bluuebunny/crossref_metadata_2025 huggingface dataset:
Antiplatelet drug interactions
Authors: Mackenzie I. S. , Coughtrie M. W. H. , MacDonald T. M. , Wei L.
Published: November 2010

Abstract.  Mackenzie IS, Coughtrie MWH, MacDonald TM, Wei L. (Medicines Monitoring Unit (MEMO); and Centre for Oncology & Molecular Medicine, Division of Medical Sciences, University of Dundee, Ninewells Hospital & Medical School; Dundee, UK). Antiplatelet drug interactions (Review‐Symposium). J Intern Med 2010; 268: 516–529.

Both laboratory studies in healthy volunteers and clinical studies have suggested adverse interactions between antiplatelet drugs and other commonly used medications. Interactions described include those between aspirin and ibuprofen, aspirin and other nonsteroidal anti‐inflammatory drugs (NSAIDs), and the thienopyridine, clopidogrel, and drugs inhibiting CYP2C19, notably the proton pump inhibitors (PPI) omeprazole and esomeprazole. Other interactions between thienopyridines and CYP3A4/5 have also been reported for statins and calcium channel blockers. The ibuprofen/aspirin interaction is thought to be caused by ibuprofen blocking the access of aspirin to platelet cyclo‐oxygenase. The thienopyridine interactions are caused by inhibition of microsomal enzymes that metabolize these pro‐drugs to their active metabolites. We review the evidence for these interactions, assess their clinical importance and suggest strategies of how to deal with them in clinical practice. We conclude that ibuprofen is likely to interact with aspirin and reduce its anti‐platelet action particularly in those patients who take ibuprofen chronically. This interaction is of greater relevance to those patients at high cardiovascular risk. A sensible strategy is to advise users of aspirin to avoid chronic ibuprofen or to ingest aspirin at least 2 h prior to ibuprofen. Clearly the use of NSAIDs that do not interact in this way is preferred. For the clopidogrel CYP2C19 and CYP3A4/5 interactions, there is good evidence that these interactions occur. However, there is less good evidence to support the clinical importance of these interactions. Again, a reasonable strategy is to avoid the chronic use of drugs that inhibit CYP2C19, notably PPIs, in subjects taking clopidogrel and use high dose H2 antagonists instead. Finally, anti‐platelet agents probably interact with other drugs that affect platelet function such as selective serotonin reuptake inhibitors, and clinicians should probably judge patients taking such combination therapies as at high risk for bleeding.
Drug–drug interactions in the treatment of HIV infection: focus on pharmacokinetic enhancement through CYP3A inhibition
Authors: Josephson F.
Published: November 2010

Abstract.  Josephson F. (Medical Products Agency, Uppsala, Sweden). Drug–drug interactions in the treatment of HIV infection: focus on pharmacokinetic enhancement through CYP3A inhibition (Review‐Symposium). J Intern Med 2010; 268: 530–539.

The aim of this review is to discuss the effect of pharmacokinetic drug–drug interactions (DDIs) in the antiretroviral treatment of HIV infection. In particular, but not exclusively, DDIs due to the cytochrome P450 3A (CYP3A) inhibitor ritonavir, which is used to increase antiretroviral drug exposure – a technique known as pharmacokinetic enhancement or ‘ritonavir boosting’– will be reviewed. The emphasis here will be on the treatment of important co‐morbidities common in patients with HIV, including dyslipidaemia, hypertension, tuberculosis and opiate dependence, as well as on the potentially life‐threatening interaction between ritonavir and inhalational steroids, and on the effect of acid‐reducing agents on some antiretroviral drugs. Finally, further developments with regard to the use of CYP3A‐blocking agents to augment the efficacy of antiviral therapy will be discussed.
Contactless determination of nuclear compressibility using 3D image‐ and model‐based analysis of drug‐induced cellular deformation
Authors: GLADILIN E. , SCHULZ M. , KAPPEL C. , EILS R.
Published: November 2010

Mechanical properties of the chromatin‐bearing nucleus in normal and pathological cells are of general interest for epigenetics and medicine. Conventional techniques for quantitative measurements of material properties of cellular matter are based on application of controlled forces onto the cellular or nuclear boundary and do not allow probing intracellular structures that are not directly accessible for physical contact inside the living cell. In this work, we present a novel approach for contactless determination of the nuclear compressibility (i.e. the Poisson's ratio ν) in living cells by means of image‐ and model‐based analysis of drug‐induced cell deformation. The Poisson's ratio of the HeLa cell nucleus is determined from time‐series of 3D images as a parameter of constitutive model that minimizes the dissimilarity between the numerically predicted and experimentally observed images.
Transcriptomic response of red grouse to gastro‐intestinal nematode parasites and testosterone: implications for population dynamics
Authors: WEBSTER L. M. I. , PATERSON S. , MOUGEOT F. , MARTINEZ‐PADILLA J. , PIERTNEY S. B.
Published: November 2010

