bluuebunny/crossref_metadata_2025 huggingface dataset:
Defective Clearance of Adenovirus in IRF‐1–/– Mice Associated with Defects in NK and T Cells but not Macrophages
Authors: Xu X. , Zhang H.‐G. , Liu Z.‐Y. , Wu Q. , Yang P.‐A. , Sun S.‐H. , Chen J. , Hsu H.‐C. , Mountz J. D.
Published: July 2004

A replication‐defective adenovirus‐LacZ recombinant virus (AdLacZ) was injected intravenously into IRF‐1–/– mice and wild‐type mice to characterize the contribution of IRF‐1 to the immune‐mediated clearance of Ad vector. Compared with wild‐type mice, IRF‐1–/– mice expressed higher levels of the LacZ gene product in the liver. After infusion of the AdLacZ, the expression of IRF‐1 mRNA was upregulated in the liver of wild‐type mice, but not in IRF‐1–/– mice. Both spleen and liver mononuclear cells from IRF‐1–/– mice initially exhibited a markedly lower number of NK, NK‐T and CD8 T cells. At day 7 after the administration of AdLacZ, there was a significantly increased population of NK, NK‐T and CD8 T cells in both spleen and liver, and also CD11b+ cells in liver of IRF‐1–/– mice, compared with the increased in wild‐type mice. As IRF‐1 is an important signal for production of IFN‐γ by CD8 T and NK cells as well as production of IL‐12 by CD11b+ cells, we determined whether there were lower levels of these cytokines in IRF‐1–/– mice after Ad challenge. Surprisingly, there were lower levels of IL‐12, but higher levels of IFN‐γ and IL‐18 in IRF‐1–/– compared with wild‐type mice at day 7 after administration with AdLacZ. These results indicate that delayed clearance of Ad is associated with partial correction of defects of the NK, NK‐T and CD8 T cells and increased production of IFN‐γ and IL‐18 in IRF‐1–/– mice.
Current Gene‐Mapping Strategies in Experimental Models of Multiple Sclerosis
Authors: Becanovic K. , Jagodic M. , Wallström E. , Olsson T.
Published: July 2004

Both family‐based linkage analyses and population‐based association studies have failed to identify disease‐regulatory non‐human leucocyte antigen genes of importance in multiple sclerosis (MS). Instead, investigators have employed experimental models, which offer major advantages in genetic studies. We summarize the current main methodologies used and the status of both the human and experimental approaches. Why is it important to find genes regulating MS? There is an immense number of cellular and molecular interactions defined in the immunological field and it is very difficult to unravel those that are critical to an inflammatory disease, such as MS, by classical hypothesis‐driven research. Unbiased genetics defines evolutionary conserved gene polymorphisms and pathways regulated by these genes, which are central in the pathogenesis. These, in turn, are of interest as therapeutic targets and pharmacogenetic markers.
Lupus Glomerulonephritis Revisited 2004: Autoimmunity and End‐Organ Damage
Authors: Bagavant H. , Deshmukh U. S. , Gaskin F. , Fu S. M.
Published: July 2004

Histopathology of the kidney and clinical presentation are critical factors in the diagnosis of immune‐mediated glomerulonephritis (GN). The histological manifestations of glomerular injury are shared by multiple underlying mechanisms. Work from our laboratory and from other investigators shows that antinuclear, antihistone or anti‐dsDNA antibodies are neither required nor sufficient for development of lupus GN. In addition, antibody to dsDNA can be generated by mechanisms other than loss of tolerance to chromatin. Genetic analyses demonstrate that although there is some interaction between autoantibody production and renal disease, the phenotypes are regulated by distinct genetic intervals. Furthermore, renal failure is not an essential outcome of the immune‐complex deposition and proliferative lupus GN. These data are also supported by published studies from systemic lupus erythematosus (SLE) patients. The immune regulation of lupus GN is distinct from other organ‐specific diseases and not influenced by CD25+ or NK1.1+ regulatory T cells. Thus, fatal GN may depend upon a kidney‐reactive T‐cell response that, in turn, may be regulated by gender and intrinsic end‐organ factors. The data discussed in this review call for a re‐evaluation of the current paradigms for pathogenesis of SLE. An interactive model separating autoimmunity from end‐organ susceptibility for the pathogenesis of SLE is proposed.
CD28nullCD4+ T Cells – Characterization of an Effector Memory T‐Cell Population in Patients with Rheumatoid Arthritis
Authors: Fasth A. E. R. , Cao D. , Van Vollenhoven R. , Trollmo C. , Malmström V.
Published: July 2004

CD4+ T cells lacking the costimulatory molecule CD28 have been described both in elderly individuals and in chronic inflammatory disorders, one being rheumatoid arthritis (RA). We, in this study, provide a comprehensive characterization of cell surface markers on and function of such CD28nullCD4+ T cells, as well as correlations with clinical parameters. We conclude that of all surface markers associated with these cells, only CD57 and CD11b are expressed on the majority of them. This CD28null population occurred in one‐third of patients with RA and was independent of clinical characteristics. The population was persistent and expanded in peripheral blood, but was excluded from the joint in most patients. Functionally, CD28nullCD4+ T cells were potent effector memory cells with regard to their proliferation and cytokine‐secretion profiles. This capacity correlated with a hitherto unpublished surface phenotype, the cells being uniformly CCR7– and CD43high. Moreover, a new terminally differentiated CD45RA+CCR7– population of CD4+ T cells was identified. We would like to suggest that in the unbalanced immune system of patients with autoimmune disease and chronic infection an expanded CD28nullCD4+ T‐cell population able to secrete high levels of cytokines is likely to contribute to disease manifestations.
Mannan‐Binding Lectin and RSV Lower Respiratory Tract Infection Leading to Hospitalization in Children: A Case–Control Study from Soweto, South Africa
Authors: Kristensen I. A. , Thiel S. , Steffensen R. , Madhi S. , Sorour G. , Olsen J.
Published: July 2004

