bluuebunny/crossref_metadata_2025 huggingface dataset:
A review of quality assessment of the methodology used in guidelines and systematic reviews on oral mucositis
Authors: Potting Carin , Mistiaen Patriek , Poot Else , Blijlevens Nicole , Donnelly Peter , Van Achterberg Theo
Published: October 2008

Aims and objectives.  The objective of this study was to identify and to assess the quality of evidence‐based guidelines and systematic reviews we used in the case of oral mucositis, to apply general quality criteria for the prevention and treatment of oral mucositis in patients receiving chemotherapy, radiotherapy or both.

Design.  Systematic review.

Methods.  Literature searches were carried out in several electronic databases and websites.

Publications were included if they concerned oral mucositis involving adults treated for cancer and had been published after 1 January 2000. As far as systematic reviews were concerned, the article had to report a search strategy, if the search was minimally conducted in the database PubMed or Medline and the articles included in the review were subjected to some kind of methodological assessment.

The Appraisal of Guidelines for Research and Education (AGREE) instrument was used to assess the quality of the guidelines and the Overview Quality Assessment Questionnaire (OQAQ) was used for the quality of systematic reviews.

Results.  Thirty‐one articles met the inclusion criteria of which 11 were guidelines and 20 were systematic reviews. Nine of the 11 guidelines did not explicitly describe how they identified, selected and summarised the available evidence. Reviews suffered from lack of clarity, for instance, in performing a thorough literature search. The quality varied among the different guidelines and reviews.

Conclusion.  Most guidelines and systematic reviews had serious methodological flaws.

Relevance to clinical practice.  There is a need to improve the methodological quality of guidelines and systematic reviews for the prevention and treatment of oral mucositis if they are to be used in clinical practice.
A hybrid zone provides evidence for incipient ecological speciation inHeliconiusbutterflies
Authors: ARIAS CARLOS F. , MUÑOZ ASTRID G. , JIGGINS CHRIS D. , MAVÁREZ JESÚS , BERMINGHAM ELDREDGE , LINARES MAURICIO
Published: October 2008

InHeliconiusbutterflies, it has been proposed that speciation occurs through a combination of divergence in ecological habitat preferences and mimetic colour patterns. Here we test this hypothesis by investigating a parapatric form of the widespread speciesHeliconius erato. Mendelian (colour patterns) and molecular genetic data permit us to address hypotheses about introgression and genetic differentiation between different populations. Combined analysis of colour pattern, microsatellite loci and mitochondrial DNA showed thatHeliconius erato venusandHeliconius erato chestertoniiform a bimodal hybrid zone implying partial reproductive isolation. In a sample of 121 individuals collected in sympatry, 25% were hybrids representing a significant deficit of heterozygotes compared to the Hardy–Weinberg expectation. Seven microsatellite loci, analysed for a subset of these individuals, showed marked differentiation between the parental taxa, and unambiguously identified two genotypic clusters concordant with our phenotypic classification of individuals. Mitochondrial DNA analysis showedH. erato venusas a monophyletic group well differentiated fromH. erato chestertonii, implying a lack of historical introgression between the populations.Heliconius erato chestertoniiis therefore an incipient species that maintains its integrity despite high levels of hybridization. Moreover,H. erato chestertoniiis found at higher altitudes than other races ofH. eratoand has a distinct colour pattern and mimetic relationship. Hence, there are now two examples of parapatric incipient species related toH. erato,H. himeraandH. erato chestertonii, both of which are associated with higher altitudes, more arid habitats and distinct mimetic relationships. This implies that parapatric habitat adaptation is a likely cause of speciation in this group.
The RNase E of Escherichia coli is a membrane‐binding protein
Authors: Khemici Vanessa , Poljak Leonora , Luisi Ben F. , Carpousis Agamemnon J.
Published: October 2008

RNase E is an essential endoribonuclease involved in RNA processing and mRNA degradation. The N‐terminal half of the protein encompasses the catalytic domain; the C‐terminal half is the scaffold for the assembly of the multienzyme RNA degradosome. Here we identify and characterize ‘segment‐A’, an element in the beginning of the non‐catalytic region of RNase E that is required for membrane binding. We demonstrate in vitro that an oligopeptide corresponding to segment‐A has the propensity to form an amphipathic α‐helix and that it avidly binds to protein‐free phospholipid vesicles. We demonstrate in vitro and in vivo that disruption of segment‐A in full‐length RNase E abolishes membrane binding. Taken together, our results show that segment‐A is necessary and sufficient for RNase E binding to membranes. Strains in which segment‐A has been disrupted grow slowly. Since in vitro experiments show that phospholipid binding does not affect the ribonuclease activity of RNase E, the slow‐growth phenotype might arise from a defect involving processes such as accessibility to substrates or interactions with other membrane‐bound machinery. This is the first report demonstrating that RNase E is a membrane‐binding protein and that its localization to the inner cytoplasmic membrane is important for normal cell growth.
Translation initiation factor IF1 of Bacillus stearothermophilus and Thermus thermophilus substitute for Escherichia coli IF1 in vivo and in vitro without a direct IF1–IF2 interaction
Authors: Kapralou Stavroula , Fabbretti Attilio , Garulli Chiara , Spurio Roberto , Gualerzi Claudio O. , Dahlberg Albert E. , Pon Cynthia L.
Published: October 2008

