bluuebunny/crossref_metadata_2025 huggingface dataset:
Thyroid autoantibody profiles in ophthalmic dominant and thyroid dominant Graves’ disease differ and suggest ophthalmopathy is a multiantigenic disease
Authors: Goh S. Y. , Ho S. C. , Seah L. L. , Fong K. S. , Khoo D. H. C.
Published: December 2004

background  Thyroid‐associated ophthalmopathy (TAO) occurs in 25–50% of patients with Graves’ disease (GD) and is occasionally seen in hypothyroid Hashimoto's disease or euthyroid individuals. The link between TAO and hyperthyroidism remains unclear. We hypothesized that qualitative or quantitative differences in thyroid antibodies might determine individual predisposition to these features.

methods  In a prospective study over 3 years, thyroid antibody levels were measured in all patients diagnosed at the Singapore National Eye Centre to have GD. These patients had no known history of thyroid disease, presented with eye complaints and diagnosis was made by an ophthalmologist. A total of 31 patients were identified. Antibody levels were compared against 71 consecutive patients referred to a thyroid clinic (TC) for thyrotoxic symptoms in whom the diagnosis of GD was confirmed by a thyroidologist.

findings  Thyroid autoantibody profiles of patients diagnosed at the ophthalmology centre (OC) and TC differed markedly. OC patients had significantly higher TSI (P = 0·003) but lower TPOAb (P = 0·008) and TgAb levels (P < 0·001). In contrast, TC patients had higher free T4 (P = 0·048) and higher TBII levels (P < 0·001). Antibody levels were correlated with four parameters of ophthalmopathy – chronic lid retraction, lid swelling, proptosis and extraocular myopathy (EOM). On univariate logistic regression analysis, TSI was a positive predictor and TPOAb and TgAb negative predictors of all four features. In the absence of TgAb, the odds ratios for individual TAO features ranged from 2·8 to 7·9, with corresponding values of 3·9–10·2 when TPOAb was absent. In stepwise logistic regression analysis, TSI was the strongest independent predictor of all aspects studied: lid fullness P = 0·001, proptosis P = 0·001, lid retraction P = 0·008, EOM P = 0·009. Among smokers, TPOAb were significantly lower (P = 0·044) but no association between smoking and the other antibodies was observed.

interpretation  The study demonstrates markedly different thyroid autoantibody profiles in newly diagnosed GD patients with ophthalmic dominant as opposed to thyroid dominant features. It suggests differing antibody patterns are associated with predisposition to hyperthyroidism and orbitopathy. In addition, an association between smoking and low TPOAb levels was noted.
Strange organelles –Plasmodium mitochondria lack a pyruvate dehydrogenase complex
Authors: Ralph Stuart A.
Published: December 2004

Our understanding of the Plasmodium mitochondrion and apicoplast has been greatly assisted by the genome sequence project. Sequence data have seeded recent research showing that the apicoplast is  the  site  of  several  anabolic  pathways  including fatty acid synthesis. The discovery of an active apicoplast pyruvate dehydrogenase complex implies this enzyme generates the acetyl‐CoA needed for fatty acid synthesis. However, the absence of a corresponding mitochondrial complex suggests that energy generation in Plasmodium is considerably different from pathways described in other eukaryotes.
Type IV pilus biogenesis in Neisseria meningitidis: PilW is involved in a step occurring after pilus assembly, essential for fibre stability and function
Authors: Carbonnelle Etienne , Hélaine Sophie , Prouvensier Laure , Nassif Xavier , Pelicic Vladimir
Published: December 2004

Type IV pili (Tfp) play a critical role in the pathogenic lifestyle of Neisseria meningitidis and N. gonorrhoeae, notably by facilitating bacterial attachment to human cells, but our understanding of their biogenesis, during which the fibres are assembled in the periplasm, then emerge onto the cell surface and are stabilized, remains fragmentary. We therefore sought to identify the genes required for Tfp formation in N. meningitidis by screening a genome‐wide collection of mutants for those that were unable to form aggregates, another phenotype mediated by these organelles. Fifteen proteins, of which only seven were previously characterized, were found to be essential for Tfp biogenesis. One novel component, named PilW, was studied in more detail. We found that PilW is an outer‐membrane protein necessary for the stabilization of the fibres but not for their assembly or surface localization, because Tfp could be restored on the surface in a pilW mutant by a mutation in the twitching motility gene pilT. However, Tfp‐linked properties, including adherence to human cells, were not restored in a pilW/T mutant, which suggests that PilW is also essential for the functionality of the fibres. Together with the finding that PilW is important for the stability of PilQ multimers, our results extend the current model for Tfp biogenesis by suggesting that a multiprotein machinery in the outer‐membrane is involved in the terminal stage of Tfp biogenesis during which growing fibres are not only stabilized, but also become perfectly functional.
The PerR regulon in peroxide resistance and virulence of Streptococcus pyogenes
Authors: Brenot Audrey , King Katherine Y. , Caparon Michael G.
Published: December 2004

