bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of the Likelihood Ratio Test and the Variance‐Stabilising Transformation‐Based Tests for Detecting Association of Rare Variants
Authors: Xing Guan , Ku Hung‐Chih , Xing Chao
Published: March 2013

In a recent paper in this journal, the use of variance‐stabilising transformation techniques was proposed to overcome the problem of inadequacy in normality approximation when testing association for a low‐frequency variant in a case‐control study. It was shown that tests based on the variance‐stabilising transformations are more powerful than Fisher's exact test while controlling for type I error rate. Earlier in the journal, another study had shown that the likelihood ratio test (LRT) is superior to Fisher's exact test, Wald's test, and Pearson's χ2 test in testing association for low‐frequency variants. Thus, it is of interest to make a direct comparison between the LRT and the tests based on the variance‐stabilising transformations. In this commentary, we show that the LRT and the variance‐stabilising transformation‐based tests have comparable power greater than Fisher's exact test, Wald's test, and Pearson's χ2 test.
Evaluation of the frequency and obstetric risk factors associated with term neonatal admissions to special care units
Authors: Alkiaat Aseel , Hutchinson Maureen , Jacques Angela , Sharp Mary J. , Dickinson Jan E.
Published: March 2013

Introduction

Approximately 10–15% of term babies may require admission to neonatal special care units. This level of care is frequently an unexpected event for parents.

Aims

To review the frequency and obstetric risk factors associated with the admission of term neonates to a tertiary hospital special care unit (SCN).

Materials and Methods

All babies born ≥37‐weeks gestation admitted to the SCN at King Edward Memorial Hospital between 2004 and 2006 were identified from the institutional maternity and neonatal databases. Maternal and obstetric factors were reviewed to identify potential predictors of admission to the SCN.

Results

During the study period, 1671 term neonates born to 1624 women were admitted to the SCN (14.4% of term deliveries). Neonatal intensive care unit admissions accounted for 10.6% of the term admissions. The most common reasons for SCN admission were respiratory complications (n = 421, 25.2%), observation postresuscitation (n = 402, 24.1%) and hypoglycaemia (n = 152, 9.1%). Elective caesarean delivery was significantly associated with admission to the special care unit for respiratory complications compared with all other delivery modes (37 vs 23%, P < 0.001), particularly if the birth occurred at <39‐weeks gestation (38 vs 24%, P < 0.001).

Conclusions

In our population of women delivering at a tertiary maternity facility, approximately 1:8 term babies were admitted to the neonatal special care unit. Elective caesarean delivery was associated with a significant risk of admission for respiratory complications compared with other birth modes, especially when <39‐weeks gestation.
Personal Politics and Being British: Political Rhetoric, Democracy and their Consequences in Colonial New South Wales
Authors: Melleuish Gregory
Published: March 2013

This paper argues that although our understanding of politics in colonial New South Wales in the period after 1856 has increased in recent times there is little appreciation of the political rhetoric employed to justify those politics. It contends that the key to understanding that rhetoric is an appreciation that politics was not understood in terms of institutional design but focused rather on the quality of political leaders. In particular, as exemplified by the case of Henry Parkes, it involved being British and being able to work British institutions. This emphasis on personal politics, rather than institutional matters such as the creation of checks and balances, helped to shape the nature of democratic institutions in Australia. In particular it encouraged a form of democracy that concentrated power. The refusal of members of the Legislative Council to oppose the Influx of Chinese Restriction Bill is an early indication of the consequences of that form of democracy.
The Curious Case of Mervyn Eades: National Service, Discrimination and Aboriginal People
Authors: Riseman Noah
Published: March 2013

In 1971, an Aboriginal man named Mervyn Eades was convicted for failing to register for national service. The magistrate determined that while Eades was indeed Aboriginal under Western Australian law, under the National Service Act he was not. Scrutiny of Eades’ case exposes the interconnected issues of Aboriginality, racial discrimination, assimilation, federalism and conscription in the period between the 1967 Referendum and the 1972 election. Eades’ conviction represented a unique junction of these seemingly disparate political issues which gradually converged. Analysis of Eades’ case and the wider issue of Aboriginal people and national service highlights ongoing legislative discrimination in the immediate post‐Referendum period, the problematic status of concurrent Aboriginal affairs powers and the McMahon Liberal government's determination — ultimately unsuccessfully — to avoid conflation of conscription and race politics.
The Development of a Multiorgan Ex Vivo Perfused Model: Results With the Porcine Liver‐Kidney Circuit Over 24 Hours
Authors: Chung Wen Yuan , Gravante Gianpiero , Al‐Leswas Dhya , Arshad Ali , Sorge Roberto , Watson Chris C. , Pollard Cristina , Metcalfe Matthew S. , Dennison Ashley R.
Published: March 2013

We already developed an ex vivo liver‐kidney model perfused for 6 h in which the kidney acted as a homeostatic organ to improve the circuit milieu compared to liver alone. In the current study, we extended the multiorgan perfusions to 24 h to evaluate the results and eventual pitfalls manifesting with longer durations. Five livers and kidneys were harvested from female pigs and perfused over 24 h. The extracorporeal circuit included a centrifugal pump, heat exchanger, and oxygenator. The primary end point of the study was the evaluation of the organ functions as gathered from biochemical and acid‐base parameters. In the combined liver‐kidney circuit, the organs survived and maintained an acceptable homeostasis for different lengths of time, longer for the liver (up to 19–23 h of perfusions) than the kidney (9–13 h of perfusions). Furthermore, glucose and creatinine values decreased significantly over time (from the 5th and 9th hour of perfusion onward). The addition of a kidney to the perfusion circuit improved the biochemical environment by removing excess products from ongoing metabolic processes. The consequence is a more physiological milieu that could improve results from future experimental studies. However, it is likely that long perfusions require some nutritional support over the hours to maintain the organ's vitality and functionality throughout the experiments.
Prolyl 4‐hydroxylases, master regulators of the hypoxia response
Authors: Myllyharju J.
Published: March 2013

