathway combined with continuous education reduced inappropriate use of enoxaparin in patients presenting with intermediate or low‐risk ACS.
Health‐care problems of Turner syndrome in the adult woman: a cross sectional study of a Victorian cohort and a case for transition
Authors: Pedreira C. C. , Hameed R. , Kanumakala S. , Zacharin M.
Published: December 2005

The aim of this study was to assess current care and to survey comorbidity in a cohort of 39 adult women with Turner syndrome in Victoria. Patients with Turner syndrome (TS) drift away from medical care as they achieve adulthood, despite the need for regular surveillance and management of associated conditions, which would reduce morbidity and prevent complications. Clinical assessment was undertaken for 39 women with TS, mean age 30.1 (±11.7) years and information was gathered through personal communication regarding past growth hormone use, oestrogen treatment, hearing loss and health problems. Twenty‐four (63.2%) had regular follow‐up, but only 17 (43.6%) had adequate recommended surveillance for comorbidities. Forty‐three percent had two or more cardiovascular risk factors. Thirty‐four (87.2%) were identified with one or more associated disorders. Uterine size was of normal adult dimensions in patients who had received oestrogen before age of 15 years. Adult care for adults with TS is suboptimal and assessment of comorbidities remains sporadic. Adequate transition guidelines and patient education are needed for long‐term management of women with TS, to impact on quality of life and longevity.
Access to tumour necrosis factor inhibitors for rheumatoid arthritis treatment under the Australian Pharmaceutical Benefits Scheme: are we on target?
Authors: Lu C. Y. , Williams K. M. , Day R. O.
Published: December 2005

Background: Access to tumour necrosis factor inhibitors (TNFI) for the treatment of rheumatoid arthritis under the Australian Pharmaceutical Benefits Scheme (PBS) is governed by a set of arrangements, operational from August 2003. Patients must meet strict criteria for both starting and continuing TNFI. Examination of utilization data is important for assessing the broader implications of arrangements for access to expensive pharmaceuticals under schemes such as the PBS.

Aim: To examine the uptake of TNFI over the first year of subsidized availability of etanercept under the PBS, and to compare these data to the predicted utilization and expenditure.

Methods: Collection and analysis of prescription and expenditure data for the three listed TNFI: etanercept, infliximab and adalimumab processed under the PBS for the period August 2003 to July 2004.

Results: A total of 8053 prescriptions for TNFI was reimbursed at a total cost of $15.2m. The total PBS expenditure on etanercept was just over $14 m, 14% of the predicted annual expenditure. The relative per capita uptake of etanercept was highest in the Australian Capital Territory and lowest in the Northern Territory. More than 50% of prescriptions for etanercept were for concessional patients ($7.3m).

Conclusion: Prescription rates and expenditure on etanercept were substantially below those forecast over the first year. There are opportunities to adjust the PBS restrictions for subsidized access to TNFI to benefit more patients.
Lung transplantation for chronic obstructive pulmonary disease at St Vincent's Hospital
Authors: Güneş A. , Aboyoun C. L. , Morton J. M. , Plit M. , Malouf M. A. , Glanville A. R.
Published: December 2005

Background: Lung transplantation (LTx) offers selected patients with end‐stage chronic obstructive pulmonary disease (COPD) an improved quality of life and possibly enhanced survival.

Aim: To determine local outcomes of LTx for COPD we analysed 173 consecutive heart–LTx (n = 8), single LTx (SLTx; n = 99) and bilateral LTx (BLTx; n = 66) carried out at a single institution during 1989–2003 for smoking‐related emphysema (E) (n = 112) and emphysema related to α‐1 antitrypsin deficiency (AATD) (n = 61).

Methods: There were 98 men and 75 women with a mean age of 50 ± 6 years (standard deviation) (range 32–63 years). Median waiting time was 113 days (interquartile range (IQR) 50–230 days), and median inpatient stay was 13 days (IQR 9–21 days).

Results: Perioperative survival (30 days) was 95% with deaths from sepsis (n = 5), cerebrovascular accident (n = 3) and multiorgan failure (n = 1). Mean follow‐up period was 1693 ± 1302 days (2–4805 days). The 1‐, 5‐ and 10‐year survivals (%) were similar for patients with E and AATD (P = 0.480 log rank) at 86 ± 5, 57 ± 7 and 31 ± 11, respectively, but 1‐ and 5‐year survivals for E were higher after BLTx than after SLTx (97 ± 2 and 81 ± 8 vs 85 ± 4 and 47 ± 6) (P = 0.015). Pretransplant body mass index, forced expiratory volume in 1 second, forced vital capacity, PaCO2, PaO2, six‐minute walk distance, home oxygen use, age, sex, cytomegalovirus donor–recipient mismatch, cardiopulmonary bypass use, year of transplant and ischaemic time did not influence survival after LTx. Increasing donor age was a survival risk factor for patients with E but not for those with AATD (hazard ratio 1.043; 95%confidence interval 1.014–1.025).

Conclusion: Survival after LTx for COPD is similar to survival for other forms of solid organ transplantation, in part reflecting risk factor management.