A central issue in ecology is in understanding the relative influences of intrinsic and extrinsic effects on population regulation. Previous studies on the cyclic population dynamics of red grouse (Lagopus lagopus scoticus) have emphasized the destabilizing effects of either nematode parasites or territorial behaviour and aggression. The potential interacting effects of these processes, mediated through density‐dependent, environmentally induced alterations of host immunocompetence influencing susceptibility to parasites have not been considered. Male red grouse at high density are more aggressive, associated with increased testosterone, which potentially could lead to reduced immunocompetence at a stage when parasites are most prevalent. This could depress individual condition, breeding performance and survival and thus drive or contribute to overall reductions in population size. Here, we characterize the transcriptomic response of grouse to nematode parasite infection and investigate how this is subsequently affected by testosterone, using a microarray approach contrasting red grouse with high and low parasite load at both high and low testosterone titre. A suite of 52 transcripts showed a significant level of up‐regulation to either chronic parasite load or experimental parasite infection. Of these, 51 (98%) showed a reduced level of expression under conditions of high parasite load and high testosterone. The genes up‐regulated by parasites and then down‐regulated at high testosterone titre were not necessarily associated with immune response, as might be intuitively expected. The results are discussed in relation to the fitness and condition of individual red grouse and factors influencing the regulation of abundance in natural populations.
Dangerous weapons: a cautionary tale of CRISPR defence
Authors: Dyall‐Smith Mike
Published: November 2010

The Cas/CRISPR system of prokaryotes is a recently recognized defence system that protects cells from invasion by foreign nucleic acids, such as plasmids or bacteriophages. Using the archaeon Sulfolobus, Gudbergsdottir et al. have demonstrated that when foreign DNA is both a target of the CRISPR system and also carries a gene that is essential for cell growth, surviving cells display mutations in the CRISPR system that eliminate the target directed spacer. This simulates natural scenarios where the invading DNA cannot be readily destroyed, such as a temperate bacteriophage that manages to evade CRISPR attack and integrate into the genome, so becoming ‘self’. CRISPR deletions ranged from precise removal of a single spacer up to elimination of an entire CRISPR array but the mechanism involved is not understood. Another surprising feature was that from one to two base mutations in the same target protospacer did not affect recognition by the Sulfolobus CRISPR system, something unexpected from studies in bacteria where spacer and target protospacer must match exactly. This study shows that even though the CRISPR system is a powerful weapon it can also be a dangerous one for the cell that carries it.
Secretion of early and late substrates of the type III secretion system from Xanthomonas is controlled by HpaC and the C‐terminal domain of HrcU
Authors: Lorenz Christian , Büttner Daniela
Published: November 2010

The plant pathogenic bacterium Xanthomonas campestris pv. vesicatoria utilizes a type III secretion (T3S) system to inject effector proteins into eukaryotic cells. T3S substrate specificity is controlled by HpaC, which promotes secretion of translocon and effector proteins but prevents efficient secretion of the early substrate HrpB2. HpaC and HrpB2 interact with the C‐terminal domain (HrcUC) of the FlhB/YscU homologue HrcU. Here, we provide experimental evidence that HrcU is proteolytically cleaved at the conserved NPTH motif, which is required for binding of both HpaC and HrpB2 to HrcUC. The results of mutant studies showed that cleavage of HrcU contributes to pathogenicity and secretion of late substrates but is dispensable for secretion of HrpB2, which is presumably secreted prior to HrcU cleavage. The introduction of a point mutation (Y318D) into HrcUC activated secretion of late substrates in the absence of HpaC and suppressed the hpaC mutant phenotype. However, secretion of HrpB2 was unaffected by HrcUY318D, suggesting that the export of early and late substrates is controlled by independent mechanisms that can be uncoupled. As HrcUY318D did not interact with HrpB2 and HpaC, we propose that the substrate specificity switch leads to the release of HrcUC‐bound HrpB2 and HpaC.
Making ends meet in mycobacteria
Authors: Warner Digby F. , Mizrahi Valerie
Published: November 2010

Genotoxic agents from endogenous and exogenous sources cause double‐strand breaks (DSBs) in chromosomal DNA. Given the threat these lesions pose to viability, it is not surprising that multiple, conserved mechanisms exist for their detection, processing and repair. Previous studies have established both functional non‐homologous end‐joining (NHEJ) and homologous recombination (HR) systems in mycobacteria. However, relative pathway utilization in these organisms, which include the major human pathogen Mycobacterium tuberculosis, remains unclear. In this issue, Glickman and colleagues describe an elegant assay to distinguish DSB repair outcomes through simple phenotypic screening. By applying their novel reporter system to a panel of repair pathway mutants, they identify an unexpected role for single‐strand annealing (SSA) in the related non‐pathogen, Mycobacterium smegmatis. As such, these results expand the mycobacterial DSB repair pathway complement to three mechanisms that are distinguishable by their differential requirements for the DSB‐resecting, helicase–nuclease machines, AdnAB and RecBCD. Notably, in an unexpected departure from classical models, they establish that mycobacterial RecBCD is a dedicated SSA nuclease, while AdnAB is required for RecA‐dependent HR. Here, we consider the implications of their observations, which include the asymmetric cross‐regulation of pathway function, for the role of DSB repair in mycobacterial pathogenesis.
A dual function of the CRISPR–Cas system in bacterial antivirus immunity and DNA repair
Authors: Babu Mohan , Beloglazova Natalia , Flick Robert , Graham Chris , Skarina Tatiana , Nocek Boguslaw , Gagarinova Alla , Pogoutse Oxana , Brown Greg , Binkowski Andrew , Phanse Sadhna , Joachimiak Andrzej , Koonin Eugene V. , Savchenko Alexei , Emili Andrew , Greenblatt Jack , Edwards Aled M. , Yakunin Alexander F.
Published: November 2010

