Amoebic crab disease (ACD) in edible crab Cancer pagurus from the English Channel, UK.

The genera Paramoeba and Neoparamoeba (Amoebozoa, Dactylopodida, Paramoebidae) include well-known opportunistic pathogens associated with fish (N. peruans; amoebic gill disease), lobsters, molluscs and sea urchins, but only rarely with crabs (grey crab disease of blue crabs). Following reports of elevated post-capture mortality in edible crabs Cancer pagurus captured from a site within the English Channel fishery in the UK, a novel disease (amoebic crab disease, ACD) was detected in significant proportions of the catch. We present histopathological, transmission electron microscopy and molecular phylogenetic data, showing that this disease is defined by colonization of haemolymph, connective tissues and fixed phagocytes by amoeboid cells, leading to tissue destruction and presumably death in severely diseased hosts. The pathology was strongly associated with a novel amoeba with a phylogenetic position on 18S rRNA gene trees robustly sister to Janickina pigmentifera (which groups within the current circumscription of Paramoeba/Neoparamoeba), herein described as Janickina feisti n. sp. We provide evidence that J. feisti is associated with ACD in 50% of C. pagurus sampled from the mortality event. A diversity of other paramoebid sequence types, clustering with known radiations of N. pemaquidensis and N. aestuarina and a novel N. aestuarina sequence type, was detected by PCR in most of the crabs investigated, but their detection was much less strongly associated with clinical signs of disease. The discovery of ACD in edible crabs from the UK is discussed relative to published historical health surveys for this species.

Undular bores generated by fracture.

Undular bores, or dispersive shock waves, are nonstationary waves propagating as oscillatory transitions between two basic states, in which the oscillatory structure gradually expands and grows in amplitude with distance traveled. In this work we report an important mechanism of generation of nonlinear dispersive shock waves in solids. We demonstrate, using high-speed pointwise photoelasticity, the generation of undular bores in solid (polymethylmethacrylate) prestrained bars by natural and induced tensile fracture. For the distances relevant to our experiments, the viscoelastic extended Korteweg-de Vries equation is shown to provide very good agreement with the key observed experimental features for suitable choice of material parameters, while some local features at the front of the bore are also captured reasonably well by the linearization near the nonzero prestrain level. The experimental and theoretical approaches presented open avenues and analytical tools for the study and applications of dispersive shock waves in solids.

Cortical ß-Amyloid in Older Adults Is Associated with Multidomain Interventions with and without Omega 3 Polyunsaturated Fatty Acid Supplementation.

Multidomain lifestyle interventions (including combinations of physical exercise, cognitive training and nutritional guidance) are attracting increasing research attention for reducing the risk of Alzheimer's disease (AD). Here we examined for the first time the cross-sectional relationship between cortical ß-amyloid (Aß) and multidomain lifestyle interventions (nutritional and exercise counselling and cognitive training), omega 3 polyunsaturated fatty acid (n-3 PUFA) supplementation or their combination in 269 participants of the Multidomain Alzheimer Preventive Trial (MAPT). In adjusted multiple linear regression models, compared to the control group (receiving placebo alone), cortical Aß, measured once during follow-up (mean 512.7 ± 249.6 days post-baseline), was significantly lower in the groups receiving multidomain lifestyle intervention + placebo (mean difference, -0.088, 95 % CI, -0.148,-0.029, p = 0.004) or multidomain lifestyle intervention + n-3 PUFA (-0.100, 95 % CI, -0.160,-0.041, p = 0.001), but there was no difference in the n-3 PUFA supplementation alone group (-0.011, 95 % CI, -0.072,0.051, p = 0.729). Secondary analysis provided mixed results. Our findings suggest that multidomain interventions both with and without n-3 PUFA supplementation might be associated with lower cerebral Aß. Future trials should investigate if such multidomain lifestyle interventions are causally associated with a reduction or the prevention of the accumulation of cerebral Aß.

Instructional and Assessment Redesign of a Sterile Compounding Course Using Immersive Simulation.

Objective. To revise a traditional sterile compounding course to include content, competencies, and immersive simulations relevant to the current practice of sterile compounding pharmacy. Methods. Faculty and staff at the University of North Texas System College of Pharmacy made significant revisions to an existing sterile compounding course. Instruction was provided in didactic and laboratory sessions and delivered in three modules: fundamental skills, integration of skills and knowledge, and exceptions and specialty topics. Integration laboratory sessions consisted primarily of repetitive but increasingly difficult simulations that included both technician and pharmacist activities. Assessment methods included checkpoint assessments, a mock objective structured clinical examination (OSCE), a written examination, and a final comprehensive OSCE. Effectiveness of the course redesign was assessed by comparing student performance on assessments, overall course performance, and student perceptions extracted from the student course evaluation. Results. Of the 364 students enrolled in the sterile compounding course across four terms, 156 were in the pre-implementation cohort (cohort 1) and 208 were in the post-implementation cohort (cohort 2). Two hundred twenty-eight students completed the course evaluation. Course evaluations significantly demonstrated students' improved perceptions related to seven of 11 survey elements, most notably, critical thinking, integration of concepts, and students feeling challenged. Student performance on laboratory summative assessments also improved. However, written examination scores did not change. Conclusion. This novel sterile compounding course provided a practice-oriented blueprint for instruction and assessment of sterile compounding.

