bluuebunny/crossref_metadata_2025 huggingface dataset:
What goes up must come down: biomarkers and novel biologicals in severe asthma
Authors: Hilvering B. , Pavord I. D.
Published: February 2015

Asthma is a heterogeneous airway disease characterized by typical symptoms in combination with variable airway obstruction. Most patients with asthma have well controlled symptoms and a low risk of asthma attacks with inhaled corticosteroid (ICS) treatment. However, a clinically important subgroup (~ 10%) remains symptomatic and/or at risk of asthma attacks despite maximum inhaled therapy. Patients with severe asthma are responsible for a significant proportion of healthcare costs attributable to asthma and have a large unmet need for better treatments. An important advance in recent years has been the recognition that severe asthma is heterogeneous with respect to clinical problems and the pattern of lower airway inflammation. Identification of eosinophilic inflammation in the airways has become an important priority as novel biologicals that target Th2 cytokines, such as anti‐IL5, anti‐IL‐13 and combined anti‐IL‐4/13 are showing considerable promise as treatments for this subgroup. It has also become clear that anti‐IgE (Omalizumab), the first monoclonal antibody registered for treatment of severe asthma, is only active in patients with active eosinophilic airway inflammation. The future will be identification of potentially responsive patients on the basis of raised biomarkers and, as suggested by the title of this review, targeted treatment with specific cytokine blockade that has a direct effect on the biomarkers. In this review, we outline an approach to the clinical assessment of patients potentially suitable for biological treatment and describe in detail the likely clinical impact of established and new biological treatments.
Dietary treatment modulates mast cell phenotype, density, and activity in adult eosinophilic oesophagitis
Authors: Arias Á. , Lucendo A. J. , Martínez‐Fernández P. , González‐Castro A. M. , Fortea M. , González‐Cervera J. , Yagüe‐Compadre J. L. , Mota‐Huertas T. , Vicario M.
Published: February 2015

Background

Mast cells (MCs) are abundant in the inflammatory infiltrate in eosinophilic oesophagitis (EoE), but decrease with disease remission. However, their phenotype, role in the pathophysiology of the disease, and modulation after effective dietary therapy are still unclear.

Objective

To define the phenotype of oesophageal MCs, their modulation through dietary therapy, and their association with clinical manifestations of EoE.

Methods

Oesophageal mucosal samples from 10 adult patients with EoE obtained before and after effective six‐food elimination diet (SFED) therapy, as well as from 10 control subjects were analysed. Eosinophil and MC density were quantified. Gene expression of chemoattractants for eosinophils (CCL11, CCL24, and CCL26), MCs (SCF), and their receptors (CCR3 and SCFR, respectively) were assessed by means of qPCR. Gene and protein expression of specific MC proteases (CPA3, CMA, and TPSB2) were evaluated with qPCR and immunofluorescence. Clinical manifestations and atopic background were recorded.

Results

MC density was significantly increased in EoE compared with controls, decreasing after dietary treatment (18.6 to 1.44 cells/hpf, respectively; P < 0.001). The MCTC subtype predominated in the oesophageal mucosa (90%) in both patients with EoE and controls. Gene expression of MC‐related proteases, eotaxins, and SCF were up‐regulated in patients with EoE, but significantly decreased after therapy, regardless of atopic background. Epithelial peaks of MCs and eosinophils were significantly associated (ρ = 0.80) in EoE and correlated with the symptom score (ρ = 0.78). Gene expression of MC proteases and eotaxins also correlated with the symptom score (P < 0.05).

Conclusions and Clinical Relevance

MC and its proteases seem to play a relevant role in the pathophysiology and symptoms of EoE, which can be reversed after effective dietary treatment.
Effects of short‐term oral corticosteroid intake on dietary intake, body weight and body composition in adults with asthma – a randomized controlled trial
Authors: Berthon B. S. , Gibson P. G. , McElduff P. , MacDonald‐Wicks L. K. , Wood L. G.
Published: February 2015

Background

Oral corticosteroids (OCS) are an efficacious treatment for asthma exacerbations, yet risk of adverse effects may decrease patient adherence to therapy. In particular, changes in appetite and dietary intake, which lead to weight gain and changes in body composition, are considered undesirable.

Objective

To determine whether 10‐day OCS therapy in adults with asthma causes changes in leptin, appetite, dietary intake, body weight and body composition.

Methods

Double‐blinded, placebo‐controlled randomized cross‐over trial of 10 days prednisolone (50 mg) in adults with stable asthma (n = 55) (ACTRN12611000562976). Pre‐ and post‐assessment included spirometry, body weight, body composition measured by dual‐energy X‐ray absorptiometry and bioelectrical impedance analysis, appetite measured using a validated visual analogue scale (VAS) and dietary intake assessed using 4‐day food records. Leptin was measured as a biomarker of appetite and eosinophils as an adherence biomarker. Outcomes were analysed by generalized linear mixed models.

