bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concomitant use of ibuprofen and paracetamol and the risk of major clinical safety outcomes
Authors: De Vries Frank , Setakis Efrosini , Van Staa Tjeerd‐Pieter 
Published: May 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Non‐steroidal anti‐inflammatory drugs (NSAIDs) and paracetamol are widely used analgesics in the prescription and non‐prescription settings. Although both classes of drug are generally well tolerated, they can lead to well‐characterized adverse effects. Both drugs are widely co‐prescribed and it is of interest to understand better safety outcomes when the two drugs are taken concomitantly. WHAT THIS STUDY ADDS? Relative rates and hazard ratio patterns of safety outcomes were broadly similar for patients prescribed ibuprofen alone, paracetamol alone and concomitant ibuprofen and paracetamol. The risks of the various safety outcomes examined do not appear to be modified by concomitant use of ibuprofen and paracetamol compared with paracetamol or ibuprofen alone.AIMSTo evaluate and compare the risk of specific safety outcomes in patients prescribed ibuprofen and paracetamol concomitantly with those in patients prescribed ibuprofen or paracetamol alone. The outcomes were evaluated according to dose, duration and exposure.METHODSThe study used a retrospective longitudinal cohort design with data from the UK General Practice Research Database (GPRD). The study population included patients aged 18 years or over who were prescribed ibuprofen alone, paracetamol alone or concomitant ibuprofen and paracetamol (tablets or capsules only). The safety outcomes evaluated were upper gastrointestinal events, myocardial infarction, stroke, renal failure (excluding chronic), congestive heart failure, intentional or accidental overdose, suicidal behaviour and mortality. Time‐dependent Cox regression was used to estimate relative rates for the safety outcomes, by treatment group. A further analysis evaluated whether the hazard rates (i.e. absolute risks) varied over time with changes in drug exposure.RESULTSThe study population included 1.2 million patients. There was considerable heterogeneity in both patient and exposure characteristics. When comparing with past users, for most safety outcomes, current users of concomitant paracetamol and ibuprofen had relative rates between those for current users of ibuprofen alone and paracetamol alone. The hazard rates were generally proportional over time, from current to past exposure, following a prescription for concomitant paracetamol and ibuprofen compared with ibuprofen alone or paracetamol alone.CONCLUSIONSThe known risk of the safety outcomes examined does not appear to be modified by concomitant use of ibuprofen and paracetamol compared with paracetamol or ibuprofen alone.
How tumour necrosis factor blockers interfere with tuberculosis immunity
Authors: Harris J , Keane J 
Published: May 2010

SummaryTumour necrosis factor (TNF) is a potent inflammatory cytokine that plays an important role in immunity to numerous bacterial infections, including Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans. Infliximab, adalimumab, certolizumab pegol and etanercept are anti-TNF agents used to treat a range of inflammatory/autoimmune diseases, such as rheumatoid arthritis. The use of some of these drugs has been linked to reactivation TB. In addition to blocking TNF-mediated immune responses, some anti-TNF drugs have been found to interfere with innate immune responses, such as phagolysosomal maturation and monocyte apoptosis, as well as cell-mediated responses, including interferon-γ secretion by memory T cells, complement-mediated lysis of Mtb-reactive CD8+ T cells and increased regulatory T cell activity. This review summarizes some of the reported effects of TNF blockers on immune cell responses in the context of the observed clinical data on TB reactivation in patients on anti-TNF therapy.
The Type 1 Diabetes PhysioLab® Platform: a validated physiologically based mathematical model of pathogenesis in the non-obese diabetic mouse
Authors: Shoda L , Kreuwel H , Gadkar K , Zheng Y , Whiting C , Atkinson M , Bluestone J , Mathis D , Young D , Ramanujan S 
Published: May 2010

