bluuebunny/crossref_metadata_2025 huggingface dataset:
Ubiquitinated proliferating cell nuclear antigen activates translesion DNA polymerases η and REV1
Authors: Garg Parie , Burgers Peter M.
Published: December 2005

In response to DNA damage, the Rad6/Rad18 ubiquitin-conjugating complex monoubiquitinates the replication clamp proliferating cell nuclear antigen (PCNA) at Lys-164. Although ubiquitination of PCNA is recognized as an essential step in initiating postreplication repair, the mechanistic relevance of this modification has remained elusive. Here, we describe a robustin vitrosystem that ubiquitinates yeast PCNA specifically on Lys-164. Significantly, only those PCNA clamps that are appropriately loaded around effector DNA by its loader, replication factor C, are ubiquitinated. This observation suggests that,in vitro, only PCNA present at stalled replication forks is ubiquitinated. Ubiquitinated PCNA displays the same replicative functions as unmodified PCNA. These functions include loading onto DNA by replication factor C, as well as Okazaki fragment synthesis and maturation by the PCNA-coordinated actions of DNA polymerase δ, the flap endonuclease FEN1, and DNA ligase I. However, whereas the activity of DNA polymerase ζ remains unaffected by ubiquitination of PCNA, ubiquitinated PCNA specifically activates two key enzymes in translesion synthesis: DNA polymerase η, the yeastXeroderma pigmentosumortholog, and Rev1, a deoxycytidyl transferase that functions in organizing the mutagenic DNA replication machinery. We propose that ubiquitination of PCNA increases its functionality as a sliding clamp to promote mutagenic DNA replication.
Crystal structure of receptor-binding C-terminal repeats from
Clostridium difficile
toxin A
Authors: Ho Jason G. S. , Greco Antonio , Rupnik Maja , Ng Kenneth K.-S.
Published: December 2005

Clostridium difficile
is a major nosocomial pathogen that produces two large protein toxins [toxin A (TcdA) and toxin B (TcdB)] capable of disrupting intestinal epithelial cells. Both belong to the family of large clostridial cytotoxins, which are characterized by the presence of a repetitive C-terminal repetitive domain (CRD). In TcdA, the CRD is composed of 39 repeats that are responsible for binding to cell surface carbohydrates. To understand the molecular structural basis of cell binding by the toxins from
C. difficile
, we have determined a 1.85-Å resolution crystal structure of a 127-aa fragment from the C terminus of the toxin A CRD. This structure reveals a β-solenoid fold containing five repeats, with each repeat consisting of a β-hairpin followed by a loop of 7–10 residues in short repeats (SRs) or 18 residues in long repeats (LRs). Adjacent pairs of β-hairpins are related to each other by either 90° or 120° screw–axis rotational relationships, depending on the nature of the amino acids at key positions in adjacent β-hairpins. Models of the complete CRDs of toxins A and B suggest that each CRD contains straight stretches of β-solenoid composed of three to five SRs that are punctuated by kinks introduced by the presence of a single LR. These structural features provide a framework for understanding how large clostridial cytotoxins bind to cell surfaces and suggest approaches for developing novel treatments for
C. difficile
-associated diseases by blocking the binding of toxins to cell surfaces.
Human La is found at RNA polymerase III-transcribed genes
in vivo
Authors: Fairley Jennifer A. , Kantidakis Theodoros , Kenneth Niall S. , Intine Robert V. , Maraia Richard J. , White Robert J.
Published: December 2005

The human La autoantigen can bind to nascent RNA transcripts and has also been postulated to act as an RNA polymerase III (pol III) transcription initiation and termination factor. Here, we show by chromatin immunoprecipitation (ChIP) that La is associated with pol III-transcribed genes
in vivo
. In contrast, the Ro autoantigen, which can also bind pol III transcripts, is not found at these genes. The putative pol III transcription factors NF1 and TFIIA are also not detected at class III genes. Binding of La remains when transcription is repressed at mitosis and does not correlate with the presence of polymerase at the gene. However, gene occupancy depends on the phosphorylation status of La, with the less prevalent, unphosphorylated form being found selectively on pol III templates.
Introduction of an additional pathway for lactate oxidation in the treatment of lactic acidosis and mitochondrial dysfunction in
Caenorhabditis elegans
Authors: Grad Leslie I. , Sayles Leanne C. , Lemire Bernard D.
Published: December 2005

Mitochondrial dysfunction, with an estimated incidence of 1 in 5,000 births, is associated with a wide variety of multisystem degenerative diseases. Among the most prevalent forms of dysfunction are defects in the NADH:ubiquinone oxidoreductase (complex I).
Caenorhabditis elegans
strains with complex I mutations exhibit characteristic features of human mitochondrial disease including decreased rates of respiration and lactic acidosis. We hypothesized that introducing an additional pathway for the direct oxidation of lactate would be beneficial for energy metabolism. The yeast
CYB2
gene encodes an
l
-lactate:cytochrome
c
oxidoreductase that oxidizes lactate, donates electrons directly into the mitochondrial respiratory chain, and supports lactate-dependent respiration. Cyb2p expression markedly increases lifespan, fertility, respiration rates, and ATP content in complex I-deficient animals. Our results indicate that metabolic imbalance leading to lactic acidosis and energy depletion are central mechanisms of pathogenesis in mitochondrial dysfunction and that introduction of an additional pathway for lactate oxidation should be considered as a treatment.
Cranial morphology of early Americans from Lagoa Santa, Brazil: Implications for the settlement of the New World
Authors: Neves Walter A. , Hubbe Mark
Published: December 2005