A decrease in oxygenation is a life‐threatening situation for most organisms. An evolutionarily conserved efficient and rapid hypoxia response mechanism activated by a hypoxia‐inducible transcription factor (HIF) is present in animals ranging from the simplest multicellular phylum Placozoa to humans. In humans, HIF induces the expression of more than 100 genes that are required to increase oxygen delivery and to reduce oxygen consumption. As its name indicates HIF is found at protein level only in hypoxic cells, whereas in normoxia, it is degraded by the proteasome pathway. Prolyl 4‐hydroxylases, enzymes that require oxygen in their reaction, are the cellular oxygen sensors regulating the stability of HIF. In normoxia, 4‐hydroxyproline residues formed in the α‐subunit of HIF by these enzymes lead to its ubiquitination by the von Hippel–Lindau E3 ubiquitin ligase and immediate destruction in proteasomes thus preventing the formation of a functional HIF αβ dimer. Prolyl 4‐hydroxylation is inhibited in hypoxia, facilitating the formation of the HIF dimer and activation of its target genes, such as those for erythropoietin and vascular endothelial growth factor. This review starts with a summary of the molecular and catalytic properties and individual functions of the four HIF prolyl 4‐hydroxylase isoenzymes. Induction of the hypoxia response via inhibition of the HIF prolyl 4‐hydroxylases may provide a novel therapeutic target in the treatment of hypoxia‐associated diseases. The current status of studies aiming at such therapeutic approaches is introduced in the final part of this review.
Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis
Authors: Parker R. , Armstrong M. J. , Corbett C. , Rowe I. A. , Houlihan D. D.
Published: March 2013

Background

Acute alcoholic hepatitis (AH) is a severe manifestation of alcoholic liver disease with a grave prognosis. Pentoxifylline, an oral antitumour necrosis factor agent, has been reported to reduce mortality and incidence of hepatorenal syndrome (HRS) in severe alcoholic hepatitis (SAH).

Aim

To summarise evidence for the use of pentoxifylline in SAH.

Methods

A literature search was undertaken using MeSH terms ‘hepatitis, alcoholic’ and ‘pentoxifylline’ using the set operator AND. We included randomised controlled trials examining pentoxifylline in SAH, published as abstracts or full manuscripts. Risk ratios (RRs) were calculated for pooled data using random effects modelling. Risk of bias was assessed using Cochrane group criteria and quality of trials assessed using ‘Consolidated Standards of Reporting Trials’ CONSORT guidelines.

Results

Ten trials including 884 participants were included, from six papers and four abstracts. There was significant heterogeneity between trials regarding control groups and trial end‐points. Treatment was given for 28 days in all trials except one. Pooling of data showed a reduced incidence of fatal HRS with pentoxifylline compared with placebo (RR: 0.47, 0.26–0.86, P = 0.01), but no survival benefit at 1 month (RR: 0.58, 0.31–1.07, P = 0.06). There were no significant differences between treatment groups in trials of pentoxifylline vs. corticosteroid, or vs. combination therapy.

Conclusions

Pentoxifylline appears superior to placebo in prevention of fatal HRS and thus may be effective treatment of SAH when corticosteroids are contraindicated. However, multiple trials have failed to show conclusive superiority of either pentoxifylline or corticosteroids.
Review article: the role of anti‐TNF in the management of ulcerative colitis – past, present and future
Authors: Danese S. , Colombel J.‐F. , Peyrin‐Biroulet L. , Rutgeerts P. , Reinisch W.
Published: March 2013

Background

Until recently, the management of ulcerative colitis (UC) consisted of the stepwise use of mesalazine, corticosteroids and immunomodulators, or consideration of surgery. Anti‐tumour necrosis factor (TNF) agents are recent additions to the UC‐treatment algorithm.

Aim

To provide clinicians with a review of the role of anti‐TNFs in UC, discussing how the drug(s) were used in the past, their current use and to determine their future role.

Methods

The scientific literature was reviewed to evaluate data on the use of anti‐TNFs in UC.

Results

In this review, we report how the management of UC has changed with the availability of anti‐TNFs. The results from landmark anti‐TNF trials have impacted clinical practice, leading to a readjustment of treatment goals. In addition, experience from clinical trials and local real‐life cohorts have helped to clarify some misunderstandings in the management of UC. New anti‐TNFs are on the horizon but questions still remain on the future role of anti‐TNFs with regard to impact on disability, digestive damage and the possible development of risk matrices. Experiences from the use of anti‐TNFs in Crohn's disease (for example, combination therapy and early treatment) now need to be addressed in UC.