Prior studies have shown that the catalase‐deficient pathogen Streptococcus pyogenes (group A streptococcus) has a robust ability to resist oxidative stress that partially involves the transcriptional regulator PerR. However, the extent of the PerR regulon and the contribution of the members of this regulon to virulence are unknown. In this study, DNase I footprinting revealed that PerR binds specifically to a single site upstream of the promoter for the gene encoding alkyl hydroperoxide reductase (ahpC). However, analyses of transcript abundance revealed that while ahpC is regulated in response to growth phase, its regulation is independent of PerR. Instead, PerR regulates transcription of a divergent gene cluster that encodes a putative cold shock protein. The gene encoding the Dps‐like peroxide resistance protein MrgA was repressed by PerR, consistent with the presence of a PerR binding site in its promoter. Phenotypic analyses of PerR–, AhpC– and MrgA– mutants revealed that while AhpC is not essential for resistance to challenge with hydrogen peroxide in vitro, AhpC does contribute to scavenging of endogenous hydrogen peroxide and is required for virulence in a murine model of infection. In contrast, a MrgA– mutant was hypersensitive to challenge with peroxide in vitro, but was fully virulent in all animal models tested. Finally, a PerR– mutant was hyper‐resistant to peroxide, yet was highly attenuated for virulence in all murine models. These data demonstrate that while a mutant's capacity to resist peroxide stress did not directly correlate with its ability to cause disease, the appropriate regulation of the peroxide stress response is critical for virulence.
PilX, a pilus‐associated protein essential for bacterial aggregation, is a key to pilus‐facilitated attachment of Neisseria meningitidis to human cells
Authors: Hélaine Sophie , Carbonnelle Etienne , Prouvensier Laure , Beretti Jean‐Luc , Nassif Xavier , Pelicic Vladimir
Published: December 2004

The attachment of pathogenic Neisseria species to human cells, in which type IV pili (Tfp) play a key but incompletely defined role, depends on the ability of these bacteria to establish contacts with the target cells but also interbacterial interactions. In an effort to improve our understanding of the molecular mechanisms of N. meningitidis adherence to human cells, we screened a collection of defined mutants for those presenting reduced attachment to a human cell line. Besides underscoring the central role of Tfp in this process, this analysis led to the identification of mutants interrupted in a novel gene termed pilX, that displayed an adherence as impaired as that of a non‐piliated mutant but quantitatively and qualitatively unaltered fibres. Moreover, the pilX gene, which encodes a pilin‐like protein that copurifies with Tfp fibres, was also found to be essential for bacterial aggregation. We provide here several piece of evidence suggesting that PilX has intrinsic aggregative but no adhesive properties and that the reduced numbers of adherent bacteria seen with a pilX mutant result from the absence of interbacterial interactions. These data extend the current model for Tfp‐facilitated adherence of N. meningitidis to human cells by suggesting that the pili lead to an increase in net initial adherence primarily by mediating a cooperation between the bacteria, which is supported by the finding that a major effect on initial adherence could be observed in a wild‐type (WT) genetic background after a mechanical removal of the bacterial aggregates.
The type IV secretion apparatus protein VirB6 of Agrobacterium tumefaciens localizes to a cell pole
Authors: Judd Paul K. , Kumar Renu B. , Das Anath
Published: December 2004

Agrobacterium tumefaciens VirB proteins assemble a type IV secretion apparatus for the transfer of DNA and proteins to plant cells. To study the role of the VirB6 protein in the assembly and function of the type IV apparatus, we determined its subcellular location by immunofluorescence microscopy. In wild‐type bacteria VirB6 localized to the cell poles but in the absence of the tumour‐inducing plasmid it localized to random sites on the cell membranes. Five of the 11 VirB proteins, VirB7–VirB11, are required for the polar localization of VirB6. We identified two regions of VirB6, a conserved tryptophan residue at position 197 and the extreme C‐terminus, that are essential for its polar localization. Topology determination by PhoA fusion analysis placed both regions in the cell cytoplasm. Alteration of tryptophan 197 or the deletion of the extreme C‐terminus led to the mislocalization of the mutant protein. The mutations abolished the DNA transfer function of the protein as well. The C‐terminus of VirB6, in silico, can form an amphipathic helix that may encode a protein–protein interaction domain essential for targeting the protein to a cell pole. We previously reported that another DNA transfer protein, VirD4, localizes to a cell pole. To determine whether VirB6 and VirD4 localize to the same pole, we performed colocalization experiments. Both proteins localized to the same pole indicating that VirB6 and VirD4 are in close proximity and VirB6 is probably a component of the transport apparatus.
Sequential binding of SeqA protein to nascent DNA segments at replication forks in synchronized cultures of Escherichia coli
Authors: Yamazoe Mitsuyoshi , Adachi Shun , Kanaya Shigehiko , Ohsumi Katsufumi , Hiraga Sota
Published: December 2004

To demonstrate that sequestration A (SeqA) protein binds preferentially to hemimethylated GATC sequences at replication forks and forms clusters in Escherichia coli growing cells, we analysed, by the chromatin immunoprecipitation (ChIP) assay using anti‐SeqA antibody, a synchronized culture of a temperature‐sensitive dnaC mutant strain in which only one round of chromosomal DNA replication was synchronously initiated. After synchronized initiation of chromosome replication, the replication origin oriC was first detected by the ChIP assay, and other six chromosomal regions having multiple GATC sequences were sequentially detected according to bidirectional replication of the chromosome. In contrast, DNA regions lacking the GATC sequence were not detected by the ChIP assay. These results indicate that SeqA binds hemimethylated nascent DNA segments according to the proceeding of replication forks in the chromosome, and SeqA releases from the DNA segments when fully methylated. Immunofluorescence microscopy reveals that a single SeqA focus containing paired replication apparatuses appears at the middle of the cell immediately after initiation of chromosome replication and the focus is subsequently separated into two foci that migrate to 1/4 and 3/4 cellular positions, when replication forks proceed bidirectionally an approximately one‐fourth distance from the replication origin towards the terminus. This supports the translocating replication apparatuses model.
New insertion sequences of Sulfolobus: functional properties and implications for genome evolution in hyperthermophilic archaea
Authors: Blount Zachary D. , Grogan Dennis W.
Published: December 2004

