bluuebunny/crossref_metadata_2025 huggingface dataset:
EHEC/EAEC O104:H4 strain linked with the 2011 German outbreak of haemolytic uremic syndrome enters into the viable but non‐culturable state in response to various stresses and resuscitates upon stress relief
Authors: Aurass Philipp , Prager Rita , Flieger Antje
Published: September 2011

Various non‐spore forming bacteria, including Escherichia coli, enter a dormant‐like state, the viable but non‐culturable (VBNC) state, characterized by the presence of viable cells but the inability to grow on routine laboratory media. Upon resuscitation, these VBNC cells recover both culturability and pathogenicity. In 2011, a large outbreak involving more than 3000 cases of bloody diarrhoea and haemolytic uremic syndrome was caused by an E. coli O104:H4 strain expressing genes characteristic of both enterohaemorrhagic (EHEC) and enteroaggregative E. coli (EAEC). The ability of the outbreak strain to enter the VBNC state may have complicated its detection in the suspected sources. In this paper, we investigated the ability of the outbreak strain to enter and subsequently recover from the VBNC state. We found that in a nutrient‐poor micro‐environment, various stresses such as toxic concentrations of copper ions or certain types of tap water are able to render the bacteria unculturable within a few days. Without copper ion stress, the majority of cells remained culturable for at least 40 days. Incubation with the stressors at 23°C compared with 4°C hastened this observed loss of culturability. The integrity of a considerable fraction of copper ion‐ and tap water 1‐stressed bacteria was demonstrated by live/dead staining and microscopy. Relieving stress by copper‐ion chelation facilitated resuscitation of these bacteria while preserving their fitness, major virulence gene markers (stx2, aggR, aggA genes) and specific phenotypes (ESBL resistance, autoaggregation typical for EAEC strains).
Five‐year results of fissurectomy for chronic anal fissure : low recurrence rate and minimal effect on continence
Authors: Schornagel I. L. , Witvliet M. , Engel A. F.
Published: September 2011

Aim  The aim of the study was to determine the long‐term outcome, recurrence rate and faecal incontinence score after fissurectomy for chronic anal fissure (CAF) not responding to conservative treatment.

Method  Fifty‐three consecutive patients (29 women) who underwent fissurectomy for a medically resistant CAF between 1998 and 2005 were included in the study. At a minimum follow‐up of 5 years a standardized questionnaire was sent to all patients, assessing recurrence, satisfaction with the operation (on a scale of 0–10) and faecal continence (Vaizey score, 0–24). The patients were compared with a control group of 50 healthy volunteers, matched for sex and age, who had never undergone anal surgery.

Results  Forty‐three (81%) patients (25 women) returned the questionnaire. The mean age was 40 (SD 12.1) years and median follow up was 8.2 (5.5–12.2) years. Five patients had a recurrent CAF (11.6%). Ninety per cent of patients would have consented to the operation again if necessary. The mean Vaizey score at follow‐up was 2.5 (SD ± 4.2). The mean Vaizey score of the four patients who had had a previous lateral sphincterotomy was 3.8 and for the eight patients who had reported a continence disturbance before fissurectomy it was 8.3. The mean Vaizey score of the 31 patients who were continent before fissurectomy was 0.8 compared with 0.4 in the control group (P = 0.9).

Conclusion  At 5 years or more fissurectomy for medically resistant CAF is effective with a low recurrence rate and minimal influence on continence.
Outcome of surgery for colonoscopic perforation
Authors: van der Sluis F. J. , Loffeld R. J. , Engel A. F.
Published: September 2011

Aim  The aetiology of colonoscopic perforation and factors related to poor outcome of surgical treatment were studied.

Method  A single‐centre review was conducted of all patients who underwent surgical treatment of a colonoscopic perforation, identified from a prospective registry of 21 981 consecutive colonoscopies carried out between 1993 and 2009.

Results  There were 29 (eight women) patients of mean age 73 years including 10 who had a nonelective colonoscopy. The perforation was not immediately recognized in 12 patients and in the remaining 17, seven were initially managed conservatively. The causes of perforation were barotrauma (11), mechanical force (14) and polypectomy‐related (3). Barotrauma was more frequent in emergency colonoscopy and mechanical force in elective colonoscopy. The outcome of surgery was as follows: mortality 10%, complications 34.5%, reoperation 14%, secondary surgery 23% and permanent colostomy 3%. The only factor related to in‐hospital mortality was an increased American Society of Anesthesiologists (ASA) score.

Conclusion  Colonoscopic perforation requiring surgery is a catastrophic event with high mortality, morbidity and reoperation rates.
The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia
Authors: DeFronzo R. A. , Davidson J. A. , Del Prato S.
Published: September 2011