SummaryType 1 diabetes is an autoimmune disease whose clinical onset signifies a lifelong requirement for insulin therapy and increased risk of medical complications. To increase the efficiency and confidence with which drug candidates advance to human type 1 diabetes clinical trials, we have generated and validated a mathematical model of type 1 diabetes pathophysiology in a well-characterized animal model of spontaneous type 1 diabetes, the non-obese diabetic (NOD) mouse. The model is based on an extensive survey of the public literature and input from an independent scientific advisory board. It reproduces key disease features including activation and expansion of autoreactive lymphocytes in the pancreatic lymph nodes (PLNs), islet infiltration and β cell loss leading to hyperglycaemia. The model uses ordinary differential and algebraic equations to represent the pancreas and PLN as well as dynamic interactions of multiple cell types (e.g. dendritic cells, macrophages, CD4+ T lymphocytes, CD8+ T lymphocytes, regulatory T cells, β cells). The simulated features of untreated pathogenesis and disease outcomes for multiple interventions compare favourably with published experimental data. Thus, a mathematical model reproducing type 1 diabetes pathophysiology in the NOD mouse, validated based on accurate reproduction of results from multiple published interventions, is available for in silico hypothesis testing. Predictive biosimulation research evaluating therapeutic strategies and underlying biological mechanisms is intended to deprioritize hypotheses that impact disease outcome weakly and focus experimental research on hypotheses likely to provide insight into the disease and its treatment.
Vaginal vault cytology tests: analysis of a decade of data from a UK tertiary centre
Authors: Stokes‐Lampard H. , Wilson S. , Waddell C. , Bentley L. 
Published: May 2010

H. Stokes‐Lampard, S. Wilson, C. Waddell and L. Bentley Vaginal vault cytology tests: analysis of a decade of data from a UK tertiary centre Objectives:  To examine temporal trends in the use of vault cytology tests in primary and secondary care and the demographics of those women tested.Methods:  Retrospective analysis of routinely collected data concerning women who had a vault cytology test processed during a 10‐year period (1 April 1995 to 31 March 2005) at Birmingham Women’s NHS Foundation Trust.Results:  A total of 8457 vault cytology tests from 3164 women (range 1–17 tests, median = 2) were processed, representing approximately 2% of the cervical cytology workload of the Department of Cytopathology at Birmingham Women's Hospital. There was a significant reduction in annual numbers processed (Pearson correlation −0.958, P < 0.001). Significant abnormalities (mild dyskaryosis or worse) were detected in 4.5%, with malignancy being detected in <0.1%. The unsatisfactory cytology test rate was 10.7% overall. There was a reduction in the numbers of vault cytology tests coming from the community, hospital outpatient clinics and operating theatres over time (χ2 for linear trend = 139.53, 9 d.f., P < 0.0001). Tests originating from community settings had the lowest disease detection rates: no malignancies and only two severe abnormalities were detected from almost 4000 primary care samples; abnormal results represented 2.8% (n = 113), of which the majority (n = 73) were borderline results. All cancers (n = 8) were detected in samples taken in gynaecology and colposcopy clinics.Conclusions:  Vault cytology test usage appears to be reducing, particularly from outpatient clinics and primary care. Community detection rates are very low. Further research is required to establish the true costs and benefits of vaginal vault cytology.
Accuracy and perceptions of virtual microscopy compared with glass slide microscopy in cervical cytology
Authors: Evered A. , Dudding N. 
Published: May 2010

A. Evered and N. Dudding Accuracy and perceptions of virtual microscopy compared with glass slide microscopy in cervical cytology Objective:  To evaluate virtual microscopy in terms of diagnostic performance and acceptability among practising cytologists.Methods:  Twenty‐four experienced cytologists were recruited to examine 20 SurePath® cervical cytology slides by virtual microscopy. Diagnostic accuracy was compared with glass slide microscopy using an unbiased crossover experimental design. Responses were allocated a score of one for a correct identification of normal or abnormal (borderline/atypical changes in squamous or glandular cells or worse) and a score of zero for an incorrect response (a normal slide reported as abnormal or vice versa). Perceptions of virtual microscopy were assessed by questionnaire analysis.Results:  Participants yielded a total of 285 responses for the virtual slide set and 300 for the glass slide set. The approximate time to screen a virtual slide was 18 minutes, compared with 8 minutes or less for a glass slide. Overall there was no significant difference between virtual microscopy and glass slide microscopy in terms of diagnostic accuracy (P = 0.22). Virtual microscopy under‐performed when images were captured over a narrow focal range (P = 0.01). Diagnostic accuracy of virtual microscopy equalled that of glass slide microscopy when participants were able to focus through the full thickness of the slide images (P = 0.07). The most common difficulties experienced by participants with virtual microscopy were freezing of the computer screen during image download, slow response of the computer during slide movement and, in some instances, ‘fuzzy’ images. Cytologists have a strong preference for glass slides over virtual microscopy despite the overall equal diagnostic performance of the two viewing modalities.Conclusions:  Diagnostic accuracy of virtual microscopy can equal that of glass slide microscopy. However, without good computer network connections, wide focal range and software that permits effortless navigation across virtual slides, cytologists are unlikely to be convinced of the utility of this technology for cytology screening and diagnosis.
A multi‐trait approach reveals the structure and the relative importance of intra‐ vs. interspecific variability in plant traits
Authors: Albert Cécile Hélène , Thuiller Wilfried , Yoccoz Nigel Gilles , Douzet Rolland , Aubert Serge , Lavorel Sandra 
Published: May 2010