Analyses of complete genomes indicate that insertion sequences (ISs) are abundant and widespread in hyperthermophilic archaea, but few experimental studies have measured their activities in these hosts. As a way to investigate the impact of ISs on Sulfolobus genomes, we identified seven transpositionally active ISs in a widely distributed Sulfolobus species, and measured their functional properties. Six of the seven were found to be distinct from previously described ISs of Sulfolobus, and one of the six could not be assigned to any known IS family. A type II ‘Miniature Inverted‐repeat Transposable Element’ (MITE) related to one of the ISs was also recovered. Rates of transposition of the different ISs into the pyrEF region of their host strains varied over a 250‐fold range. The Sulfolobus ISs also differed with respect to target‐site selectivity, although several shared an apparent preference for the pyrEF promoter region. Despite the number of distinct ISs assayed and their molecular diversity, only one demonstrated precise excision from the chromosomal target region. The fact that this IS is the only one lacking inverted repeats and target‐site duplication suggests that the observed precise excision may be promoted by the IS itself. Sequence searches revealed previously unidentified partial copies of the newly identified ISs in the Sulfolobus tokodaii and Sulfolobus solfataricus genomes. The structures of these fragmentary copies suggest several distinct molecular mechanisms which, in the absence of precise excision, inactivate ISs and gradually eliminate the defective copies from Sulfolobus genomes.
PfPK7, an atypical MEK‐related protein kinase, reflects the absence of classical three‐component MAPK pathways in the human malaria parasite Plasmodium falciparum
Authors: Dorin Dominique , Semblat Jean‐Philippe , Poullet Patrick , Alano Pietro , Goldring J. P. Dean , Whittle Christina , Patterson Shelley , Chakrabarti Debopam , Doerig Christian
Published: December 2004

Two members of the mitogen‐activated protein kinase (MAPK) family have been previously characterized in Plasmodium falciparum, but in vitro attempts at identifying MAP kinase kinase (MAPKK) homologues have failed. Here we report the characterization of a novel plasmodial protein kinase, PfPK7, whose top scores in blastp analysis belong to the MAPKK3/6 subgroup of MAPKKs. However, homology to MAPKKs is restricted to regions of the C‐terminal lobe of the kinase domain, whereas the N‐terminal region is closer to fungal protein kinase A enzymes (PKA, members of the AGC group of protein kinases). Hence, PfPK7 is a ‘composite’ enzyme displaying regions of similarity to more than one protein kinase family, similar to a few other plasmodial protein kinases. PfPK7 is expressed in several developmental stages of the parasite, both in the mosquito vector and in the human host. Recombinant PfPK7 displayed kinase activity towards a variety of substrates, but was unable to phosphorylate the two P. falciparum MAPK homologues in vitro, and was insensitive to PKA and MEK inhibitors. Together with the absence of a typical MAPKK activation site in its T‐loop, this suggests that PfPK7 is not a MAPKK orthologue, despite the fact that this enzyme is the most ‘MAPKK‐like’ enzyme encoded in the P. falciparum genome. This is consistent with recent observations that the plasmodial MAPKs are not true orthologues of the ERK1/2, p38 or JNK MAPKs, and strengthens the evidence that classical three‐component module‐dependent MAPK signalling pathways do not operate in malaria parasites, a feature that has not been described in any other eukaryote.
Discovery of Late Jurassic fossils inside modern sediments at Gorringe Bank (Eastern Atlantic Ocean) and some geological implications.
Authors: Conti Maria Alessandra , De Alteriis Giovanni , Marino Maria Concetta , Pallini Giovanni , Tonielli Renato
Published: December 2004

During a recent expedition at the Gorringe Bank (eastern Atlantic, 150 miles SW off Portugal), one of the rare sites in the ocean where mantle rocks crop out at very shallow depths (− 30 m), the Gettysburg and Ormonde seamounts, the two summits on the Gorringe Bank, were surveyed in detail. At Gettysburg seamount, within the modern bioclastic material, which is continually produced on the summit and exported to deep water, several examples of Mesozoic cephalopods were found. These fossils, reworked ‘in situ’, gave an age spanning from Kimmeridgian–Tithonian to Hauterivian (145–155 Ma) and recall some condensed Jurassic sequences of the Thetyan region compatible with shallow water (< 200 m). The serendipitous discovery of such ancient faunas within modern sediments suggests that Gorringe Bank was a seamount at the early opening of the Atlantic Ocean and requires us to reassess the age of rifting along the Iberian margin and the importance of vertical tectonics for non‐volcanic, mantle‐rooted seamounts.
Temperature distribution in karst systems: the role of air and water fluxes
Authors: Luetscher Marc , Jeannin Pierre‐Yves
Published: December 2004