The maintenance of normal glucose homeostasis requires a complex, highly integrated interaction among the liver, muscle, adipocytes, pancreas and neuroendocrine system. Recent studies have showed that the kidneys also play a central role in glucose homeostasis by reabsorbing all the filtered glucose, an adaptive mechanism that ensures sufficient energy is available during fasting periods. This mechanism becomes maladaptive in diabetes, however, as hyperglycaemia augments the expression and activity of the sodium–glucose cotransporter (SGLT) 2 in the proximal tubule of the kidney. As a result, glucose reabsorption may be increased by as much as 20% in individuals with poorly controlled diabetes. SGLT2 is a low‐affinity, high‐capacity glucose transport protein that reabsorbs 90% of filtered glucose, while the high‐affinity, low‐capacity SGLT1 transporter reabsorbs the remaining 10%. SGLT2 represents a novel target for the treatment of diabetes. In animal studies, SGLT2 inhibition reduces plasma glucose levels, resulting in improved β‐cell function and enhanced insulin sensitivity in liver and muscle. Human studies have confirmed the efficacy of SLGT2 inhibitors in improving glucose control and reducing the A1c. Because the mechanism of SGLT2 inhibition is independent of circulating insulin levels or insulin sensitivity, these agents can be combined with all other antidiabetic classes, including exogenous insulin. Although the long‐term efficacy and safety of SGLT2 inhibitors remain under study, the class represents a novel therapeutic approach with potential for the treatment of both type 2 and 1 diabetes.
Effects of Schisandra chinensis extract on the contractility of corpus cavernosal smooth muscle (CSM) and Ca2+ homeostasis in CSM cells
Authors: Han Deok Hyun , Lee Jun Ho , Kim Hyunjung , Ko Mi Kyeong , Chae Mee Ree , Kim Hye Kyung , So Insuk , Jeon Ju‐Hong , Park Jong Kwan , Lee Sung Won
Published: September 2011

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

Schisandra chinensis extract (SCE) has been known to have relaxative effects on penile smooth muscle. A recent study showed that SCE could enhance slidenafil citrate‐induced relaxation of penile corpus cavernosum.

The current study investigated the mechanism of action of SCE and its constituents on corporal smooth muscle cells. And this study shows that SCE induced relaxation of CSM primarily through an endothelium independent pathway and the relaxation effects of SCE on corporal smooth muscle are, in part, due to the activation of K+ channels and inhibition of TRPC6 channels, resulting in decreased [Ca2+].

OBJECTIVE

To evaluate the relaxant effects of Schisandra chinensis extract (SCE) on corporal tissue in the penis and to investigate the mechanism of action of SCE and its constituents on corporal smooth muscle (CSM) cells.

MATERIALS AND METHODS

The fruit of SC was collected and extracted with ethanol. Six SC lignans (schisandrol A, schisandrol B, schisandrin A, schisandrin B, gomisin N, and schisandrin C) were isolated and purified, and the chemical structures were confirmed by 1H‐nuclear magnetic resonance (NMR) and 13C‐NMR data.

Isolated rabbit CSM strips were mounted in an organ‐bath system, and the effects of SCE were evaluated.

To estimate the intracellular Ca2+ level ([Ca2+]i), we used a Fura‐2 fluorescent technique, and a conventional whole‐cell patch‐clamp technique was used to measure the calcium‐sensitive K+ channels (KCa), inward rectifier K+ channels (KIR), and canonical transient receptor potential cation channel 6 (TRPC6) currents.

RESULTS

SCE induced concentration‐dependent relaxation in contracted CSM tissue, and the removal of the endothelium did not significantly affect their relaxation potencies.

In CSM cells, extracellular application of SCE significantly increased whole‐cell KCa currents (117.4%) and KIR currents (110.0%). These effects were completely abolished by charybdotoxin or BaCl2.

In contrast, carbachol‐induced TRPC6 channel activity was significantly inhibited (87.3%) by SCE in green fluorescent protein‐TRPC6 pcDNA transfected HEK 293 cells. [Ca2+]i measurements showed that SCE effectively reduced basal [Ca2+]i in both cell lines (CSM cells and A7r5 cells) and the [Arg8]‐vasopressin (AVP)‐induced [Ca2+]i increase in A7r5 cells.

Among the six SC lignans, schisandrin A and schisandrin B most effectively attenuated the AVP‐induced [Ca2+]i increase.

CONCLUSIONS

SCE induced relaxation of CSM that occurred primarily via an endothelium‐independent pathway.

The relaxation effects of SCE on CSM were, in part, due to the activation of K+ channels and inhibition of TRPC6 channels, resulting in decreased [Ca2+]i.
Current perspectives of insulin resistance and polycystic ovary syndrome
Authors: Pauli J. M. , Raja‐Khan N. , Wu X. , Legro R. S.
Published: September 2011

Diabet. Med. 28, 1445–1454 (2011)

Aims  To review the relationship between insulin resistance and polycystic ovary syndrome.

Methods  A literature review.

Results  Insulin resistance likely plays a central pathogenic role in polycystic ovary syndrome and may explain the pleiotropic presentation and involvement of multiple organ systems. Insulin resistance in the skeletal muscle of women with polycystic ovary syndrome involves both intrinsic and acquired defects in insulin signalling. The cellular insulin resistance in polycystic ovary syndrome has been further shown to involve a novel post‐binding defect in insulin signal transduction. Treatment of insulin resistance through lifestyle therapy or with a diabetes drug has become mainstream therapy in women with polycystic ovary syndrome. However, effects with current pharmacologic treatment with metformin tend to be modest, with limited benefit as an agent to treat infertility. Insulin resistance contributes to increased risk for pregnancy complications, diabetes and cardiovascular disease risk profile in polycystic ovary syndrome, which is further exacerbated by obesity. While numerous studies demonstrate increased prevalence of cardiovascular disease risk factors in women with polycystic ovary syndrome, there are limited data showing that women with polycystic ovary syndrome are at increased risk for cardiovascular disease events.