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) and the associated proteins (Cas) comprise a system of adaptive immunity against viruses and plasmids in prokaryotes. Cas1 is a CRISPR‐associated protein that is common to all CRISPR‐containing prokaryotes but its function remains obscure. Here we show that the purified Cas1 protein of Escherichia coli (YgbT) exhibits nuclease activity against single‐stranded and branched DNAs including Holliday junctions, replication forks and 5′‐flaps. The crystal structure of YgbT and site‐directed mutagenesis have revealed the potential active site. Genome‐wide screens show that YgbT physically and genetically interacts with key components of DNA repair systems, including recB, recC and ruvB. Consistent with these findings, the ygbT deletion strain showed increased sensitivity to DNA damage and impaired chromosomal segregation. Similar phenotypes were observed in strains with deletion of CRISPR clusters, suggesting that the function of YgbT in repair involves interaction with the CRISPRs. These results show that YgbT belongs to a novel, structurally distinct family of nucleases acting on branched DNAs and suggest that, in addition to antiviral immunity, at least some components of the CRISPR–Cas system have a function in DNA repair.
Deletion of the RluD pseudouridine synthase promotes SsrA peptide tagging of ribosomal protein S7
Authors: Schaub Ryan E. , Hayes Christopher S.
Published: November 2010

RluD catalyses formation of three pseudouridine residues within helix 69 of the 50S ribosome subunit. Helix 69 makes important contacts with the decoding centre on the 30S subunit and deletion of rluD was recently shown to interfere with translation termination in Escherichia coli. Here, we show that deletion of rluD increases tmRNA activity on ribosomes undergoing release factor 2 (RF2)‐mediated termination at UGA stop codons. Strikingly, tmRNA‐mediated SsrA peptide tagging of two proteins, ribosomal protein S7 and LacI, was dramatically increased in ΔrluD cells. S7 tagging was due to a unique C‐terminal peptide extension found in E. coli K‐12 strains. Introduction of the rpsG gene (encoding S7) from an E. coli B strain abrogated S7 tagging in the ΔrluD background, and partially complemented the mutant's slow‐growth phenotype. Additionally, exchange of the K‐12 prfB gene (encoding RF2) with the B strain allele greatly reduced tagging in ΔrluD cells. In contrast to E. coli K‐12 cells, deletion of rluD in an E. coli B strain resulted in no growth phenotype. These findings indicate that the originally observed rluD phenotypes result from synthetic interactions with rpsG and prfB alleles found within E. coli K‐12 strains.
Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy
Authors: Khorsand N. , Veeger N. J. G. M. , Muller M. , Overdiek J. W. P. M. , Huisman W. , van Hest R. M. , Meijer K.
Published: November 2010

Background: Although prothrombin complex concentrate (PCC) is often used to counteract vitamin K antagonist (VKA) therapy, evidence regarding the optimal dose for this indication is lacking. In Dutch hospitals, either a variable dose, based on body weight, target INR (international normalised ratio) and initial INR, or a fixed dose is used.

Aim/objectives: In this observational, pilot study, the efficacy and feasibility of the fixed dose strategy compared to the variable dosing regimen, is investigated.

Materials and Methods: Consecutive patients receiving PCC (Cofact®, Sanquin, Amsterdam) for VKA reversal because of a major non‐cranial bleed or an invasive procedure were enrolled in two cohorts. Data were collected prospectively in the fixed dose group, cohort 1, and retrospectively in the variable dose regimen, cohort 2. Study endpoints were proportion of patients reaching target INR and successful clinical outcome.

Results: Cohort 1 consisted of 35 and cohort 2 of 32 patients. Target INR was reached in 70% of patients in cohort 1 versus 81% in cohort 2 (P = 0·37). Successful clinical outcome was seen in 91% of patients in cohort 1 versus 94% in cohort 2 (P = 1·00). Median INR decreased from 4·7 to 1·8 with a median dosage of 1040 IU factor IX (F IX) in cohort 1 and from 4·7 to 1·6 with a median dosage of 1580 IU F IX in cohort 2.

Conclusion: This study suggests that a fixed dose of 1040 IU of F IX may be an effective way to rapidly counteract VKA therapy in our patient population and provides a basis for future research.
Prevalence of intestinal parasites among school children in northern districts of West Bank‐ Palestine
Authors: Hussein Ayman S.
Published: November 2010

Objectives  To assess the prevalence of intestinal parasite infections in northern districts of West Bank, Palestine and to determine associated sociodemographic factors.

Methods  Random sampling of schoolchildren from rural and urban areas was carried out. Participants provided faecal samples and answered a questionnaire about their demographics and hygiene habits. Faecal samples underwent microscopy and PCR to screen for protozoan and helminths.

Results  Seven hundred and thirty‐five samples were collected from children aged 9.5 years on average. The overall prevalence of parasitic infection was 22.2%. The rates of infections with amoeba, Giardia intestinalis, Entrobius vermicularis and Ascaris lumbricoides were 9.7%, 4.1%, 1.6% and 3.8%, respectively. Real‐time PCR was performed to differentiate between Entamoeba histolytica and Entamoeba dispar. Results showed that 14% of samples positive with microscopy for amoeba were positive for E. histolytica. There was no significant association between sex and rates of infections (P‐value > 0.05). There were, however, significant association between parasite infections and parents’ education, place of residence, washing hands habits (P‐value > 0.05). No significant association was found with number of family members or eating in school canteens (P‐value > 0.05).