Conclusions

The use of anti‐TNFs in the management of UC has matured rapidly. Clinical experience has helped shape the current role of anti‐TNFs, but more clinical research is needed to optimise their future role.
The ‘Semblance of Immortality'? Resinous Materials and Mortuary Rites in Roman Britain
Authors: Brettell R. C. , Stern B. , Reifarth N. , Heron C.
Published: March 2013

There is increasing evidence for complexity in mortuary practices in Britain during the Roman period. One class of burials demonstrates an association between inhumation in stone sarcophagi or lead‐lined coffins, ‘plaster’ coatings, textile shrouds and natural resins. It has been suggested that this ‘package’ represents a deliberate attempt at body preservation. Fragments with a resinous appearance found in one such burial from Arrington, Cambridgeshire, UK were analysed using gas chromatography–mass spectrometry. The triterpenic compounds identified are biomarkers for the genus Pistacia and provide the first chemical evidence for an exotic resin in a mortuary context in Roman Britain.
Effects of changes in management on resistance and resilience in three grassland communities
Authors: Klimeš Leoš , Hájek Michal , Mudrák Ondřej , Dančák Martin , Preislerová Zdenka , Hájková Petra , Jongepierová Ivana , Klimešová Jitka
Published: March 2013

Question

Diversification of grassland management is recommended as a tool for conservation of different taxonomic groups living in those habitats. How resistant and resilient are species‐rich grasslands in terms of plant species richness and vegetation composition to short‐term, small‐scale perturbations caused by changes in management practice?

Location

Bílé Karpaty Mountains, SE Czech Republic.

Methods

The experiment included the effect of six management regimes (mowing in June; mowing in September; mowing in June and September; mowing in June and high stubble left; no management; mowing in June and mulching). It was conducted in species‐rich wooded grasslands in the White Carpathians Mts., Czech Republic, represented by three types of plant community: a Bromus erectus community (with high species richness and low productivity), a Molinia arundinacea community (with high species richness and high productivity), and a Calamagrostis epigejos community (with low species richness and high productivity). After 3 yr, resistance was assessed, and traditional management (mowing once each year in June) was resumed; resilience was evaluated after three more years.

Results

While the species‐rich, unproductive Bromus community was relatively resistant to less intensive management in terms of species richness, and therefore its resilience could not be assessed, it changed substantially in terms of vegetation composition (maximum dissimilarity between control and abandoned plots was 63%). The more productive Molinia and Calamagrostis communities lost up to 37% of species due to abandonment, but not as a consequence of other changes management regimes. After the traditional management was resumed, resilience was higher in the Calamagrostis community than in the Molinia community. Vegetation composition was not affected by treatments.

Conclusions

The results show that short‐term abandonment causes loss of plant diversity in productive grasslands but not in less productive, species‐rich grasslands in the short term. Other relaxed management regimes (e.g. high stubble and delayed mowing) were comparable with the control and can be used for a short time to increase diversity of management without an effect on plant species richness. However, further research is needed to assess the effects of these management practices when they are applied repeatedly or over the long term.
Dissemination and uptake of a new treatment pathway for paracetamol poisoning in the UK: a survey of healthcare professionals
Authors: Hitchings Andrew W. , Wood David M. , Dargan Paul I.
Published: March 2013

Aims

On 3 September 2012, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) notified healthcare professionals of immediate changes to the intravenous acetylcysteine license terms, altering the treatment pathway for paracetamol poisoning. We sought to evaluate awareness of this amongst healthcare professionals.

Methods

We surveyed doctors, nurses and pharmacists in the 1–12 week period following the implementation date.

Results

Forty‐four individuals completed the survey in paper form (response rate 86%) and 220 in electronic form (response rate unknown). The resulting sample of 264 individuals was drawn from 41 institutions, and included 143 doctors, 58 pharmacists and 50 nurses. Of these individuals, 157 (59%) were aware of the changes, and 133 (50%) had adopted them in practice. Awareness differed between healthcare professions (P = 0.001) and specialties (P = 0.002). For respondents aware of the changes, the main sources of information were alerts issued internally (reported by 57%), from the MHRA (25%) and from other professional bodies (24%). The proportion of individuals who reported receiving practical implementation instructions (e.g. a protocol) was higher among respondents who had changed their practice than for those who had not (86 vs. 25%, respectively; P < 0.001).

Conclusions

Less than two‐thirds of healthcare professionals in specialties managing patients with paracetamol poisoning were aware of important changes to its treatment pathway in the 12 weeks after they took effect, and only half had adopted them in practice. Alternative communication strategies should be explored to improve dissemination of similar information from the MHRA and other medicines regulators in the future.
Effects of Chimeric Decoy Oligodeoxynucleotide in the Regulation of Transcription Factors NF‐κB and Sp1 in an Animal Model of Atherosclerosis
Authors: Lee Woo‐Ram , Kim Kyung‐Hyun , An Hyun‐Jin , Park Yoon‐Yub , Kim Kee‐Sik , Lee Chong‐Kee , Min Bo‐Kyung , Park Kwan‐kyu
Published: March 2013