Conclusions  Insulin resistance is linked to polycystic ovary syndrome. Further study of lifestyle and pharmacologic interventions that reduce insulin resistance, such as metformin, are needed to demonstrate that they are effective in reducing the risk of diabetes, endometrial abnormalities and cardiovascular disease events in women with polycystic ovary syndrome.
Gateway‐compatible vectors for high‐throughput gene functional analysis in switchgrass (Panicum virgatum L.) and other monocot species
Authors: Mann David G.J. , LaFayette Peter R. , Abercrombie Laura L. , King Zachary R. , Mazarei Mitra , Halter Mathew C. , Poovaiah Charleson R. , Baxter Holly , Shen Hui , Dixon Richard A. , Parrott Wayne A. , Neal Stewart Jr C.
Published: September 2011

Switchgrass (Panicum virgatum L.) is a C4 perennial grass and has been identified as a potential bioenergy crop for cellulosic ethanol because of its rapid growth rate, nutrient use efficiency and widespread distribution throughout North America. The improvement of bioenergy feedstocks is needed to make cellulosic ethanol economically feasible, and genetic engineering of switchgrass is a promising approach towards this goal. A crucial component of creating transgenic switchgrass is having the capability of transforming the explants with DNA sequences of interest using vector constructs. However, there are limited options with the monocot plant vectors currently available. With this in mind, a versatile set of Gateway‐compatible destination vectors (termed pANIC) was constructed to be used in monocot plants for transgenic crop improvement. The pANIC vectors can be used for transgene overexpression or RNAi‐mediated gene suppression. The pANIC vector set includes vectors that can be utilized for particle bombardment or Agrobacterium‐mediated transformation. All the vectors contain (i) a Gateway cassette for overexpression or silencing of the target sequence, (ii) a plant selection cassette and (iii) a visual reporter cassette. The pANIC vector set was functionally validated in switchgrass and rice and allows for high‐throughput screening of sequences of interest in other monocot species as well.
Significance of microbleeds in patients with transient ischaemic attack
Authors: Fluri F. , Jax F. , Amort M. , Wetzel S. G. , Lyrer P. A. , Katan M. , Hatz F. , Engelter S. T.
Published: September 2011

Background and purpose:  The aim of this study was to determine the prognostic significance of microbleeds in TIA‐patients. In patients with a transient ischaemic attack (TIA), the prognostic value of microbleeds is unknown.

Methods:  In 176 consecutive TIA patients, the number, size, and location of microbleeds with or without acute ischaemic lesions were assessed. We compared microbleed‐positive and microbleed‐negative patients with regard to the end‐point stroke within 3 months.

Results:  Four of the seven patients with subsequent stroke had microbleeds. Microbleed‐positive patients had a higher risk for stroke [odds ratios (OR) 8.91, 95% CI 1.87–42.51, P < 0.01] than those without microbleeds. Microbleed‐positive patients with accompanying acute ischaemic lesions had a higher stroke risk than those with neither an acute ischaemia nor a microbleed (OR 6.20, 95% CI 1.10–35.12; P = 0.04).

Conclusion:  Microbleeds alone or in combination with acute ischaemic lesions may increase the risk for subsequent ischaemic stroke after TIA within 3 months.
Assessing Components of Empathy in Sex‐ Offenders with Intellectual Disabilities
Authors: Ralfs Sonya , Beail Nigel
Published: September 2011

Background Because of a lack of research investigating empathy in sex offenders with intellectual disabilities, this study explored empathy in sex offenders and non‐offenders with intellectual disabilities. Specific aims were to explore differences between these groups on measures of the components of empathy.

Methods The scores of 21 sex‐offenders and 21 non‐offenders with intellectual disabilities, matched by age, gender and IQ, were compared on the Test of Emotional Perception.

Results No differences were found between the two groups across the components of empathy. However, sex offenders who had received treatment performed better on tasks of emotion recognition, emotion replication and response decision than the non‐offenders.

Conclusions Further research is needed to understand empathy in sex offenders with intellectual disabilities before any recommendations can be made regarding treatment programmes.
Tree hollows are of conservation importance for a Near‐Threatened python species
Authors: Bryant G. L. , Dundas S. J. , Fleming P. A.
Published: September 2011

Understanding microhabitat requirements for species vulnerable to anthropogenic threats can provide important information to conservation managers. This may be particularly true for ectotherms, where behaviour and physiology (e.g. digestion, responsiveness and activity patterns) are strongly influenced by thermal conditions of microhabitat retreat sites. Retreat sites selected by south‐west carpet pythons (Morelia spilota imbricata) were identified through radiotracking 46 pythons over 3 years. Tree hollows appear to be a very important resource for pythons: 61% (22 of 36 individuals tracked over winter) used tree hollows as retreat sites (56% of all observations in winter), and remained in hollows for an average of 124 ± 49 (range 34 to 210) days. If pythons did not use tree hollows over winter, they found refuge in one of four alternative microhabitats: low vegetation cover (26% of winter observations), ground cover (10%), on tree branches (6%) or in hollow logs on the ground (2%). We tested whether tree hollows provide a thermally distinct environment compared with alternative microhabitats, but found no difference in minimum, average, maximum or range of temperatures recorded between microhabitats. When within tree hollows over winter, pythons had colder daily average and maximum body temperatures (cf. pythons that used other microhabitats), but this did not give them an energy saving (in terms of body condition scores). Pythons ate very little over winter and we predict that animals sequestered within tree hollows do not access prey at this time. Tree hollows provide a critical refuge over winter when python body temperature is low, and their responsiveness is limited, rendering individuals vulnerable to predation by terrestrial predators (e.g. introduced red fox). Destruction of hollows through fire, land clearing, competition with other fauna species and the significant age required for hollows to form in trees all contribute to the decline in availability of this important microhabitat.
Phylogeography and cryptic diversity of the solitary‐dwelling silvery mole‐rat, genus Heliophobius (family: Bathyergidae)
Authors: Faulkes C. G. , Bennett N. C. , Cotterill F. P. D. , Stanley W. , Mgode G. F. , Verheyen E.
Published: September 2011