Conclusions  Intestinal parasite infections are endemic in West Bank. Interventions such as health education and sanitation are needed.
Characterizing the relationship between sesame, coconut, and nut allergy in children
Authors: Stutius Lisa M. , Sheehan William J. , Rangsithienchai Pitud , Bharmanee Apinya , Scott Jordan E. , Young Michael C. , Dioun Anahita F. , Schneider Lynda C. , Phipatanakul Wanda
Published: November 2010

Stutius LM, Sheehan WJ, Rangsithienchai P, Bharmanee A, Scott JE, Young MC, Dioun AF, Schneider LC, Phipatanakul W. Characterizing the relationship between sesame, coconut, and nut allergy in children. Pediatr Allergy Immunol 2010: 21: 1114–1118. © 2010 John Wiley & Sons A/S

Sesame and coconut are emerging food allergens in the United States. We sought to examine whether children allergic to peanuts and tree nuts are at increased risk of having an allergy to sesame or coconut. We performed a retrospective chart review of children who underwent skin prick testing (SPT) to sesame and coconut and identified 191 children who underwent SPT to sesame and 40 to coconut. Sensitization to sesame was more likely in children with positive SPT to peanuts (odds ratio [OR] = 6.7, 95% confidence interval [CI] [2.7–16.8], p < 0.001) and tree nuts (OR = 10.5, 95% CI [4.0–27.7], p < 0.001). Children with histories of both peanut and tree nut reaction were more likely to have a history of sesame reaction (OR = 10.2, 95% CI [2.7–38.7], p < 0.001). Children with sensitization or allergy to peanuts or tree nuts were not more likely to be sensitized or allergic to coconut. In conclusion, children with peanut or tree nut sensitization were more likely to be sensitized to sesame but not coconut. Children with clinical histories of both peanut and tree nut allergy were more likely to be allergic to sesame.
Safety of ultra‐rush titration of sublingual immunotherapy in asthmatic children with tree‐pollen allergy
Authors: Mösges Ralph , Graute Vera , Christ Hildegard , Sieber Hans‐Jochen , Wahn Ulrich , Niggemann Bodo
Published: November 2010

Mösges R, Graute V, Christ H, Sieber H‐Jochen, Wahn U, Niggemann B. Safety of ultra‐rush titration of sublingual immunotherapy in asthmatic children with tree‐pollen allergy. Pediatr Allergy Immunol 2010: 21: 1135–1138. © 2010 John Wiley & Sons A/S

The recommendation to use sublingual‐swallow immunotherapy (SLIT) in children and adults with allergic rhinitis has been established over the past decade. Recently, ultra‐rush titration of SLIT has become more and more common, raising concerns about its safety in children with asthma. Fifty‐four children with asthma and adolescents aged 6–14 with documented allergic disease because of tree pollen (birch and possibly alder and/or hazel) from 14 study centers in Germany participated in a randomized, double‐blind, and placebo‐controlled study. Twenty‐seven were randomized to receive SLIT with standardized birch pollen allergen extract and the other 27 to receive placebo. An ultra‐rush high‐dose SLIT titration regimen reaching the maintenance dose of 300 index of reactivity (IR) within 90 min (30–90–150–300 IR) was used. The difference in mean PFR changes during ultra‐rush titration between SLIT and placebo was not significant (p = 0.056). A 95% probability that SLIT does not decrease PFR during ultra‐rush titration was demonstrated. Neither anaphylactic shock nor else serious systemic reactions to the study drug occurred. No serious adverse event assessed by the investigator as related to study drug treatment was reported.
A latitudinal gradient in seed nutrients of the forest herb Anemone nemorosa
Authors: De Frenne P. , Kolb A. , Graae B. J. , Decocq G. , Baltora S. , De Schrijver A. , Brunet J. , Chabrerie O. , Cousins S. A. O. , Dhondt R. , Diekmann M. , Gruwez R. , Heinken T. , Hermy M. , Liira J. , Saguez R. , Shevtsova A. , Baskin C. C. , Verheyen K.
Published: November 2010

The nutrient concentration in seeds determines many aspects of potential success of the sexual reproductive phase of plants, including the seed predation probability, efficiency of seed dispersal and seedling performance. Despite considerable research interest in latitudinal gradients of foliar nutrients, a similar gradient for seeds remains unexplored. We investigated a potential latitudinal gradient in seed nutrient concentrations within the widespread European understorey forest herb Anemone nemorosa L. We sampled seeds of A. nemorosa in 15 populations along a 1900‐km long latitudinal gradient at three to seven seed collection dates post‐anthesis and investigated the relative effects of growing degree‐hours >5 °C, soil characteristics and latitude on seed nutrient concentrations. Seed nitrogen, nitrogen:phosphorus ratio and calcium concentration decreased towards northern latitudes, while carbon:nitrogen ratios increased. When taking differences in growing degree‐hours and measured soil characteristics into account and only considering the most mature seeds, the latitudinal decline remained particularly significant for seed nitrogen concentration. We argue that the decline in seed nitrogen concentration can be attributed to northward decreasing seed provisioning due to lower soil nitrogen availability or greater investment in clonal reproduction. This pattern may have large implications for the reproductive performance of this forest herb as the degree of seed provisioning ultimately co‐determines seedling survival and reproductive success.
A SCAR molecular marker to distinguish Bursaphelenchus mucronatus from the pinewood nematode, B. xylophilus
Authors: Chen F.‐M. , Negi S. , Ye J.‐R.
Published: November 2010