Atherosclerosis is a multifactorial and progressive disease in which the inflammatory reaction and inflammation‐related factors play important roles at all stages. Modulation of NF‐κB and Sp1 expression may be important targets for the prevention and treatment of atherosclerotic vascular disease. To develop a novel therapeutic approach in atherosclerosis, we examined the simultaneous suppression of the transcription factors NF‐κB and Sp1 which regulate inflammation. We employed chimeric decoy oligodeoxynucleotide (ODN) containing the consensus of NF‐κB and Sp1‐binding sites to suppress these transcription factors simultaneously and to test chimeric decoy for anti‐atherogenic effects in an atherogenic diet‐induced atherosclerotic mouse model with inflammatory stimulation. C57BL/6 mice were fed with an atherogenic diet (15% fat, 1.25% cholesterol and 0.5% cholic acid) for 12 weeks to induce atherosclerosis; lipopolysaccharide (LPS, 2 mg/kg) was intraperitoneally injected in the first week of study to simulate underlying infectious burden during development of atherosclerosis. Decoy ODNs were injected into tail vein at 2, 4, 6, 8, 10 and 12 weeks after only three LPS injections in mice fed the atherogenic diet. Chimeric decoy ODN alleviated atherosclerotic changes and reduced serum cholesterol and inflammatory cytokines. In accordance with these results, the expressions of atherosclerotic markers were inhibited by chimeric decoy ODN. Chimeric decoy ODN modulates multiple pathogenic aspects of an atherogenic diet‐induced atherosclerosis with inflammatory stimulation: hypercholesterolaemia and inflammation. Therefore, this study demonstrates the efficacy of chimeric decoy ODN on atherosclerosis with immunological complication.
An Observational Study of Umbilical Cord Clamping Practices of Maternity Care Providers in a Tertiary Care Center
Authors: Hutton Eileen K. , Stoll Kathrin , Taha Natalie
Published: March 2013

Background

Severing the umbilical cord at birth is likely the oldest intervention, the timing of which remains fraught with controversy. Emerging evidence suggests benefit in delaying cord clamping for both term and preterm infants. The objective of this study was to investigate actual cord clamping time and circumstances at a large tertiary care center in Canada.

Methods

We used a stopwatch to time the interval from the time the infant was born as far as the umbilicus until the time that the umbilical cord was clamped before cutting. We reported on timing of the umbilical cord clamping overall and by practitioner group (obstetrician, midwife, and family practitioner).

Results

A total of 98 women and their practitioners consented to be observed at the British Columbia Women's Hospital and Health Center, Vancouver, Canada. More than one‐half (56.2%) of all infants had their umbilical cord clamped within 15 seconds. The median (5th, 95th percentile) clamping time in seconds for the full sample was 12 (4, 402) with practitioner subgroups as follows: obstetricians (12 [3, 107]), family physicians (19 [6, 325]), and midwives (81 [6, undefined]). The median clamping time was likely to be longer when the birth occurred spontaneously, no umbilical cord blood was collected, and no birth or neonatal complications occurred.

Conclusions

In our sample taken in 2006 to 2007, most infants had umbilical cords clamped immediately after the birth, with more than one‐half clamped within 15 seconds of birth. Since the time of our study, delayed umbilical cord clamping for the healthy term newborn has become a part of recommended management of third stage of labor and resuscitation guidelines. It would be informative to repeat a study like this one to determine compliance with the current standards of care. (BIRTH 40:1 March 2013)
“Taking Its Toll”: The Challenges of Working in Fetal Medicine
Authors: Menezes Melody A. , Hodgson Jan M. , Sahhar Margaret , Metcalfe Sylvia A.
Published: March 2013

Background

Advances in genetic technologies have resulted in the diagnosis during pregnancy of increasing numbers of fetal abnormalities. A few published personal commentaries have indicated that health professionals' interactions with couples at risk of a fetal abnormality can be emotionally and ethically challenging, highlighting the need for empirical research in this area. This study sought to explore whether working in the fetal medicine setting has an effect on health professionals and to ascertain any supports used to manage these effects.

Methods

In‐depth interviews were conducted with 40 medical and allied health professionals working in fetal medicine settings in Melbourne, Australia. Qualitative analysis of the interview data was performed using thematic analysis.

Results

Participants discussed at length the emotional impact of working with patients who were experiencing adverse pregnancy outcomes. All participants reported that working in fetal medicine had an impact on their daily lives, and many spoke about dreaming about or losing sleep over patient outcomes. Participants described working in this setting as being particularly difficult when they were pregnant themselves. Most spoke about feeling largely unsupported in their work and felt that these effects resulted in burnout and staff turnover.

Conclusions

This study explored several work force concerns in fetal medicine. Health professionals working with couples at risk of a fetal abnormality are vulnerable to the phenomena of compassion fatigue and burnout. The need for formal support and self‐care management is suggested. (BIRTH 40:1 March 2013)
Bridging intragroup processes and intergroup relations: Needing the twain to meet
Authors: Dovidio John F.
Published: March 2013

Despite their shared focus on groups, research bridging intragroup processes and intergroup relations is surprisingly rare. The goal of the present article is to highlight how understanding the reciprocal relationship between intragroup processes and intergroup relations offers valuable new insights into both topics and suggests new, productive avenues for research and theory development – particularly for understanding and improving intergroup relations. The article next briefly reviews key findings from three dominant frameworks in the field of intergroup relations: social cognition, social identity, and functional relations. It then discusses the complementary role of intergroup and intragroup dynamics, reviewing how intergroup relations can affect intragroup processes and then discussing how intragroup dynamics can shape intergroup relations. The final section considers the implications, theoretical and practical, of the proposed reciprocal relationships between intragroup and intergroup processes.
Can transrectal needle biopsy be optimised to detect nearly all prostate cancer with a volume of ≥0.5 mL? A three‐dimensional analysis
Authors: Kanao Kent , Eastham James A. , Scardino Peter T. , Reuter Victor E. , Fine Samson W.
Published: March 2013

Objective

To investigate whether transrectal needle biopsy can be optimised to detect nearly all prostate cancer with a tumour volume (TV) of ≥0.5 mL.