Summary 1. Functional traits have been extensively used to describe, group and rank species according to their functions. There is now growing evidence that intraspecific functional variability, as well as interspecific variability, can have significant effects on community dynamics and ecosystem functioning. A core hypothesis for the use of functional traits expressed as species means, that their intraspecific variability is negligible compared with their interspecific variability, has however been too rarely tested empirically. We then addressed four questions: Is intraspecific functional variability across species ranges negligible compared with interspecific variability? Are the major resource economics trade‐off and functional strategies robust to individual trait variability? Are species rankings or ordination robust across species ranges once considering intraspecific variability? Can species be discriminated by their leaf traits? 2. Using an environmentally stratified sampling design within an alpine catchment, we collected five functional traits for 13 common plant species with contrasting life histories and traits. Several populations from a range of environmental conditions were then sampled for each species across their ranges. 3. With an original combination of single‐trait and multi‐trait analyses, we highlighted a non‐negligible contribution of intraspecific variability to overall functional trait variability (∼30%). Although not affecting general and well‐known functional trade‐offs and strategies, intraspecific functional variability had the potential to alter species ordination and produced a functional continuum rather than a clear‐cut species classification. 4. Deciding whether intraspecific functional variability can be considered as negligible – species being represented by mean trait values –, or not – species being represented by multivariate trait distributions –, is an essential question for multiple ecological issues. However, this decision cannot be generic, but will depend on the studied system and selected traits and species, as well as on study objectives.
Energy management on a nectar diet: can sunbirds meet the challenges of low temperature and dilute food?
Authors: Köhler Angela , Verburgt Luke , McWhorter Todd J. , Nicolson Susan W. 
Published: May 2010

Summary 1. Animals commonly experience variation in both food quality and metabolic requirements, and must regulate their food intake to maintain energy balance. 2. We exposed captive whitebellied (Cinnyris talatala) and amethyst (Chalcomitra amethystina) sunbirds (Nectariniidae) to different nectar sugar concentrations (0·25, 0·5 and 1 m sucrose), i.e. food qualities, and ambient temperatures (5, 15 and 25 °C), i.e. energy requirements, to examine the effects on food intake, feeding patterns and body mass of the birds. 3. Both species compensated for decreased dietary sugar concentration by increasing food intake. While whitebellied sunbirds showed a constant sugar intake over the range of diet concentrations, amethyst sunbirds ingested less sugar on 0·25 m than on 0·5 m sucrose. During acute short‐term exposure to 5 °C, birds increased food and thus sugar intake on all diet concentrations by almost 27%, compared to the similar intake at 15 and 25 °C. Despite increased food consumption, all birds lost more body mass at 5 and 15 °C than at 25 °C. 4. Adjustment of food intake in both species took place via changes in feeding frequency, with the duration of feeding events unchanged. 5. Apparent sugar assimilation in whitebellied sunbirds was >99%, irrespective of diet concentration and temperature. A chemical reactor model of digestive capacity based on measurements of intestinal hydrolytic capacity mostly underestimated the maximal food intake of whitebellied sunbirds in the cold, but predicted higher maximal intake for amethyst sunbirds than observed on most diet concentrations. 6. We conclude that physiological constraints impose upper limits on compensatory feeding in sunbirds. These constraints are mainly digestive at low temperature and osmoregulatory on dilute diets, while the combination of both stresses leads to additional metabolic costs. 7. The moderate mass loss of both species when exposed to these energy challenges suggests that behavioural changes and/or hypothermia may be used to reduce energy expenditure.
Changing clinicopathological practice in parathyroid disease
Authors: Johnson Sarah J 
Published: May 2010