Alongside the eusocial naked mole‐rat, Heterocephalus glaber, Heliophobius argenteocinereus represents the second oldest lineage within the African mole‐rat family Bathyergidae, and phylogenetically intermediate between the East African Het. glaber and the South African genera Bathyergus and Georychus. Across its geographic range, Hel.. argenteocinereus is widely distributed on both sides of the East African Rift System (EARS), and is a key taxon for understanding the phylogeographic patterns of divergence of the family as a whole. Phylogenetic analysis of 62 mitochondrial cyt b sequences, representing 48 distinct haplotypes from 26 geographic locations across the range of Heliophobius, consistently and robustly resolved six genetically divergent clades that we recognize as distinct evolutionary species. Early species descriptions of Heliophobius were synonymized into a monotypic taxonomy that recognized only Hel. argentocinereus. These synonyms constitute available names for these rediscovered cryptic lineages, for which combined morphological and genetic evidence for topotypical populations endorses the recognition of six to eight distinct taxa. Bayesian estimates of divergence times using the fossil Proheliophobius as a calibration for the molecular clock suggest that the adaptive radiation of the genus began in the early Miocene, and that cladogenesis, represented in the extant species, reflects a strident signature of tectonic activity that forged the principal graben in the EARS.
Nonrandom spatial structuring of orchids in a hybrid zone of three Orchis species
Authors: Jacquemyn Hans , Brys Rein , Honnay Olivier , Roldán‐Ruiz Isabel , Lievens Bart , Wiegand Thorsten
Published: September 2011

Nonrandom  species–species associations may arise from a range of factors, including localized dispersal, intra‐ and interspecific interactions and heterogeneous environmental conditions. Because seed germination and establishment in orchids are critically dependent upon the availability of suitable mycorrhizal fungi, species–species associations in orchids may reflect associations with mycorrhizal fungi.

To test this hypothesis, we examined spatial association patterns, mycorrhizal associations and germination success in a hybrid zone containing three species of the genus Orchis (Orchis anthropophora, Orchis militaris and Orchis purpurea).

Hybridization occurred predominantly between O. purpurea and O. militaris. The spatial distribution patterns of most pure species and hybrids were independent from each other, except that of O. purpurea and its hybrids. The fungal community composition of established individuals differed significantly between pure species, but not between hybrids and O. purpurea. Seed germination experiments using pure seeds showed that the highest number of protocorms were found in regions where adult individuals were most abundant. In the case of hybrid seeds, germination was restricted to areas where the mother plant was most abundant.

Overall, these results suggest that the observed nonrandom spatial distribution of both pure and hybrid plants is dependent on the contingencies of the spatial distribution of suitable mycorrhizal fungi.
Landscape‐scale effects of fire on bird assemblages: does pyrodiversity beget biodiversity?
Authors: Taylor Rick S. , Watson Simon J. , Nimmo Dale G. , Kelly Luke T. , Bennett Andrew F. , Clarke Michael F.
Published: September 2011

Aim A common strategy for conserving biodiversity in fire‐prone environments is to maintain a diversity of post‐fire age classes at the landscape scale, under the assumption that ‘pyrodiversity begets biodiversity’. Another strategy is to maintain extensive areas of a particular seral state regarded as vital for the persistence of threatened species, under the assumption that this will also cater for the habitat needs of other species. We investigated the likely effects of these strategies on bird assemblages in tree mallee vegetation, characterized by multi‐stemmedEucalyptusspecies, where both strategies are currently employed.

Location The semi‐arid Murray Mallee region of south‐eastern Australia.

Methods We systematically surveyed birds in 26 landscapes (each 4‐km diameter), selected to represent gradients in the diversity of fire age classes and the proportion of older vegetation (> 35 years since fire). Additional variables were measured to represent underlying vegetation‐ or fire‐mediated properties of the landscape, as well as its biogeographic context. We used an information‐theoretic approach to investigate the relationships between these predictor variables and the species richness of birds (total species, threatened species and rare species).

Results Species richness of birds was not strongly associated with fire‐mediated heterogeneity. Species richness was associated with increasing amounts of older vegetation in landscapes, but not with the proportion of recently burned vegetation in landscapes.

Main conclusions The preference of many mallee birds for older vegetation highlights the risk of a blanket application of the ‘pyrodiversity begets biodiversity’ paradigm. If application of this paradigm involved converting large areas from long unburned to recently burned vegetation to increase fire‐mediated heterogeneity in tree mallee landscapes, our findings suggest that this could threaten birds. This research highlights the value of adopting a landscape‐scale perspective when evaluating the utility of fire‐management strategies intended to benefit biodiversity.
High‐Resolution Strain Mapping Through Time‐of‐Flight Neutron Transmission Diffraction with a Microchannel Plate Neutron Counting Detector
Authors: Tremsin A. S. , McPhate J. B. , Steuwer A. , Kockelmann W. , M Paradowska A. , Kelleher J. F. , Vallerga J. V. , Siegmund O. H. W. , Feller W. B.
Published: September 2011