Results

Subject adherence was confirmed by a significant decrease in blood eosinophils (× 109/L) following prednisolone compared to placebo [Coef. −0.29, 95% CI: (−0.39, −0.19) P < 0.001]. There was no difference in serum leptin (ng/mL) [Coef. 0.13, 95% CI: (−3.47, 3.72) P = 0.945] or appetite measured by VAS (mm) [Coef. −4.93, 95% CI: (−13.64, 3.79) P = 0.267] following prednisolone vs. placebo. There was no difference in dietary intake (kJ/day) [Coef. 255, 95% CI: (−380, 891) P = 0.431], body weight (kg) [Coef. −0.38, 95% CI: (−0.81, 0.05) P = 0.083] or body fat (%) [Coef. −0.31, 95% CI: (−0.81, 0.20) P = 0.230]. Symptoms including sleep and gastrointestinal disturbance were reported significantly more often during prednisolone vs. placebo.

Conclusions and Clinical Relevance

Short‐term OCS in stable asthma did not induce significant changes in appetite, dietary intake, body weight or composition, although other adverse effects may require medical management. This evidence may assist in increasing medication adherence of asthmatics prescribed OCS for exacerbations.
What is the optimal bone‐preserving strategy for patients with Addison's disease?
Authors: Lee Paul , Greenfield Jerry R.
Published: February 2015

Addison's disease is associated with low bone mineral density and increased risk of hip fractures. Causes are multifactorial, contributed by underlying adrenocortical hormonal deficiency, associated autoimmune endocrinopathies, electrolyte disturbances and, in some patients, supraphysiologic glucocorticoid replacement. Recent realization of physiologic cortisol production rate has revised downwards glucocorticoid replacement dosages. Meanwhile, new research has emerged suggesting complex interplay between sodium and calcium homoeostasis under the influence of mineralocorticoid and parathyroid hormone that may impact bone health. As the prevalence of Addison's disease is rising, and osteoporosis and fractures are associated with significant morbidity and increased mortality, attention to bone preservation in Addison's disease is of clinical relevance and importance. We suggest an approach to bone health in Addison's disease integrating physiologic adrenocortical hormonal replacement with electrolyte and mineral homoeostasis optimization.
Attenuation of the oestrogen positive feedback mechanism with the age in postmenopausal women
Authors: Dimitraki Marina , Koutlaki Nikoletta , Gioka Theodora , Messini Christina I. , Dafopoulos Konstantinos , Anifandis George , Messinis Ioannis E.
Published: February 2015

Objective

It has been reported that the positive feedback mechanism of oestrogens and progesterone is preserved, although attenuated, in late postmenopausal years. Whether this is also true for the positive feedback effect of oestrogens alone has not been investigated.

Design

Prospective intervention study.

Patients

Thirty healthy postmenopausal women.

Measurements

The women were divided into three groups according to the years since menopause (group I: 2–8 years, group II: 9–17 years, group III: 18–25 years). They were studied during a period of 41 days. Two acute experiments (EP) of exogenous oestradiol, given via skin patches, were performed from days 1 to 7 (EP1) and from days 35 to 41 (EP2) to induce an LH surge. Between the two experiments (days 7–34), oestradiol was given at the dose of 100 μg every 3 days, while oral progesterone was added from day 21 to day 34 in order to simulate a luteal phase. Blood samples were taken every 6 h during EP1 and EP2 as well as on days 8, 13, 20, 21, 27 and 34. FSH, LH, oestradiol and progesterone were measured in all blood samples.

Results

An LH surge occurred as a result of the oestradiol positive feedback mechanism in group I and in group II, in both EP1 and EP2. Peak LH values during the surge were significantly lower in group II than in group I in both experiments. None of the patients in group III displayed an LH surge.

Conclusions

These results demonstrate for the first time a gradual attenuation of the pituitary response to oestrogenic provocation over a certain period following the menopause, with complete abolition after 20 years. It is suggested that the reserves of pituitary gonadotrophs diminish with age.
Risk factors for postoperative bleeding in ABO‐incompatible kidney transplantation
Authors: Kim Mi Hyeong , Jun Kang Woong , Hwang Jeong Kye , Kim Ji Il , Chung Byung Ha , Choi Bum Soon , Kim Yong Soo , Yang Chul Woo , Moon In Sung
Published: February 2015

Introduction

The outcome of ABO‐incompatible kidney transplantation (ABOi KT) has improved and is now comparable to that of ABO‐compatible kidney transplantation (ABOc KT). However, ABOi KT may be associated with a higher risk of postoperative bleeding than ABOc KT.

Methods

Seventy patients with ABOi KT were divided into a bleeding group (n = 9) and non‐bleeding group (n = 61). General, immunologic, and hematological characteristics were compared to identify the risk factors for postoperative bleeding.

Results

Pre‐emptive transplantation and a high pre‐transplant blood urea nitrogen level were more common in the bleeding group (p = 0.0176 and 0.023, respectively). A high anti‐ABO antibody titer after plasmapheresis (median, ≥16; p = 0.0226), a low platelet count of ≤100 000/mm3 after plasmapheresis (p = 0.0289), a prolonged activated partial thromboplastin time (p = 0.0073), and impaired platelet function (p = 0.0274) were associated with an increased risk of bleeding after ABOi KT.

Conclusion

Postoperative bleeding after ABOi KT was difficult to control and increased the risk of immediate graft loss (p = 0.015). Our results suggest that changes in coagulability associated with uremia and plasmapheresis may increase the risk of bleeding after ABOi KT.
Community‐based learning in a challenging context: the development and evaluation of an outreach dental public health programme in Damascus University, Syria
Authors: Joury E.
Published: February 2015

Introduction

This study aimed to describe the development and evaluation of an outreach dental public health (DPH) programme in Damascus University, in terms of developing undergraduates' required knowledge, skills and attitudes (KSA), improving the quality aspects of training and assessment (T&A), and achieving the satisfaction of served children and their social network.