Respiratory syncytial virus (RSV) is the most important microbiological cause of lower respiratory tract infection (LRTI) in infants. Mannan‐binding lectin (MBL) is believed to play a major protective role in the vulnerable period in infancy where the maternal antibodies have been catabolized, and the adaptive immune system has not yet matured. Mutations in the promoter region and in exon 1 of the gene‐encoding MBL result in low serum levels of MBL. MBL deficiency is the most common immunodeficiency on the African Continent with frequencies of the variant alleles up to 0.29. We investigated whether MBL deficiency has an impact on the hospitalization for LRTI caused by RSV in infants from Soweto, South Africa. The cases were ethnic black Africans identified through surveillance for RSV‐LRTI at Chris Hani Baragwanath Hospital, Soweto, and the controls were sampled from four immunization clinics in the area. Fifty‐five cases and 113 age‐ and sex‐matched controls were identified. Seventy‐six per cent were under 6 months of age, and 42% (n = 23) were under 3 months of age. No association was found between low levels of MBL or carriage of variant alleles and LRTI caused by RSV, odds ratio (OR) 1.00 (CI 0.99–1.03) and OR 1.24 (0.73–2.12). We did not find support for the hypothesis that MBL deficiency leads to the hospitalization for LRTI caused by RSV.
Immunoglobulin Heavy‐Chain Receptor Editing is Observed in the NOD/SCID Model of Human B‐Cell Development
Authors: Kolar G. R. , Capra J. D.
Published: July 2004

Receptor editing and receptor revision are the two mechanisms of antibody diversity that result in either complete V‐gene replacement or the formation of hybrid V genes. We do not yet understand how this process unfolds, because they are rare and difficult to study in vivo. In this study, we describe a family of VH4‐34:VH4‐61 hybrids isolated from a human B‐cell chimeric non‐obese diabetic/severe combined immunodeficient mouse. The observation of hybrid immunoglobulin sequences in human B cells that developed in this model system makes it useful for the study of this mechanism of diversification and tolerance.
Release of DNA from Dead and Dying Lymphocyte and Monocyte Cell Lines In Vitro
Authors: Choi J.‐J. , Reich C. F. , Pisetsky D. S.
Published: July 2004

DNA is a nuclear macromolecule that circulates in the blood where its levels can reflect the activity of inflammatory and malignant diseases. While dead and dying cells have usually been considered the source of blood DNA, the mechanisms for its release during apoptosis and necrosis are not well defined. To elucidate DNA release, an in vitro model system was used, assessing DNA in the media of living, apoptotic or necrotic Jurkat and U937 cells. Apoptosis was induced by etoposide, camptothecin or staurosporine, while necrosis was induced by heating at 56 °C. DNA release was measured by fluorometry with the dye PicoGreen while the extent of death was measured by fluorescence‐activated cell sorter analysis with propidium iodide and annexin. Apoptotic Jurkat cells released significantly more DNA in the media than untreated cells while necrotic cells did not show significant DNA release. U937 cells showed similar findings. Pretreatment of Jurkat cells with z‐VAD‐fmk, a caspase inhibitor, reduced both apoptosis and DNA release. By gel electrophoresis, extracellular DNA from apoptotic cells showed laddering with low molecular weight fragments. These studies suggest that extracellular release of DNA is a consequence of apoptosis and may account for some of the DNA in the blood.
Inhibition of the Proteasome Reduces Transfer‐Induced Diabetes in Nonobese Diabetic Mice
Authors: Petrovic J. , Hall H. , Mehr R. , Glas R. , Höglund P.
Published: July 2004

Inhibition of the 26S proteasome reduces the severity of several immune‐mediated diseases. Here, we report that the proteasome also regulates transfer‐induced diabetes in nonobese mice. Treatment of recipient mice with the proteasome inhibitor Nα‐benzyloxycarbonyl‐l‐leucyl‐l‐leucyl‐l‐leucinal (MG132) resulted in a 76% reduction in transfer‐induced diabetes. The closely related inhibitor carbobenzoxy‐l‐leucyl‐l‐leucinal that inhibits calpains but not the proteasome had no protective effect, suggesting that MG132 acted via inhibition of the proteasome. MG132 decreased proliferation of transferred T cells in the pancreatic lymph nodes in vivo and prevented their expansion in a dose‐dependent manner in vitro, consistent with a direct effect by MG132 on the T cells. MG132 did not prevent migration of transferred T cells into the islets but reduced the number of mice with severe infiltration. We suggest that MG132 prevents transfer‐induced diabetes by directly targeting the autoreactive T cells and lowering their diabetogenic potential.
Activation of Natural Killer Cells: Underlying Molecular Mechanisms Revealed
Authors: Backström E. , Kristensson K. , Ljunggren H.‐G.
Published: July 2004

Natural killer (NK) cells, the third major lymphocyte population, are important effector cells against certain infections and tumours. They have also been implicated as a link between innate and adaptive immune responses. In recent years, much attention has been paid to the NK cell inhibitory receptors and their interaction with major histocompatibility complex class I molecules on target cells. This review summarizes recent findings on regulation of NK cell activity with an emphasis on NK cell stimulatory receptors. A particular emphasis is devoted to the receptor NKG2D that is expressed on all NK cells.
Antinucleosome Autoantibodies Bind Directly to Cell Lines In Vitro and via the FcγRIIB Receptor to B Lymphocytes In Vivo: A Role for Immune Complexes in Interactions between Antinucleosome IgG2a and B cells of BXSB Lupus Mice
Authors: Li X. , Egorina E. , Bertelsen E. L. , Dahlen H. , Hannestad K.
Published: July 2004