Abstract:  Conventional neutron radiography can be strongly enhanced by obtaining Bragg‐edge information spatially correlated with the attenuation coefficient. This can now be achieved through time‐of‐flight techniques at pulsed neutron sources, utilising a neutron counting detector with high‐spatial and high‐temporal resolution. In these measurements, the positions of Bragg edges can in principle be obtained for each 55 × 55 μm2 pixel of the radiographic image. The combination of both Bragg‐edge and attenuation information enables high spatial resolution studies to be carried out on material composition, phase transitions, texture variations, as well as residual strain mapping. In this article, we present the results of high‐resolution strain maps of a ferritic steel cantilever sample measured at different loads by both transmission and conventional diffraction modes, as well as strains in an austenitic steel compact‐tension (CT) crack sample. The proof of principle experiments performed on the ENGIN‐X beamline on a bent cantilever arrangement resulting in a uni‐axial stress field verified that the strain values measured in diffraction and transmission mode are in good agreement. The characteristics of the transmission mode detector as well as the measured strain maps and future possibilities of this technology are discussed.
Effects of P2Y1 receptor antagonism on the reactivity of platelets from patients with stable coronary artery disease using aspirin and clopidogrel
Authors: Labarthe B , Babin J , Bryckaert M , Théroux P , Bonnefoy A
Published: September 2011

BACKGROUND AND PURPOSE P2Y1 is a purine receptor that triggers platelet aggregation. Its inhibition was studied in patients with stable coronary artery disease (CAD) receiving standard anti‐platelet therapy.

EXPERIMENTAL APPROACH Blood samples from 10 patients on aspirin therapy (ASA, 80 mg·day−1) were withdrawn before and 24 h after the administration of 450 mg clopidogrel (ASA/C) and were anti‐coagulated with citrate or hirudin/PPACK in the presence or absence of the P2Y1 inhibitor MRS2179 (M, 100 µM). Platelet responses to ADP (2.5 µM) and TRAP (2.5 µM), and collagen‐induced thrombosis under flow conditions were analysed.

KEY RESULTS Compared with ASA, ASA + M strongly inhibited ADP‐induced peak platelet aggregation (88%), late aggregation (84%), P‐selectin expression (85%) and αIIbβ3 activation (62%) (28%, 65%, 70% and 51% inhibition, respectively, for ASA/C vs. ASA). ASA + M also inhibited platelet/monocyte and platelet/neutrophil conjugate formation by 69% and 71% (57% and 59% for ASA/C vs. ASA). In TRAP‐activated blood, ASA + M unexpectedly inhibited αIIbb3 activation by 30%. In blood perfused in collagen‐coated glass capillaries (shear rate of 1500 s−1), ASA/C prevented thrombus growth beyond 5 min in relation to thrombus fragments embolization. ASA + M with or without clopidogrel completely prevented thrombus formation. Finally, ex vivo addition of MRS2179 and ASA to the blood of healthy donors markedly blocked thrombus formation on collagen in flow conditions, in contrast to ASA plus the P2Y12 inhibitor 2‐MeSAMP.

CONCLUSIONS AND IMPLICATIONS Through particularly efficient complementarities with ASA to inhibit platelet activation and thrombus formation, the inhibition of P2Y1 in the blood of patients with CAD appears to play a more important role than previously anticipated.
High potency inhibition of hERG potassium channels by the sodium–calcium exchange inhibitor KB‐R7943
Authors: Cheng Hongwei , Zhang Yihong , Du Chunyun , Dempsey Christopher E , Hancox Jules C
Published: September 2011

BACKGROUND AND PURPOSE KB‐R7943 is an isothiourea derivative that is used widely as a pharmacological inhibitor of sodium–calcium exchange (NCX) in experiments on cardiac and other tissue types. This study investigated KB‐R7943 inhibition of hERG (human ether‐à‐go‐go‐related gene) K+ channels that underpin the cardiac rapid delayed rectifier potassium current, IKr.

EXPERIMENTAL APPROACH Whole‐cell patch‐clamp measurements were made of hERG current (IhERG) carried by wild‐type or mutant hERG channels and of native rabbit ventricular IKr. Docking simulations utilized a hERG homology model built on a MthK‐based template.

KEY RESULTS KB‐R7943 inhibited both IhERG and native IKr rapidly on membrane depolarization with IC50 values of ∼89 and ∼120 nM, respectively, for current tails at −40 mV following depolarizing voltage commands to +20 mV. Marked IhERG inhibition also occurred under ventricular action potential voltage clamp. IhERG inhibition by KB‐R7943 exhibited both time‐ and voltage‐dependence but showed no preference for inactivated over activated channels. Results of alanine mutagenesis and docking simulations indicate that KB‐R7943 can bind to a pocket formed of the side chains of aromatic residues Y652 and F656, with the compound's nitrobenzyl group orientated towards the cytoplasmic side of the channel pore. The structurally related NCX inhibitor SN‐6 also inhibited IhERG, but with a markedly reduced potency.

CONCLUSIONS AND IMPLICATIONS KB‐R7943 inhibits IhERG/IKr with a potency that exceeds that reported previously for acute cardiac NCX inhibition. Our results also support the feasibility of benzyloxyphenyl‐containing NCX inhibitors with reduced potential, in comparison with KB‐R7943, to inhibit hERG.
The metabolism and pharmacokinetics of phospho‐sulindac (OXT‐328) and the effect of difluoromethylornithine
Authors: Xie G , Nie T , Mackenzie GG , Sun Y , Huang L , Ouyang N , Alston N , Zhu C , Murray OT , Constantinides PP , Kopelovich L , Rigas B
Published: September 2011

BACKGROUND AND PURPOSE Phospho‐sulindac (PS; OXT‐328) prevents colon cancer in mice, especially when combined with difluoromethylornithine (DFMO). Here, we explored its metabolism and pharmacokinetics.

EXPERIMENTAL APPROACH PS metabolism was studied in cultured cells, liver microsomes and cytosol, intestinal microsomes and in mice. Pharmacokinetics and biodistribution of PS were studied in mice.