Comparative morphological studies of the earliest human skeletons of the New World have shown that, whereas late prehistoric, recent, and present Native Americans tend to exhibit a cranial morphology similar to late and modern Northern Asians (short and wide neurocrania; high, orthognatic and broad faces; and relatively high and narrow orbits and noses), the earliest South Americans tend to be more similar to present Australians, Melanesians, and Sub-Saharan Africans (narrow and long neurocrania; prognatic, low faces; and relatively low and broad orbits and noses). However, most of the previous studies of early American human remains were based on small cranial samples. Herein we compare the largest sample of early American skulls ever studied (81 skulls of the Lagoa Santa region) with worldwide data sets representing global morphological variation in humans, through three different multivariate analyses. The results obtained from all multivariate analyses confirm a close morphological affinity between SouthAmerican Paleoindians and extant Australo-Melanesians groups, supporting the hypothesis that two distinct biological populations could have colonized the New World in the Pleistocene/Holocene transition.
Stereostructure of luminamicin, an anaerobic antibiotic, via molecular dynamics, NMR spectroscopy, and the modified Mosher method
Authors: Gouda Hiroaki , Sunazuka Toshiaki , Ui Hideaki , Handa Masaki , Sakoh Yusuke , Iwai Yuzuru , Hirono Shuichi , Ōmura Satoshi
Published: December 2005

The absolute stereostructure of luminamicin, an anaerobic antibiotic, has been determined by using conformational analysis via high-temperature molecular dynamics, NMR spectroscopy, and the modified Mosher method. It was found that luminamicin has the
S
,
S
,
R
,
R
,
R
,
R
,
S
,
S
,
S
,
R
, and
S
configurations at C2, C4, C7, C9, C10, C11, C12, C13, C16, C28, and C29, respectively. This configuration is the same as that found in nodusmicin, which has a chemical structure quite similar to luminamicin. The structure of luminamicin consists of three different rings, i.e., a decalin ring, a 10-membered macrolactone ring, and a 14-membered macrolactone ring. The resulting three-dimensional structure of luminamicin shows an interesting feature in that the maleic anhydride functionality in conjugation with the enol ether group of the 14-membered macrolactone is nearly perpendicular to the plane of the other two rings.
Differential cis-regulation of human versus mouse
TERT
gene expression
in vivo
: Identification of a human-specific repressive element
Authors: Horikawa Izumi , Chiang Y. Jeffrey , Patterson Tricia , Feigenbaum Lionel , Leem Sun-Hee , Michishita Eriko , Larionov Vladimir , Hodes Richard J. , Barrett J. Carl
Published: December 2005

In vivo
expression of human telomerase is significantly different from that of mouse telomerase. To assess the basis for this difference, a bacterial artificial chromosome clone containing the entire
hTERT
(human telomerase reverse transcriptase) gene was introduced in mice. In these transgenic mice, expression of the
hTERT
transgene was similar to that of endogenous
hTERT
in humans, rather than endogenous
mTERT
(mouse telomerase reverse transcriptase). In tissues and cells showing a striking difference in expression levels between
hTERT
in humans and
mTERT
in mice (i.e., liver, kidney, lung, uterus, and fibroblasts), expression of the
hTERT
transgene in transgenic mice was repressed, mimicking
hTERT
in humans. The transcriptional activity of the
hTERT
promoter was much lower than that of the
mTERT
promoter in mouse embryonic fibroblasts or human fibroblasts. Mutational analysis of the
hTERT
and
mTERT
promoters revealed that a nonconserved GC-box within the
hTERT
promoter was responsible for the human-specific repression. These results reveal that a difference in cis-regulation of transcription, rather than transacting transcription factors, is critical to species differences in tissue-specific
TERT
expression. Our data also suggest that the GC-box-mediated, human-specific mechanism for
TERT
repression is impaired in human cancers. This study represents a detailed characterization of the functional difference in a gene promoter of mice versus humans and provides not only important insight into species-specific regulation of telomerase and telomeres but also an experimental basis for generating mice humanized for telomerase enzyme and its pattern of expression.
Pinpointing and preventing imminent extinctions
Authors: Ricketts Taylor H. , Dinerstein Eric , Boucher Tim , Brooks Thomas M. , Butchart Stuart H. M. , Hoffmann Michael , Lamoreux John F. , Morrison John , Parr Mike , Pilgrim John D. , Rodrigues Ana S. L. , Sechrest Wes , Wallace George E. , Berlin Ken , Bielby Jon , Burgess Neil D. , Church Don R. , Cox Neil , Knox David , Loucks Colby , Luck Gary W. , Master Lawrence L. , Moore Robin , Naidoo Robin , Ridgely Robert , Schatz George E. , Shire Gavin , Strand Holly , Wettengel Wes , Wikramanayake Eric
Published: December 2005

Slowing rates of global biodiversity loss requires preventing species extinctions. Here we pinpoint centers of imminent extinction, where highly threatened species are confined to single sites. Within five globally assessed taxa (i.e., mammals, birds, selected reptiles, amphibians, and conifers), we find 794 such species, three times the number recorded as having gone extinct since 1500. These species occur in 595 sites, concentrated in tropical forests, on islands, and in mountainous areas. Their taxonomic and geographical distribution differs significantly from that of historical extinctions, indicating an expansion of the current extinction episode beyond sensitive species and places toward the planet's most biodiverse mainland regions. Only one-third of the sites are legally protected, and most are surrounded by intense human development. These sites represent clear opportunities for urgent conservation action to prevent species loss.
Intraepithelial CD8+tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer
Authors: Sato Eiichi , Olson Sara H. , Ahn Jiyoung , Bundy Brian , Nishikawa Hiroyoshi , Qian Feng , Jungbluth Achim A. , Frosina Denise , Gnjatic Sacha , Ambrosone Christine , Kepner James , Odunsi Tosin , Ritter Gerd , Lele Shashikant , Chen Yao-Tseng , Ohtani Haruo , Old Lloyd J. , Odunsi Kunle
Published: December 2005