The initial novel observation of this study was that most B cells of male BXSB lupus mice bear surface IgG2ab of extrinsic origin. To define the surface antigen, we here examine three (NZBxBXSB)F1‐derived IgG2ab monoclonal antibodies (mAbs) selected for binding to cell surfaces. Surprisingly, all three mAbs bound the nucleosome (nuc) particle, the fundamental unit of chromatin and an early target of autoimmunity in systemic lupus erythematosus. Their tentative dissociation constant (Kd) for soluble nuc particles was approximately 7 × 10−10 m. The mAbs bound more weakly to both H2A–H2B‐DNA and H3–H4‐DNA complexes, and in immunoblot they stained all four core histones. The mAbs detected a surface antigen on all cell lines examined, present on viable cells. When stripped of nuc , and in the presence of DNase I, their binding to cell lines improved. Heparin displaced the antigen from the cell surface. In vivo, the three mAbs stained B cells of several BALB/c mice clearly stronger than the isotype control; this differential staining was significantly reduced in FcγRIIB‐deficient mice. The results indicate that the three mAbs recognize (a) planted antigen on viable cultured cells and (b) soluble autoantigen in vivo, leading to immune complexes that bind to FcγRIIB. Further experiments demonstrated that antinuc IgG2a could be eluted from splenocytes of a male BXSB lupus mouse. Hence, at least part of the extrinsic IgG2ab found on BXSB B cells may represent FcγRIIB‐bound nuc‐IgG2ab complexes.
Avian Helios and Evolution of the Ikaros Family
Authors: Kohonen P. , Nera K.‐P. , Lassila O.
Published: July 2004

Helios (Znfn1a2) is an Ikaros‐related lymphoid regulatory protein with possible involvement in T‐cell development and function as well as in the early events of haematopoietic stem cell differentiation. To evaluate the role of Helios in avian haemato/lymphopoiesis, we have characterized the avian Helios gene. In contrast to studies in mouse and human, we have found that the highly conserved avian Helios encodes a novel exon and three isoforms. Furthermore, the avian Helios expression precedes Ikaros in the ontogeny, being present already on the first day of embryonic development. Additionally, expression in the bursa of Fabricius, germinal centres and B‐cell lines suggests a role for Helios also in the B‐cell lineage. Phylogenetic studies of the Ikaros family along with data on paralogous chromosome segments in the human genome connect the expansion of the Ikaros family and thus possibly the emergence of the adaptive immune system with the putative second round of genome duplications and indicate that the Ikaros gene family is linked with the Hox gene clusters.
Linear nevus comedonicus with epidermolytic hyperkeratosis
Authors: Schecter Amy K. , Lester Brian , Pan Teddy D. , Robinson‐Bostom Leslie
Published: July 2004

Background:  Nevus comedonicus (NC) is rarely associated with the histopathologic pattern of follicular epidermolytic hyperkeratosis (EHK). We found eight cases reported. In one case, the condition was transmitted to the offspring in the form of generalized EHK.

Methods:  We describe a case of linear NC with EHK in a 46‐year‐old woman.

Results:  Histopathologic examination revealed the typical features of NC. Additionally, the follicular epithelial walls showed EHK with characteristic perinuclear vacuolization in the stratum spinosum and stratum granulosum and large, irregular keratohyalin granules in the granular cell layer.

Conclusions:  The clinical and histopathologic features of this case are consistent with a diagnosis of linear NC with EHK. Lesions of NC suspected by clinical exam should be examined microscopically to look for features of EHK. If present, patients should be educated about the risk, albeit rare, of passing on a more severe form of the disorder to subsequent generations.
Matrilysin‐1 (MMP‐7) and MMP‐19 are expressed by Paget's cells in extramammary Paget's disease
Authors: Kuivanen Tiina , Tanskanen Maarit , Jahkola Tiina , Impola Ulla , Asko‐Seljavaara Sirpa , Saarialho‐Kere Ulpu
Published: July 2004

Background:  Extramammary Paget's disease (EMPD) is a rare malignant neoplasm of apocrine gland bearing skin characterized by intraepidermal proliferation of adenocarcinoma cells. Tumor growth depends on the ability of tumor cells to migrate by proteolysis and on angiogenesis. The matrix metalloproteinase (MMP) enzymes have been implicated in both of these processes in other types of skin cancer.

Methods:  The expression of MMP‐1, MMP‐2, MMP‐3, MMP‐7, MMP‐9, MMP‐13, and MMP‐19 was analyzed by immuno‐ histochemistry and/or in situ hybridization in 27 EMPD and five mammary PD (MMPD) specimens. The distribution of laminin‐5 (LN‐5) and tenascin‐C, two extracellular matrix proteins associated with tumor invasion, was studied by immunohistochemistry.

Results:  MMP‐7 (matrilysin‐1) and MMP‐19 were the most frequently expressed MMPs in Paget's cells. Overexpression of MMP‐2, MMP‐9, or MMP‐13, which is seen in many cancers, was not evident in EMPD. LN‐5 and tenascin‐C positivity did not correlate with the level of invasion. MMP‐7, MMP‐13, and MMP‐19 were detected abundantly in MMPD, while MMP‐9 was absent.