Bursaphelenchus mucronatus is closely related to the pinewood nematode Bursaphelenchus xylophilus, the causative agent of pine wilt disease. B. xylophilus became a devastating pest when it was introduced in the Far East; however, B. mucronatus is considered to have low virulence. Morphological similarities between B. xylophilus and B. mucronatus make the accurate morphological identification of both species difficult. Thus, it has become important to pay attention towards B. mucronatus impact and the need of discrimination of these two species. To distinguish among the two species, a B. mucronatus‐specific sequence‐characterized amplified region (SCAR) marker has been developed. The specific Random amplified polymorphic DNA (RAPD) fragment of B. mucronatus, OPY01‐M850 was excised from agarose gels and purified. The gel‐purified fragment was cloned into the pGEM®‐T Vector and subjected to sequencing. Based on the sequenced RAPD fragments, a number of SCAR primers were designed. It is demonstrated that OPY01‐M850 through primers Y01F/R can be transformed into a B. mucronatus‐specific SCAR‐Y01‐M609 marker. Primers set Y01F/R had high specificity that could be used for the discriminative identification of B. mucronatus versus B. xylophilus.
Long‐term outcomes of obscure gastrointestinal bleeding after CT enterography: Does negative CT enterography predict lower long‐term rebleeding rate?
Authors: Shin Jae Kook , Cheon Jae Hee , Lim Joon Seok , Park Jae Jun , Moon Chang Mo , Jeon Soung Min , Lee Jin Ha , Hong Sung Pil , Kim Tae Il , Kim Won Ho
Published: November 2010

Background and Aim:  Computed tomography enterography (CTE) is a promising modality for small bowel imaging. However, the role of CTE in the evaluation of obscure gastrointestinal bleeding (OGIB) has not been established. We investigated the efficacy of CTE in diagnosing OGIB and the long‐term outcomes based on CTE findings, with special reference to negative CTE.

Methods:  A total of 63 consecutive patients who had undergone CTE for OGIB were enrolled, and their pre‐ and post‐CTE clinical data were collected. “Specific treatments” were defined as treatments directly aimed at resolving presumed bleeding causes, including hemostasis and operation, while “non‐specific treatments” were defined as symptomatic treatments for anemia.

Results:  Among 60 patients for whom long‐term follow‐up data were available, positive lesions were found in 16 patients (26.7%). The overall rebleeding rate was 21.7% during a mean follow up of 17.6 ± 4.7 months. There was no significant difference in the cumulative rebleeding rates between patients with positive and negative CTE results (P = 0.241). All patients who received specific treatments after CTE did not rebleed (0/8). In positive CTE patients, specific treatments significantly reduced the rebleeding rate (P = 0.023).

Conclusions:  CTE has a high rate of detecting overt OGIB. However, negative CTE results do not predict lower long‐term rebleeding, and such patients with OGIB should be closely observed. In patients with positive CTE, more vigorous management significantly reduces the incidence of rebleeding.
Update on uncommon pleural effusions
Authors: RYU Jay H. , TOMASSETTI Sara , MALDONADO Fabien
Published: November 2010

Although infections, malignancies and heart failure are responsible for the majority of pleural effusions, there are many other causes and several uncommon but distinctive types of pleural fluid. For this update we have chosen several uncommon forms of pleural effusions or disorders in which there have been recent advances in our understanding over the past several years. Chylothorax, pseudochylothorax and urinothorax are associated with characteristic clinical contexts and pleural fluid parameters but are likely underdiagnosed. Yellow nail syndrome is a rare disorder that can be associated with chylothorax and manifests multisystem features. Recognition of these entities is important because each of these disorders is associated with distinctive aetiology and management modalities. Correct diagnosis depends on the clinician's awareness of the clinical contexts and manifestations along with diagnostic pleural fluid findings in these disorders.
Quantitative localisation of synaptic and extrasynaptic GABAAreceptor subunits on hippocampal pyramidal cells by freeze‐fracture replica immunolabelling
Authors: Kasugai Yu , Swinny Jerome D. , Roberts J. David B. , Dalezios Yannis , Fukazawa Yugo , Sieghart Werner , Shigemoto Ryuichi , Somogyi Peter
Published: November 2010

Hippocampal CA1 pyramidal cells, which receive γ‐aminobutyric acid (GABA)ergic input from at least 18 types of presynaptic neuron, express 14 subunits of the pentameric GABAAreceptor. The relative contribution of any subunit to synaptic and extrasynaptic receptors influences the dynamics of GABA and drug actions. Synaptic receptors mediate phasic GABA‐evoked conductance and extrasynaptic receptors contribute to a tonic conductance. We used freeze‐fracture replica‐immunogold labelling, a sensitive quantitative immunocytochemical method, to detect synaptic and extrasynaptic pools of the alpha1, alpha2 and beta3 subunits. Antibodies to the cytoplasmic loop of the subunits showed immunogold particles concentrated on distinct clusters of intramembrane particles (IMPs) on the cytoplasmic face of the plasma membrane on the somata, dendrites and axon initial segments, with an abrupt decrease in labelling at the edge of the IMP cluster. Neuroligin‐2, a GABAergic synapse‐specific adhesion molecule, co‐labels all beta3 subunit‐rich IMP clusters, therefore we considered them synapses. Double‐labelling for two subunits showed that virtually all somatic synapses contain the alpha1, alpha2 and beta3 subunits. The extrasynaptic plasma membrane of the somata, dendrites and dendritic spines showed low‐density immunolabelling. Synaptic labelling densities on somata for the alpha1, alpha2 and beta3 subunits were 78–132, 94 and 79 times higher than on the extrasynaptic membranes, respectively. As GABAergic synapses occupy 0.72% of the soma surface, the fraction of synaptic labelling was 33–48 (alpha1), 40 (alpha2) and 36 (beta3)% of the total somatic surface immunolabelling. Assuming similar antibody access to all receptors, about 60% of these subunits are in extrasynaptic receptors.
Perioperative complications in children with Apert syndrome: a review of 509 anesthetics
Authors: Barnett Sarah , Moloney Claire , Bingham Robert
Published: November 2010

Objectives:  To perform a retrospective, anesthesia case note review in children with Apert Syndrome.