In a recent report, [Zhanget al.(2003)N. Engl. J. Med.348, 203–213], the presence of CD3+tumor-infiltrating lymphocytes (TILs) was found to correlate with improved survival in epithelial ovarian cancer. We performed immunohistochemical analysis for TILs and cancer testis antigens in 117 cases of epithelial ovarian cancer. The interrelationship between subpopulations of TILs and expression of cancer testis antigens was investigated, as well as between TILs and overall survival. The median follow-up of the patients was 31 months. Patients with higher frequencies of intraepithelial CD8+T cells demonstrated improved survival compared with patients with lower frequencies [median = 55 versus 26 months; hazard ratio = 0.33; confidence interval (C.I.) = 0.18–0.60;P= 0.0003]. No association was found for CD3+TILs or other subtypes of intraepithelial or stromal TILs. However, the subgroups with high versus low intraepithelial CD8+/CD4+TIL ratios had median survival of 74 and 25 months, respectively (hazard ratio = 0.30; C.I. = 0.16–0.55;P= 0.0001). These results indicate that CD4+TILs influence the beneficial effects of CD8+TIL. This unfavorable effect of CD4+T cells on prognosis was found to be due to CD25+forkhead box P3 (FOXP3)+regulatory T cells (Treg; suppressor T cells), as indicated by survival of patients with high versus low CD8+/Treg ratios (median = 58 versus 23 months; hazard ratio = 0.31; C.I. = 0.17–0.58;P= 0.0002). The favorable prognostic effect of intraepithelial CD8+TILs did not correlate with concurrent expression of NY-ESO-1 or MAGE antigens. We conclude that intraepithelial CD8+TILs and a high CD8+/Treg ratio are associated with favorable prognosis in epithelial ovarian cancer.
The proficiency of a thermophilic chorismate mutase enzyme is solely through an entropic advantage in the enzyme reaction
Authors: Zhang Xiaohua , Bruice Thomas C.
Published: December 2005

A study of the
Thermus thermophilus
chorismate mutase (TtCM) is described by using quantum mechanics (self-consistent-charge density-functional tight binding)/molecular mechanics, umbrella sampling, and the weighted histogram analysis method. The computed free energies of activation for the reactions in water and TtCM are comparable to the experimental values. The free energies for formation of near attack conformer have been determined to be 8.06 and 0.05 kcal/mol in water and TtCM, respectively. The near attack conformer stabilization contributes ≈90% to the proficiency of the enzymatic reaction compared with the reaction in water. The transition state (TS) structures and partial atom charges are much the same in the enzymatic and water reactions. The difference in the electrostatic interactions of Arg-89 with O13 in the enzyme–substrate complex and enzyme–TS complex provides the latter with but 0.55 kcal/mol of 1.92 kcal/mol total TS stabilization. Differences in electrostatic interactions between components at the active site in the enzyme–substrate complex and enzyme–TS complex are barely significant, such that TS stabilization is of minor importance and the enzymatic catalysis is through an entropic advantage.
Sequence determinants of a conformational switch in a protein structure
Authors: Anderson Thomas A. , Cordes Matthew H. J. , Sauer Robert T.
Published: December 2005

The Arc repressor of bacteriophage P22 is a dimeric member of the ribbon–helix–helix family of transcription factors. Residues 9–14 of each wild-type Arc subunit pair to form two antiparallel β-strands and have the alternating pattern of polar and nonpolar residues expected for a β-ribbon with one solvent-exposed face and one face that forms part of the hydrophobic core. Simultaneously switching Asn-11 to Leu and Leu-12 to Asn changes the local binary sequence pattern to that of an amphipathic helix. Previous studies have shown that this double mutation results in replacement of the wild-type β-ribbon by two right-handed 310-helices. Moreover, an Arc variant bearing just the Asn-11 → Leu mutation has an ambiguous binary pattern and can form either the ribbon or the helical structures, which interchange rapidly. Here, we study Arc mutants in which position 11 is occupied by Gly, Ala, Val, Ile, Leu, Met, Phe, or Tyr. These mutants adopt the wild-type β-ribbon structure in a sequence context that stabilizes this fold, but they assume the alternative helical structure in a sequence background in which the wild-type fold is precluded by negative design. In an otherwise wild-type sequence background, the detailed chemical properties of the position 11 side chain dictate which of the two competing conformational folds is preferred.
Constructing Multivariate Analyses (of Dangerous Dyads)
Authors: Lee Ray James
Published: December 2005

Most multivariate models aimed at evaluating the impact of democracy on interstate conflict contain a set of control variables sufficiently large to have a confusing impact. Partly for that reason, the potentially confounding impacts of such variables as wealth, political stability, and political similarity on the relationship of democracy to conflict have still not been evaluated in a definitive manner. In other cases, multivariate models contain intervening variables that are likely to produce misleading results. Multivariate analyses aimed specifically at uncovering spurious relationships in a more straightforward and incremental manner are better able to produce clear and informative results.
Heeding Ray's Advice: An Exegesis on Control Variables in Systemic Democratic Peace Research
Authors: Kadera Kelly M. , McLaughlin Mitchell Sara
Published: December 2005