Conclusions:  MMP expression did not generally associate with the level of invasion of EMPD. In three samples positive for MMP‐7 and four samples positive for MMP‐19, an underlying carcinoma was detected, suggesting the importance of these two MMPs as predictors of secondary EMPD or the putative origin of Paget's cells from the dermal adenocarcinoma cells of apocrine duct origin.
Early histopathologic changes in purple glove syndrome
Authors: Bhattacharjee Pradip , Glusac Earl J.
Published: July 2004

Abstract:  An 86‐year‐old African‐American man presented with tonic‐clonic seizures. Intravenous phenytoin was urgently administered into the dorsum of the right hand. The patient developed a raised purple area of discoloration around the intravenous insertion site within 2 h and edema and vesiculobullous lesions of the distal forearm, hands, and fingers within 8 h. Microscopic sections from a biopsy at 12 h revealed epidermal necrosis, superficial ulceration, and a mild superficial and deep perivascular lymphoid infiltrate, associated with numerous thrombi of small vessels throughout the dermis. The findings were judged to be consistent with soft‐tissue injury associated with intravenous administration of phenytoin, also termed purple glove syndrome. Purple glove syndrome, named for its distinctive purple discoloration and swelling of the hands in the distribution of a glove, is an uncommon complication of intravenous phenytoin administration through small dorsal veins of the hands. It is comprised by pain, discoloration, and edema in the vicinity of intravenous infusion of phenytoin through dorsal veins of the hand. The histopathologic features of fully developed lesions have been reported; however, early‐stage findings have not been previously described, and the histogenesis of this lesion is controversial. The presence of thrombi in this early‐stage lesion suggests that thrombosis plays a role in the initial pathogenesis of this condition.
The geometric mean length, a new statistic to describe the distribution of character steps on a tree
Authors: Grandcolas Philippe , Robillard Tony , D'Haese Cyrille , Desutter‐Grandcolas Laure , Guilbert Eric , Murienne Jérôme
Published: July 2004

The geometric mean length (GML) is proposed as a new statistic aimed at describing the evenness of character changes on a tree for a given set of character optimizations. It is the geometric mean of the number of steps on each branch of the tree, varying between a maximum value when all branch lengths are equal, and a minimum value when all branches but one have only one character step. It can be scaled according to its theoretical maximum value, thus indicating a relative GML that allows a comparison of the evenness of character steps between different tree topologies.
Phylogenetic relationships of the genera of Theaceae based on morphology
Authors: Luna Isolda , Ochoterena Helga
Published: July 2004

This work represents the first phylogenetic analysis of all genera belonging to the plant family Theaceae (sensu lato). The study is based on 60 morphological characters derived from herbarium specimens and an extensive literature review of 37 genera (including the outgroup). In contrast to the results from molecular data, Theaceae is here found to consist of one clade in which the recognition of two families or subfamilies would leave Theaceae s.s. paraphyletic. Within that clade, Ternstroemiaceae is supported as monophyletic and includesAdinandra,Anneslea,Archboldiodendron,Balthasaria,Cleyera,Eurya,Euryodendron,Ficalhoa,Freziera,Symplococarpon,TernstroemiaandVisnea. The paraphyletic Theaceae s.s. includesApterosperma, Camellia, Dankia,Gordonia,Pyrenaria,Schima, andStewartia. Tetrameristaceae (PentameristaandTetramerista) are supported as a monophyletic family, with Pellicieraceae (Pelliciera) as sister group, and that clade is sister to the rest of the taxa. Bonnetiaceae (ArchytaeaandBonnetia) and Kielmeyeroideae of the Clusiaceae (Caraipa,Haploclathra,Kielmeyera,Mahurea,Marila, andNeotatea) are also supported as monophyletic. Given the differences between the results obtained from morphological and molecular data, we consider that there is still a need for further research, including combined analyses.
Phylogeny and the modalities of acoustic diversification in extant Eneopterinae (Insecta, Orthoptera, Grylloidea, Eneopteridae)
Authors: Robillard Tony , Desutter‐Grandcolas Laure
Published: July 2004

Calling with a tegminal stridulatory apparatus is widespread in crickets. However, the evolution of cricket stridulums has been poorly studied and then only on the basis of prephylogenetic models, which are unable to account for the huge diversity recently documented for acoustic features in crickets. The present paper focuses on the evolution of acoustic devices in the subfamily Eneopterinae. This is the first attempt to reconstruct the phylogeny of a large and diverse cricket clade in order to analyze the evolution of emitting structures using precise homology statements. In the first step, we reconstruct the phylogeny of this clade using a morphological data set of 193 characters and 45 taxa. The resultant phylogeny supports the monophyly of the subfamily and that of the 13 genera represented by at least two species in our taxonomic sample. Phylogenetic relationships within the subfamily also support the definition of five tribes: Eurepini, Eneopterini, Nisitrini, Xenogryllini and Lebinthini. In the second step, the evolution of acoustic devices is studied by optimization of venation characters defined on precise homology statements. As hypothesized by previous authors, losses of acoustic communication occur independently in the course of eneopterine evolution; however, they happen abruptly with no intermediate state. Our results also document for the first time the modalities of forewing evolution: the diversification of male forewing venation originates from two processes, a continuous and regular modification process, responsible for slight venation change; and an irregular, more intense punctuated process, allowing the emergence of different venations. This diversification process with sudden changes could be related to the occurrence of acoustic novelties in advertisement calls.
Risks of interleukin‐1 genetic polymorphisms and Helicobacter pylori infection in the development of gastric cancer
Authors: Chen A. , Li C.‐N. , Hsu P.‐I. , Lai K.‐H. , Tseng H.‐H. , Hsu P.‐N. , Lo G.‐H. , Lo C.‐C. , Lin C.‐K. , Hwang I.‐R. , Yamaoka Y. , Chen H.‐C.
Published: July 2004

Background : The host genetic factors that determine the clinical outcomes of Helicobacter pylori‐infected individuals remain unclear.

Aim : To elucidate the risks of host interleukin‐1 (IL‐1) genetic polymorphisms and H. pylori infection in the development of gastric cancer.