Methods

The outreach DPH programme offered opportunities to undergraduates to carry out outreach health‐promotion activities, conduct and communicate the results of applied DPH research, and build partnership with students in other higher education sectors. A cross‐sectional evaluation collected mixed qualitative and quantitative data, by a means of a short‐essay and a self‐completed questionnaire, from 400 third‐year dental undergraduates, on KSA gained from outreach activities and quality aspects of T&A. The latter were compared with corresponding figures of other traditional dental programmes (TDP). Satisfaction with the outreach activities were collected from 215 children with special needs and 130 parents and school staff, by questionnaires.

Results

The response rates were 74.8%, 100% and 100% for undergraduates, children and parents/school staff, respectively. The derived categories of students' gained KSA included the following: unique clinical skills, social responsibility, voluntarism, communication, team working, personal growth, reflection on career aspirations and self‐satisfaction with the contribution to needy groups. Their satisfaction with quality aspects of T&A was significantly higher than TDP (P < 0.001). Children's and parents/school staff's satisfaction was high.

Conclusion

The outreach DPH programme in Damascus University is a successful example of developing undergraduates' required KSA, improving the quality aspects of T&A, and achieving the satisfaction of served community.
Parietal transcranial direct current stimulation modulates primary motor cortex excitability
Authors: Rivera‐Urbina Guadalupe Nathzidy , Batsikadze Giorgi , Molero‐Chamizo Andrés , Paulus Walter , Kuo Min‐Fang , Nitsche Michael A.
Published: February 2015

The posterior parietal cortex is part of the cortical network involved in motor learning and is structurally and functionally connected with the primary motor cortex (M1). Neuroplastic alterations of neuronal connectivity might be an important basis for learning processes. These have however not been explored for parieto‐motor connections in humans by transcranial direct current stimulation (tDCS). Exploring tDCS effects on parieto‐motor cortical connectivity might be functionally relevant, because tDCS has been shown to improve motor learning. We aimed to explore plastic alterations of parieto‐motor cortical connections by tDCS in healthy humans. We measured neuroplastic changes of corticospinal excitability via motor evoked potentials (MEP) elicited by single‐pulse transcranial magnetic stimulation (TMS) before and after tDCS over the left posterior parietal cortex (P3), and 3 cm posterior or lateral to P3, to explore the spatial specificity of the effects. Furthermore, short‐interval intracortical inhibition/intracortical facilitation (SICI/ICF) over M1, and parieto‐motor cortical connectivity were obtained before and after P3 tDCS. The results show polarity‐dependent M1 excitability alterations primarily after P3 tDCS. Single‐pulse TMS‐elicited MEPs, M1 SICI/ICF at 5 and 7 ms and 10 and 15 ms interstimulus intervals (ISIs), and parieto‐motor connectivity at 10 and 15 ms ISIs were all enhanced by anodal stimulation. Single pulse‐TMS‐elicited MEPs, and parieto‐motor connectivity at 10 and 15 ms ISIs were reduced by cathodal tDCS. The respective corticospinal excitability alterations lasted for at least 120 min after stimulation. These results show an effect of remote stimulation of parietal areas on M1 excitability. The spatial specificity of the effects and the impact on parietal cortex–motor cortex connections suggest a relevant connectivity‐driven effect.
Plants poisonous to horses in Europe
Authors: Caloni F. , Cortinovis C.
Published: February 2015

Poisoning of horses by plants is a relatively common veterinary problem and may occur when the fresh plant is ingested in pasture or when the plant contaminates hay, silage and feed. In Europe, horses are particularly at risk of poisoning by Cynoglossum officinale (houndstongue), Datura stramonium (jimson weed), Hypericum perforatum (St. John's wort), Nerium oleander (oleander), Pteridium aquilinum (bracken fern), Robinia pseudoacacia (black locust), Senecio jacobaea (tansy ragwort), Taxus baccata (European yew) and Thuja occidentalis (white cedar). For each of these poisonous plants the information given in this review includes plant distribution, conditions of poisoning, toxic active principles and clinical signs.
Fatigue fracture behaviour of spot welded B1500HS steel under tensile‐shear load
Authors: Wang B. , Duan Q. Q. , Yao G. , Pang J. C. , Zhang Z. F. , Wang L. , Li X. W.
Published: February 2015

The microstructural characterizations, micro‐hardness measurements and fatigue tests of B1500HS steel spot welded tensile‐shear specimens were performed. The high hardness values of base material (470 HV) and nugget (515 HV) are closely related to the dominant formation of martensitic microstructures, while the occurrence of soft zone is the result of the formation of ferrite phases in inter‐critical heat‐affected zone (HAZ), as well as martensite tempering in sub‐critical HAZ. The fatigue failure modes involve the fracture along the circumference or along the direction of width. The fatigue property of spot welded B1500HS is found to be better than that of spot welded M190 because of the thicker sheet and suitable nugget size, which follows the standard rule of 5t0.5, where t is the sheet thickness.
Large‐scale manipulation of oviposition substrata affects egg supply to populations of some stream‐dwelling caddisflies
Authors: Macqueen Ashley , Downes Barbara J.
Published: February 2015

Oviposition substrata are a crucial resource for many stream‐dwelling insects and may have a strong effect on population densities.