We submit our recent systemic democratic peace research to the control variable doctrine of James Lee Ray, as codified in his 2003 treatise. In particular, we seek to determine whether international institutions intervene in the relationship between the democratic community's strength and the use and effectiveness of third party conflict management, whether hegemony is a competing explanation of third party settlement, and whether our extant model is robust when several control variables are specified. Two important conclusions are reached: (1) the democratic community's strength and institutional vitality promote third party mediation and its success, regardless of hegemonic might and other controls; and 2) Ray's teaching is properly understood as an exhortation for scholars to more carefully consider the theoretical role of each control variable and its proper treatment in statistical models, not as an edict banning the use of control variables.
Ubiquitin/SUMO modification of PCNA promotes replication fork progression in Xenopus laevis egg extracts
Authors: Leach Craig A. , Michael W. Matthew
Published: December 2005

The homotrimeric DNA replication protein proliferating cell nuclear antigen (PCNA) is regulated by both ubiquitylation and sumoylation. We study the appearance and the impact of these modifications on chromosomal replication in frog egg extracts. Xenopus laevis PCNA is modified on lysine 164 by sumoylation, monoubiquitylation, and diubiquitylation. Sumoylation and monoubiquitylation occur during the replication of undamaged DNA, whereas diubiquitylation occurs specifically in response to DNA damage. When lysine 164 modification is prevented, replication fork movement through undamaged DNA slows down and DNA polymerase δ fails to associate with replicating chromatin. When sumoylation alone is prevented, replication occurs normally and neither monoubiquitylation nor sumoylation are required for the replication of simple single-strand DNA templates. Our findings expand the repertoire of functions for PCNA ubiquitylation and sumoylation by elucidating a role for these modifications during the replication of undamaged DNA. Furthermore, they suggest that PCNA monoubiquitylation serves as a molecular gas pedal that controls the speed of replisome movement during S phase.
Weakly non-local fluid mechanics: the Schrödinger equation
Authors: Ván Peter , Fülöp Tamás
Published: December 2005

A weakly non-local extension of ideal fluid dynamics is derived from the Second Law of thermodynamics. It is proved that in the reversible limit, the additional pressure term can be derived from a potential. The requirement of the additivity of the specific entropy function determines the quantum potential uniquely. The relation to other known derivations of the Schrödinger equation (stochastic, Fisher information, exact uncertainty) is clarified.
Transcription-mediated gene fusion in the human genome
Authors: Akiva Pinchas , Toporik Amir , Edelheit Sarit , Peretz Yifat , Diber Alex , Shemesh Ronen , Novik Amit , Sorek Rotem
Published: December 2005

Transcription of a gene usually ends at a regulated termination point, preventing the RNA-polymerase from reading through the next gene. However, sporadic reports suggest that chimeric transcripts, formed by transcription of two consecutive genes into one RNA, can occur in human. The splicing and translation of such RNAs can lead to a new, fused protein, having domains from both original proteins. Here, we systematically identified over 200 cases of intergenic splicing in the human genome (involving 421 genes), and experimentally demonstrated that at least half of these fusions exist in human tissues. We showed that unique splicing patterns dominate the functional and regulatory nature of the resulting transcripts, and found intergenic distance bias in fused compared with nonfused genes. We demonstrate that the hundreds of fused genes we identified are only a subset of the actual number of fused genes in human. We describe a novel evolutionary mechanism where transcription-induced chimerism followed by retroposition results in a new, active fused gene. Finally, we provide evidence that transcription-induced chimerism can be a mechanism contributing to the evolution of protein complexes.
Tandem chimerism as a means to increase protein complexity in the human genome
Authors: Parra Genís , Reymond Alexandre , Dabbouseh Noura , Dermitzakis Emmanouil T. , Castelo Robert , Thomson Timothy M. , Antonarakis Stylianos E. , Guigó Roderic
Published: December 2005

The “one-gene, one-protein” rule, coined by Beadle and Tatum, has been fundamental to molecular biology. The rule implies that the genetic complexity of an organism depends essentially on its gene number. The discovery, however, that alternative gene splicing and transcription are widespread phenomena dramatically altered our understanding of the genetic complexity of higher eukaryotic organisms; in these, a limited number of genes may potentially encode a much larger number of proteins. Here we investigate yet another phenomenon that may contribute to generate additional protein diversity. Indeed, by relying on both computational and experimental analysis, we estimate that at least 4%–5% of the tandem gene pairs in the human genome can be eventually transcribed into a single RNA sequence encoding a putative chimeric protein. While the functional significance of most of these chimeric transcripts remains to be determined, we provide strong evidence that this phenomenon does not correspond to mere technical artifacts and that it is a common mechanism with the potential of generating hundreds of additional proteins in the human genome.
Poor response to 18‐month lamivudine monotherapy in chronic hepatitis B patients with IgM anti‐HBc and acute exacerbation
Authors: CHEN J‐J. , LIN C‐Y. , SHEU M‐J. , KUO H‐T. , SUN C‐S. , TANG L‐Y. , WANG S‐L. , TSAI S‐L.
Published: December 2005

Background

Appearance of immunoglobulin class M antibody against hepatitis B core antigen is a predictor of beneficial response to interferon‐alpha therapy in chronic hepatitis B patients, but its relationship with the efficacy of lamivudine therapy remains unclear.