Methods : In a case–control study of 164 controls and 142 patients with gastric cancer, the IL‐1B‐511 biallelic polymorphisms and the IL‐1RN penta‐allelic variable number of tandem repeats were genotyped.

Results : The carriage of IL‐1RN*2, male gender, old age and H. pylori infection independently increased the risk of gastric cancer, with odds ratios of 3.3 [95% confidence interval (CI), 1.4–7.7], 2.1 (95% CI, 1.2–3.8), 5.3 (95% CI, 3.1–9.0) and 2.2 (95% CI, 1.3–3.8), respectively. H. pylori‐infected individuals who were carriers of IL‐1RN*2 showed increased risks of both intestinal and diffuse types of gastric cancer, with odds ratios of 11.0 and 8.7, respectively. In addition, these individuals also had a higher score of intestinal metaplasia in the corpus than did uninfected non‐carriers.

Conclusions : This study is the first to verify IL‐1RN*2 as an independent factor governing the development of gastric cancer in Asian individuals. A combination of H. pylori testing and host genotyping may target the eradication of H. pylori to high‐risk individuals.
Hepatitis C virus‐related extra‐hepatic disease — aetiopathogenesis and management
Authors: Medina J. , García‐Buey L. , Moreno‐Otero R.
Published: July 2004

Hepatitis C virus infection is often associated with extra‐hepatic manifestations, secondary to the elicitation of autoimmune reactions, generalized deposition of immune complexes and lymphoproliferative disorders. The most clearly established associations are those linking chronic hepatitis C with mixed cryoglobulinaemia (and the related glomerulonephritis and cutaneous vasculitis), as well as with the presence of autoantibodies. Less well‐documented disorders include non‐Hodgkin's lymphoma, thrombocytopenia, sialadenitis, thyroid disease, lichen planus, porphyria cutanea tarda, rheumatoid disorders and neurological disorders. Extra‐hepatic manifestations are most frequent in patients of female sex, advanced age, long‐lasting infection and cirrhosis. Optimal treatment strategies should be based on the predominant manifestation of the disease. In the case of autoimmune disorders not clearly attributable to the viral infection, corticosteroids may be the most effective option. Interferon‐α alone or in combination with ribavirin may be indicated for those disorders related to immune complex deposition, such as mixed cryoglobulinaemia, although relapses of extra‐hepatic signs often occur on discontinuation of treatment. In some cases, interferon‐α may induce or exacerbate some extra‐hepatic manifestations.
Effect of asimadoline, a κ opioid agonist, on pain induced by colonic distension in patients with irritable bowel syndrome
Authors: Delvaux M. , Beck A. , Jacob J. , Bouzamondo H. , Weber F. T. , Frexinos J.
Published: July 2004

Background : Visceral hypersensitivity plays a major role in irritable bowel syndrome pathophysiology. Opioid κ receptors on afferent nerves may modulate it and be the target for new irritable bowel syndrome treatments.

Aim : This study evaluated the effect of the κ opioid agonist asimadoline on perception of colonic distension and colonic compliance in irritable bowel syndrome patients.

Method : Twenty irritable bowel syndrome female patients (Rome II criteria; 40 ± 13 years) and hypersensitivity to colonic distension (Pain threshold ≤32 mmHg) were included in a randomized double‐blind cross‐over trial comparing the effect of a single oral dose of asimadoline 0.5 mg or placebo on sensory thresholds (defined as a constant and sustained sensation) elicited by left colon phasic distension (5 mmHg steps, 5 min) up to a sensation of abdominal pain. Colonic compliance was compared by the slope of the pressure–volume curves.

Results : On asimadoline, pain threshold (mean ± s.d.) (29.8 ± 7.2 mmHg) was higher than on placebo (26.3 ± 7.8 mmHg), difference not statistically significant (P = 0.1756, anova). Area under curve of pain intensity rated at each distension step was significantly lower on asimadoline (89.3 ± 33.9, anova) than on placebo (108.1 ± 29.7) (P = 0.0411). Thresholds of perception of nonpainful distensions were not altered on asimadoline, as compared with placebo. Colonic compliance was not different on placebo and asimadoline.

Conclusion : Asimadoline decreases overall perception of pain over a wide range of pressure distension of the colon in irritable bowel syndrome patients, without altering its compliance. These data suggest that further studies should explore the potential benefit of asimadoline in treatment of pain in irritable bowel syndrome patients.
Six‐month trial of on‐demand rabeprazole 10 mg maintains symptom relief in patients with non‐erosive reflux disease
Authors: Bytzer P. , Blum A. , De Herdt D. , Dubois D. ,   the trial investigators
Published: July 2004

Background : Compliance studies have shown that patients with reflux symptoms generally take their medication only when experiencing these symptoms.

Aim : To evaluate the efficacy of on‐demand rabeprazole maintenance therapy in patients with non‐erosive reflux disease.

Methods : This multicentre, randomized, double‐blind, placebo‐controlled, withdrawal study compared 6 months of on‐demand treatment with rabeprazole 10 mg vs. placebo. Adults with a history of reflux symptoms, a negative endoscopy, and ≥3 days of moderate to very severe heartburn in the 7 days before enrolment (N = 535) entered 4 weeks of open‐label, acute treatment with rabeprazole 10 mg once daily. Patients with complete symptom relief then entered the on‐demand phase. The primary end‐point was discontinuation due to lack of heartburn control during the on‐demand phase.

Results : Eighty‐three percent (432 of 523) of patients reported complete symptom relief at the end of the acute phase. During on‐demand treatment, rates of discontinuation because of inadequate heartburn control were 20% (28 of 139) for placebo vs. 6% (16 of 279) for rabeprazole (P < 0.00001). Antacid use was twofold higher in the placebo group vs. the rabeprazole group (P = 0.0009).