From February to March 2010, we conducted a large‐scale experiment manipulating the density of oviposition substrata available to two taxa, Cheumatopsyche spp. and Ecnomus spp. in Hughes Creek (south‐east Australia). These caddisflies oviposit on hard surfaces underwater. Hughes Creek has a sandy bed, and females rely predominantly on bark and wood as oviposition substrata.

Bark density was manipulated in 25‐m‐long sites, creating a range of bark surface areas (SAs) spanning an order of magnitude, with appropriate controls. Estimates of the number of egg masses and bark SAs were obtained 22 and 55 days after the experiment commenced in each site. To characterise taxon‐specific oviposition site preferences and test whether preferences were dependent on overall bark availability, the conditions (velocity and emergence) of individual substrata were manipulated within sites. Egg masses were enumerated at approximately weekly intervals for 7 weeks.

We found a strong relationship between the SA of bark at sites and the number of masses of Ecnomus spp., demonstrating that oviposition is limited by substrata availability. In contrast, the number of Cheumatopsyche spp. egg masses was not related to the total amount of bark available. Ecnomus spp. showed a weak preference for emergent compared to submerged bark, but did not respond to water velocity. Cheumatopsyche laid eggs predominantly in fast flows, regardless of bark emergence, which may explain the lack of a site‐level response because only a small proportion of bark occurred in fast flows even when bark was plentiful.

Our results suggest that the strength of oviposition preferences may depend on overall background densities of substrata. Oviposition preferences and substrata availability interact to set the initial distribution (and density) of the next generation. Our study has wide implications for the management of streams with soft sediment beds, where bark and wood inputs from riparian vegetation provide not only food and habitat for larvae but also oviposition substrata that are critical to successful recruitment for some taxa.
Invasive mussels modify the cycling, storage and distribution of nutrients and carbon in a large lake
Authors: Ozersky Ted , Evans David O. , Ginn Brian K.
Published: February 2015

This study examined the effect of invasive dreissenid mussels on nutrient and carbon dynamics in a large lake (Lake Simcoe, Ontario). We measured rates of nutrient (phosphorus and nitrogen) and carbon excretion and biodeposition by zebra and quagga mussels and the P, N and C content of their soft tissues and shells at different depths throughout the open‐water season. Measurements were combined with detailed information about dreissenid biomass and lakewide distribution to examine the impacts of dreissenids on whole‐lake dynamics of P, N and C.

Mussel tissue P, N and C content and rates of excretion and biodepositon varied among species, seasons and depths, apparently driven by metabolic and stoichiometric factors.

Dreissenid mussels excreted, deposited and stored large quantities of P, N and C when compared to lake standing stocks and loadings, and represent an important driver of nutrient cycling in the lake. Living and discarded mussel shell material is shown to represent a potentially important, and hitherto largely overlooked, long‐term sink for P, N and C.

The concentration of dreissenid biomass in the well‐mixed and illuminated littoral portion of L. Simcoe results in redirection of nutrients and carbon from offshore areas to the nearshore zone of the lake.

Changes in nutrient and carbon distribution and cycling patterns caused by dreissenid establishment in L. Simcoe and other ecosystems can have implications for the distribution of primary and secondary production and should be considered in the context of water quality and nutrient input management.
Analysis of young Miscanthus × giganteus yield variability: a survey of farmers’ fields in east central France
Authors: Lesur‐Dumoulin Claire , Lorin Mathieu , Bazot Mathieu , Jeuffroy Marie‐Hélène , Loyce Chantal
Published: February 2015

Miscanthus × giganteus is often regarded as one of the most promising crops to produce bioenergy because it is renowned for its high biomass yields, combined with low input requirements. However, its productivity has been mainly studied in experimental conditions. Our study aimed at characterizing and explaining young M. giganteus yield variability on a farmers’ field network located in the supply area of a cooperative society in east central France. It included the first three growth years of the crop. We defined and calculated a set of indicators of limiting factors that could be involved in yield variations and used the mixed‐model method to identify those explaining most of the yield variation. Commercial yields averaged 8.1 and 12.8 t DM ha−1 for the second and third growth year, respectively. However, these mean results concealed a high variability, ranging from 3 to 19 t DM ha−1. Commercial yields, measured on whole fields, were on average 20% lower than plot yields, measured on a small area (two plots of 25 m2). Yields were found to be much more related to shoot density than to shoot mass, and particularly to the shoot density established at the end of the planting year. We highlighted that planting success was decisive and was built during the whole plantation year. Fields with the lowest yields also had the highest weed cover, which was influenced by the distance between the field and the farmhouse, the preceding crop and the soil type. Our findings show that growing young M. giganteus on farmers’ fields involves limiting factors different from those commonly reported in the literature for experimental conditions and they could be useful to assess the economic and environmental impacts of growing M. giganteus on farmers’ fields. They could also stimulate the discussion about growing bioenergy crops on marginal lands.
Oral health and depression in older Japanese people
Authors: Takiguchi Tomoya , Yoshihara Akihiro , Takano Naoko , Miyazaki Hideo
Published: February 2015

Objective

The aim of this study was to investigate the relationship between oral dysfunction and depressive symptoms in Japanese community‐dwelling seniors.