Johnson S J (2010)Histopathology 56,835–851 Changing clinicopathological practice in parathyroid diseaseParathyroid glands are received for histological examination during treatment of hyperparathyroidism. There are a small number of likely diagnoses available to the histopathologist, but distinction between these can be difficult due to overlap of morphological features. Recent developments in surgical approaches and preoperative imaging techniques have led to increased use of focused surgical approaches after preoperative localization of any abnormal parathyroid glands, thereby reducing the number of glands received for histological examination. Pathologists need to be aware of these clinical developments and the possible impact on their diagnostic practice. The pathogenesis of hyperparathyroidism is also reviewed, as is the rare but important diagnosis of parathyroid carcinoma.
Expression of key hypoxia sensing prolyl‐hydroxylases PHD1, ‐2 and ‐3 in pancreaticobiliary cancer
Authors: Gossage Lucy , Zaitoun Abed , Fareed Khaleel R , Turley Helen , Aloysius Mark , Lobo Dileep N , Harris Adrian L , Madhusudan Srinivasan 
Published: May 2010

Gossage L, Zaitoun A, Fareed K R, Turley H, Aloysius M, Lobo D N, Harris A L & Madhusudan S (2010) Histopathology 56, 908–920 Expression of key hypoxia sensing prolyl‐hydroxylases PHD1, ‐2 and ‐3 in pancreaticobiliary cancerAims:  Tumour hypoxia is associated with an aggressive phenotype and resistance to chemotherapy and radiotherapy. The aim was to investigate whether key hypoxia sensing prolyl hydroxylases PHD1, PHD2 and PHD3 are dysregulated in pancreaticobiliary cancers, and to evaluate their potential clinical significance.Methods and results:  Formalin‐fixed human pancreatic tissue from 120 consecutive patients undergoing pancreatic resections between June 2001 and June 2006 was constructed into tissue microarrays. Expression of PHD1, PHD2 and PHD3 was analysed using immunohistochemistry and correlated with clinicopathological variables and disease‐specific overall survival. PHD1, PHD2 and PHD3 were significantly overexpressed in pancreaticobiliary tumours compared with normal pancreatic ductal tissues (P = 0.03, P < 0.0001 and P < 0.0001, respectively). PHD3 expression in tumour tissue was associated with a trend towards worse overall disease‐specific survival in ampullary adenocarcinomas (P = 0.035) and pancreatic adenocarcinomas (P = 0.084). Absence of PHD1 expression was significantly associated with perineural invasion in pancreatic adenocarcinomas (P = 0.02) and a trend towards significance was also seen for absence of PHD2 expression in pancreatic adenocarcinomas (P = 0.04).Conclusions:  Our results provide the first clinical evidence that PHD1, PHD2 and PHD3 may be involved in pancreaticobiliary tumorigenesis.
Innate immune responses to human rotavirus in the neonatal gnotobiotic piglet disease model
Authors: González Ana M. , Azevedo Marli S. P. , Jung Kwonil , Vlasova Anastasia , Zhang Wei , Saif Linda J. 
Published: May 2010