A better understanding of heat fluxes and temperature distribution in continental rocks is of great importance for many engineering aspects (tunnelling, mining, geothermal research, etc.). This paper aims at providing a conceptual model of temperature distribution in karst environments which display thermal ‘anomalies’ as compared with other rocks. In temperate regions, water circulation is usually high enough to ‘drain‐out’ completely the geothermal heat flux at the bottom of karst systems (phreatic zone). A theoretical approach based on temperature measurements carried out in deep caves and boreholes demonstrates, however, that air circulation can largely dominate water infiltration in the karst vadose zone, which can be as thick as 2000 m. Consequently, temperature gradients within this zone are similar to the lapse rate of humid air (∼0.5 °C 100 m−1). Yet, this value depends on the regional climatic context and might present some significant variations.
THE 5‐HT2 RECEPTOR ANTAGONIST SARPOGRELATE REDUCES URINARY AND PLASMA LEVELS OF THROMBOXANE A2 AND URINARY ALBUMIN EXCRETION IN NON‐INSULIN‐DEPENDENT DIABETES MELLITUS PATIENTS†
Authors: Ogawa Susumu , Takeuchi Kazuhisa , Sugimura Kazuhiko , Sato Chiharu , Fukuda Motoshi , Lee Ribun , Ito Sadayoshi , Sato Tokutaro
Published: December 2004

1. Therapeutic effects of a 5‐HT2 receptor antagonist sarpogrelate on microalbuminuria and thromboxane (TX)A2 biosynthesis were examined in non‐insulin‐dependent diabetes mellitus (NIDDM) patients.

2. In protocol I, the ankle‐brachial pressure index (API; an indicator of peripheral blood flow) and urinary albumin excretion (UalbV; an indicator of renal function) were determined in 42 NIDDM patients who had been treated with 300 mg/day sarpogrelate for 8 weeks. In an analysis of the results, the NIDDM patients were divided into four groups based on the severity of either vasculopathy or nephropathy as follows: group A, API < 0.9, UalbV ≥ 100 mg/day; group B, API < 0.9, UalbV < 100 mg/day; group C API ≥ 0.9, UalbV ≥ 100 mg/day; and group D, API ≥ 0.9, UalbV < 100 mg/day.

3. In protocol II, 10 NIDDM patients with UalbV values > 100 mg/day were divided into two groups to further confirm the effect of sarpogrelate on albuminuria: group E, the sarpogrelate treatment group (n = 5); and group F, the no treatment group (n = 5).

4. In protocol I, the incidence of a cold sensation in the lower extremities was reduced from 45.2 to 21.4% following sarpogrelate treatment. In patients with UalbV ≥ 100 mg/day (groups A and C), UalbV was significantly decreased independent of API, while it did not change in patients with UalbV < 100 mg/day (groups B and D). Plasma TXB2 levels were significantly decreased following sarpogrelate treatment, whereas plasma 6‐keto‐prostaglandin F1α levels were not.

5. In protocol II, in the sarpogrelate treatment group (group E), albuminuria was significantly improved and both plasma levels TXB2 and urinary TXB2 excretion were significantly decreased. In contrast, in the untreated group (group F), neither plasma levels TXB2 nor urinary TXB2 excretion was changed.

6. In conclusion, microalbuminuria was improved by treatment with the 5‐HT2 receptor antagonist sarpogrelate independent of latent vasculopathy. Blockade of 5‐HT2 receptors is suggested to be beneficial for the treatment of nephropathy in NIDDM patients. It is possible that the inhibition of TXA2 biosynthesis is involved in the therapeutic effect of 5‐HT2 receptor antagonists.
Delayed stoma formation in Fournier's gangrene
Authors: Bronder C. S. , Cowey A. , Hill J.
Published: December 2004

Fournier's gangrene is traditionally treated with prompt surgical debridement and in many cases a diverting colostomy is also fashioned during the same procedure. We present four cases where stoma formation was delayed until the second look procedure. The physiological states at the time of either procedure were compared using POSSUM. The results showed an improvement in the physiological condition in all patients at the time of the second operation, suggesting that a delay can potentially improve prognosis in such cases.
Colorectal surgery: the risk and burden of adhesion‐related complications
Authors: Parker M. C. , Wilson M. S. , Menzies D. , Sunderland G. , Thompson J. N. , Clark D. N. , Knight A. D. , Crowe A. M. ,   Surgical and Clinical Adhesions Research (SCAR) Group
Published: December 2004

Objectives  Adhesions are associated with serious medical complications. This study examines the real‐time burden of adhesion‐related readmissions following colorectal surgery and assesses the impact of previous surgery on adhesion‐related outcomes.

Patients and methods  The study used data from the Scottish National Health Service Medical Record Linkage Database to identify three cohorts of patients who had undergone open colorectal surgery during the financial years 1996–97, 1997–98 and 1998–99. Each cohort was followed up for at least 2 years and the number and category of adhesion‐related readmissions was recorded. The influence of any previous operations on adhesion‐related readmissions was also determined by performing a subanalysis within the 1996–97 cohort of patients who had no record of abdominal surgery within either the previous 5 or 15 years. The relative risk of adhesion‐related readmissions was also assessed.

Results  In the 1996–97 cohort, 9.0% of patients were readmitted within a year after surgery; 2.1% had complications directly related to adhesions and 6.9% had complications that were possibly related. After 4 years, 19.0% of patients were readmitted for reasons directly or possibly related to adhesions. Many patients were readmitted on more than one occasion and the relative risk of adhesion‐related complications was 29.7 per 100 initial procedures over 4 years. In the subgroups that had no record of abdominal surgery within the previous 5 or 15 years, the relative risks of adhesion‐related complications were 24.8% and 23.5%, respectively. There was no change in the rate of adhesion‐related readmissions following colorectal surgery between 1996 and 1999.