Materials and methods

Participants included 351 community‐dwelling seniors (189 men, 162 women) aged 77 years. During dental examination, teeth and periodontal condition, including number of teeth, number of dental caries, pocket depth and clinical attachment level, were assessed, and unstimulated and stimulated salivary flow rates were measured. The General Health Questionnaire 30 (GHQ‐30) was used to assess depression. The Tokyo Metropolitan Institute of Gerontology (TMIG) Index of Competence was used to assess activities of daily living.

Results

Multiple logistic regression analysis revealed that gender (odds ratio [OR] = 2.3), low unstimulated salivary flow rate (OR = 2.1), ‘Complaint of mouth pain’ (OR = 2.4), ‘Complaint of physical disorders’ (OR = 2.1), and the total TMIG Index of Competence score (OR = 2.0) were positively associated with the high GHQ‐30 score.

Conclusion

Subjective and objective oral dryness and oral pain are associated with depressive symptoms.
The prevalence of intestinal parasites in hemodialysis patients in Bushehr, Iran
Authors: Barazesh Afshin , Fouladvand Moradali , Tahmasebi Rahim , Heydari Ali , Fallahi Jamal
Published: February 2015

Hemodialysis patients, due to a dysfunction of the immune response, are prone to a variety of opportunistic infections. Studies of intestinal parasitic infections in these patients are limited. Therefore, the present study was performed to determine the prevalence of these infections in patients on hemodialysis in Bushehr. In this cross‐sectional study, fecal samples have been collected from all hemodialysis patients who were continuously referred from September 2011 to September 2012 to the dialysis center at Bushehr and tested using routine parasitological methods. From a total of 88 patients studied, 25 patients (28.4%) were infected with one or more intestinal parasites. Blastocystis hominis and Entamoeba coli with 13.6% and 6.7% prevalence had the highest prevalence among the patients, respectively. The age group 51–70 years had the highest rates of infection. Statistical analysis showed no relationship between sex and the risk of intestinal parasites. Seventeen percent of infected patients showed up with diarrhea and this relationship was statistically significant. Considering the high prevalence of intestinal parasitic infection among hemodialysis patients in Bushehr and also the high probability of infection in these patients, it is recommended that periodic examinations and screening patients during dialysis and before kidney transplantation should be a part of routine medical care.
Successful medical treatment of emphysematous pyelonephritis in chronic hemodialysis
Authors: Vlachopanos Georgios , Kassimatis Theodoros , Zerva Adamantia , Kokkona Anastasia , Stavroulaki Eirini , Zacharogiannis Charilaos , Agrafiotis Athanasios
Published: February 2015

Emphysematous pyelonephritis (EPN) is a life‐threatening renal infection caused by gas‐producing bacteria and fungi. It usually occurs in patients with diabetes and patients with urinary tract obstruction. A combination of systemic antibiotics, percutaneous catheter drainage, or open nephrectomy is typically required to achieve cure. Because of grim prognosis, resorting to interventional methods is frequently inevitable. We report the case of a 77‐year‐old woman with diabetes and end‐stage renal disease on chronic hemodialysis that presented with fever and left flank pain. A bubbly gas pattern inside the left kidney was demonstrated on abdominal computed tomography scan and blood cultures grew Escherichia coli. She was successfully treated solely with systemic antibiotics. This highlights the fact that prompt recognition of imaging findings associated with benign prognosis is essential for a favorable outcome. It allows for an effective management avoiding high‐risk interventions, especially in frail patients with multiple comorbidities. Finally, we review all published cases of EPN in chronic dialysis patients.
Expression of vitamin D receptor as a potential prognostic factor and therapeutic target in pancreatic cancer
Authors: Wang Kewei , Dong Ming , Sheng Weiwei , Liu Qingfeng , Yu Dongyang , Dong Qi , Li Qingchang , Wang Junqiang
Published: February 2015

Aims

Vitamin D insufficiency and deficiency are common among patients with pancreatic carcinoma, but epidemiological studies have shown inconsistent results for vitamin D intake/circulation level and pancreatic cancer risk. The study aims were to investigate the effects of vitamin D on patient survival, and the proliferation or survival of pancreatic cancer cell lines.

Methods and results

The present study examined the local expression of vitamin D receptor (VDR) in pancreatic normal and tumour tissues from a cohort of 61 patients, and analysed the potential correlation between VDR and pathological characteristics, including disease prognosis. Among 61 pairs of normal and tumour specimens, VDR was detected in all normal tissues, and was abundantly expressed in 62.5% (15/24) of tumour tissues with high differentiation, but had a significantly lower or undetectable expression level in 75.7% (28/37) of tissues with moderate or low differentiation (P = 0.004). Moreover, high VDR expression was detected in 63.6% (14/22) of small tumours (≤25 mm) and in only 25.6% (10/39) of large tumours (>25 mm) (P = 0.06). Kaplan–Meier analysis showed that a low level of VDR expression in tumour tissues was associated with a poor prognosis (P = 0.037).