Bacterial translation initiation factor IF1 is homologous to archaeal aIF1A and eukaryal eIF1A, which form a complex with their homologous IF2‐like factors (aIF5B and eIF5B respectively) during initiation of protein synthesis. A similar IF1–IF2 interaction is assumed to occur in all bacteria and supported by cross‐linking data and stabilization of the 30S–IF2 interaction by IF1. Here we compare Escherichia coli IF1 with thermophilic factors from Bacillus stearothermophilus and Thermus thermophilus. All three IF1s are structurally similar and functionally interchangeable in vivo and in vitro. However, the thermophilic factors do not stimulate ribosomal binding of IF2ΔN, regardless of 30S subunits and IF2 origin. We conclude that an IF1–IF2 interaction is not universally conserved and is not essential for cell survival.
A RING‐finger protein regulates carotenogenesis via proteolysis‐independent ubiquitylation of a White Collar‐1‐like activator
Authors: Silva Fátima , Navarro Eusebio , Peñaranda Ascensión , Murcia‐Flores Laura , Torres‐Martínez Santiago , Garre Victoriano
Published: October 2008

Protein ubiquitylation plays a major role in the regulation of cellular processes mainly through proteasome‐dependent degradation, although it has become increasingly clear that it is also involved in other processes. In the fungus Mucor circinelloides, blue light regulates carotene biosynthesis, with this response controlled by crgA and mcwc‐1c genes. CrgA shows characteristics of ubiquitin ligases and represses carotenogenesis in the dark, whereas mcwc‐1c is a white collar 1‐like gene required for its light induction. Another two white collar 1‐like genes have been identified in M. circinelloides: mcwc‐1a, which is involved in phototropism, and mcwc‐1b, of unknown function. Analysis of double knockout mutants generated for crgA and every mcwc‐1 gene demonstrated that crgA and mcwc‐1c regulate carotenogenesis by independent pathways. It was also shown that the effect of crgA on carotenogenesis is mediated by mcwc‐1b, which acts as a carotenogenesis activator. CrgA is involved in proteolysis‐independent mono‐ and di‐ubiquitylation of MCWC‐1b, which results in its inactivation. Regulation of carotenogenesis in M. circinelloides by proteolysis‐independent ubiquitylation suggests that this mechanism of control could be more widespread than previously thought.
Complex extracellular interactions of proteases and a protease inhibitor influence multicellular development of Streptomyces coelicolor
Authors: Kim Dae Wi , Hesketh Andy , Kim Eun Sook , Song Ju Yeon , Lee Dae Hoon , Kim In Seop , Chater Keith F. , Lee Kye Joon
Published: October 2008

Streptomyces coelicolor produces an extracellular protease inhibitor protein, STI (Streptomyces trypsin inhibitor). We show that post‐growth elimination of STI is needed for colonies to develop aerial mycelium efficiently. Inactivation of STI, and thus the normal progression of colony development, at least partly involves an extracellular protease specified by gene SCO5913. Two‐hybrid analysis identified two possible targets of STI inhibition (the products of SCO1355 and SCO5447), both extracellular proteases containing a domain homologous with the P‐domain of eukaryotic convertases, proteases that mediate the processing of many precursors with important cellular or developmental roles. At least the SCO1355 protease is needed for the normal progression of development. Two components of the proposed cascade are dependent on the tRNA for the rare UUA (leucine) codon, which is specified by the developmental gene bldA. A model is presented that links intracellular regulatory events with an extracellular protease cascade to facilitate normal development.
Yersinia enterocolitica type III secretion of YopR requires a structure in its mRNA
Authors: Blaylock Bill , Sorg Joseph A. , Schneewind Olaf
Published: October 2008

Yersinia type III secretion machines transport substrate proteins into the extracellular medium or into the cytoplasm of host cells. Translational hybrids, involving genes that encode substrates as well as reporter proteins that otherwise cannot travel the type III pathway, identified signals that promote transport of effector Yops into host cells. Signals for the secretion of substrates into high calcium media were hitherto unknown. By exploiting attributes of translational hybrids between yopR, whose product is secreted, and genes that encode impassable proteins that jam the secretion machine, we isolated yopR mutations that abolish substrate recognition. Similar to effector Yops, an N‐terminal or 5′ signal in codons 1–11 is required to initiate YopR into the type III pathway. YopR secretion cannot be completed and translational hybrids cannot impose a block without a second signal, positioned at codons 131–149. Silent mutations in the second signal abrogate function and the phenotype of other mutations can be suppressed by secondary mutations predicted to restore base complementary in a 3′ stem‐loop structure of the yopR mRNA.
Phylogenetic relationships of Holarctic Teleiodini (Lepidoptera: Gelechiidae) based on analysis of morphological and molecular data
Authors: LEE SANGMI , BROWN RICHARD L.
Published: October 2008