Conclusion  Colorectal surgery is associated with a considerable rate of adhesion‐related readmissions. Preventative measures should be considered to reduce this risk.
Long‐term follow‐up of dynamic graciloplasty for faecal incontinence
Authors: Thornton M. J. , Kennedy M. L. , Lubowski D. Z. , King D. W.
Published: December 2004

Objective  This paper presents the long‐term morbidity, function and quality of life data for patients who have undergone dynamic graciloplasty (DGP) for faecal incontinence.

Patients and methods  All patients (n = 38) who had undergone DGP at one institution between 1993 and 2003 are presented. Thirty‐three were available for long‐term follow‐up (median 60 months) and completed a telephone questionnaire assessing quality of life (QOL), bowel and sexual function and patient satisfaction. All patients had interval anorectal physiology studies.

Results  At a median follow‐up of 5 years, 72% had pain, swelling or paraesthesia in the donor leg and 27% had sexual dysfunction. Sixteen percent of patients had been converted to an end‐colostomy for persisting incontinence and 11% for obstructed defaecation. All other patients have a normally functioning graciloplasty. Sixteen percent of patients reported a faecal continence score < 12. Of those patients with a functioning graciloplasty, 50% had obstructed defaecation and 64% reported that their bowel dysfunction had a negative impacted on their QOL. Age, medical comorbidity and anal manometry did not correlate with functional outcome. Quality of life scores and patient satisfaction scores correlated significantly with continence scores. There was a trend toward higher QOL and satisfaction scores with conversion to colostomy compared with a continence score > 12. Sixty percent of patients rated their satisfaction with DGP as 50% or better on a visual analogue scale, and this correlated strongly with the continence score at the time of the assessment (P < 0.001).

Conclusion  Dynamic graciloplasty significantly improves patient quality of life and anal continence for some patients. Despite increased experience, morbidity remains high and long‐term continence scores are poor in a majority of cases. Obstructed defaecation is a significant problem after graciloplasty and antegrade colonic enemas may be needed. Significant prognostic factors for obstructed defaecation remain to be identified. The mechanism of both continence failure and surgical morbidity remains poorly defined in many patients and requires further investigation. The individual patient can expect a 16% chance of normal faecal continence at 5 years, with at least one surgical morbidity as a result of the procedure.
Effects of ovariectomy and hormone replacement on submucosal collagen and blood vessels of the anal canal of rats
Authors: Mensah‐Brown E. P. , Rizk Diaa E. E. , Patel Mahendra , Chandranath Swaminathan I. , Adem Abdu
Published: December 2004

Objective  To study the effects of oestrogen and progesterone on submucosal collagen fibres and vascular plexus of the anal canal.

Materials and methods  Experiments were performed on sections of the anal canal of ovariectomized rats following 28 daily subcutaneous injections of 17‐β oestradiol (n = 6, OVX + E, Group 1), medroxyprogesterone acetate (n = 6, OVX + P, Group 2), both drugs (n = 6, OVX + E + P, Group 3) or vehicle (n = 6, OVX) and after sham surgery without castration or injection (n = 6). Investigations included immunohistochemistry of oestrogen and progesterone receptors and collagen fibres, Western blot analysis of collagen types I and III and counting of perianal vessels by light microscopy.

Results  There was positive immunostaining for oestrogen and progesterone receptors in the mucosa and for collagen types I and III in the submucosa in all samples. Type I collagen levels increased significantly with ovariectomy but were normalized with treatment with oestrogen and progesterone. Type III collagen levels decreased after ovariectomy. Administration of oestrogen and progesterone appeared to restore level to near sham values. Semi‐quantitative measurement of Type I/III collagen ratios by signal intensity demonstrated a very high ratio after ovariectomy. This appeared to be restored by both oestrogen and progesterone administration either individually or in combination. Mean vessel count was significantly lower in sham animals compared to values in OVX animals (P = 0.006). However, while only oestrogen treatment increased significantly the number of vessels compared to sham animals (P = 0.04), replacement with progesterone did not affect and in combination with oestrogen reduced submucosal vessel number.

Conclusion  Oestrogen and progesterone have synergistic effects on collagen types I and III and probably antagonistic effects on the vascular plexus of the anal canal submucosa in adult female rats.
The risk of dysplasia and cancer in the ileal pouch mucosa after restorative proctocolectomy for ulcerative proctocolitis is low: A long‐term term follow‐up study
Authors: Börjesson L. , Willén R. , Haboubi N. , Duff S. E. , Hultén L.
Published: December 2004

Aim  Some of the rare complications reported in patients with an ileopouch anal anastomosis (IPAA) after coloectomy for chronic ulcerative colitis are dysplasia and carcinoma. The supposed pathway is for the ileal pouch mucosa to go through adaptational changes then is to progress through the phases of chronic pouchitis, dysplasia and subsequently to adenocarcinoma. In many of these studies however, the dysplasia – cancer sequence is inconclusive since the carcinoma might have developed from the ileal mucosa itself or from residual viable rectal mucosa left behind. The purpose of this study was therefore to study the long‐term ileal mucosal adaptation patterns and the incidence and grading of dysplasia in the ileal pouch mucosa in patients previously operated on for ulcerative proctocolitis.