Conclusions

VDR expression could be a potential prognostic factor for patients with pancreatic adenocarcinoma, and its effects should be examined in a prospective study. Vitamin D analogues may provide a therapeutic choice for patients with high VDR expression in tumours but a low vitamin D level in the circulation.
Clinical triage for colonoscopy is useful in young women
Authors: Williamson K. D. , Steveling K. , Holtmann G. , Schoeman M. , Andrews J. M.
Published: February 2015

Background

Colonoscopy is an invasive procedure and a limited resource. It is therefore desirable to restrict its use to those in whom it yields an important diagnosis, without missing pathology in others.

Aim

The aim of this study was to determine whether standard clinical criteria can be used to reliably distinguish when colonoscopy is advisable in women 30 years and younger.

Methods

A retrospective audit was performed at a single centre of 100 consecutive colonoscopies performed in women 30 years old and younger. The indications for the colonoscopy were recorded, and divided into clear and relative indications. The primary outcome of whether an endoscopic diagnosis was made was compared between the two groups. Clear indications for colonoscopy included overt rectal bleeding, elevated inflammatory markers, anaemia, iron deficiency and strong family history of colorectal cancer. Relative indications included abdominal pain or discomfort, bloating and altered bowel habit/motions.

Results

The average age was 23 years. Sixty women had both relative and clear indications. Eleven had only clear indications and 28 only relative indications. Altogether, 58 colonoscopies were normal, and 17 showed inflammatory bowel disease. No subject with only relative indications had an abnormal finding (0/28). The diagnostic yield was significantly different between those with only relative indications (0%) versus those with at least one clear indication (59%; P < 0.0001).

Conclusions

Standard clinical criteria can be used to restrict safely the use of colonoscopy in young women. This will avoid performing procedures in people without clear indications, saving costs, resources and complications.
Clinical selection criteria can predict futile intervention in patients referred for percutaneous endoscopic gastrostomy insertion
Authors: Holt D. Q. , McDonald J. F. , Murray M. L. , Hair C. , Devonshire D. A. , Strauss B. J. , Moore G. T.
Published: February 2015

Background

Percutaneous endoscopic gastrostomy (PEG) placement is performed in a patient group with high mortality in the short and medium term. For a significant proportion of patients, the procedure provides no increase in survival. There are no standardised assessment tools available to determine the clinical appropriateness of PEG placement, nor any to predict clinical outcome.

Aim

The study aims to determine whether clinical assessment, by a trained dietitian, of the appropriateness of PEG placement is predictive of mortality in the short and medium terms.

Methods

A prospective audit was undertaken of all requests for PEG placement at a single large, publicly funded Australian tertiary hospital. The clinical appropriateness of each request was assessed by a trained dietitian, and data on age, sex, reason for referral, comorbidities and satisfaction of assessment criteria were collected, and patient outcome and survival were compared for all patients according to whether a PEG was inserted or not. Main outcome measures were mortality at 30 and 150 days after referral.

Results

During the period 2005–2008, 198 patients were referred for PEG; 94 were assessed as appropriate referrals, 104 as inappropriate. Eighty‐four patients who underwent gastrostomy, after being assessed as appropriate, had significantly reduced mortality at 30 days (96.4% vs 74.6%, P < 0.0001) and 150 days (82.1% vs 57.9%, P = 0.0001) compared with all other patients. Patients who received PEG despite contrary advice had no significant survival advantage, at 30 days or 150 days, over patients who did not receive PEG.

Conclusion

The application of selection criteria by trained assessors improves patient selection for PEG insertion and predicts mortality at early and later time points, by identifying patients unlikely to benefit from PEG. The group of patients who received a gastrostomy despite an adverse assessment had no mortality benefit – in these patients, the procedure may have been futile.
Nonbuckling Vertical Four‐Point Bend Setup for Measuring Edge Strength of Thin Glass
Authors: Vepakomma K. Hemanth , Carley Stephen H. , Westbrook Jamie T. , Morgan Glenn V.
Published: February 2015

The four‐point bend test is widely used for testing the edge strength of glass specimens. Vertical four‐point bend (V4PB) setup involves orienting the specimen in a vertical fashion. However, thin specimens tend to buckle when using V4PB setup. In this study, a finite element model was built to simulate the buckling that occurs during V4PB testing. To validate this model, experiments were conducted on the existing setup. Upon validation, the finite element model was used to propose an improved setup. Then, experiments were carried out on the improved setup to verify that it worked as intended. The primary advantage of the proposed setup is that the standard ASTM [ASTM (2007), C158–02] four‐point bending formula can continue to be used to calculate the stress from the applied force.
Peripheral adipose tissue insulin resistance alters lipid composition and function of hippocampal synapses
Authors: Sallam Hanaa S. , Tumurbaatar Batbayar , Zhang Wen‐Ru , Tuvdendorj Demidmaa , Chandalia Manisha , Tempia Filippo , Laezza Fernanda , Taglialatela Giulio , Abate Nicola
Published: February 2015

Compelling evidence indicates that type 2 diabetes mellitus, insulin resistance (IR), and metabolic syndrome are often accompanied by cognitive impairment. However, the mechanistic link between these metabolic abnormalities and CNS dysfunction requires further investigations. Here, we evaluated whether adipose tissue IR and related metabolic alterations resulted in CNS changes by studying synapse lipid composition and function in the adipocyte‐specific ecto‐nucleotide pyrophosphate phosphodiesterase over‐expressing transgenic (AtENPP1‐Tg) mouse, a model characterized by white adipocyte IR, systemic IR, and ectopic fat deposition. When fed a high‐fat diet, AtENPP1‐Tg mice recapitulate essential features of the human metabolic syndrome, making them an ideal model to characterize peripherally induced CNS deficits. Using a combination of gas chromatography and western blot analysis, we found evidence of altered lipid composition, including decreased phospholipids and increased triglycerides (TG) and free fatty acid in hippocampal synaptosomes isolated from high‐fat diet‐fed AtENPP1‐Tg mice. These changes were associated with impaired basal synaptic transmission at the Schaffer collaterals to hippocampal cornu ammonis 1 (CA1) synapses, decreased phosphorylation of the GluN1 glutamate receptor subunit, down‐regulation of insulin receptor expression, and up‐regulation of the free fatty acid receptor 1.