AbstractPhylogenetic relationships of 25 genera of Holarctic Teleiodini (Gelechiidae) are postulated based on morphology and molecular characters, including CO‐I, CO‐II, and 28S genes. The phylogenetic analysis of the morphology matrix yielded four equal most‐parsimonious trees (length 330 steps, CI = 0.36, RI = 0.55) and a strict consensus tree (length 335 steps, CI = 0.36, RI = 0.54) with one polytomy and one trichotomy. The phylogenetic analysis of the combined morphology and CO‐I + CO‐II + 28S matrices yielded two equally most‐parsimonious trees (length 1184 steps, CI = 0.50, RI = 0.42) and a strict consensus tree (length 1187 steps, CI = 0.50, RI = 0.42) that reinforced results from the morphological analysis and resolved the one polytomy present in the morphology consensus tree. Teleiodini are defined as a monophyletic clade with a Bremer support value greater than 5 in the consensus tree based on morphological and molecular data. Twenty‐three clades of genera are defined with Bremer support values provided. An analysis of larval host‐plant preferences based on the consensus tree for combined data indicates derivation of feeding on woody hosts from genera feeding on herbaceous hosts and a single origin of feeding on coniferous hosts. An area cladogram indicates five independent origins of Nearctic genera from Holarctic ancestors and one origin from a Palearctic genus.
Detecting hydrogen peroxide in leaves in vivo – a comparison of methods
Authors: Šnyrychová Iva , Ayaydin Ferhan , Hideg Éva
Published: October 2008

Four hydrogen peroxide detecting probes, 3,3′‐diaminobenzidine (DAB), Amplex Red (AR), Amplex Ultra Red (AUR) and a europium–tetracycline complex (Eu3Tc) were infiltrated into tobacco leaves and tested for sensitivity to light, toxicity, subcellular localization and capacity to detect H2O2 in vivo. In the absence of leaves, in water solutions, AUR was very much sensitive to strong light, AR showed slight light sensitivity, while DAB and Eu3Tc were insensitive to irradiation. When infiltrated into the leaves, the probes decreased the photochemical yield (ΦPSII) in the following order of effect AR > DAB > AUR > Eu3Tc. With the exception of Eu3Tc, all probes stimulated the build‐up of non‐photochemical quenching either temporally (DAB, AUR) or permanently (AR), showing that their presence may already limit the photosynthetic capacity of leaves, even in the absence of additional stress. This should be taken into account when using these probes in plant stress experiments. Confocal laser scanning microscopy studies with the three fluorescent H2O2 probes showed that the localizations of Eu3Tc and AUR were mainly intercellular. AR partly penetrated into leaf chloroplasts but probably not into the thylakoid membranes. Photosynthesis‐related stress applications of AR seem to be limited by the low availability of internal leaf peroxidases. Applications of AR for kinetic H2O2 measurements would require a co‐infiltration of external peroxidase, imposing another artificial modifying factor and thus taking experiments further from ideal, in vivo conditions. Our results suggest that the studied H2O2 probes should be used in leaf studies with caution, carefully balancing benefits and artifacts.
Evaluation of tissue collection for postmortem studies of bipolar disorder
Authors: Deep‐Soboslay Amy , Iglesias Bianca , Hyde Thomas M , Bigelow Llewelyn B , Imamovic Vesna , Herman Mary M , Kleinman Joel E
Published: October 2008

Objectives:  Postmortem human brain is a valuable resource for studying the neuropathology, neurochemistry, and molecular pathways of genes associated with bipolar disorder (BPD), yet available, well‐characterized BPD brain tissue appears scarce. We set out to evaluate BPD postmortem brain collections in order to identify both successful methods as well as barriers to collection.

Methods:  We conducted a literature review of postmortem studies of BPD over the past 30 years, compared and contrasted characteristics of established BPD collections, and identified possible barriers specific to BPD brain collection based on our experience at the NIMH Brain Collection.

Results:  Currently, 80% of postmortem BPD studies were derived from just two brain repositories worldwide: the Stanley Brain Collection (69%) and Harvard Brain Tissue Resource Center (HBTRC) (11%) (combined subjects n = 72). The NIMH Brain Collection collected BPD cases four times less frequently than cases with schizophrenia, despite similar prevalence rates for these disorders. Only 53% of cases referred to the NIMH collection as BPD met DSM‐IV criteria, with inadequate documentation and comorbid substance abuse as primary confounds for diagnosis in the remaining 47% of cases.

Conclusions:  Accurate identification and diagnosis of BPD is a central obstacle to BPD brain collection. Comorbid substance abuse and manner of death are two of many critical factors to consider in BPD postmortem studies. Difficulties in BPD brain collection, coupled with the cessation of brain collection by the Stanley Brain Collection, make the need for alternative BPD brain sources imperative. Recommendations for future BPD tissue collection are offered.
Lack of insight may predict impaired decision making in manic patients
Authors: Adida Marc , Clark Luke , Pomietto Pascale , Kaladjian Arthur , Besnier Nathalie , Azorin Jean‐Michel , Jeanningros Régine , Goodwin Guy M
Published: October 2008

Objectives:  The tendency to engage in risky behaviours is a core feature of the manic episodes of bipolar disorder. The aim of this study was to establish whether this characteristic can be quantified with a laboratory measure of decision making [the Iowa Gambling Task (IGT)] and to determine clinical correlates of the IGT performance in mania.

Methods:  Inpatients with acute mania (n = 45) and healthy volunteers (n = 45) were assessed on the IGT. Affective symptomatology was assessed with the Young Mania Rating Scale and Hamilton Depression Rating Scale, and item scores were subjected to factor analysis. Multivariate regression was used to assess clinical predictors of impaired decision making in the manic patients.

Results:  On the IGT, manic patients selected more cards from the risky decks than healthy controls, and showed little capacity to learn from incurred losses. In a multivariate analysis, impaired decision making ability in the manic patients was significantly predicted by a symptom factor associated with lack of insight.