Conclusions : Rabeprazole 10 mg once daily is highly effective in acute symptom relief and as on‐demand long‐term maintenance therapy in non‐erosive reflux disease patients.
Improvement in quality of life of children with acute Crohn's disease does not parallel mucosal healing after treatment with exclusive enteral nutrition
Authors: Afzal N. A. , Van Der Zaag‐Loonen H. J. , Arnaud‐Battandier F. , Davies S. , Murch S. , Derkx B. , Heuschkel R. , Fell J. M.
Published: July 2004

Background : Crohn's disease is a chronic debilitating disorder affecting a child's physical and emotional well‐being. Recent emphasis on ‘quality of life’ (QOL) has led to re‐evaluation of available medical treatments.

Aim : To assess prospectively change in QOL, clinical disease activity and intestinal mucosal inflammation in active paediatric Crohn's disease after treatment with exclusive enteral nutrition. In addition, we evaluated whether change in QOL could predict changes in paediatric Crohn's disease activity index (PCDAI) and mucosal inflammation (endoscopic and histologic).

Methods : The IMPACT II questionnaire was used prospectively and longitudinally in 26 consecutively recruited children [16 males (67%), median 14 years, s.d. = 1.7 years] with active Crohn's disease (PCDAI > 20). They were treated with a new polymeric enteral feed (ACD004, Nestle) for a period of 8 weeks. All had PCDAI, QOL and endoscopic assessment at the time of diagnosis and after 8 weeks of treatment.

Results : Twenty‐three of 26 children achieved a clinical remission at 8 weeks, with improvement in the QOL scores (P < 0.05). The change in QOL score after treatment was predictive of achieving a clinical remission, but not of histological improvement.

Conclusions : Although children may find dietary restrictions difficult, this study confirms a clear improvement in QOL after treatment with exclusive enteral nutrition. However, improvement in QOL scores is not reflected by improvement in mucosal inflammation. Whilst improving QOL remains a core principal in patient management, the long‐term consequences of ongoing mucosal inflammation must be better understood before relying only on short‐term QOL measures to dictate treatment choices.
How effective are the usual treatments for ulcerative colitis?
Authors: Bebb J. R. , Scott B. B.
Published: July 2004

Background : Details of the efficacy of the drugs used in ulcerative colitis are not readily available.

Methods : We have reviewed all placebo‐controlled trials of the commonly used drugs for both induction and maintenance of remission to determine the efficacy and to calculate the numbers needed to treat (NNTs) to achieve a specified benefit for each drug.

Results : The drug response rates and the NNTs (with 95% CI) are tabulated for each drug.

Conclusion : Corticosteroids give a remission rate of 68% in mild or moderate disease and an NNT for remission of 2 (95% CI 1.4–5) in mild disease. Intravenous hydrocortisone gives a remission rate of 60–73%. Aminosalicylates are relatively ineffective in inducing remission with an NNT of 10 (95% CI 7–21) improving to 8 (95% CI 5–20) if the dose ≥3 g daily. They are better at maintenance (NNT = 6; 95% CI 4–8). Intravenous ciclosporin is very effective in achieving remission in severe colitis with an NNT of 1.2 (95% CI 1–2.5). Although there is fairly good evidence that azathioprine is effective in maintaining remission and is used widely, there are no suitable placebo‐controlled trials to calculate the NNT.
Efficacy and safety of thiopurinic immunomodulators (azathioprine and mercaptopurine) in steroid‐dependent ulcerative colitis
Authors: Lopez‐Sanroman A. , Bermejo F. , Carrera E. , Garcia‐Plaza A.
Published: July 2004

Background : The efficacy of azathioprine in the management of steroid‐dependent ulcerative colitis is taken for granted. However, study populations frequently include together steroid‐dependent and refractory patients.

Aim : To assess the efficacy and safety of thiopurinic immunomodulators in strictly defined steroid‐dependent ulcerative colitis.

Methods : Survey of 34 patients with steroid‐dependent ulcerative colitis, treated with azathioprine according to protocol. Therapeutical success: glucocorticoid withdrawal within 12 months, without steroid requirements during another year.

Results : Mean age was 39.1 ± 17 years. Pancolitis and extensive colitis accounted for 50% of cases. Therapeutic success of immunomodulator treatment reached 70.6%, intention to treat analysis (confidence interval 95%: 52–84%) and 72.7%, as per protocol (confidence interval 95%: 54–86%). Mean time to steroid withdrawal was 4.6 months. In therapy successes, mean corpuscular volume and total serum bilirubin increased with treatment time (P = 0.0001). Fifteen adverse effects were observed in 13 patients (38%). Azathioprine was withdrawn in seven cases (20.6%); in four of them (with liver toxicity), treatment with mercaptopurine was indicated.

Conclusions : Therapy with thiopurinic immunomodulators (azathioprine) represents the first option in the management of steroid‐dependent ulcerative colitis. Its efficacy (70%) and its acceptable safety support this view. Increasing mean corpuscular volume and serum bilirubin values may be a surrogate marker of a beneficial effect.
Alosetron repeat dose pharmacokinetics, effects on enzyme activities, and influence of demographic factors
Authors: Koch K. M. , Corrigan B. W. , Manzo J. , James C. D. , Scott R. J. , Stead A. G. , Kersey K. E.
Published: July 2004

Aim : To assess the pharmacokinetics of alosetron, its effect on in vivo enzyme activities, and influence of demographic factors during repeated dosing.

Methods : Thirty healthy men and women received 1 mg oral alosetron twice‐daily for 29.5 days and a single oral dose of a metabolic probe cocktail before and on the last day of alosetron dosing. Serum alosetron concentrations were measured on days 1, 8, 15, 22 and 29. Probe‐substrate and metabolite concentrations were measured after each cocktail dose.