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We observed evidence of biochemical and functional changes in hippocampal synapses in mice in response to high‐fat diet. Such effects were more pronounced in a transgenic animal model of adipocyte insulin resistance (AtENPP1‐Tg) compared to their wild‐type littermates. Animals exhibited alterations in synaptic lipid composition, decreased basal synaptic transmission at the Schaffer collaterals to CA1 synapses, decreased GluN1 receptor phosphorylation, decreased insulin receptor expression, and increased FFA1 receptor expression. We believe that our results provide a novel mechanistic link between obesity, adipose tissue dysfunction, and increased risk for cognitive impairment. CA, cornu ammonis; CA1, hippocampal cornu ammonis 1; DAG, diacylglycerol; FFA, free fatty acids; FFA1, free fatty acid receptor 1; GluN1, NMDA receptor 1 subunit; HFD, high‐fat diet.
Ligand‐directed delivery of fluorophores to track native calcium‐permeable AMPA receptors in neuronal cultures
Authors: Combs‐Bachmann Rosamund E. , Johnson Jeffreys Nate , Vytla Devaiah , Hussey Amanda M. , Kilfoil Maria L. , Chambers James J.
Published: February 2015

Subcellular trafficking of neuronal receptors is known to play a key role in synaptic development, homeostasis, and plasticity. We have developed a ligand‐targeted and photo‐cleavable probe for delivering a synthetic fluorophore to AMPA receptors natively expressed in neurons. After a receptor is bound to the ligand portion of the probe molecule, a proteinaceous nucleophile reacts with an electrophile on the probe, covalently bonding the two species. The ligand may then be removed by photolysis, returning the receptor to its non‐liganded state while leaving intact the new covalent bond between the receptor and the fluorophore. This strategy was used to label polyamine‐sensitive receptors, including calcium‐permeable AMPA receptors, in live hippocampal neurons from rats. Here, we describe experiments where we examined specificity, competition, and concentration on labeling efficacy as well as quantified receptor trafficking. Pharmacological competition during the labeling step with either a competitive or non‐competitive glutamate receptor antagonist prevented the majority of labeling observed without a blocker. In other experiments, labeled receptors were observed to alter their locations and we were able to track and quantify their movements.

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We used a small molecule, ligand‐directed probe to deliver synthetic fluorophores to endogenously expressed glutamate receptors for the purpose of tracking these receptors on live, hippocampal neurons. We found that clusters of receptors appear to move at similar rates to previous studies. We also found that the polyamine toxin pharmacophore likely binds to receptors in addition to calcium‐permeable AMPA receptors.
Potential safety issues in the use of the hormone melatonin in paediatrics
Authors: Kennaway David J
Published: February 2015

Melatonin is a hormone produced by the pineal gland during the night in response to light/dark information received by the retina and its integration by the suprachiasmatic nucleus. When administered to selected populations of adults, in particular those displaying delayed sleep phase disorder, melatonin may advance the time of sleep onset. It is, however, being increasingly prescribed for children with sleep disorders despite the fact that (i) it is not registered for use in children anywhere in the world; (ii) it has not undergone the formal safety testing expected for a new drug, especially long‐term safety in children; (iii) it is known to have profound effects on the reproductive systems of rodents, sheep and primates, as well as effects on the cardiovascular, immune and metabolic systems; and (iv) there is the potential for important interactions with drugs sometimes prescribed for children. In this review, I discuss properties of melatonin outside its ability to alter sleep timing that have been widely ignored but which raise questions about the safety of its use in infants and adolescents.
Prediction of in-vivo pharmacokinetic profile for immediate and modified release oral dosage forms of furosemide using an in-vitro–in-silico–in-vivo approach
Authors: Otsuka Keiichi , Wagner Christian , Selen Arzu , Dressman Jennifer
Published: February 2015

Objectives

To develop a physiologically based pharmacokinetic (PBPK) model for furosemide immediate release (IR) tablets and modified release (MR) capsules by coupling biorelevant dissolution testing results with pharmacokinetic (PK) and physiologic parameters, and to investigate the key factors influencing furosemide absorption using simulation approaches and the PBPK model.

Methods

Using solubility, dissolution kinetics, gastrointestinal (GI) parameters and disposition parameters, a PBPK model for furosemide was developed with STELLA software. Solubility and dissolution profiles for both formulations were evaluated in biorelevant and compendial media. The simulated plasma profiles were compared with in-vivo profiles using point estimates of area under plasma concentration-time curve, maximal concentration after the dose and time to maximal concentration after the dose.