Conclusions:  Manic patients clearly show defects in decision making, which are strongly related to their lack of insight. Neural circuitry supporting effective decision making, including the ventromedial prefrontal cortex and somatosensory cortex, may be implicated in the pathophysiology of acute mania.
Induction of RNA‐mediated Multiple Virus Resistance to Potato virus Y, Tobacco mosaic virus and Cucumber mosaic virus
Authors: Zhu Chang‐Xiang , Song Yun‐Zhi , Yin Guo‐Hua , Wen Fu‐Jiang
Published: October 2008

Potato virus Y (PVY), Tobacco mosaic virus (TMV) and Cucumber mosaic virus (CMV) are three major tobacco viruses, which are widely spread and cause serious damage to tobacco. We sub‐cloned the cDNA fragments from the 5′ ends of the coat protein (CP) gene of PVY, TMV and CMV, with lengths of 200, 200 and 250 bp, respectively. The three cDNA fragments were cloned into one chimeric cDNA, and introduced into the binary vector pROKII in a way of inverted repeat which was supposed to form a hairpin RNA (hpRNA) after transcription. The corresponding construct pRHPTC was introduced into tobacco NC89 via Agrobacterium tumefaciens, and 1018 transgenic tobacco plants were obtained. Resistance assay indicated that up to 18% of the transgenic plants were immune to co‐infection with PVY, TMV and CMV. Molecular analysis demonstrated that multiple virus resistance was RNA‐mediated and stably inherited in T2 progeny.
Temporally structured replay of neural activity in a model of entorhinal cortex, hippocampus and postsubiculum
Authors: Hasselmo Michael E.
Published: October 2008

The spiking activity of hippocampal neurons during rapid eye movement (REM) sleep exhibits temporally structured replay of spiking occurring during previously experienced trajectories. Here, temporally structured replay of place cell activity during REM sleep is modeled in a large‐scale network simulation of grid cells, place cells and head direction cells. During simulated waking behavior, the movement of the simulated rat drives activity of a population of head direction cells that updates the activity of a population of entorhinal grid cells. The population of grid cells drives the activity of place cells coding individual locations. Associations between location and movement direction are encoded by modification of excitatory synaptic connections from place cells to speed modulated head direction cells. During simulated REM sleep, the population of place cells coding an experienced location activates the head direction cells coding the associated movement direction. Spiking of head direction cells then causes frequency shifts within the population of entorhinal grid cells to update a phase representation of location. Spiking grid cells then activate new place cells that drive new head direction activity. In contrast to models that perform temporally compressed sequence retrieval similar to sharp wave activity, this model can simulate data on temporally structured replay of hippocampal place cell activity during REM sleep at time scales similar to those observed during waking. These mechanisms could be important for episodic memory of trajectories.
The role of spatial information in advance task‐set control: an event‐related potential study
Authors: Astle D. E. , Jackson G. M. , Swainson R.
Published: October 2008

Task‐switching has proved to be a fruitful paradigm for studying cognitive control mechanisms. Interestingly, this avenue of study has revealed that subjects are, to some degree, able to bring about a change in task‐set prior to the performance of that task (provided that they are given advance warning of the upcoming task, for instance in the form of a cue). Event‐related potentials (ERPs) have proved to be a good way of measuring these rapid anticipatory control processes. To explore these processes further, the current study examined the relationship between the availability of spatial information and cue‐locked task‐switching ERP effects. Two groups of subjects were compared: one group could separate the task‐sets on the basis of the targets’ colour (the ‘colour’ group), the second on the basis of the targets’ location (the ‘spatial’ group). The performance of both groups benefited to the same extent from advance cueing of task‐transitions (switches or repeats), yet the ERP data revealed cue‐locked (but not target‐locked) differences between the two groups. The most striking of these differences was the absence of both a late positivity over posterior scalp and a late negativity over frontal scalp when the spatial group switched between tasks. Thus, it seems unlikely that these effects index stimulus‐response ‘reconfiguration’per se– as the mappings were identical for both groups of subjects – but rather that these task‐switching processes are sensitive to how the mappings are represented.
Thermal adaptation of soil microbial respiration to elevated temperature
Authors: Bradford Mark A. , Davies Christian A. , Frey Serita D. , Maddox Thomas R. , Melillo Jerry M. , Mohan Jacqueline E. , Reynolds James F. , Treseder Kathleen K. , Wallenstein Matthew D.
Published: October 2008

In the short‐term heterotrophic soil respiration is strongly and positively related to temperature. In the long‐term, its response to temperature is uncertain. One reason for this is because in field experiments increases in respiration due to warming are relatively short‐lived. The explanations proposed for this ephemeral response include depletion of fast‐cycling, soil carbon pools and thermal adaptation of microbial respiration. Using a > 15 year soil warming experiment in a mid‐latitude forest, we show that the apparent ‘acclimation’ of soil respiration at the ecosystem scale results from combined effects of reductions in soil carbon pools and microbial biomass, and thermal adaptation of microbial respiration. Mass‐specific respiration rates were lower when seasonal temperatures were higher, suggesting that rate reductions under experimental warming likely occurred through temperature‐induced changes in the microbial community. Our results imply that stimulatory effects of global temperature rise on soil respiration rates may be lower than currently predicted.
Coupling of canopy and understory food webs by ground‐dwelling predators
Authors: Pringle Robert M. , Fox‐Dobbs Kena
Published: October 2008