Aim

To investigate the outcome of lamivudine therapy in chronic hepatitis B patients with immunoglobulin class M antibody against hepatitis B core antigen and acute exacerbation.

Methods

Chronic hepatitis B patients with acute exacerbation receiving a national‐wide therapeutic trial of 18‐month lamivudine monotherapy were enrolled for the analysis. Four consecutive seronegative patients were recruited as individual matching controls of one positive subject. Immunoglobulin class M antibody against hepatitis B core antigen in serum was assayed monthly by an automated microparticle enzyme immunoassay.

Results

Fifteen (8.9%) of 167 chronic hepatitis B patients with acute exacerbation were seropositive for IgM anti‐HBc. Thus 60 seronegative patients were consecutively recruited as control group. At the end of therapy, two (13.3%) of the 15 seropositive patients achieved a sustained response, significantly lower than 26 (43.3%) of the control group.

Conclusions

Appearance of immunoglobulin class M antibody against hepatitis B core antigen in chronic hepatitis B patients with acute exacerbation is a predictor of poor response to lamivudine monotherapy. This is clinically relevant to the decision‐making in treating chronic hepatitis B patients with acute exacerbation.
5‐aminosalicylic acid release from a new controlled‐release mesalazine formulation during gastrointestinal transit in healthy volunteers
Authors: BRUNNER M. , LACKNER E. , EXLER P. S. , DE FLUITER H. C. , KLETTER K. , TSCHURLOVITS M. , DUDCZAK R. , EICHLER H.‐G. , MÜLLER M.
Published: December 2005

Background

Mesalazine (5‐aminosalicylic acid, 5‐ASA) containing formulations represent a cornerstone in the treatment of inflammatory bowel diseases. A novel formulation with an Eudragit L/S mixture coating has been developed to provide selective release of 5‐ASA to the ileo‐caecal region and the colon.

Aim

To determine the release of 5‐ASA during the gastrointestinal transit.

Methods

A single oral dose of mesalazine EC 500 mg gastroresistant tablets (Asamax) was administered to eight healthy male volunteers. Gastrointestinal transit and tablet disintegration were monitored by scintigraphy. 5‐ASA release was verified by assessing plasma pharmacokinetics.

Results

Initial tablet disintegration was observed 5.65 ± 0.86 h after dosing, corresponding to the detection of 5‐ASA in plasma. This occurred in the ileo‐caecal region in three subjects and the ascending colon in the remaining five. The relative percentage of 5‐ASA absorption was more pronounced in the ascending colon (41 ± 27.4%) than the ileo‐caecal region (6.6 ± 9.2%).

Conclusion

This mesalazine EC gastroresistant tablets release locally active 5‐ASA specifically in the ileo‐caecal region and the ascending colon.
Stability of irritable bowel syndrome using a Rome II‐based classification
Authors: WILLIAMS R. E. , BLACK C. L. , KIM H.‐Y. , ANDREWS E. B. , MANGEL A. W. , BUDA J. J. , COOK S. F.
Published: December 2005

Background

As there is no biological marker for irritable bowel syndrome, a diagnosis is made using symptom‐based criteria.

Aim

To evaluate the stability of self‐reported symptoms consistent with Rome II‐based irritable bowel syndrome classification.

Methods

Irritable bowel syndrome subjects identified in a 2001 population‐based study by modified Rome II criteria were re‐contacted 2 years later. Data were collected via a web‐based questionnaire.

Results

Of the 697 subjects, 30% remained in the same irritable bowel syndrome subtype in both surveys, 18.4% changed irritable bowel syndrome subtype and 52% no longer met the irritable bowel syndrome criteria at follow‐up. Subjects continuing to meet the irritable bowel syndrome criteria were more likely to have been initially classified in the alternating irritable bowel syndrome subtype and had more psychological impairment and lower irritable bowel syndrome‐related quality of life than subjects not fulfilling the irritable bowel syndrome criteria at follow‐up. Lack of pain caused more subjects to fall out of the irritable bowel syndrome criteria than the absence of non‐painful bowel symptoms. However, the majority of subjects that did not fulfill the pain component of the irritable bowel syndrome criteria continued to report abdominal pain of at least moderate severity.

Conclusion

In a US population‐based follow‐up study using modified Rome II criteria, we found irritable bowel syndrome is episodic in nature and current classification is limited in capturing fluctuation of disease over time.
Lifestyle factors and symptoms of gastro‐oesophageal reflux – a population‐based study
Authors: NOCON M. , LABENZ J. , WILLICH S. N.
Published: December 2005

Background

Although the symptoms of gastro‐oesophageal reflux disease are common in the general adult population, the aetiology of gastro‐oesophageal reflux disease is still largely unknown. Lifestyle factors such as diet, body mass index, and smoking have been frequently suggested as possible risk factors.

Aim

In the present study, we investigated the relationship between various lifestyle factors and gastro‐oesophageal reflux disease symptoms.

Methods

A total of 7124 subjects were interviewed as part of the German National Health Interview and Examination Survey, a representative sample of the general adult population. We examined a variety of possible risk factors, including age, gender, body mass index, smoking, alcohol consumption, sports and different foods. To investigate the association between lifestyle and symptoms, we used a multiple logistic regression model, including various gastro‐oesophageal reflux disease patient characteristics.

Results

We found an association among those with reflux symptoms who were overweight and obese (odds ratio: 1.8, 95% confidence interval: 1.5–2.2; odds ratio: 2.6, 95% confidence interval: 2.2–3.2), respectively. Further risk factors included smoking and the frequent consumption of spirits, sweets, or white bread. Physical activity and the consumption of fruits seemed to have some protective effect.