Aim:  To identify perioperative complications in this group of patients.

Background:  Apert syndrome is a rare autosomal dominant disorder characterized by craniosynostosis, craniofacial anomalies, and severe symmetrical syndactyly (cutaneous and bony fusion) of the hands and feet. Children with this syndrome require general anesthetics for a number of different operations and procedures. Our institution has records of 71 children with Apert syndrome. Analysis of their general anesthetic records was undertaken, and the incidence of perioperative complications was investigated.

Methods:  A retrospective case note review was performed on 61 children with Apert syndrome over a 14‐year period. There were a total of 509 general anesthetics administered to these children during this period of time.

Results:  There were a total of 31 perioperative respiratory complications occurring in 21 patients (6.1% of the total cases). Twenty‐three of these complications were supraglottic airway obstruction (4.5% of total cases).

Conclusions:  We found there to be a low incidence of major perioperative major complications in this group of patients. Nevertheless, a significant proportion of these children have obstructive sleep apnoea and may develop supraglottic airway obstruction on induction and emergence from anesthesia due to the associated mid‐face anatomical abnormalities.
Niche construction in the light of niche theory
Authors: Kylafis Grigoris , Loreau Michel
Published: November 2010

Ecology Letters (2011) 14: 82–90

Ecological niche construction, the process whereby an organism improves its environment to enhance its growth and persistence, is an important missing element of niche theory. Niche theory has mainly focused on niche‐deteriorating processes, such as resource consumption, predation and competition, which have negative effects on population growth. Here, we integrate niche construction explicitly into modern niche theory. We use a graphical approach to analyse how a species’ niche‐improving impacts interplay with niche‐deteriorating impacts to modify its response to the environment. In a model of two consumers that compete for one limiting resource and one predator, we show how niche construction modifies the traditional niche‐deteriorating impacts of its agent or of competing species, and hence the potential for species coexistence. By altering the balance between intraspecific and interspecific competitive effects, niche construction can either generate net interspecific facilitation or strengthen interspecific competition. The adaptive benefit derived from niche construction also strongly affects the realized niche of a niche‐constructing species.
Role of positron emission tomography in urological oncology
Authors: Rioja Jorge , Rodríguez‐Fraile Macarena , Lima‐Favaretto Ricardo , Rincón‐Mayans Anibal , Peñuelas‐Sánchez Iván , Zudaire‐Bergera Juan Javier , Parra Raul O.
Published: November 2010

• Positron emission tomography (PET) is a diagnostic tool using radiotracers to show changes in metabolic activities in tissues. We analysed the role of PET and PET/computed tomography (CT) in the diagnosis, staging, and follow‐up of urological tumours.

• A critical, non‐structured review of the literature of the role of PET and PET/CT in urological oncology was conducted.

• PET and PET/CT can play a role in the management of urological malignancies. For prostate cancer, the advances in radiotracers seems promising, with novel radiotracers yielding better diagnostic and staging results than 18F‐fluorodeoxyglucose (18F‐FDG). In kidney cancer, PET and PET/CT allow a proper diagnosis before the pathological examination of the surgical specimen. For testis cancer, PET and PET/CT have been shown to be useful in the management of seminoma tumours. In bladder cancer, these scans allow a better initial diagnosis for invasive cancer, while detecting occult metastases.

• PET and its combined modality PET/CT have shown their potential in the diagnosis of urological malignancies. However, further studies are needed to establish the role of PET in the management of these diseases. Future applications of PET may involve fusion techniques such as magnetic resonance imaging with PET.
p53‐Associated Parkin‐like cytoplasmic protein (Parc) short‐interfering RNA (siRNA) alters p53 location and biology of Peyronie’s disease fibroblasts
Authors: Mulhall John P. , Barnas Jennifer , Kobylarz Keith , Mueller Alexander
Published: November 2010

Study Type – Aetiology (case control) Level of Evidence 3b

OBJECTIVE • To evaluate the impact of p53‐associated Parkin‐like cytoplasmic protein (Parc) short‐interfering RNA (siRNA) on the location of p53 as well as the biology of Peyronie’s disease (PD) plaque‐derived fibroblasts after Parc knockdown.

PATIENTS AND METHODS • Plaque tissue was excised from men with stable PD undergoing penile reconstructive surgery and used to produce cultured PD plaque‐derived fibroblasts.

• Immunofluorescence (IF) and reverse transcription‐polymerase chain reaction (RT‐PCR) were then used to define the location of p53 and Parc before and after siRNA.

• Nuclear fractionation studies were used to assess the chronology of translocation of p53 from cytoplasm to nucleus on Parc knockdown.

• The terminal transferase dUTP Nick end labelling (TUNEL) assay was used to assess the apoptotic indices of the PD fibroblasts after Parc knockdown.

RESULTS • IF and PCR showed high cytoplasmic levels of p53 and Parc before siRNA. On IF, there was little or no p53 present within the nucleus before Parc knockdown.

• After Parc siRNA, IF showed translocation of p53 to the fibroblast nucleus, while Parc levels dropped significantly, but what Parc remained was confined to the cytoplasm with none present in the nucleus.

• Nuclear fractionation studies using RT‐PCR confirmed this translocation phenomenon and showed the chronology of the event. All p53 had moved from the cytoplasm to the nucleus within 16 h of Parc siRNA.

• On TUNEL assay, apoptotic indices increased dramatically after Parc siRNA.