Understanding food‐web dynamics requires knowing whether species assemblages are compartmentalized into distinct energy channels, and, if so, how these channels are structured in space. We used isotopic analyses to reconstruct the food web of a Kenyan wooded grassland. Insect prey were relatively specialized consumers of either C3(trees and shrubs) or C4(grasses) plants. Arboreal predators (arthropods and geckos) were also specialized, derivingc. 90% of their diet from C3‐feeding prey. In contrast, ground‐dwelling predators preyed considerably upon both C3‐ and C4‐feeding prey. This asymmetry suggests a gravity‐driven subsidy of the terrestrial predator community, whereby tree‐dwelling prey fall and are consumed by ground‐dwelling predators. Thus, predators in general couple the C3and C4components of this food web, but ground‐dwelling predators perform this ecosystem function more effectively than tree‐dwelling ones. Although prey subsidies in vertically structured terrestrial habitats have received little attention, they are likely to be common and important to food‐web organization.
Phenotypic and genotypic characterization of multiple strains of the diazotrophic cyanobacterium, Crocosphaera watsonii, isolated from the open ocean
Authors: Webb Eric A. , Ehrenreich Ian M. , Brown Susan L. , Valois Frederica W. , Waterbury John B.
Published: October 2008

Diazotrophic cyanobacteria have long been recognized as important sources of reduced nitrogen (N) and therefore are important ecosystem components. Until recently, species of the filamentous cyanobacterium Trichodesmium were thought to be the primary sources of fixed N to the open ocean euphotic zone. It is now recognized that unicellular cyanobacteria are also important contributors, with members of the oligotrophic genus Crocosphaera being the only cultured examples. Herein we genetically and phenotypically characterize 10 strains isolated from the tropical Atlantic and North Pacific Oceans, and show that although all of the strains are highly similar at the genetic level, with the internal transcribed sequence (ITS) region sequence varying by ∼2 bp on average, there are many unexpected phenotypic differences between the isolates (e.g. cell size, temperature optima and range, extracellular material excretion and variability in rates of nitrogen fixation). However based on the observed sequence similarity, we propose that all of these isolates are members of the genus Crocosphaera (type strain Crocosphaera watsonii WH8501), and that the phenotypic diversity we see may reflect ecologically important variation relevant for modelling N2 fixation in the oligotrophic ocean.
Morbidity and complications of protective loop ileostomy
Authors: Giannakopoulos G. F. , Veenhof A. A. F. A. , Van Der Peet D. L. , Sietses C. , Meijerink W. J. H. J. , Cuesta M. A.
Published: October 2008

Objective  The creation of a loop ileostomy is considered suitable to protect a distal anastomosis in colorectal surgery. This technique is, however, associated with failure, complications and even mortality. The aim of this study was to quantify retrospectively the morbidity associated with an ileostomy and its subsequent closure.

Method  One hundred and nineteen patients with a temporary loop ileostomy, created between January 2000 and July 2007 were retrospectively analysed from a review of patient records.

Results  All ileostomies were closed after a median period of 106 days (interquartile range: 69–174 days). Stoma‐related morbidity occurred in 23 (19%) patients. After ileostomy closure, 16 major complications were seen in 14 (12%) patients and 43 minor complications occurred in 25 (21%) patients. Sixty‐three patients (53%) had neither stoma‐related morbidity or peri‐ or postoperative complications after stoma closure.

Conclusion  Protective loop ileostomy was found to be associated with a high morbidity. This raises the question of the mode of identifying the specific patients with a low anastomosis who should be provided an ileostomy for protection, set against the potential complications of the formation and closure of the ileostomy.
Primary anastomosis vs Hartmann’s procedure in patients undergoing emergency left colectomy for perforated diverticulitis
Authors: Zingg U. , Pasternak I. , Dietrich M. , Seifert B. , Oertli D. , Metzger U.
Published: October 2008

Objective  Comparison of primary anastomosis (PA) and Hartmann’s procedure (HP) in perforated diverticulitis is biased as the patient groups are different in age, comorbidity and severity of disease. Still, PA has been advocated as the procedure of choice. The aim of this study was to compare the two surgical procedures after eliminating this selection bias using a propensity score model.

Method  Sixty‐five HP and 46 PA patients who underwent emergency laparotomy for perforated diverticulitis were analysed. Multivariate logistic regression using the Mannheim peritonitis index, Colorectal Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity, Charlson comorbidity index and Hinchey score was performed to determine the propensity score.

Results  Patients with HP had significantly higher scores, median age and were more often on immunosuppressive medication. Unadjusted logistic regression for outcome showed a significant risk of HP vs PA for nonsurgical morbidity (odds ratio 3.25, 95% CI: 1.26–8.43; P = 0.015), but not for mortality and surgical morbidity. After adjusting for the propensity score, outcome was not significantly different. Patients with PA had a clinical leak rate of 28% and none of the patients with leakage had a protective ileostomy. Patients with PA and leak had higher Charlson scores whereas all other scores were similar to nonleak patients.