Key findings

Simulated plasma profiles of both furosemide IR tablets and MR capsules were similar to the observed in-vivo profile in terms of PK parameters. Sensitivity analysis of the IR tablet model indicated that both the gastric emptying and absorption rate have an influence on the plasma profile. For the MR capsules, the sensitivity analysis suggested that the release rate in the small intestine, gastric emptying and the absorption rate all have an influence on the plasma profile.

Conclusions

A predictive model to describe both IR and MR dosage forms containing furosemide was attained. Because sensitivity analysis of the model is able to identify key factors influencing the plasma profile, this in-vitro–in-silico–in-vivo approach could be a useful tool for facilitating formulation development of drug products.
Danshen (S
alvia miltiorrhiza) water extract inhibits paracetamol-induced toxicity in primary rat hepatocytes via reducing CYP2E1 activity and oxidative stress
Authors: Zhou Xuelin , Cheung Ching Mei , Yang Jia-ming , Or Penelope M Y , Lee Wayne Y W , Yeung John H K
Published: February 2015

Objectives

This study aimed to investigate the protective effects of Danshen (Salvia miltiorrhiza) water extract (DSE) and its major phenolic acid components against CYP2E1-mediated paracetamol (APAP)-induced hepatic toxicity.

Methods

The protection and underlying mechanisms were detected in CYP2E1 overexpression primary rat hepatocytes by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, alamar blue assay, CYP2E1 inhibition assay and glutathione assay.

Key findings

After APAP treatment, DSE (0.06–1 mg/ml) significantly increased cell viability in MTT assay. Two major components danshensu (8.2–130.5 μm) and salvianolic acid B (Sal B; 3.3–53.5 μm) mainly contributed to this protection, but rosmarinic acid, protocatechuic aldehyde and Sal A did not. Alamar blue assay showed that DSE, danshensu and Sal B maintained mitochondrial metabolic activity. DSE inhibited CYP2E1 (Ki = 1.46 mg/ml) in a mixed mode in rat liver microsomes in vitro; DSE decreased APAP-induced total glutathione depletion and preserved redox status (GSH/GSSG ratio) in hepatocytes. Danshensu and Sal B did not inhibit CYP2E1 or decrease total glutathione depletion, but preserved redox status.

Conclusions

DSE protected hepatocytes against APAP-induced injury via maintenance of mitochondrial metabolic activity, CYP2E1 inhibition, reduction of total glutathione depletion and preservation of redox status. Danshensu and Sal B were mainly responsible for this protection.
Genetic variability and taxonomic revision of the genus Auxenochlorella (Shihira et Krauss) Kalina et Puncocharova (Trebouxiophyceae, Chlorophyta)
Authors: Darienko Tatyana , Pröschold Thomas
Published: February 2015

The monotypic genus Auxenochlorella with its type species A. protothecoides is so far only known from specific habitats such as the sap of several tree species. Several varieties were described according to physiological performances in culture on different organic substrates. However, two strains designated as Auxenochlorella were isolated from other habitats (an endosymbiont of Hydra viridis and an aquatic strain from an acidic volcano stream). We studied those isolates and compared them with six strains of Auxenochlorella belonging to different varieties. The integrative approach used in this study revealed that all strains showed similar morphology but differed in their SSU and ITS rDNA sequences. The Hydra endosymbiont formed a sister taxon to A. protothecoides, which included the varieties protothecoides, galactophila, and communis. The variety acidicola is not closely related to Auxenochlorella and represented its own lineage within the Trebouxiophyceae. In view of these results, we propose a new species of Auxenochlorella, A. symbiontica, for the Hydra symbiont, and a new genus Pumiliosphaera, with its type species, P. acidophila, for acidophilic strain. These results are supported by several compensatory base changes in the conserved region of ITS‐2 and ITS‐2 DNA barcodes.
Biofilm and capsule formation of the diatom Achnanthidium minutissimum are affected by a bacterium
Authors: Windler Miriam , Leinweber Katrin , Bartulos Carolina Rio , Philipp Bodo , Kroth Peter G.
Published: February 2015

Photoautotrophic biofilms play an important role in various aquatic habitats and are composed of prokaryotic and/or eukaryotic organisms embedded in extracellular polymeric substances (EPS). We have isolated diatoms as well as bacteria from freshwater biofilms to study organismal interactions between representative isolates. We found that bacteria have a strong impact on the biofilm formation of the pennate diatom Achnanthidium minutissimum. This alga produces extracellular capsules of insoluble EPS, mostly carbohydrates (CHO), only in the presence of bacteria (xenic culture). The EPS themselves also have a strong impact on the aggregation and attachment of the algae. In the absence of bacteria (axenic culture), A. minutissimum did not form capsules and the cells grew completely suspended. Fractionation and quantification of CHO revealed that the diatom in axenic culture produces large amounts of soluble CHO, whereas in the xenic culture mainly insoluble CHO were detected. For investigation of biofilm formation by A. minutissimum, a bioassay was established using a diatom satellite Bacteroidetes bacterium that had been shown to induce capsule formation of A. minutissimum. Interestingly, capsule and biofilm induction can be achieved by addition of bacterial spent medium, indicating that soluble hydrophobic molecules produced by the bacterium may mediate the diatom/bacteria interaction. With the designed bioassay, a reliable tool is now available to study the chemical interactions between diatoms and bacteria with consequences for biofilm formation.