KEY RESULTS PS undergoes reduction and oxidation yielding PS sulphide and PS sulphone; is hydrolysed releasing sulindac, which generates sulindac sulphide (SSide) and sulindac sulphone (SSone), all of which are glucuronidated. Liver and intestinal microsomes metabolized PS extensively but cultured cells converted only 10% of it to PS sulphide and PS sulphone. In mice, oral PS is rapidly absorbed, metabolized and distributed to the blood and other tissues. PS survives only partially intact in blood; of its three major metabolites (sulindac, SSide and SSone), sulindac has the highest Cmax and SSone the highest t1/2; their AUC0–24h are similar. Compared with conventional sulindac, PS generated more SSone but less SSide, which may contribute to the safety of PS. In the gastroduodenal wall of mice, 71% of PS was intact; sulindac, SSide and SSone together accounted for <30% of the total. This finding may explain the lack of gastrointestinal toxicity by PS. DFMO had no effect on PS metabolism but significantly reduced drug level in mouse plasma and other tissues.

CONCLUSIONS AND IMPLICATIONS Our findings establish the metabolism of PS define its pharmacokinetics and biodistribution, describe its interactions with DFMO and largely explain its gastrointestinal safety.
Molecular pharmacological profile of a novel thiazolinone‐based direct and selective 5‐lipoxygenase inhibitor
Authors: Hofmann B , Rödl CB , Kahnt AS , Maier TJ , Michel AA , Hoffmann M , Rau O , Awwad K , Pellowska M , Wurglics M , Wacker M , Živković A , Fleming I , Schubert‐Zsilavecz M , Stark H , Schneider G , Steinhilber D
Published: September 2011

BACKGROUND AND PURPOSE The potency of many 5‐lipoxygenase (5‐LOX) inhibitors depends on the cellular peroxide tone and the mechanism of 5‐LOX enzyme activation. Therefore, new inhibitors that act regardless of the mode of enzyme activation need to be developed. Recently, we identified a novel class of thiazolinone‐based compounds as potent 5‐LOX inhibitors. Here, we present the molecular pharmacological profile of (Z)‐5‐(4‐methoxybenzylidene)‐2‐(p‐tolyl)‐5H‐thiazol‐4‐one, compound C06.

EXPERIMENTAL APPROACH Inhibition of 5‐LOX product formation was determined in intact cells [polymorphonuclear leukocytes (PMNL), rat basophilic leukaemia‐1, RAW264.7] and in cell‐free assays [homogenates, 100 000×g supernatant (S100), partially purified 5‐LOX] applying different stimuli for 5‐LOX activation. Inhibition of peroxisome proliferator‐activated receptor (PPAR), cytosolic phospholipase A2 (cPLA2), 12‐LOX, 15‐LOX‐1 and 15‐LOX‐2 as well as cyclooxygenase‐2 (COX‐2) were measured in vitro.

KEY RESULTS C06 induced non‐cytotoxic, direct 5‐LOX inhibition with IC50 values about 0.66 µM (intact PMNL, PMNL homogenates) and approximately 0.3 µM (cell‐free PMNL S100, partially purified 5‐LOX). Action of C06 was independent of the stimulus used for 5‐LOX activation and cellular redox tone and was selective for 5‐LOX compared with other arachidonic acid binding proteins (PPAR, cPLA2, 12‐LOX, 15‐LOX‐1, 15‐LOX‐2, COX‐2). Experimental results suggest an allosteric binding distinct from the active site and the C2‐like domain of 5‐LOX.

CONCLUSIONS AND IMPLICATIONS C06 was identified as a potent selective direct 5‐LOX inhibitor exhibiting a novel and unique mode of action, different from other established 5‐LOX inhibitors. This thiazolinone may possess potential for intervention with inflammatory and allergic diseases and certain types of cancer.
Preexisting Mitral Valve Prosthesis in Patients Undergoing Left Ventricular Assist Device Implantation
Authors: Schweiger Martin , Stepanenko Alexander , Vierecke Juliane , Drews Thorsten , Potapov Evgenij , Hetzer Roland , Krabatsch Thomas
Published: September 2011

Experience with patients undergoing left ventricular assist device (LVAD) implantation with preexisting mitral valve prostheses is limited. Patients with mechanical heart valves might have an increased risk of thromboembolism; in patients with biologic valves, there might be a risk of structural deterioration of the leaflets. Out of 597 patients supported with a LVAD system between 2000 and 2009, 18 patients had mitral valve surgery prior to implantation. We excluded all patients below 18 years of age, those with postcardiotomy failure, and patients who had had mitral valve reconstruction. Only 1% of the studied patient population (n= 6) had mitral valve replacement. The mitral valve implantation has been performed 7.4 ± 9.4 years prior to LVAD insertion. None of the valves (one biologic, five mechanical) were exchanged or explanted. LVAD implantation was done either with left lateral thoracotomy (n= 5) or with midline resternotomy (n= 1). Temporary right ventricular assist device support was necessary in one case (16.6%); 30‐day mortality was 16.6% (n= 1). Median support time was 14 ± 15 months. Two patients received heart transplantation after 6 and 26 months on the device; four patients died on mechanical circulatory support after 1, 2, 5, and 40 months. No valve or pump thrombosis or other clinically relevant thromboembolic events were observed. Only a small number of patients (1%) had a preexisting mitral valve prosthesis prior to LVAD implantation. No severe adverse events were observed when the prosthesis was left in place. Attention should be paid to the anticoagulation regime.
A Double‐Blind, Placebo‐Controlled Trial to Assess the Efficacy of Quetiapine Fumarate XR in Very Heavy‐Drinking Alcohol‐Dependent Patients
Authors: Litten Raye Z. , Fertig Joanne B. , Falk Daniel E. , Ryan Megan L. , Mattson Margaret E. , Collins Joseph F. , Murtaugh Cristin , Ciraulo Domenic , Green Alan I. , Johnson Bankole , Pettinati Helen , Swift Robert , Afshar Maryam , Brunette Mary F. , Tiouririne Nassima A.‐D. , Kampman Kyle , Stout Robert ,   the NCIG 001 Study Group
Published: September 2011

Background:  Despite advances in developing medications to treat alcohol dependence, few such medications have been approved by the Food and Drug Administration. Identified molecular targets are encouraging and can lead to the development and testing of new compounds. Atypical antipsychotic medications have been explored with varying results. Prior research suggests that the antipsychotic quetiapine may be beneficial in an alcohol‐dependent population of very heavy drinkers.