Conclusion  The theory that PA is generally superior to HP cannot be supported. HP remains a safe technique for emergency colectomy in perforated diverticulitis, especially in elderly patients with multiple comorbidities. If PA is performed, a protective ileostomy must be considered.
Management of the asymptomatic primary in the palliative treatment of metastatic colorectal cancer
Authors: Clements D. , Dhruva Rao P. , Ramanathan D. , Adams R. , Maughan T. S. , Davies M. M.
Published: October 2008

Objective  The management of the asymptomatic primary in stage IV colorectal cancer presents a dilemma. There is an increased morbidity and mortality from surgical resection. Nonresectional management of the primary is associated with the risks of obstruction, perforation or haemorrhage. Our practice in patients with stage IV disease is palliative chemotherapy and symptom control. We reviewed our nonoperatively managed patients with colorectal liver metastases in order to identify the percentage of patients requiring urgent operative interventions for symptoms related to the primary.

Subjects/patients and method  A retrospective review of all patients treated for stage IV disease at our institution from 2003–2006 was undertaken. Patients were identified from multidisciplinary team (MDT) records. Demographic detail, treatment, and follow‐up data were extracted from hospital records. These were analysed with Microsoft Excel.

Results  Thirty‐seven patients were identified. 26 Male:11 Female. Median age 63 years (range 38–78). The median survival from diagnosis was 14 months. Three (8%) patients developed obstruction whilst having palliative chemotherapy. Two required a defunctioning stoma, and one was treated by means of a stent. There were no similarities between these three patients in terms of age, sex, site or stage of primary, volume of liver metastases, and alkaline phosphatase (ALP) or carcinoembryonic antigen (CEA) levels.

Conclusion  Of 37 patients initially treated palliatively for stage IV colorectal cancer, 92% required no surgical treatment of their primary. Therefore it is the experience of this MDT that it is acceptable to treat such patients in an expectant manner. It is not possible to predict those patients, likely to require surgical intervention.
Rectal cancer with macroscopic peritoneal involvement – clinical challenges and consequences
Authors: Sigurdsson H. K. , Kørner H. , Dahl O. , Skarstein A. , Søreide J. A. ,   On behalf of The Norwegian Colorectal Cancer Group
Published: October 2008

Objective  In gastrointestinal cancer, serosal involvement indicates advanced disease. We looked at the possible role of clinical peritoneal involvement (CPI) in local recurrences (LRs) and the overall survival of patients with rectal cancer (RC).

Method  Between 1993 and 2002, 6404 patients were diagnosed with RC. Based on macroscopic findings at surgery and corresponding histological findings, 166 patients (3%) had CPI. Surgery was stratified according to type and extent of operation: as resective or nonresective surgery and as curative (R0) or noncurative (R1 or R2) resection.

Results  The presence of CPI was a negative factor for survival with a median of 15 months (95% CI, 12–19) in the presence of CPI compared with 65 months (95% CI, 61–70) without it (P < 0.001). In R0 resections, the median survival was 97 months (95% CI, 90–102) in patients without CPI compared with 48 months (95% CI, 22–74) in patients with CPI (P < 0.001). In R1 or R2 resections, the median survival was 16 months (95% CI, 15–17) in the absence of CPI and 9 months (95% CI, 8–10) in the presence of CPI. The LR rate in patients without CPI was 10.2% compared with 15.7% in patients with CPI (P = 0.022).

Conclusions  Clinical peritoneal involvement is a significant detrimental prognostic factor for the LR of RC and survival in the absence of metastases. Observations from this large national cohort add to what is known about peritoneal involvement. Diagnosed CPI should be taken into consideration when adjuvant treatment strategies are addressed.
Cardiovascular cell therapy and endogenous repair
Authors: Taylor D. A. , Zenovich A. G.
Published: October 2008

Cardiovascular disease (CVD) exceeds infection and cancer as the leading cause of death. In the USA alone, approximately a million individuals suffer an acute myocardial infarction (AMI) annually. As the prevalence of CVD risk factors (e.g. hypertension, obesity and type 2 diabetes) rises, CVD is increasing in younger individuals. Fortunately, existing therapies have improved post‐AMI mortality, but in turn have increased the prevalence of post‐AMI heart failure (HF). Approximately half‐a‐million new HF cases are diagnosed each year in the USA. In the next 25 years, up to 15% of the population over the age of 65 in the USA is projected to have HF. Therapeutic interventions that prevent/reverse atherosclerosis, prevent post‐AMI HF and halt the progressive functional deterioration once HF occurs are all needed. Cell therapy – either via exogenous delivery or by endogenous mobilization of cells – may be able to do so, in part, by improving the body’s capacity for repair. To date, primarily bone marrow‐ or blood‐derived cells have been utilized after AMI to prevent left ventricular dysfunction, and skeletal myoblasts have been transplanted into failing myocardium. Preclinical studies are directed at prevention/reversal of atherosclerosis with bone marrow precursors, and ultimately at replacing failing heart with a cell‐based bioartificial construct.
The biology of organ size determination
Authors: Stanger B. Z.
Published: October 2008

The mechanisms that control the size of cells, organs, and organisms have long interested biologists, and are also important in malignant progression. Despite this, basic features of in vivo growth control – the level at which regulation is exerted and the degree to which size is controlled autonomously – are poorly understood. Similarly, it is unknown whether adult tissues measure and respond to size cues in the same manner as those of embryos, a question that is relevant to tissue homeostasis and regeneration. This article will review the determinants of organ size during development and discuss the concept of a ‘size set‐point,’ which incorporates the mass of tissue parenchyma and scaffold established at the end of development.
Anatomical versus functional β‐cell mass in experimental diabetes
Authors: Kargar C. , Ktorza A.
Published: October 2008

