bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prolyl 4‐hydroxylases, master regulators of the hypoxia response
Authors: Myllyharju J. 
Published: March 2013

AbstractA 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

SummaryBackgroundAcute 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).AimTo summarise evidence for the use of pentoxifylline in SAH.MethodsA 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.ResultsTen 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.ConclusionsPentoxifylline 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

SummaryBackgroundUntil 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.AimTo 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.MethodsThe scientific literature was reviewed to evaluate data on the use of anti‐TNFs in UC.ResultsIn 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.ConclusionsThe 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.
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

AbstractQuestionDiversification 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?LocationBílé Karpaty Mountains, SE Czech Republic.MethodsThe 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.ResultsWhile 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.ConclusionsThe 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

AimsOn 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.MethodsWe surveyed doctors, nurses and pharmacists in the 1–12 week period following the implementation date.ResultsForty‐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).ConclusionsLess 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

AbstractAtherosclerosis 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

AbstractBackgroundSevering 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.MethodsWe 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).ResultsA 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.ConclusionsIn 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

AbstractBackgroundAdvances 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.MethodsIn‐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.ResultsParticipants 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.ConclusionsThis 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)
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.
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

AbstractMost 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 PurposeNutrient 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 ApproachA 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 ResultsGPBAR1 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 ImplicationsSelective 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 PurposeTo 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 ApproachWe 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 ResultsCBDA (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 ImplicationsCBDA 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.