Conclusions

Lifestyle factors – in particular overweight, obesity and smoking – were associated with increased reflux symptoms.
The efficacy and safety of ɛ‐aminocaproic acid treatment in patients with cirrhosis and hyperfibrinolysis
Authors: GUNAWAN B. , RUNYON B.
Published: December 2005

Background

Patients with decompensated cirrhosis are at risk for hyperfibrinolysis; this is potentially fatal. ɛ‐aminocaproic acid has been used to treat patients with hyperfibrinolysis; however, the data about its benefit in the setting of cirrhosis are minimal.

Aim

To analyse the efficacy of ɛ‐aminocaproic acid and its safety in cirrhotic patients with hyperfibrinolysis.

Methods

All patients with an abnormal euglobin lysis time who were admitted to Rancho Los Amigos Medical Center from 1 January 2001 to 31 December 2002 were included in the study. Their medical records were reviewed and analysed.

Results

There were 60 cirrhotic patients with shortened euglobin lysis time. Fifty‐two patients received ɛ‐aminocaproic acid. Of the 52 patients, seven had one or more bleeding episodes with the subcutaneous or soft tissue bleeding as the most common indication for ɛ‐aminocaproic acid use. Of the 37 patients, 34 (92%) had improvement or resolution of their bleeding. Only two (3%) patients had ɛ‐aminocaproic acid treatment discontinued because of minor side effects, rash and lightheadedness. There were no thromboembolic complications of treatment.

Conclusions

ɛ‐aminocaproic acid was found to be effective and safe for treatment of hyperfibrinolysis in patients with cirrhosis.
Prevalence of gastro‐oesophageal reflux disease in Spain and associated factors
Authors: PONCE J. , VEGAZO O. , BELTRÁN B. , JIMÉNEZ J. , ZAPARDIEL J. , CALLE D. , PIQUÉ J. M. ,   MEMBERS OF THE IBERGE STUDY GROUP
Published: December 2005

Background

The prevalence of gastro‐oesophageal reflux disease (GERD), has not been characterized in Spain.

Aim

To measure the prevalence of GERD in Spain, and the factors associated with it, by means of a primary care‐based study.

Methods

An epidemiological, multicentre, cross‐sectional, population‐based study. A self‐administered questionnaire was sent out to randomly selected patients. Data were statistically analysed to provide the prevalence of GERD and to compare it with that of gastro‐oesophageal reflux symptoms. Factors associated with GERD were studied using logistic regression models.

Results

The response rate was 45%. The prevalence of GERD was 15% (95% CI: 13.2–16.2). When compared with gastro‐oesophageal reflux symptoms patients, those with GERD experienced more intense symptoms (moderate–severe: 35% vs. 8%, P < 0.001) and suffered heartburn more frequently both at day and night (48% vs. 25%, P < 0.001) and for longer period of times (69% vs. 62%, P = 0.057). A body mass index of >25% (odds ratio: 1.07; 95% CI: 1.03–1.11) was the only independent variable associated with GERD. The risk of suffering GERD increases by 7% for each kg/m2 that the body mass index increases.

Conclusions

The prevalence of GERD among the Spanish population is 15%. Body mass index is the only risk factor significantly associated with GERD.
Systematic review and meta‐analysis: levofloxacin‐based rescue regimens after Helicobacter pylori treatment failure
Authors: GISBERT J. P. , DE LA MORENA F.
Published: December 2005

Background

A quadruple therapy has been generally recommended as rescue regimen for Helicobacter pylori eradication failures.

Aims

To systematically review the efficacy and tolerance of levofloxacin‐based rescue regimens, and to conduct a meta‐analysis of studies comparing these regimens with quadruple therapy for H. pylori eradication failures.

Methods

Selection of studies – levofloxacin‐based rescue regimens. For the meta‐analysis, randomized‐controlled trials comparing levofloxacin‐based and quadruple regimens. Search strategy – electronic and manual. Assessment of study quality – independently by two reviewers. Data synthesis –‘intention‐to‐treat’ eradication rate.

Results

Mean eradication rate with levofloxacin‐based regimens was 80%. Ten‐day regimens were more effective than 7‐day combinations (81% vs. 73%; P < 0.01). The meta‐analysis showed better results with levofloxacin than with the quadruple combination (81% vs. 70%; OR = 1.80; 95% CI = 0.94–3.46). This difference reached statistical significance and heterogeneity markedly decreased when a single outlier study was excluded or when only high‐quality studies were considered. Meta‐analysis showed less adverse effects with levofloxacin than with quadruple regimen, both overall (19% vs. 44%; OR = 0.27; 95% CI = 0.16–0.46) and regarding severe adverse effects (0.8% vs. 8.4%; OR = 0.20; 95% CI =0.06–0.67).

Conclusions

After H. pylori eradication failure, levofloxacin‐based rescue regimen is more effective and better tolerated than the generally recommended quadruple therapy. A 10‐day combination of levofloxacin–amoxicillin–proton pump inhibitor constitutes an encouraging second‐line alternative.
Disposition and pharmacodynamics of propofol during isovolaemic haemorrhage followed by crystalloid resuscitation in humans
Authors: Takizawa Eri , Takizawa Daisuke , Hiraoka Haruhiko , Saito Shigeru , Goto Fumio
Published: December 2005

Aims

The purpose of this study was to estimate the changes in unbound propofol concentration and pharmacodynamics of propofol during isovolaemic haemorrhage followed by crystalloid resuscitation.