Materials and Methods

Retrospectively analysed 109 whole‐mounted and entirely submitted radical prostatectomy specimens with prostate cancer.

All tumours in each prostate were outlined on whole‐mount slides and digitally scanned to produce tumour maps. Tumour map images were exported to three‐dimensional (3D) slicer software (http://www.slicer.org) to develop a 3D‐prostate cancer model.

In all, 20 transrectal biopsy schemes involving two to 40 cores and two to six anteriorly directed biopsy (ADBx) cores (including transition zone, TZ) were simulated, as well as models with various biopsy cutting lengths.

Detection rates for tumours of different volumes were determined for the various biopsy simulation schemes.

Results

In 109 prostates, 800 tumours were detected, 90 with a TV of ≥0.5 mL (mean TV 0.24 mL).

Detection rate for tumours with a TV of ≥0.5 mL plateaued at 77% (69/90) using a 12‐core (3 × 4) scheme, standard 17‐mm biopsy cutting length without ADBx cores. In all, 20 of 21 (95%) tumours with a TV of ≥0.5 mL not detected by this scheme originated in the anterior peripheral zone or TZ.

Increasing the biopsy cutting length and depth/number of ADBx cores improved the detection rate for tumours with a TVof ≥0.5 mL in the 12‐core scheme.

Using a 22‐mm cutting length and a 12‐core scheme with additional volume‐adjusted ADBx cores, 100% of ≥0.5 mL tumours in prostates ≤ 50 mL in volume and 94.7% of ≥0.5 mL tumours in prostates > 50 mL in volume were detected.

Conclusions

Our 3D‐prostate cancer model analysis suggests that nearly all prostate cancers with a TV of ≥0.5 mL can be detected by 14–18 transrectal needle‐biopsy cores.

Using longer biopsy cutting lengths and increasing the depth and number of ADBx cores (including TZ) according to prostate volume are necessary as well.
Complementary and alternative medicine (CAM) in prostate and bladder cancer
Authors: Philippou Yiannis , Hadjipavlou Marios , Khan Shahid , Rane Abhay
Published: March 2013

To provide an overview of the scientific and clinical studies underlying the most common vitamin and herbal preparations used in prostate and bladder cancer and evaluate the evidence behind them. A literature search was undertaken on PubMed using various keywords relating to the use of complementary and alternative medicine (CAM) in prostate and bladder cancer. Vitamin E and selenium supplementation can potentially have adverse effects by increasing the risk of prostate cancer. Initial clinical studies of pomegranate and green tea, investigating their chemotherapeutic properties in prostate and bladder cancer have yielded encouraging results. Curcumin, resveratrol, and silibinin have potential anticancer properties through multiple molecular targets; their clinical effectiveness in prostate and bladder cancer is yet to be evaluated. Zyflamend, like PC‐SPES, is a combined CAM therapy used in prostate cancer. Acupuncture is popular among patients experiencing hot flushes who are receiving androgen‐deprivation therapy for prostate cancer. Conclusive evidence for the use of CAM in prostate and bladder cancer is lacking and not without risk.
Familial Dementia With Frontotemporal Features Associated With M146V Presenilin‐1 Mutation
Authors: Riudavets Miguel A. , Bartoloni Leonardo , Troncoso Juan C. , Pletnikova Olga , St. George‐Hyslop Peter , Schultz Marcelo , Sevlever Gustavo , Allegri Ricardo F.
Published: March 2013

Most of the mutations in the presenilin‐1 gene (PS‐1) are associated with familial Alzheimer's disease (AD). However, certain examples can be associated with frontotemporal dementia (FTD). We performed a clinical evaluation of individuals belonging to a family with the FTD phenotype, and additional molecular studies and neuropathological assessment of the proband. The PS‐1 M146V mutation was found in the 50‐year‐old subject (the proband) with family history of early‐onset FTD. Neuropathological examination showed abundant amyloid plaques, widespread neurofibrillary pathology, Pick bodies in the hippocampus and cortex, cortical globose tangles and ubiquitin‐positive nuclear inclusions in white matter oligodendrocytes. We report a kindred with clinical features of FTD, whose proband bore the PS‐1 M146V mutation and showed diffuse Alzheimer's type pathology and Pick bodies on post‐mortem neuropathological examination. As with other mutations within the same codon, this substitution may predispose to both diseases by affecting APP and/or tau processing.
Systemic bile acid sensing by G protein‐coupled bile acid receptor 1 (GPBAR1) promotes PYY and GLP‐1 release
Authors: Ullmer C , Alvarez Sanchez R , Sprecher U , Raab S , Mattei P , Dehmlow H , Sewing S , Iglesias A , Beauchamp J , Conde‐Knape K
Published: March 2013

Background and Purpose

Nutrient sensing in the gut is believed to be accomplished through activation of GPCRs expressed on enteroendocrine cells. In particular, L‐cells located predominantly in distal regions of the gut secrete glucagon‐like peptide 1 (GLP‐1) and peptide tyrosine‐tyrosine (PYY) upon stimulation by nutrients and bile acids (BA). The study was designed to address the mechanism of hormone secretion in L‐cells stimulated by the BA receptor G protein‐coupled bile acid receptor 1 (GPBAR1).