Results : Alosetron accumulation in serum was negligible. Exposure to alosetron did not alter probe‐metabolite/substrate ratios associated with CYP2C19, 2E1, 2C9, or 3A4 activity, but modestly decreased those associated with CYP1A2 and N‐acetyltransferase activity. Systemic exposure to alosetron was higher in women, positively correlated with age and body mass index, and negatively correlated with CYP1A2 activity. Incidence of constipation was higher in women, but not associated with alosetron concentration.

Conclusions : Single dose data can reliably predict the pharmacokinetics of alosetron after repeated doses. Alosetron exhibits limited potential for inhibition of cytochrome P450‐mediated metabolism. Interindividual differences in alosetron pharmacokinetics associated with demographic factors may be related to strong dependence on metabolism by CYP1A2.
The effects of withdrawing tegaserod treatment in comparison with continuous treatment in irritable bowel syndrome patients with abdominal pain/discomfort, bloating and constipation: a clinical study
Authors: Bardhan K. D. , Forbes A. , Marsden C. L. , Mason T. , Short G.
Published: July 2004

Background : The post‐withdrawal characteristics of tegaserod treatment in patients with irritable bowel syndrome with constipation remain undefined.

Aim : To evaluate the effects of continuous tegaserod treatment, versus intermittent or withdrawal of treatment in patients with irritable bowel syndrome with constipation.

Methods : In a randomized, open‐label trial, all patients initially received tegaserod 6 mg b.d. Responders were randomized to continue or withdraw from treatment for 8 weeks and symptom recurrence was assessed. Tegaserod was re‐introduced in withdrawal patients who experienced symptom recurrence, allowing an assessment of intermittent treatment. Two separate analyses assessed the effects of intermittent and withdrawal of treatment on symptom recurrence.

Results : Five hundred irritable bowel syndrome with constipation patients initially received tegaserod; 410 completed treatment. Time to symptom recurrence was shorter in withdrawal patients than those maintained on tegaserod. Significantly more patients maintained on tegaserod had not experienced symptom recurrence by week 8, compared with intermittent (86.5% vs. 58.1%, respectively) or withdrawal of treatment (69.2% vs. 11.3%, respectively) (P < 0.0001 for both). Significant treatment effects were observed for bloating (P < 0.01) and abdominal pain/discomfort (P < 0.02). Most adverse events were mild to moderate.

Conclusions : Irritable bowel syndrome with constipation patients who receive continuous or intermittent tegaserod are less likely to experience symptom recurrence than patients withdrawn from treatment.
The cost‐effectiveness of high‐dose oral proton pump inhibition after endoscopy in the acute treatment of peptic ulcer bleeding
Authors: Barkun A. N. , Herba K. , Adam V. , Kennedy W. , Fallone C. A. , Bardou M.
Published: July 2004

Background : Recent data suggest a role for high‐dose oral proton pump inhibition in ulcer bleeding.

Aim : To compare the cost‐effectiveness of oral high‐dose proton pump inhibition to both high‐dose intravenous proton pump inhibition and placebo administration.

Methods : The model adopted a 30‐day time horizon, and focused on patients with ulcer haemorrhage initially treated endoscopically for high‐risk stigmata. Re‐bleeding rates were set a priori based on non‐head‐to‐head data from the literature, and charges and lengths of stay from a national American database. Sensitivity analyses were carried across a broad range of clinically relevant assumptions.

Results : Re‐bleeding rates for patients receiving intravenous, oral, or placebo therapies were 5.9%, 11.8%, and 27%, respectively. The mean lengths of stay and costs for admitted patients with and without re‐bleeding were 4.7 and 3 days; $11 802, and $7993, respectively. High‐dose intravenous proton pump inhibition was more effective and less costly (dominant) than high‐dose oral proton pump inhibition with incremental savings of $136.40 per patient treated. The oral high‐dose strategy in turn dominated placebo administration. Results remained robust according to one‐ and two‐way sensitivity analyses.

Conclusion : In patients undergoing endoscopic haemostasis, subsequent high‐dose intravenous proton pump inhibition is more cost‐effective than high‐dose oral proton pump inhibition, which in turn dominates placebo. The results from this exploratory‐type cost analysis require confirmation by head‐to‐head prospective trials performed in Western populations.
Wireless capsule endoscopy in patients with obscure gastrointestinal bleeding: a comparative study with push enteroscopy
Authors: Mata A. , Bordas J. M. , Feu F. , Ginés A. , Pellisé M. , Fernández‐Esparrach G. , Balaguer F. , Piqué J. M. , Llach J.
Published: July 2004

Background : The identification and treatment of lesions located in the small intestine in obscure gastrointestinal bleeding is always a clinical challenge.

Aim : To examine prospectively the diagnostic precision and the clinical efficacy of capsule endoscopy compared with push enteroscopy in obscure gastrointestinal bleeding.

Methods : Forty‐two patients (22 men and 20 women) with obscure gastrointestinal bleeding (overt bleeding in 26 cases and occult blood loss with chronic anaemia in 16) and normal oesophagogastroduodenoscopy and colonoscopy were analysed. All patients were instructed to receive the capsule endoscopy and push enteroscopy was performed within the next 7 days. Both techniques were blindly performed by separate examiners. The diagnostic yield for each technique was defined as the frequency of detection of clinically relevant intestinal lesions carrying potential for bleeding.

Results : A bleeding site potentially related to gastrointestinal bleeding or evidence of active bleeding was identified in a greater proportion of patients using capsule endoscopy (74%; 31 of 42) than enteroscopy (19%; eight of 42) (P = 0.05). The most frequent capsule endoscopy findings were: angiodysplasia (45%), fresh blood (23%), jejunal ulcers (10%), ileal inflammatory mucosa (6%) and ileal tumour (6%). No additional intestinal diagnoses were made by enteroscopy. In seven patients (22%), the results obtained with capsule endoscopy led to a successful change in the therapeutic approach.