Patients and methods  Forty‐five patients who had been operated on with an IPAA (25 males/20 females), with a median age of 54 years (range 34–76), were invited for clinical examination and pouch endoscopy including mucosal biopsies. The duration of their colitis until surgery was median 6 years (range 1–28) and the time median interval from start of disease until time of follow up 24.8 years (range 17–46). Three independent pathologists from two different centres reviewed sequential mucosal biopsies taken from separate sites of the pouch for dysplasia and mucosal adaptation patterns.

Results  The type C pattern with a severe inflammation in lamina propria together with severe atrophy of villi, sometimes with ulceration and granulation tissue, was observed by the two pathologists from one centre in 15 of 45 (33.3%) patients and in 11 (24.4%) of 45 by the third pathologist, respectively. As regards dysplasia one pathologist group evaluated 2/45 (4.4%) cases as low‐grade dysplasia while the third pathologist considered one of these cases as indefinite for dysplasia and one as reactive. There was in this respect full agreement between the two centres in 43 (95.6%) of 45 cases. Neither high‐grade dysplasia nor invasive carcinoma was diagnosed.

Conclusion  Dysplastic transformation within the ileal pouch mucosa in patients operated for ulcerative proctocolitis is rare even after a long follow‐up. These results are reassuring for both patients and surgeons. There seem to be no solid grounds to support routine surveillance for dysplasia in the ileal pouch mucosa in these patients. The surveillance for neoplastic changes in the remaining muscular/epithelial cuff is a separate issue however.
Effect of High-Dose Intravenous Eletriptan on Coronary Artery Diameter
Authors: Goldstein JA , Massey KD , Kirby S , Gibson M , Hettiarachchi J , Rankin AJ , Jackson NC
Published: December 2004

The goal of this study was to evaluate the coronary vasoconstrictive effects of high doses of eletriptan compared with a standard dose of sumatriptan. Patients with no clinically significant coronary artery disease were randomized to receive high-dose intravenous eletriptan ( n = 24) vs a standard dose of sumatriptan ( n = 18; 6 mg subcutaneously) vs placebo ( n = 18). Serial angiograms were obtained. The primary non-inferiority analysis found equivalence between the mean maximum change in left anterior descending coronary artery diameter for eletriptan, -22% [95% confidence interval (CI) -26, -19], and sumatriptan, -19% (95% CI -22, -16). The change due to placebo was -16% (95% CI -20, -12). No individual cases of clinically significant vasoconstriction were observed. The results confirm that eletriptan has a broad cardiovascular safety margin, with plasma concentrations comparable to three to five times the Cmax of an oral 80-mg dose associated with modest vasoconstriction equivalent to standard therapeutic doses of sumatriptan.
Auditory Event-Related Potentials and Reaction Times in Migraine Children
Authors: Buodo G , Palomba D , Sarlo M , Naccarella C , Battistella PA
Published: December 2004

Cognitive processing was investigated interictally in 18 children with migraine without aura and 18 age-matched controls by measuring event-related potentials (ERPs) and reaction times (RTs) during an acoustic oddball paradigm. Results showed that N100 amplitude evoked by frequent stimuli was significantly smaller in patients compared with controls. Habituation of target P300 amplitude was observed in patients but not in controls. Mean RTs were equivalent in the two groups, but migraine children made more errors than controls.
Clinical Characteristics of 362 Patients with Familial Migraine with Aura
Authors: Eriksen MK , Thomsen LL , Andersen I , Nazim F , Olesen J
Published: December 2004

The objectives of the present study were to describe the clinical characteristics of patients with severe familial non-hemiplegic migraine with aura (NHMA) and to compare these data to those from cases in previous population-based Danish studies using the same methodology. NHMA families were recruited from the Danish patient registry and from Danish neurology practices. A total of 362 NHMA patients were diagnosed according to the 1988 International Headache Society criteria using a validated semistructured physician-conducted interview. Visual aura occurred in almost every NHMA attack. In aura without headache visual aura occurred primarily in isolation. Aura without headache was most common in older, male patients. Several clinical characteristics of familial NHMA differed from migraine with aura in the general population: firstly, the age at onset was lower, secondly, the age at cessation was higher, thirdly, aura symptoms were more severe and finally, the co-occurrence of migraine without aura was higher in familial NHMA. There seems to be a correlation between more severe symptoms and familial aggregation. These results have both clinical and scientific implications.
Effectiveness and safety of the oxytocin antagonist atosiban versus beta‐adrenergic agonists in the treatment of preterm labour
Authors:   The Worldwide Atosiban versus Beta‐agonists Study Group Participants are listed in
Published: December 2004

Objective To compare the effectiveness and safety of the oxytocin antagonist atosiban with conventional beta‐adrenergic agonist (beta‐agonist) therapy in the treatment of preterm labour.

Design Three multinational, multicentre, double‐blind, randomised, controlled trials.

Setting Hospitals in Australia, Canada, Czech Republic, Denmark, France, Israel, Sweden, and the UK.

Population Women diagnosed with preterm labour at 23–33 completed weeks of gestation.