Experimental Approach

A novel, selective, orally bioavailable, and potent GPBAR1 agonist, RO5527239, was synthesized in order to investigate L‐cell secretion in vitro and in vivo in mice and monkey. In analogy to BA, RO5527239 was conjugated with taurine to reduce p.o. bioavailability yet retaining its potency. Using RO5527239 and tauro‐RO5527239, the acute secretion effects on L‐cells were addressed via different routes of administration.

Key Results

GPBAR1 signalling triggers the co‐secretion of PYY and GLP‐1, and leads to improved glucose tolerance. The strong correlation of plasma drug exposure and plasma PYY levels suggests activation of GPBAR1 from systemically accessible compartments. In contrast to the orally bioavailable agonist RO5527239, we show that tauro‐RO5527239 triggers PYY release only when applied intravenously. Compared to mice, a slower and more sustained PYY secretion was observed in monkeys.

Conclusion and Implications

Selective GPBAR1 activation elicits a strong secretagogue effect on L‐cells, which primarily requires systemic exposure. We suggest that GPBAR1 is a key player in the intestinal proximal‐distal loop that mediates the early phase of nutrient‐evoked L‐cell secretion effects.
Effect of low doses of cannabidiolic acid and ondansetron on LiCl‐induced conditioned gaping (a model of nausea‐induced behaviour) in rats
Authors: Rock EM , Parker LA
Published: March 2013

Background and Purpose

To determine the minimally effective dose of cannabidiolic acid (CBDA) that effectively reduces lithium chloride (LiCl)‐induced conditioned gaping reactions (nausea‐induced behaviour) in rats and to determine if these low systemic doses of CBDA (5–0.1 μg·kg−1) relative to those of CBD could potentiate the anti‐nausea effects of the classic 5‐hydroxytryptamine 3 (5‐HT3) receptor antagonist, ondansetron (OND).

Experimental Approach

We investigated the efficacy of low doses of CBDA to suppress acute nausea, assessed by the establishment of conditioned gaping to a LiCl‐paired flavour in rats. The potential of threshold and subthreshold doses of CBDA to enhance the reduction of nausea‐induced conditioned gaping by OND were then determined.

Key Results

CBDA (at doses as low as 0.5 μg·kg−1) suppressed nausea‐induced conditioned gaping to a flavour. A low dose of OND (1.0 μg·kg−1) alone reduced nausea‐induced conditioned gaping, but when it was combined with a subthreshold dose of CBDA (0.1 μg·kg−1) there was an enhancement in the suppression of LiCl‐induced conditioned gaping.

Conclusions and Implications

CBDA potently reduced conditioned gaping in rats, even at low doses and enhanced the anti‐nausea effect of a low dose of OND. These findings suggest that combining low doses of CBDA and OND will more effectively treat acute nausea in chemotherapy patients.
Treatment with hydrogen sulfide alleviates streptozotocin‐induced diabetic retinopathy in rats
Authors: Si Yan‐Fang , Wang Jun , Guan Juan , Zhou Li , Sheng Yu , Zhao Juan
Published: March 2013

Background and Purpose

Retinopathy, as a common complication of diabetes, is a leading cause of reduced visual acuity and acquired blindness in the adult population. The aim of present study was to investigate the therapeutic effect of hydrogen sulfide on streptozotocin (STZ)‐induced diabetic retinopathy in rats.

Experimental Approach

Rats were injected with a single i.p. injection of STZ (60 mg·kg−1) to induce diabetic retinopathy. Two weeks later, the rats were treated with NaHS (i.p. injection of 0.1 mL·kg−1·d−1 of 0.28 mol·L−1 NaHS, a donor of H2S) for 14 weeks.

Key Results

Treatment with H2S had no significant effect on blood glucose in STZ‐induced diabetic rats. Treatment with exogenous H2S enhanced H2S levels in both plasma and retinas of STZ‐induced diabetic rats. Treatment with H2S in STZ‐treated rats improved the retinal neuronal dysfunction marked by enhanced amplitudes of b‐waves and oscillatory potentials and expression of synaptophysin and brain‐derived neurotrophic factor, alleviated retinal vascular abnormalities marked by reduced retinal vascular permeability and acellular capillary formation, decreased vitreous VEGF content, down‐regulated expressions of HIF‐1α and VEGFR2, and enhanced occludin expression, and attenuated retinal thickening and suppressed expression of extracellular matrix molecules including laminin β1 and collagen IVα3 expression in retinas of STZ‐induced diabetic rats. Treatment with H2S in retinas of STZ‐induced diabetic rats abated oxidative stress, alleviated mitochondrial dysfunction, suppressed NF‐κB activation and attenuated inflammation.

Conclusions and Implications

Treatment with H2S alleviates STZ‐induced diabetic retinopathy in rats possibly through abating oxidative stress and suppressing inflammation.
PDE3, but not PDE4, reduces β1‐ and β2‐adrenoceptor‐mediated inotropic and lusitropic effects in failing ventricle from metoprolol‐treated patients
Authors: Molenaar Peter , Christ Torsten , Hussain Rizwan I , Engel Andreas , Berk Emanuel , Gillette Katherine T , Chen Lu , Galindo‐Tovar Alejandro , Krobert Kurt A , Ravens Ursula , Levy Finn Olav , Kaumann Alberto J
Published: March 2013

Background and Purpose

PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3‐selective inhibitor cilostamide (0.3–1 μM) or PDE4 inhibitor rolipram (1–10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium.