Methods

Ten patients undergoing measure elective surgery were enrolled in this study. Anaesthesia was maintained by 60% nitrous oxide in oxygen, fentanyl 10–20 µg kg−1 and an infusion of propofol at 8 mg kg−1 h−1 until the end of the operation. Radial arterial samples were collected for measurement of propofol concentration just before the start of the operation, and at the point when blood loss was > 10 ml kg−1, 20 ml kg−1 and 30 ml kg−1. Cardiac output (CO), haemoglobin values and plasma concentrations of albumin were also determined. Patients were resuscitated with lactated Ringer's solution to maintain a mean arterial blood pressure (± 20% of prehaemorrhage). Bispectral index (BIS) was measured continuously.

Results

Mean blood pressure, heart rate and CO were well maintained during the operation in all patients. Haemoglobin values and plasma albumin concentrations decreased significantly during surgery. There were no significant differences in total propofol concentrations across the time points. The unbound propofol concentration was increased from 0.10 ± 0.040 µg ml−1 to 0.17 ± 0.041 µg ml−1 after the haemorrhage of 30 ml kg−1 (P < 0.05). BIS was significantly decreased from 47 ± 5.9 to 39 ± 3.7 (P < 0.05) after the haemorrhage of 30 ml kg−1.

Conclusions

The hypnotic potency of propofol is increased during isovolaemic haemorrhage in crystalloid resuscitated patients even if CO is maintained.
Influence of gender and pubertal stage at diagnosis on growth outcome in childhood thyrotoxicosis: results of a collaborative study
Authors: Cassio A. , Corrias A. , Gualandi S. , Tato’ L. , Cesaretti G. , Volta C. , Weber G. , Bona G. , Cappa M. , Bal M. , Bellone J. , Cicognani A.
Published: December 2005

Objective   To evaluate the influence of sex as well as pubertal stage at diagnosis on the growth outcome of childhood thyrotoxicosis.

Design  Retrospective, collaborative study.

Patients and methods   Longitudinal auxological evaluation in 101 patients (M/F 23/78) for 4·7 ± 3·1 years subdivided according to pubertal stage at diagnosis into prepubertal (group I) and pubertal (group II).

Results   At diagnosis height and bone age (BA) standard deviation score (SDS) were positive both in girls and boys of groups I and II. In boys of group II, height SDS was significantly higher than in girls of the same group (P = 0·007) and in boys of group I (P = 0·026). During the follow‐up, in group I, height SDS remained positive without significant differences between boys and girls, and in group II, height SDS remained significantly lower in girls than in boys. The age at onset of puberty and the age at menarche were within the normal range. Final height (FH) was within target height (TH) range in all groups The FH SDS and the height gain (FH–TH) were similar in girls and in boys in group I and significantly higher in boys than in girls (P < 0·05) in group II. The boys of group II showed a mean height gain significantly greater than that found in all the other groups.

Conclusions   Despite the advancement of BA at presentation, there were no adverse effects on subsequent growth and FH; the growth outcome seems to be better in boys than in girls in group II.
Identification of wild type and variants of oestrogen receptors in polymorphonuclear and mononuclear leucocytes
Authors: Stygar Denis , Westlund Pär , Eriksson Håkan , Sahlin Lena
Published: December 2005

Objective   Leucocytes play an important role in the pathogenesis of autoimmune and cardiovascular diseases. Clinical and epidemiological observations indicate that the sex steroid hormones, particularly oestrogens, may regulate leucocyte functions. The assumption that oestrogens have a direct effect on leucocytes has to be supported by identification of functional oestrogen receptors (ER) in leucocytes. This study aimed at investigating the presence of ER subtypes in different types of leucocytes isolated from peripheral blood of female and male donors.

Design and patients   A total of nine men (age range 18–43 years) and nine women (age range 19–42 years) all healthy blood donors, were recruited for the study. The donors did not receive any medication or hormonal contraceptives for the last three months. Ten millilitres of peripheral blood was collected from each donor. Polymorphonuclear leucocytes (PMN) and peripheral blood mononuclear cells (PBMC) were purified by density gradient centrifugation.

Measurements   ERα and ERβ mRNA expression was measured by real‐time reverse transcriptase–polymerase chain reaction (RT‐PCR), and ER proteins were analysed by Western blot in the PBMC and PMN leucocyte populations. In addition, expression profiles of ER variant isoforms were characterized by conventional PCR using the splice‐targeted primer approach.

Results   Although we detected wild‐type ERα and ERβ mRNAs in PBMC but not in PMN cells, the ERα and ERβ proteins were found in both cell types using Western blot. We observed that both ERα and ERβ proteins differ in size between PMN and PBMC, suggesting that the two leucocyte populations contain diverse variant isoforms of ERα and ERβ. RT‐PCR analysis of exon‐deleted ER splice variants revealed that PBMC express several exon‐deleted variants of ERα and ERβ, along with wild‐type receptor, whereas the PMN cells only express exon‐deleted variant isoforms and no wild‐type ERα or ERβ.