Methods:  In this double‐blind, placebo‐controlled trial, 224 alcohol‐dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either quetiapine or placebo and Medical Management behavioral intervention. Patients were stratified on gender, clinical site, and reduction in drinking prior to randomization.

Results:  No differences between the quetiapine and placebo groups were detected in the primary outcome, percentage heavy‐drinking days, or other drinking outcomes. Quetiapine significantly reduced depressive symptoms and improved sleep but had no effect on other nondrinking outcomes. Results from a subgroup analysis suggest that patients who reduced their drinking prior to randomization had significantly better drinking outcomes during the maintenance phase (p < 0.0001). No significant interactions, however, were observed between reducer status and treatment group. Finally, quetiapine was generally well tolerated. Statistically significant adverse events that were more common with quetiapine versus placebo include dizziness (14 vs. 4%), dry mouth (32 vs. 9%), dyspepsia (13 vs. 2%), increased appetite (11 vs. 1%), sedation (15 vs. 3%), and somnolence (34 vs. 9%).

Conclusions:  This multisite clinical trial showed no efficacy for quetiapine compared with placebo at reducing alcohol consumption in heavy‐drinking alcohol‐dependent patients.
Predictors of Duloxetine versus Other Treatments among Veterans with Diabetic Peripheral Neuropathic Pain: A Retrospective Study
Authors: Zhao Yingnan , Liu Jinan , Zhao Yang , Thethi Tina , Fonseca Vivian , Shi Lizheng
Published: September 2011

Objective:  This study used medical and pharmacy records from the Veterans Affairs (VA) health system to explore the predictors of duloxetine versus other treatments for patients with diabetic peripheral neuropathic pain (DPNP).

Methods:  The electronic medical and pharmacy records from January 2004 to December 2008 were requested from the Veterans Integrated Service Network 16 data warehouse. All select patients received either duloxetine or other treatments [tricyclic antidepressants (TCAs), venlafaxine, gabapentin, and pregabalin] over the study period, with the first dispense date of the index agent as the index date. All patients must have 1+ prior DPNP diagnosis (ICD‐9‐CM: 250.6x or 357.2), but no diagnoses of prior depression (ICD‐9‐CM: 296.2, 296.3, 300.4, 309.1, or 311.0), fibromyalgia (ICD‐9‐CM: 729.1), or neuralgia (ICD‐9‐CM: 729.2). Logistic regression was used to examine the predictors of receiving duloxetine versus other treatments, controlling for demographics, comorbidities, prior pain level, prior use of other medications, and opioid use.

Results:  The analytical sample included 2,694 patients (duloxetine cohort, n = 216; other‐treatment cohort, n = 2,478). Prior uses of gabapentin (odds ratio [OR] = 13.66, 95% confidence interval [CI]: 9.70–19.24), TCAs (OR = 5.40, 95% CI: 3.73–7.82), or venlafaxine (OR = 3.67, 95% CI: 1.67–8.06) were strong predictors of duloxetine. Other comorbidities associated with duloxetine were anxiety (OR = 2.08, 95% CI: 1.40–3.08), cerebrovascular disease (OR = 1.44, 95% CI: 1.01–2.07), and substance abuse (OR = 2.11, 95% CI: 1.10–4.03). Prior opioid users were 1.47 (95% CI: 1.02–2.12) times as likely to receive duloxetine as those without prior opioid use. Patients with self‐reported severe pain were 1.66 (95% CI: 1.11–2.50) times as likely to receive duloxetine as those with no pain reported.

Conclusion:  DPNP patients in the VA healthcare system with prior other treatment use, select comorbid conditions, prior substance abuse, prior opioid use, and higher pain level were more likely to receive duloxetine.
Variant screening of the RHD gene in a large cohort of subjects with D phenotype ambiguity: report of 17 novel rare alleles
Authors: Fichou Yann , Le Maréchal Cédric , Bryckaert Laurence , Guerry Christine , Bénech Caroline , Dupont Isabelle , Jamet Déborah , Férec Claude , Chen Jian‐Min
Published: September 2011

BACKGROUND: A considerable number of RHD alleles responsible for weak and partial D phenotypes have been identified over the past decade. Two particular concerns, namely, 1) that red blood cells of these phenotypes may cause anti‐D immunization when transfused to D– recipients and 2) that serologic determination of these phenotypes is often doubtful, make genetic analysis of the RHD gene highly desirable.

STUDY DESIGN AND METHODS: Blood samples that displayed D phenotype ambiguity (as determined by serologic analyses) were collected from several sites of the Etablissement Français du Sang and subjected to RHD variant screening by means of a previously established denaturing high‐performance liquid chromatography method followed by direct sequencing.

RESULTS: Systematic screening of the RHD coding sequences as well as the exon‐intron boundaries identified DNA variants in 755 of the 806 samples analyzed. In particular, this resulted in the identification of 10 novel single‐nucleotide substitutions and seven novel complex alleles.