Conclusions : Compared with push enteroscopy, capsule endoscopy increases the diagnosis yield in patients with obscure gastrointestinal bleeding, and allows modification on therapy strategy in a remarkable proportion of patients.
Hyperamylasaemia and acute pancreatitis in paracetamol poisoning
Authors: Schmidt L. E. , Dalhoff K.
Published: July 2004

Background : Hyperamylasaemia and even acute pancreatitis have been reported in patients with paracetamol poisoning.

Aims : To describe the incidence, clinical characteristics, and prognostic implications of hyperamylasaemia in paracetamol poisoning.

Patients : Six hundred and two patients transferred to a specialized unit with severe paracetamol poisoning and 212 unselected patients admitted from the local region.

Methods : Retrospective study based on hospital charts. The optimum threshold of serum amylase to discriminate non‐survivors was identified.

Results : An elevated serum amylase (>100 U/L) occurred in 28 of the unselected patients (13%), in 218 of the transferred patients (36%), and in 118 of 148 patients (80%) with fulminant hepatic failure. Only 33 cases of paracetamol‐associated acute pancreatitis were diagnosed. A threshold serum amylase of 150 U/L to discriminate non‐survivors had sensitivity 76%, specificity 85%, positive predictive value 33%, and negative predictive value 97%. In a logistic regression analysis, a serum amylase > 150 U/L was associated with an excess mortality (odds ratio 5.0, 2.6–9.7).

Conclusions : Hyperamylasaemia is frequent in patients with paracetamol poisoning, whereas clinical acute pancreatitis occurs rarely. The incidence of hyperamylasaemia increases with the degree of hepatic dysfunction. A serum amylase exceeding 1.5 times the upper normal limit indicates a poor prognosis.
Insulin reduces apoptosis and increases DNA synthesis and cell size via distinct signalling pathways in Drosophila Kc cells
Authors: Bikopoulos G. , Ceddia R. B. , Sweeney G. , Hilliker A. J.
Published: July 2004

Abstract.  During development of Drosophila, cell proliferation and size are known to be regulated by insulin. Here we use Drosophila Kc cells to examine the molecular basis for the control of cell growth by insulin. Growing cells in the presence of insulin increased cell number above control levels at 16, 24, 48 and 72 h. We have demonstrated a novel anti‐apoptotic effect of insulin (∼50%) in these cells, measured by caspase 3‐like activity, which contributed to the increase in cell number. The anti‐apoptotic effect was observed both in control cells and those in which apoptosis was induced by ultraviolet irradiation. An approximately 2‐fold stimulation of bromodeoxyuridine incorporation demonstrated that insulin also increased Kc cell proliferation by stimulating new DNA synthesis. The ability of insulin to increase cell number, stimulate bromodeoxyuridine incorporation and reduce caspase 3‐like activity was prevented by PD98059, which inhibits activation of the Drosophila extracellular signal regulated kinase (DERK) pathway, and was unaffected by wortmannin, an inhibitor of Drosophila phosphatidylinositol 3‐kinase (DPI3K). Insulin also increased cell size approximately 2‐fold and this was prevented by wortmannin and rapamycin, an inhibitor of Drosphilia target of rapamycin (DTOR). In summary, we show that DERK plays an important role in mediating the effect of insulin to reduce apoptosis and increase DNA synthesis whereas the DPI3K/DTOR/Dp70S6 kinase pathway mediates effects of insulin on cell size in Drosophila Kc cells.
Feature: The sedimentary signature of deserts and their response to environmental change
Authors: Mountney Nigel P.
Published: July 2004

Desert sedimentary systems comprise a variety of related sub‐environments including aeolian dunes, intervening interdunes, sandsheets, salt flats, playa lakes, ephemeral fluvial systems and alluvial fans. These are highly sensitive, and undergo subtle but systematic morphological and sedimentary adjustments in response to externally‐imposed environmental change. This article presents a dynamic model explaining how desert successions – particularly aeolian dune and interdune environments – are determined both by intrinsic sedimentary behaviour, such as dune migration, and by the imposition of externally‐forced changes such as climate change.
Topic: Perception or reality – waste, landfill and the environment
Authors: Joseph Jeremy
Published: July 2004

When Einstein was asked to define the environment he gave the excellent answer ‘everything that isn’t me'. This article is about Einstein's environment, and its protection.
How many do I need? Basic principles of sample size estimation
Authors: Devane Declan , Begley Cecily M. , Clarke Mike
Published: July 2004

Background.  In conducting randomized trials, formal estimations of sample size are required to ensure that the probability of missing an important difference is small, to reduce unnecessary cost and to reduce wastage. Nevertheless, this aspect of research design often causes confusion for the novice researcher.

Aim.  This paper attempts to demystify the process of sample size estimation by explaining some of the basic concepts and issues to consider in determining appropriate sample sizes.

Method.  Using a hypothetical two group, randomized trial as an example, we examine each of the basic issues that require consideration in estimating appropriate sample sizes. Issues discussed include: the ethics of randomized trials, the randomized trial, the null hypothesis, effect size, probability, significance level and type I error, and power and type II error. The paper concludes with examples of sample size estimations with varying effect size, power and alpha levels.

Conclusion.  Health care researchers should carefully consider each of the aspects inherent in sample size estimations. Such consideration is essential if care is to be based on sound evidence, which has been collected with due consideration of resource use, clinically important differences and the need to avoid, as far as possible, types I and II errors. If the techniques they employ are not appropriate, researchers run the risk of misinterpreting findings due to inappropriate, unrepresentative and biased samples.