Experimental Approach

Right and left ventricular trabeculae from freshly explanted hearts of 5 non‐β‐blocker‐treated and 15 metoprolol‐treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (‐)‐noradrenaline, mediated through β1 adrenoceptors (β2 adrenoceptors blocked with ICI118551), and (‐)‐adrenaline, mediated through β2 adrenoceptors (β1 adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from –logEC50s.

Key Results

Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non‐β‐blocker‐treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (‐)‐adrenaline (0.78 ± 0.12 log units) than (‐)‐noradrenaline (0.47 ± 0.12 log units) in metoprolol‐treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (‐)‐noradrenaline or (‐)‐adrenaline on right and left ventricular trabeculae from metoprolol‐treated patients.

Conclusions and Implications

Metoprolol induces a control by PDE3 of ventricular effects mediated through both β1 and β2 adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β2 adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle.

Linked Article

This article is commented on by Eschenhagen, pp 524–527 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12168
PDE4 in the human heart – major player or little helper?
Authors: Eschenhagen Thomas
Published: March 2013

PDEs restrict the positive inotropic effects of β‐adrenoceptor stimulation by degrading cAMP. Hence, PDE inhibitors sensitize the heart to catecholamines and are therefore used as positive inotropes. On the downside, this is accompanied by exaggerated energy expenditure, cell death and arrhythmias. For many years, PDE3 was considered to be the major isoform responsible for the control of cardiac force and rhythm. However, recent work in gene‐targeted mice and rodent cells has indicated that PDE4 is also involved. Furthermore, selective PDE4 inhibitors augment catecholamine‐stimulated cAMP levels and induce arrhythmias in human atrial preparations, which suggests that PDE4 has a more prominent role in the human heart than anticipated, and that PDE4 inhibitors such as roflumilast may carry an arrhythmogenic risk. In this issue of the journal, a team of researchers from three laboratories report on the effect of PDE3 and PDE4 inhibitors on ventricular trabeculae from explanted human hearts. The key result is that the PDE4 inhibitor rolipram does not affect the positive inotropic effects of β1‐ or β2‐adrenoceptor stimulation. Given that the ventricle rather than the atria is the critical region in terms of arrhythmogenic consequences, this is an important and reassuring finding.

Linked Article

This article is a commentary on the research paper by Molenaar et al., pp. 528–538 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12167
Endothelium‐dependent hyperpolarization‐related relaxations diminish with age in murine saphenous arteries of both sexes
Authors: Chennupati Ramesh , Lamers Wouter H , Koehler S Eleonore , De Mey Jo G R
Published: March 2013

Background and Purpose

We investigated the effects of aging on the contributions of NO and endothelium‐dependent hyperpolarization (EDH) to endothelium‐dependent relaxation in saphenous arteries of male and female C57BL/6J mice aged 12, 34 and 64 weeks.

Experimental Approach

Vasomotor responses of saphenous arteries were analysed by wire myography in the absence and presence of stimuli of the endothelium, inhibitors of NOS, and inhibitors and stimulants of small (KCa2.3) and intermediate (KCa3.1) conductance calcium‐activated potassium channels.

Key Results

Arterial relaxing responses to sodium nitroprusside and to ACh in the absence of pharmacological inhibitors (indomethacin and L‐NAME), were similar in all age groups and sexes, but those mediated by endothelium‐derived NO were slightly but significantly increased in 64‐week‐old male mice. In the presence of inhibitors, 12‐week‐old animals showed pronounced ACh‐induced relaxation, which was significantly reduced in 34‐ and 64‐week‐old mice of both sexes. The EDH‐related component of ACh‐induced relaxations was abolished by TRAM‐34 (KCa3.1 blocker) or UCL 1684 (KCa2.3 blocker). Although the maximal relaxation induced by NS309 (KCa activator) was not affected by aging, the sensitivity for NS309 significantly decreased with aging. The presence of SKA‐31 (KCa modulator) potentiated relaxations induced by ACh in arteries of 12‐week‐old but not older mice.

Conclusion and Implications

In a small muscular artery of mice of either sex, total endothelium‐dependent relaxation is not affected by age. However, possibly due to changes in KCa channel function, the contribution of EDH to endothelium‐dependent relaxations decreased with age. The contribution of endothelium‐derived NO increases in old male mice.
RGD capsid modification enhances mucosal protective immunity of a non-human primate adenovirus vector expressing Pseudomonas aeruginosa OprF
Authors: Krause A , Whu W Z , Qiu J , Wafadari D , Hackett N R , Sharma A , Crystal R G , Worgall S
Published: March 2013