SummaryIntestinal and systemic dendritic cell (DC) frequencies, serum and small intestinal content cytokines and uptake/binding of human rotavirus (HRV) virus‐like particles (VLP) were studied in HRV acutely infected or mock‐inoculated neonatal gnotobiotic piglets. Intestinal, mesenteric lymph node (MLN) and splenic plasmacytoid DCs (pDCs), conventional DCs (cDCs) and macrophages/monocytes were assessed by flow cytometry. In infected pigs, serum and small intestinal content interferon‐α (IFN‐α) were highest, interleukin‐12 (IL‐12) was lower and IL‐10, tumour necrosis factor‐α and IL‐6 were minimal. Compared with mock‐inoculated piglets, frequencies of total intestinal DCs were higher; splenic and MLN DC frequencies were lower. Most intestinal pDCs, but few cDCs, were IFN‐α+ and intestinal macrophages/monocytes were negative for IFN‐α. Serum IFN‐α levels and IFN‐α+ intestinal pDCs were highly correlated, suggesting IFN‐α production in vivo by intestinal pDCs (r = 0·8; P < 0·01). The intestinal pDCs and cDCs, but not intestinal macrophages/monocytes, of HRV‐infected piglets showed significantly lower VLP uptake/binding compared with mock‐inoculated piglets, suggesting higher activation of pDCs and cDCs in infected piglets. Both intestinal pDCs and cDCs were activated (IFN‐α+ and lower VLP binding) after HRV infection, suggesting their role in induction of HRV‐specific immunity. Dose‐effects of HRV on serum IFN‐α and IFN‐α+ DCs were studied by infecting piglets with 100‐fold higher HRV dose. A high dose increased parameters associated with inflammation (diarrhoea, intestinal pathology) but serum IFN‐α and IFN‐α+ DCs were similar between both groups. The pDCs have both anti‐ and pro‐inflammatory functions. Stimulation of the anti‐inflammatory effects of pDCs after the high dose, without increasing their pro‐inflammatory impacts, may be critical to reduce further immunopathology during HRV infection.
Human and mouse perforin are processed in part through cleavage by the lysosomal cysteine proteinase cathepsin L
Authors: Konjar Špela , Sutton Vivien R. , Hoves Sabine , Repnik Urška , Yagita Hideo , Reinheckel Thomas , Peters Christoph , Turk Vito , Turk Boris , Trapani Joseph A. , Kopitar‐Jerala Nataša 
Published: May 2010

SummaryThe pore‐forming protein perforin is synthesized as an inactive precursor in natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), and becomes active when a short C‐terminal peptide is cleaved within acidic lysosome‐like cytotoxic granules. Although it was shown more than a decade ago that this cleavage is pH dependent and can be inhibited by the generic cysteine cathepsin inhibitor E‐64d, no protease capable of processing the perforin C terminus has been identified. Neither is it known whether a single protease is responsible or the processing has inbuilt redundancy. Here, we show that incubation of human NK cells and primary antigen‐restricted mouse CTLs with the cathepsin L (CatL) inhibitor L1 resulted in a marked inhibition of perforin‐dependent target cell death and reduced perforin processing. In vitro, CatL preferentially cleaved a site on full‐length recombinant perforin close to its C terminus. The NK cells of mice deficient in CatL showed a reduction but not a complete absence of processed perforin, indicating that cysteine proteases other than CatL are also able to process perforin. We conclude that granule‐bound cathepsins are essential for processing perforin to its active form, and that CatL is an important, but not exclusive, participant in this process.
Stronger inducible defences enhance persistence of intraguild prey
Authors: Kratina Pavel , Hammill Edd , Anholt Bradley R. 
Published: May 2010

Summary 1. Intraguild predation is widespread in nature despite its potentially destabilizing effect on food web dynamics. 2. Anti‐predator inducible defences affect both birth and death rates of populations and have the potential to substantially modify food web dynamics and possibly increase persistence of intaguild prey. 3. In a chemostat experiment, we investigated the long‐term effects of inducible defences on the dynamics of aquatic microbial food webs consisting of an intraguild predator, intraguild prey, and a basal resource. We controlled environmental conditions and selected strains of intraguild prey that varied in the strength of expressed inducible defences. 4. We found that intraguild prey with a stronger tendency to induce an anti‐predator morphology persist for significantly longer periods of time. In addition, model selection analysis implied that flexibility in defensive phenotype (inducibility itself) is most likely the factor responsible for the enhanced persistence. 5. As patterns at the community level often emerge as a result of the life‐history traits of individuals, we propose that inducible defences increase the persistence of populations and may contribute to the widespread occurrence of theoretically unstable intraguild predation systems in nature.