The ability of pancreatic β‐cell mass to vary according to insulin requirements is an important component of optimal long‐term control of glucose homeostasis. It is generally assumed that alteration of this property largely contributes to the impairment of insulin secretion in type 2 diabetes. However, data in humans are scarce and it is impossible to correlate β‐cell mass and function with the various stages of the disease. Thus, the importance of animal models is obvious. In rodents, increased β‐cell mass associated with an increase in the function of individual β‐cells contributes to the adaptation of the insulin response to insulin resistance in late pregnancy and in obesity. A reduction in β‐cell mass always corresponds to an alteration in insulin secretory capacity of islet tissue (Zucker diabetic fatty and Goto‐Kakisaki rats, db/db mice). During regenerative processes following experimental reduction of β‐cell mass [partial pancreatectomy, streptozocin (STZ) injection], β‐cell mass increase is not associated with a corresponding improvement of β‐cell function, thus indicating that regenerative β‐cells did not achieve functional maturity. The main lesson from experimental diabetes is therefore that β‐cell mass cannot always predict functional capacity of the β‐cell tissue and that the functional β‐cell mass rather than the anatomical β‐cell mass must be taken into account at all times.
Crucial role of insulin receptor substrate‐2 in compensatory β‐cell hyperplasia in response to high fat diet–induced insulin resistance
Authors: Takamoto I. , Terauchi Y. , Kubota N. , Ohsugi M. , Ueki K. , Kadowaki T.
Published: October 2008

In type 2 diabetes, there is a defect in the regulation of functional β‐cell mass to overcome high‐fat (HF) diet–induced insulin resistance. Many signals and pathways have been implicated in β‐cell function, proliferation and apoptosis. The co‐ordinated regulation of functional β‐cell mass by insulin signalling and glucose metabolism under HF diet–induced insulin‐resistant conditions is discussed in this article. Insulin receptor substrate (IRS)‐2 is one of the two major substrates for the insulin signalling. Interestingly, IRS‐2 is involved in the regulation of β‐cell proliferation, as has been demonstrated using knockout mice models. On the other hand, in an animal model for human type 2 diabetes with impaired insulin secretion because of insufficiency of glucose metabolism, decreased β‐cell proliferation was observed in mice with β‐cell–specific glucokinase haploinsufficiency (Gck+/−) fed a HF diet without upregulation of IRS‐2 in β‐cells, which was reversed by overexpression of IRS‐2 in β‐cells. As to the mechanism underlying the upregulation of IRS‐2 in β‐cells, glucose metabolism plays an important role independently of insulin, and phosphorylation of cAMP response element‐binding protein triggered by calcium‐dependent signalling is the critical pathway. Downstream from insulin signalling via IRS‐2 in β‐cells, a reduction in FoxO1 nuclear exclusion contributes to the insufficient proliferative response of β‐cells to insulin resistance. These findings suggest that IRS‐2 is critical for β‐cell hyperplasia in response to HF diet–induced insulin resistance.
The role of mTOR in the adaptation and failure of β‐cells in type 2 diabetes
Authors: Leibowitz G. , Cerasi E. , Ketzinel‐Gilad M.
Published: October 2008

Mammalian target of rapamycin (mTOR) is an important nutrient sensor that plays a critical role in cellular metabolism, growth, proliferation and apoptosis and in the cellular response to oxidative stress. In addition, mTOR–raptor complex, also called mammalian target of rapamycin complex 1 (mTORC1), generates an inhibitory feedback loop on insulin receptor substrate proteins. It was suggested that nutrient overload leads to insulin/insulin‐like growth factor 1 resistance in peripheral insulin‐responsive tissues and in the β‐cells through sustained activation of mTORC1. In this review, we summarize the literature on the regulation and function of mTOR, its role in the organism’s response to nutrients and its potential impact on lifespan, insulin resistance and the metabolic adaptation to hyperglycaemia in type 2 diabetes. We also propose a hypothesis based on data in the literature as well as data generated in our laboratory, which assigns a central positive role to mTOR in the maintenance of β‐cell function and mass in the diabetic environment.
Unique basement membrane structure of human pancreatic islets: implications for β‐cell growth and differentiation
Authors: Otonkoski T. , Banerjee M. , Korsgren O. , Thornell L.‐E. , Virtanen I.
Published: October 2008

Basement membranes (BMs) are an important part of the physiological microenvironment of pancreatic islet cells. In mouse islets, β‐cells interact directly with BMs of capillary endothelial cells. We have shown that in the human islets, the capillaries are surrounded by a double BM both in foetal and adult tissues. The endocrine islet cells are facing a BM that is separate from the endothelia. Laminins are the functionally most important component of BMs. The only laminin isoform present in the human endocrine islet BM is laminin‐511 (previously known as laminin 10). The islet cells facing this BM have a strong and polarized expression of Lutheran glycoprotein, which is a well‐known receptor for the laminin α5 chain. Dispersed human islet cells adhere to purified human laminin‐511 and the binding is equally effectively blocked by a soluble form of Lutheran as by antibody against integrin β1. Our results reveal unique features of the BM structure of human islets, different from rodents. This information has potentially important implications for the generation of an optimal microenvironment for β‐cell function, proliferation and differentiation.
Production of β‐cells from human embryonic stem cells
Authors: Baetge E. E.
Published: October 2008