Methods Seven hundred and forty‐two women were randomised; 733 received atosiban (n=363; intravenous (iv) bolus dose of 6.75 mg, then 300 μg/minute iv. for 3h and 100 μg/min iv thereafter) or beta‐agonist (n=379; ritodrine, salbutamol or terbutaline iv; dose titrated) for at least 18h and up to 48 hours. Uterine contraction rate, cervical dilatation and effacement were used to assess progression of labour. An all patients treated analysis, using the Cochran‐Mantel‐Haenszel test, was performed.

Main outcome measures Tocolytic effectiveness was assessed in terms of the number of women undelivered after 48 hours and seven days. Safety was assessed in terms of maternal side effects and neonatal morbidity.

Results There were no significant differences between atosiban and β‐agonists in delaying delivery for 48h (88.1% vs 88.9%; P=0.99) or seven days (79.7% versus 77.6%; P=0.28). Tocolytic effectiveness was also similar in terms of mean [SD] gestational age at delivery (35.8 [3.9] weeks vs 35.5 [4.1] weeks) and mean [SD] birthweight (2491 [813] g versus 2461 [831] g). Maternal side effects, particularly cardiovascular adverse events (8.3% vs 81.2%, P < 0.001), were reported more frequently in women given β‐agonists, resulting in more treatment discontinuations due to side effects (1.1% vs 15.4%, P=0.0001). No statistical differences in neonatal/infant outcomes were observed with either study medication.

Conclusions In the largest study of tocolytic therapy to date, atosiban was comparable in clinical effectiveness to conventional beta‐agonist therapy, but was associated with fewer maternal cardiovascular side effects. We conclude that atosiban has clinical advantages over current tocolytic therapy.
Oxytocin mRNA content in the endometrium of non‐pregnant women
Authors: Steinwall Margareta , Hansson Stefan , Bossmar Thomas , Larsson Iréne , Pilka Radovan , Åkerlund Mats
Published: December 2004

Objective  To study oxytocin mRNA in the human endometrium at different phases of the menstrual cycle.

Design  An exploratory study in non‐pregnant women.

Setting  The Department of Obstetrics and Gynecology, Lund University Hospital, Sweden.

Participants  Thirty‐three women of fertile age undergoing hysterectomy or endometrial curettage on routine benign gynaecologic indications.

Methods  Endometrial tissue was obtained throughout the menstrual cycle. The presence of oxytocin mRNA was investigated by in situ hybridisation and by real time PCR.

Main outcome measures  Oxytocin mRNA signalling intensity found by in situ hybridisation of tissue obtained at different times of the menstrual cycle. Relative amounts of oxytocin mRNA measured by real time PCR.

Results  The signal for oxytocin mRNA obtained by in situ hybridisation was more pronounced in glandular epithelial cells than in stromal cells. Furthermore, it was most marked around mid‐cycle. The expression of oxytocin mRNA was confirmed by real time PCR.

Conclusions  The results indicate that oxytocin may be synthesised in the endometrium of non‐pregnant women, particularly in the glandular epithelial cells. Hormone released from these sources may have a paracrine action on the uterus. Oxytocin mRNA expression seems to be ovarian hormone dependent with the highest concentration around mid‐cycle.
Duloxetine versus placebo in the treatment of European and Canadian women with stress urinary incontinence
Authors: van Kerrebroeck Philip , Abrams Paul , Lange Rainer , Slack Mark , Wyndaele Jean‐Jacques , Yalcin Ilker , Bump Richard C. ,   for the Duloxetine UI Study Group
Published: December 2004

Objective  To assess the efficacy and safety of duloxetine in women with stress urinary incontinence.

Design  Randomised double‐blind, placebo‐controlled clinical trial.

Setting  Fort‐six centres in seven European countries and Canada.

Population  Four hundred and ninety‐four women aged 24–83 years identified as having predominant symptoms of stress urinary incontinence using a clinical algorithm that was 100% predictive of urodynamic stress urinary incontinence in a subgroup of 34 women.

Methods  The case definition included a predominant symptom of stress urinary incontinence with a weekly incontinence episode frequency ≥7, the absence of predominant symptoms of urge incontinence, normal diurnal and nocturnal frequencies, a bladder capacity ≥400 mL and both a positive cough stress test and positive stress pad test. Subjects completed two urinary diaries prior to randomisation and three diaries during the active treatment phase of the study, each completed during the week prior to monthly visits. Subjects also completed quality of life questionnaires at each visit. Safety was assessed by the evaluation of treatment‐emergent adverse events, discontinuation of treatment because of adverse events, serious adverse events, vital sign measurements, electrocardiograms (ECG) and clinical laboratory tests.

Intervention  After a two‐week placebo lead‐in, women received placebo or duloxetine 40 mg BD for 12 weeks.

Main outcome measures  The percentage decrease in incontinence episode frequency and the change in the Incontinence Quality of Life (I‐QOL) questionnaire total score were prespecified as co‐primary outcome variables in the protocol.

Results  Incontinence episode frequency decreased significantly with duloxetine compared with placebo (median decrease of 50%vs 29%; P= 0.002) with comparable improvements in the more severely incontinent subgroup (those experiencing at least 14 incontinence episodes per week at baseline; 56%vs 27% decreases; P < 0.001). The primary analysis of I‐QOL scores did not reveal a significant difference between treatment groups, due primarily to the carrying forward of low scores from patients who discontinued treatment very early due to duloxetine‐associated adverse events. The increase in I‐QOL scores was significantly greater for duloxetine than for placebo at each of the three postrandomisation visits after 4, 8, and 12 weeks of treatment. Discontinuation rates for adverse events were higher for duloxetine (22%vs 5%; P < 0.001) with nausea being the most common reason for discontinuation (5.3%). Nausea tended to be mild to moderate, not progressive, and transient.