CONCLUSIONS • These data prove that Parc is a cytoplasmic anchor for p53 in PD plaque‐derived fibroblasts and may be the primary cause of the stabilization and defunctionalization of p53 in these cells.

• These findings support Parc as a novel target for PD pharmacotherapy, perhaps using human siRNA technologies once commercially available.
Low dose of ketoconazole in patients with prostate adenocarcinoma resistant to pharmacological castration
Authors: Procopio Giuseppe , Guadalupi Valentina , Giganti Maria Olga , Mariani Luigi , Salvioni Roberto , Nicolai Nicola , Capone Filippo , Valdagni Riccardo , Bajetta Emilio
Published: November 2010

Study Type – Therapy (case series)

Level of Evidence 4

What’s known on the subject? and What does the study add?

Ketoconazole is an inhibitor of adrenal androgen synthesis which carries on the anti‐tumour activity by interfering with different enzymes, cytochrome P450 14‐α‐demethylase, C 17,20 lyase and C 17 α‐hydroxylase. Some studies have shown an anti‐tumour activity of ketoconazole employed at different dose levels following the failure of androgen‐suppressive therapies.

Patients refractory to pharmacological castration and/or chemotherapy could have an additional benefit in terms of disease control from the use of low dose of ketoconazole. The safety profile was good.

OBJECTIVE

To assess the efficacy of ketoconazole in patients with castration‐resistant prostate cancer (CRPC).

PATIENTS AND METHODS

From April 2008 to November 2009, 37 patients with CRPC have been treated with ketoconazole. The primary endpoint was the prostate‐specific antigen (PSA) response; the secondary endpoints were progression‐free survival and safety profile.

Ketoconazole was administered by oral route at a dose of 200 mg every 8 h continuous dosing until the onset of serious adverse events or disease progression.

The study was based on a two‐step design with an interim efficacy analysis carried out on the first 12 patients accrued.

RESULTS

Main characteristics of population were: median age 75 years (range 60–88); baseline mean PSA 28.8 ng/mL (4.3–1000); 30 patients previously challenged with at least two lines of hormone therapy; 15 patients previously treated with chemotherapy.

Biochemical responses accounted for: two complete responses (5%), six partial responses (16%), 13 patients with stable disease (35%), and 14 with progressive disease (38%). Of 15 patients resistant to chemotherapy, overall disease control (complete plus partial responses plus stable disease) was recorded in seven of them.

Treatment was feasible without inducing grade 3–4 adverse events. The most common grade 1–2 adverse events were asthenia (27%), vomiting (8%) and abdominal pain (8%).

CONCLUSION

Treatment with low‐dose ketoconazole is feasible and well tolerated. The efficacy was satisfactory in patients previously treated with chemotherapy.
Oncological outcomes after laparoscopic and open radical nephroureterectomy: results from an international cohort
Authors: Walton Thomas J. , Novara Giacomo , Matsumoto Kazumasa , Kassouf Wassim , Fritsche Hans‐Martin , Artibani Walter , Bastian Patrick J. , Martínez‐Salamanca Juan I. , Seitz Christian , Thomas Stephen A. , Ficarra Vincenzo , Burger Maximilian , Tritschler Stefan , Karakiewicz Pierre I. , Shariat Shahrokh F.
Published: November 2010

Study Type – Therapy (case series)

Level of Evidence 4

What’s known on the subject? and What does the study add?

Despite widespread adoption of laparoscopic nephroureterectomy (LNU) for upper tract urothelial cancer (UTUC), few studies have confirmed that it shares equivalent oncological outcomes with conventional open nephroureterectomy.

This second large multicentre study confirms oncological equivalence for ONU and LNU in cohorts of both low and high risk patients.

OBJECTIVE

• To compare oncological outcomes in patients undergoing open radical nephroureterectomy (ONU) with those in patients undergoing laparoscopic radical nephroureterectomy (LNU).

PATIENTS AND METHODS

• A total of 773 patients underwent radical nephroureterectomy at nine centres worldwide; 703 patients underwent ONU and 70 underwent LNU.

• Demographic, perioperative and oncological outcome data were collected retrospectively.

• Statistical analysis of data was performed using chi‐squared, Mann–Whitney U‐ and log‐rank tests, and Cox regression analyses.

• The median (interquartile range) follow‐up for the cohort was 34 (15–65) months.

RESULTS

• The two groups were well matched for tumour stage, presence of lymphovascular invasion (LVI) and concomitant carcinoma in situ (CIS).

• There were more high‐grade tumours (77.1% vs. 56.3%; P < 0.001) but fewer lymph node positive patients (2.9% vs. 6.8%; P= 0.041) in the LNU group.

• Estimated 5‐year recurrence‐free survival (RFS) was 73.7% and 63.4% for the ONU and LNU groups, respectively (P= 0.124) and estimated 5‐year cancer‐specific survival (CSS) was 75.4% and 75.2% for the ONU and LNU groups, respectively (P= 0.897).

• On multivariable analyses, which included age, gender, race, previous endoscopic treatment for bladder cancer, technique for distal ureter management, tumour location, pathological stage, grade, lymph node status, LVI and concomitant CIS, the procedure type (LNU vs. ONU) was not predictive of RFS (Hazard ratio [HR] 0.80; P= 0.534) or CSS (HR 0.96; P= 0.907).