The making of functional pancreatic islets in renewable numbers has been a goal of stem cell biologists since early 2000. Since that time, many studies have reported successful creation of glucose‐responsive pancreatic β‐cells. Not until the more recent systematic application of developmental principles to stem cell biology systems were breakthroughs achieved on directed specification of the required early developmental intermediates. The most important first step is the formation of the definitive endoderm (DE) lineage which is compulsory for production of the epithelium of the pancreas and the other important endoderm‐derived organs such as the liver, intestine and lung. The formation of DE from embryonic stem cells made possible additional experimentation aimed at directing the endoderm to further specified foregut and pancreatic endoderm lineages. With these discoveries came the first production of immature pancreatic endocrine cells. Most recently, the production in vivo of glucose‐responsive insulin‐producing cells with the capacity to correct Steptozotocin‐induced hyperglycaemia in mice has been achieved. The work leading up to this achievement, in relation to the other principle human stem cell studies conducted in this area, will be briefly described. The necessary steps and ideal characteristics of embryonic stem cell‐based differentiation to pancreatic β‐cells capable of glucose stimulated insulin secretion will be underscored.
Prostate‐specific antigen flare phenomenon with docetaxel‐based chemotherapy in patients with androgen‐independent prostate cancer
Authors: Sella Avishay , Sternberg Cora N. , Skoneczna Iwona , Kovel Svetlana
Published: October 2008

OBJECTIVE

To evaluate the prostate‐specific antigen (PSA) ‘flare’ phenomenon in patients with androgen‐independent prostate cancer (AIPC) treated with docetaxel, as flare is a known effect of androgen‐deprivation therapy in hormone‐dependent prostate cancer.

PATIENTS AND METHODS

The charts of 56 patients who received docetaxel‐based chemotherapy in three different centres from August 1999 to August 2007 were reviewed retrospectively. The biochemical response was characterized according to the Bubley criteria. There was an immediate PSA response (PSA decline ≥ 50%) in 23 (41%) patients, PSA stabilization (PSA decline < 50%) in 16 (29%) and PSA progression in nine (16%). There was also a fourth response, i.e. PSA flare, defined as an increase in PSA level with no symptomatic progression, after starting docetaxel‐based chemotherapy administered every 3 weeks.

RESULTS

Eight (14%) patients with PSA flare were identified; all had osseous disease and five had additional soft‐tissue disease. The PSA flare lasted a median (range) of 21 (21–42) days and it spread over a median of 1 (1–2) cycles. The temporary PSA surge exceeded baseline values by a median (range) of 61.5 (12–404)%. There was a subsequent PSA response in six of the eight patients and PSA stabilized in the remaining two. Patients with flare received a median of 8.5 (5–12) treatment cycles, vs a median of 8 (2–12) in the immediate PSA response group (P = 0.103, Student’s t‐test). The Response Evaluation Criteria in Solid Tumors criteria evaluation showed one patient with a partial response and six with stable disease. The median survival of patients with PSA flare was 12.5 months, while that of the immediate PSA responders was 20.1 months (not statistically significant, P = 0.168, log‐rank test).

CONCLUSION

Of patients with AIPC, 14% had an initial PSA flare after starting docetaxel‐based chemotherapy. The occurrence of PSA flare had no effect on treatment duration or outcome. With lack of clinical progression, docetaxel‐based chemotherapy should be administered for at least two 3‐week cycles before further decisions are made about efficacy.
The NCEP‐ATPIII but not the IDF criteria for the metabolic syndrome identify Type 2 diabetic patients at increased risk of chronic kidney disease
Authors: Luk A. O. Y. , Ma R. C. W. , So W‐Y. , Yang X‐L. , Kong A. P. S. , Ozaki R. , Ko G. T. C. , Chow C‐C. , Cockram C. S. , Chan J. C. N. , Tong P. C. Y.
Published: October 2008

Aim  To examine the association between chronic kidney disease (CKD) and the metabolic syndrome (MetS) using both International Diabetes Federation (IDF) and National Cholesterol Education Program's Adult Treatment Panel III (NCEP‐ATPIII) definitions in Chinese subjects with Type 2 diabetes.

Methods  Subjects with Type 2 diabetes were categorized according to the presence or absence of MetS by IDF or NCEP‐ATPIII criteria. CKD was considered present if glomerular filtration rate, calculated using the abbreviated equation developed by the Modification of Diet in Renal Disease study with Chinese modification, was < 60 ml/min per 1.73 m2. Multivariate logistic regression analysis of the association between CKD and MetS by either definition was performed.

Results  Of 6350 subjects (mean age 55.1 ± 13.3 years), 3439 (54.2%) and 3204 (50.5%) had MetS by IDF and NCEP‐ATPIII definitions, respectively. Using the IDF definition, the presence of MetS was not associated with CKD [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.71, 1.29, P = 0.784]. In contrast, the association with CKD was significant when MetS was defined by the NCEP‐ATPIII definition (OR 1.75, 95% CI 1.37, 2.24, P < 0.001). In subjects who did not have MetS (n = 2911) as defined by IDF criteria, 997 fulfilled the MetS criteria of NCEP‐ATP III. The association with CKD was stronger, after adjustment for covariates, in these subjects (OR 1.42, 95% CI 1.03, 1.97, P = 0.032) compared with subjects who met IDF criteria of MetS.

Conclusion  In Type 2 diabetes, NCEP‐ATPIII, but not the IDF definition of MetS, identifies a subgroup of patients who have a higher risk of CKD.