Replication-deficient adenoviral (Ad) vectors of non-human serotypes can serve as Ad vaccine platforms to circumvent pre-existing anti-human Ad immunity. We found previously that, in addition to that feature, a non-human primate-based AdC7 vector expressing outer membrane protein F of P. aeruginosa (AdC7OprF) was more potent in inducing lung mucosal and protective immunity compared to a human Ad5-based vector. In this study we analysed if genetic modification of the AdC7 fibre to display an integrin-binding arginine–glycine–aspartic acid (RGD) sequence can further enhance lung mucosal immunogenicity of AdC7OprF. Intratracheal immunization of mice with either AdC7OprF.RGD or AdC7OprF induced robust serum levels of anti-OprF immunoglobulin (Ig)G up to 12 weeks that were higher compared to immunization with the human vectors Ad5OprF or Ad5OprF.RGD. OprF-specific cellular responses in lung T cells isolated from mice immunized with AdC7OprF.RGD and AdC7OprF were similar for T helper type 1 (Th1) [interferon (IFN)-γ in CD8+ and interleukin (IL)-12 in CD4+], Th2 (IL-4, IL-5 and IL-13 in CD4+) and Th17 (IL-17 in CD4+). Interestingly, AdC7OprF.RGD induced more robust protective immunity against pulmonary infection with P. aeruginosa compared to AdC7OprF or the control Ad5 vectors. The enhanced protective immunity induced by AdC7OprF.RGD was maintained in the absence of alveolar macrophages (AM) or CD1d natural killer T cells. Together, the data suggest that addition of RGD to the fibre of an AdC7-based vaccine is useful to enhance its mucosal protective immunogenicity.
Mechanism of cell fate choice between neural and mesodermal development during early embryogenesis
Authors: Takemoto Tatsuya
Published: March 2013

During early embryogenesis, Sox2 expression distinguishes the neural plate from other embryonic domains, suggesting that the mechanism underlying the activation of the Sox2 gene is highly relevant to the development of this tissue. At the earliest stages of neural plate development, the Sox2 enhancer N1 regulates Sox2 expression in the extending posterior end of the neural plate. The N1 enhancer is initially activated in the axial stem cells, bipotential precursors of both neural and mesodermal lineages, therefore the activation does not immediately lead to Sox2 expression. A population of axial stem cells that remains in the superficial layer starts expressing Sox2, whereas another population that migrates through the primitive streak loses the N1 activity and becomes mesoderm. Multiple signaling cascades and transcription factors, including Wnt, fibroblast growth factor (FGF), bone morphogenetic protein (BMP) and Tbx6, are responsible for the regulation of Sox2 expression in axial stem cells to guide the development of the posterior neural plate and paraxial mesoderm.
Effect of chemical and mechanical debridement techniques on bacterial re‐growth on rough titanium surfaces: an in vitro study
Authors: Gustumhaugen Eva , Lönn‐Stensrud Jessica , Scheie Anne A. , Lyngstadaas S. P. , Ekfeldt Anders , Taxt‐Lamolle Sébastien
Published: March 2013

Objective

The aim of this in vitro study was to compare the effect of combined chemical and mechanical debridement of titanium (Ti) surfaces inoculated with Staphylococcus epidermidis, compared with the effect of chemical debridement alone.

Material and Methods

Different Ti surfaces were characterized with respect to roughness and subsequently inoculated with S. epidermidis. NaCl (0.9 vol.%), EDTA (12 vol.%), H2O2 (3 vol.%) or H2O2 + TiO2 nanoparticles served as chemical debridement agents, while TiBrush™ was used as the mechanical debridement tool. Safranin staining assessed biomass still attached to surfaces after debridement. Biofilm viability was assessed after re‐incubation of the debrided samples. SEM analysis was performed before and after the cleaning process.

Results

Surface average roughness (Sa) of the samples was measured at 2.22 ± 0.19 μm for group A, 0.19 ± 0.02 μm for group B, and 1.99 ± 0.10 μm for group C. When chemical debridement agents were used alone, H2O2‐containing products were most efficient in reducing the biomass load. The surface roughness did not affect the outcome of chemical debridement. However, when combining chemical and mechanical debridement, a further reduction of biofilm load and viability was observed with best effect on the smoothest surface.

Conclusions

Combining H2O2‐containing chemical agents with mechanical debridement (TiBrush™) provided best reduction in biofilm mass and re‐growth, when studied in vitro.
Transperineal ultrasonography in perianal Crohn's disease and recurrent cryptogenic fistula‐in‐ano
Authors: Nevler A. , Beer‐Gabel M. , Lebedyev A. , Soffer A. , Gutman M. , Carter D. , Zbar A. P.
Published: March 2013

Aim

Successful anal fistula care is aided by specialized imaging accurately defining the site of the internal opening and fistula type. Imaging techniques are complementary, designed to answer specific anatomical questions. There are limited data concerning the clinical value of transperineal ultrasound (TP‐US) in both cryptogenic fistula‐in‐ano and perianal Crohn's disease (PACD). The aim of the study was to assess the accuracy of TP‐US compared with operative findings in patients with perirectal sepsis.

Method

Patients with recurrent cryptogenic anal fistula and PACD referred for sonography were examined using TP‐US by a single examiner blinded to the operative results. Fistulae were categorized by the Parks classification predicting the site of the internal fistula opening. Ancillary horseshoe collections, abscesses and secondary tracks were defined.

Results

Fourteen patients with PACD and 27 patients with recurrent cryptogenic fistula‐in‐ano were analysed with comparative images and operative data. Correlation of fistula type for cryptogenic and PACD patients respectively was 23/27 (85.2%) and 12/14 (85.7%), with a correlative internal opening site (when found at surgery) of 16/22 (72.3%) and 12/14 (85.7%). Misclassification of fistula type in cryptogenic cases occurred in the presence of ancillary abscesses with associated acoustic shadowing. In PACD patients, TP‐US was used when anal stenosis precluded endoanal ultrasonography, assisting in the diagnosis of recto‐vaginal fistulae.

Conclusion

TP‐US is a useful complementary technique to assess fistula‐in‐ano and has special advantage when there is anal canal distortion, complex fistula type or suspicion of a recto‐vaginal fistula.