Conclusions  The findings support duloxetine as a potential treatment for women with stress urinary incontinence.
Needle versus loop diathermy excision of the transformation zone for the treatment of cervical intraepithelial neoplasia: a randomised controlled trial
Authors: Panoskaltsis Theo , Ind Thomas Edward James , Perryman Karen , Dina Roberto , Abrahams Yusuf , Soutter W. Patrick
Published: December 2004

Objective  To determine whether lowwwer rates or incomplete resection of cervical intraepithelial neoplasia (CIN) may be achieved by needle excision of the transformation zone (NETZ) than with loop excision (LLETZ).

Design A prospective randomised controlled trial.

Setting A gynaecological oncology centre and a teaching hospital in West London.

Population Four hundred and four women due to receive treatment for suspected CIN.

Methods  Women were randomised to receive either LLETZ or NETZ.

Main outcome measures The study was designed to demostrate a difference in the proportion of women with clear histological margins of 82% for LLETZ compared to 94% for NETZ with 90% power at a 5% significance level, allowing for absence of CIN in the treatment specimen in 15%.

Results  Four randomised women were excluded from the analysis, as they were ineligible for the study. Three hundred and forty‐seven (87%) had CIN in the treatment specimen and could be included in the analysis of excision margins. More women in the NETZ arm had clear histological margins (84.8%vs 75%, (P= 0.03). The median volume of specimens in the NETZ arm was 739 mm3 larger (P= 0.33) and they were less likely to be removed in multiple pieces (2.5%vs 29.5%, RR 0.09, 95% CI 0.04 to 0.20). Needle excision took longer to perform (median treatment time 210 vs 90 seconds, P<0.0001) and surgeons more often reported the procedure as ‘difficult’ (9.5%vs 3.0%, RR = 3.17%, 95% CI 1.33 to 7.58). No difference in peri‐operative or post‐operative complication rates could be demonstrated between the two groups.

Conclusion  NETZ is more likely to produce a specimen in one piece and with clear margins compared to LLETZ.
Preventing postnatal depression in mothers of very preterm infants: a randomised controlled trial
Authors: Hagan Ronald , Evans Sharon F. , Pope Sherryl
Published: December 2004

Objective  To test whether a cognitive–behaviour therapy intervention program reduces the prevalence of depression during the first postnatal year in mothers of very preterm babies.

Design  Prospective, single blind, randomised, controlled study.

Setting  Perinatal centre in Western Australia.

Participants  One hundred and ninety‐nine out of 673 English‐speaking mothers of infants admitted to the neonatal unit.

Intervention  A six‐session cognitive–behaviour therapy intervention program provided by a research midwife between weeks two and six after birth. Women in the control group received standard care.

Main outcome measures  Depression and anxiety disorders occurring in the first year assessed by a clinical psychologist at structured interview using the Schedule for Affective Disorders and Schizophrenia (SADS) at 2 weeks, 2, 6 and 12 months.

Results  One hundred and one women were randomised to the intervention group and 98 to the control group. Fifty‐four mothers (27%) in the trial were diagnosed with minor or major depression in the 12 months following very preterm delivery, 29 (29%) in the intervention group and 25 (26%) in the control group (relative risk 1.1 [95% CI 0.80–1.5]). There were no differences in the time of onset or the duration of the episodes of depression between the groups. Overall, 74 mothers (37%) of the 199 met criteria for a diagnosis of psychological morbidity during the first year.

Conclusions  Our intervention program did not alter the prevalence of depression in these mothers. Rates of depression and stress reactions are high in these mothers.
Pregnancy outcome in women with heart disease undergoing induction of labour
Authors: Oron Galia , Hirsch Rafael , Ben‐Haroush Avi , Hod Moshe , Gilboa Yinon , Davidi Ofer , Bar Jacob
Published: December 2004

Objective  To examine the safety and outcome of induction of labour in women with heart disease.

Design  Prospective single‐centre comparative study.

Setting  Major university‐based medical centre.

Population/Sample  One hundred and twenty‐one pregnant women with heart disease.

Methods  The sample included all women with acquired or congenital heart disease who attended our High‐Risk Pregnancy Outpatient Clinic from 1995 to 2001. The files were reviewed for baseline data, cardiac and obstetric history, course of pregnancy and induction of labour and outcome of pregnancy. Findings were compared between women who underwent induction of labour and those who did not. Forty‐seven healthy women in whom labour was induced for obstetric reasons served as controls.

Main outcome measures  Pregnancy outcome.

Results  Of the 121 women with heart disease, 47 (39%) underwent induction of labour. There was no difference in the caesarean delivery rate after induction of labour between the women with heart disease (21%) and the healthy controls (19%). Although the women with heart disease had a higher rate of maternal and neonatal complications than controls (17%vs 2%, P= 0.015), within the study group, there was no difference in complication rate between the patients who did and did not undergo induction of labour.

Conclusion  Induction of labour is a relatively safe procedure in women with cardiac disease. It is not associated with a higher rate of caesarean delivery than in healthy women undergoing induction of labour for obstetric indications, or with more maternal and neonatal complications than in women with a milder form of cardiac disease and spontaneous labour.