CONCLUSION: This study further increased the already large repertoire of RHD allelic variants. Whereas most of the newly found variants are putative weak or partial D alleles, most of the complex alleles are readily understandable in the present phylogenetic model of RHD.
Apheresis‐related enrichment of CD26++ T lymphocytes: phenotypic characterization and correlation with unfavorable outcome in autologous hematopoietic progenitor cell transplantation
Authors: Hildebrandt Martin , Dijkstra Dorothea , Gollasch Hella , Daemen Kerstin , Stevanovic‐Meyer Maja , Ludwig Wolf‐Dieter
Published: September 2011

BACKGROUND: The lymphocyte surface glycoprotein CD26 anchors adenosine deaminase to the lymphocyte surface and possesses dipeptidyl peptidase IV activity. A distinct subset of CD26++ lymphocytes in autologous hematopoietic progenitor cell transplants (HPCTs) was investigated with regard to clinical outcome after autologous HPCT. The phenotype of these cells was characterized in more detail.

STUDY DESIGN AND METHODS: Forty‐two eligible patients (multiple myeloma, n = 31; Hodgkin's disease, n = 3; non‐Hodgkin's lymphoma, n = 6; peripheral neuroectodermal tumor, n = 1; acute myeloid leukemia, n = 1) were included in a retrospective analysis. Distinct cellular subsets, including CD26+/− and CD26++ subpopulations, were analyzed for correlations with kinetics of engraftment, progression‐free survival, and overall survival.

RESULTS: The numbers of CD26++ T lymphocytes in the autograft correlated inversely with progression‐free survival (p = 0.013). CD26++ T lymphocytes transfused per kg of body weight were predictive for the occurrence of disease progression or relapse (p = 0.006). Importantly, the numbers of CD26++ cells showed a highly variable degree of enrichment in the autograft, but no significant variations in the peripheral blood before apheresis. The characterization of CD26++ cells revealed that CD26++/CD8+ cells form a homogeneous population with a distinct T memory cell phenotype (CD45RO+, CD161++, interleukin‐18Rα++, CCR7−).

CONCLUSION: CD26++ lymphocytes define a discrete phenotype of T memory cells with known chemoresistance and T‐cell‐repopulating capacity. Their enrichment during apheresis and corresponding depletion from the circulation are associated with an adverse outcome in autologous HPCT.
Bank Finance versus Bond Finance
Authors: DE FIORE FIORELLA , UHLIG HARALD
Published: September 2011

We present a model with agency costs where heterogeneous firms raise finance through either bank loans or corporate bonds and where banks are more efficient than the market in resolving informational problems. We document some major long‐run differences in corporate finance between the United States and the euro area, and show that our model can explain those differences based on information availability. The model fits the data best when the euro area is characterized by lower availability of public information about corporate credit risk relative to the United States, and when European firms value more than United States firms banks’ flexibility and information acquisition role.
Convergence of Real Capital Market Interest Rates—Evidence from Inflation Indexed Bonds
Authors: HERWARTZ HELMUT , ROESTEL JAN
Published: September 2011

This paper investigates the convergence of long‐term ex ante real interest rates (RIRs) obtained from Canadian, French, UK, and U.S. inflation indexed government bonds. In contrast to previous research, our evidence suggests full convergence in the long run and, hence, capital market integration. For the same sample period, global convergence is rejected for RIRs measured in conventional terms. From these results, we conclude that previous tests of the long‐run real interest rate parity might have suffered from weak measurement of real capital market interest rates.
Implantable Cardioverter Defibrillator Implantation without Using Fluoroscopy in a Pregnant Patient
Authors: TUZCU VOLKAN , KILINC ORHAN U.
Published: September 2011

Conventional lead implantation requires fluoroscopic guidance. This may be problematic in certain patient groups such as pregnant patients. We report a case of an implantable cardioverter defibrillator implantation without fluoroscopy in a pregnant patient. (PACE 2012; 35:e265–e266)
Pediatric and Adult Congenital Endocardial Lead Extraction or Abandonment Decision (PACELEAD) Survey of Lead Management
Authors: McCANTA ANTHONY C. , SCHAFFER MICHAEL S. , COLLINS KATHRYN K.
Published: September 2011

Background:
 Nonfunctional, dysfunctional, recalled, or additional endocardial leads in pediatric and congenital heart disease patients pose significant challenges for management. There are no set standards for lead extraction in this patient population.

Methods:
 Physician members of the Pediatric and Adult Congenital Electrophysiology Society (PACES) were contacted via e‐mail and invited to respond to a 33‐question online Pediatric and Adult Congenital Endocardial Lead Extraction or Abandonment (PACELEAD) survey.

Results:
 Responses were received from 75 of 138 (54%) physician members of PACES. Institutional volumes of device placement (<25 devices/year for 51% of responders), patients with abandoned leads (<25 patients for 71%), and lead extractions (<10 extractions/year for 51% and no extractions for 29%) were low for the majority of responders. Personal experience with lead extraction was also minimal with 49% not performing the procedure and 39% with less than 40 leads extracted as primary operator. Most responders (54, 72%) refer their lead extractions to another practitioner or facility with more experience. Responders were more likely to recommend lead extraction (>70%) for class IIa indications such as bacteremia, chronic pain that is not medically manageable, and functional leads with ipsilateral venous occlusion. Lead abandonment was favored (>70%) for one class IIb indication, a functional lead that is not currently being used.

Conclusions:
 Optimal lead management is challenging in pediatric and congenital heart disease patients, and considerable variability of practice is reported in their care. Low institutional and personal volumes may account for this variability. (PACE 2011; 34:1621–1627)