CONCLUSION

• The present study is the second large, independent, multicentre cohort to show oncological equivalence between ONU and LNU for well selected patients with upper urinary tract urothelial cancer, and the first to suggest parity for the techniques in patients with unfavourable disease.
R D Lawrence Lecture 2010^. The brain as a target organ in Type 2 diabetes: exploring the links with cognitive impairment and dementia
Authors: Strachan M. W. J.
Published: November 2010

Diabet. Med. 28, 141–147 (2011)

Type 2 diabetes is associated with cognitive impairment and dementia, but the precise underlying mechanisms remain unresolved. Very high blood glucose concentrations are associated with mood changes and poor memory function, possibly by causing alterations in cerebral blood flow or osmotic changes in neurones, and correction of acute hyperglycaemia appears beneficial. Chronic hyperglycaemia may cause structural changes in the brain, such as cerebral microvascular disease, and there are strong associations between the presence of retinal microvascular abnormalities and cognitive function. Functional insulin deficiency in the brain may also be a factor, but trials with rosiglitazone in people with diabetes and other trials in people with Alzheimer's disease have shown no specific benefit of insulin sensitization. There is an association between hypoglycaemia and cognitive impairment in people with Type 2 diabetes; part of that association may simply be a consequence of the fact that people with cognitive impairment find it more difficult to manage their diabetes and so are more prone to hypoglycaemia. The potential for hypoglycaemia to cause harm to the brain has been debated for many years, and the issue remains unresolved. An ongoing prospective study of risk factors for cognitive impairment in people with Type 2 diabetes (Edinburgh Type 2 Diabetes Study) should improve our understanding of the aetiology of cognitive impairment and inform the design of future intervention trials.
Epidemiology of tornado destruction in rural northern Bangladesh: risk factors for death and injury
Authors: Sugimoto Jonathan D. , Labrique Alain B. , Ahmad Salahuddin , Rashid Mahbubur , Shamim Abu Ahmed , Ullah Barkat , Klemm Rolf D.W. , Christian Parul , West Keith P.
Published: November 2010

The epidemiology of tornado‐related disasters in the developing world is poorly understood. An August 2005 post‐tornado cohort study in rural Bangladesh identified elevated levels of death and injury among the elderly (≥ 60 years of age) (adjusted odds ratio (AOR) = 8.9 (95 per cent confidence interval (CI): 3.9–20.2) and AOR = 1.6 (95 per cent CI: 1.4–1.8), respectively), as compared to 15–24 year‐olds, and among those outdoors versus indoors during the tornado (AOR = 10.4 (95 per cent CI: 5.5–19.9) and AOR = 6.6 (95 per cent CI: 5.8–7.5), respectively). Females were 1.24 times (95 per cent CI: 1.15–1.33) more likely to be injured than males. Elevated risk of injury was significantly associated with structural damage to the house and tin construction materials. Seeking treatment was protective against death among the injured, odds ratio = 0.08 (95 per cent CI: 0.03–0.21). Further research is needed to develop injury prevention strategies and to address disparities in risk between age groups and between men and women.
Exploring the feasibility of private micro flood insurance provision in Bangladesh
Authors: Akter Sonia , Brouwer Roy , van Beukering Pieter J.H. , French Laura , Silver Efrath , Choudhury Saria , Aziz Syeda Salina
Published: November 2010

This paper aims to contribute to the debate on the feasibility of the provision of micro flood insurance as an effective tool for spreading disaster risks in developing countries and examines the role of the institutional–organisational framework in assisting the design and implementation of such a micro flood insurance market. In Bangladesh, a private insurance market for property damage and livelihood risk due to natural disasters does not exist. Private insurance companies are reluctant to embark on an evidently unprofitable venture. Testing two different institutional–organisational models, this research reveals that the administration costs of micro‐insurance play an important part in determining the long‐term viability of micro flood insurance schemes. A government‐facilitated process to overcome the differences observed in this study between the nonprofit micro‐credit providers and profit‐oriented private insurance companies is needed, building on the particular competence each party brings to the development of a viable micro flood insurance market through a public–private partnership.
Enhancing Innovation Capacity in SMEs through Early Network Relationships
Authors: Jørgensen Frances , Ulhøi John P.
Published: November 2010

Networks can offer SMEs a number of advantages, especially in terms of providing greater opportunities for knowledge activities that support innovation, but there is little in the literature to suggest how firms develop their innovation capacity through network participation. In this paper, we present an in‐depth longitudinal case study of a small entrepreneurial firm within the mobile‐commerce industry. A principal finding from the study is that network relationships formed during the earliest stages of the firm's life cycle played a critical role in developing the SME's capacity for sustained innovation. Further, the study contributes to network theory by calling into question the weak and strong tie dichotomy, as relationships critical to the SME's innovation capacity possessed characteristics of both types of ties. The paper also contributes to managerial practice by emphasizing the importance of establishing strong relationships in the earliest stages of network formation.
Product and Process Novelty in Small Companies' Design Processes
Authors: Löfqvist Lars
Published: November 2010

This article explores the design processes in small companies and investigates how these design processes are executed. The influence of two different kinds of novelty on the design processes is further examined: the relative novelty of the product being developed and the relative novelty of design processes. The relative novelty of the product is high if it is a radically new product to develop. High relative novelty for design processes typically means no experience or knowledge about design processes. Based on an embedded multiple case study of three small companies in Sweden, eight different design processes are described and analysed. The results show that the design processes differ, even within the same company, and that relative novelty affects the design process. If the relative novelty of both the product to be developed and of the design processes is low, a formalized and linear design process was found to work. A design process that is cyclical, iterative and knowledge‐creating was found to work irrespective of the relative novelty. Customers and users were found to play a large and important role in the design processes.