Conclusions   Our study demonstrates the presence of ERα and ERβ in PBMC and PMN cells from female and male donors. The ERα and ERβ genes have complex transcriptional profiles, with many receptor variant isoforms being expressed. Considering the diversity of ER isoforms in leucocyte subtypes, we conclude that the expected effect of oestrogen would be highly cell type‐specific. Further studies are needed to test the functional activity of ER isoforms and their relation to disease.
Investigations of thyroid hormones and antibodies based on a community health survey: the Busselton thyroid study
Authors: O'Leary Peter C. , Feddema Peter H. , Michelangeli Valdo P. , Leedman Peter J. , Chew Gerard T. , Knuiman Matthew , Kaye Joey , Walsh John P.
Published: December 2005

Objective  Overt or subclinical thyroid dysfunction is common within the community, yet the significance of subtle anomalies in thyroid function tests remains contentious. The aims of this study were to: (a) establish reference intervals for serum‐free thyroxine (FT4), thyroid‐stimulating hormone (TSH) and thyroid antibodies (antithyroperoxidase, TPOAb and antithyroglobulin, TgAb) in the Busselton community of south‐western Western Australia; and (b) determine the prevalence of thyroid hormone anomalies in this community.

Subjects and design  In 1981, 2115 adults residing in Busselton participated in a cross‐sectional health survey that involved blood collection and a questionnaire on lifestyle and general health history.

Measurements  Serum samples were analysed for FT4, TSH, TPOAb and TgAb by immunochemiluminescent assays.

Results  Based on standard statistical approaches and using guidelines recommended by the National Academy of Clinical Biochemistry (NACB), reference intervals were derived for each analyte: 9–23 pmol/l for FT4, 0·4–4·0 mIU/l (TSH), < 35 KIU/l (TPOAb) and < 55 KIU/l (TgAb). The prevalence of elevated thyroid antibodies was 12·4% among subjects without a history of thyroid disease and is more common in women than in men. Elevated thyroid antibody levels were observed at both extremes of TSH abnormality, but were more commonly increased when TSH levels were above 4·0 mIU/l (63% subjects) than for those with TSH levels 0·4–4·0mIU/l (7·8% subjects).

Conclusions  This study establishes the prevalence of antibodies to thyroperoxidase and thyroglobulin in a community‐based sample and reference intervals for free T4 and TSH. When the NACB decision limits are applied to older men or women, there is a markedly increased number with ‘elevated’ autoantibody levels compared to sex‐ and age‐specific reference intervals.
Discordant twin growth in utero and differences in blood pressure and endothelial function at 8 years of age
Authors: HALVORSEN C. P. , ANDOLF E. , HU J. , PILO C. , WINBLADH B. , NORMAN M.
Published: December 2005

Objective.  Low birth weight is associated with increased prevalence of hypertension and cardiovascular disease in adults. The aim of this study was to evaluate genetic and intrauterine environmental contributions to blood pressure (BP) and vascular functions in twins with discordant growth in utero.

Subjects.  We studied 31 twin pairs (21 monozygous and nine dizygous), mean age 8 years) with large within‐pair differences in birth weight. Among the monozygous pairs, nine had suffered from twin‐to‐twin‐transfusion syndrome (TTTS).

Methods.  Apart from BP, we determined diameters and elasticity of the carotid artery and abdominal aorta with ultrasonography, and endothelial function in skin vessels with a laser Doppler technique, before and after transdermal delivery of acetylcholine and nitroglycerin.

Results.  Eight of 62 twin subjects had a systolic BP above the 90th percentile in a North‐American reference population. Among these, seven/eight were monozygous with a history of poor fetal growth and/or TTTS. In monozygous twin pairs without TTTS, systolic BP and pulse pressure were higher and vascular endothelial function was impaired in the lower birth weight twin. In the TTTS group, the lighter twin had a narrower carotid artery but there was no within‐pair difference in arterial elasticity. Pre‐eclampsia during the index pregnancy enhanced within‐pair differences in BP but abolished within‐pair differences in endothelial function.

Conclusions.  Severe fetal growth retardation contributes to higher BP, arterial narrowing and endothelial dysfunction in childhood. Pre‐eclampsia may act both as an effect modifier and confounder of these associations.
Survival rate 28 days after hospital admission with first myocardial infarction. Inverse relationship with socio‐economic circumstances
Authors: GERWARD S. , TYDÉN P. , HANSEN O. , ENGSTRÖM G. , JANZON L. , HEDBLAD B.
Published: December 2005

Objective.  To study to what extent geographical differences of the mortality from ischaemic heart disease (IHD) can be accounted for by the 28‐day case fatality rate (CFR) following first hospital admittance for acute myocardial infarction (MI) and whether the geographical pattern of survival has any relationship with socio‐economic circumstances.

Design.  Register‐based surveillance study.

Setting.  Seventeen residential areas in Malmö, Sweden.

Subjects.  All 5533 patients were admitted during 1986–1995 for a first acute MI at Malmö University Hospital.

Main outcome measures.  CFR is based on record linkage with national registers. Area‐specific cardiovascular and socio‐economic scores (SES) are based on previous cross‐sectional studies.

Results.  In patients below 75 years of age, differences of the 28‐day CFR accounted for 20–30% of the geographical variance in mortality from IHD. No corresponding association was found in older age groups. Patients from areas with low SES had the highest CFR, 23.8%. The odds ratios of fatal outcome for patients from areas with median and low SES (versus high SES) were 1.23 (95% CI: 1.01–1.50) and 1.25 (95% CI: 1.03–1.52), respectively (P for trend: 0.060). The strongest correlation was observed in men below 75 years of age (P for trend: 0.007). During the study period there was an improvement of the survival rate for patients from high and medium SES areas but no corresponding change for patients coming from areas having a low SES.

Conclusions.  In patients below 75 years, geographical differences of the mortality from IHD were related to differences of the 28‐day CFR following hospital admittance for a first MI. Rates of survival were inversely related to socio‐economic circumstances in the patient's residential area.