Opioid analgesia on the battlefield: a retrospective review of data from Operation HERRICK.

BACKGROUND: Acute pain secondary to trauma is commonly encountered on the battlefield. The use of morphine to manage pain during combat has been well established since the 19th century. Despite this, there is relatively little research on analgesia use in this environment. This study aims to review the use and complications of morphine and other opioids during Operation HERRICK. METHODS: A database search of the Joint Theatre Trauma Registry was completed looking for all incidences of morphine, fentanyl or naloxone use from February 2007 to September 2014. Microsoft Excel was used to analyse the results. RESULTS: Opioid analgesia was administered to 5801 casualties. Morphine was administered 6742 times to 3808 patients. Fentanyl was administered 9672 times to 4318 patients. Naloxone was used 18 times on 14 patients, giving a complication rate of 0.24%. Opioid doses prior to naloxone administration range from 0 to 72 mg of morphine and from 0 to 100 mcg of fentanyl. Four casualties (two local civilians and two coalition forces) received naloxone despite no recorded opioids being administered. Opium abuse was prevalent among the local population in Afghanistan, and this could explain the rationale behind two local national casualties receiving naloxone without any documented opioids being given. CONCLUSION: The use of opioids in a battlefield environment is extremely safe. Complication rates are similar to previously published data which is reassuring. The efficacy of different opioids was not covered by this study, and further analysis is required, particularly following the introduction of oral transmucosal fentanyl citrate and the availability of novel non-opioid analgesics.

The Relationship of Omega 3 Polyunsaturated Fatty Acids in Red Blood Cell Membranes with Cognitive Function and Brain Structure: A Review Focussed on Alzheimer's Disease.

Significant research attention has focussed on the identification of nutraceutical agents for the prevention of cognitive decline as a natural means of cognitive preservation in the elderly. There is some evidence for a reduction of brain omega 3 polyunsaturated fatty acids (n-3 PUFAs) in normal aging and in Alzheimer's disease. n-3 PUFAs exhibit anti-inflammatory and anti-amyloidogenic properties as well as being able to reduce tau phosphorylation. Many observational studies have demonstrated a link between n-3 PUFAs and cognitive aging, and some, but not all, randomized controlled trials have demonstrated a benefit of n-3 PUFA supplementation on cognition, particularly in those subjects with mild cognitive impairment. The identification of a biomarker that reflects n-3 PUFA intake over time and consequent tissue levels is required. In this narrative review we discuss the evidence associating red blood cell membrane n-3 PUFAs with cognitive function and structural brain changes associated with Alzheimer's disease.

Cross-Sectional Associations of Total Plasma Homocysteine with Cortical ß-Amyloid Independently and as a Function of Omega 3 Polyunsaturated Fatty Acid Status in Older Adults at Risk of Dementia.

OBJECTIVES: Elevated total plasma homocysteine is a risk factor for Alzheimer's disease (AD) and there is some evidence that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can modulate the effects of homocysteine-lowering B vitamins on AD related pathologies. Hence we investigated the relationship between total plasma homocysteine and cortical ß-amyloid (Aß) in older adults at risk of dementia. The role of erythrocyte membrane n-3 PUFAs (omega 3 index) on this relationship was also explored. DESIGN: This is a cross-sectional study using data from the Multidomain Alzheimer Preventive Trial (MAPT); a randomised controlled trial. SETTING: French community dwellers aged 70 or over reporting subjective memory complaints, but free from a diagnosis of clinical dementia. PARTICIPANTS: Individuals were from the MAPT trial (n = 177) with data on total plasma homocysteine at baseline and cortical Aß load. MEASUREMENTS: Cortical-to-cerebellar standard uptake value ratios were assessed using [18F] florbetapir positron emission tomography (PET). Total baseline plasma homocysteine was measured using an enzymatic cycling assay. Baseline omega 3 index was measured using gas chromatography. Cross-sectional associations were explored using adjusted multiple linear regression models. RESULTS: We found that total baseline plasma homocysteine was not significantly associated with cortical Aß as demonstrated using multiple linear regression models adjusted for age, sex, education, cognitive status, time interval between baseline and PET-scan, omega-3 index, MAPT group allocation and Apolipoprotein E ε4 status (B-coefficient -0.001, 95 % CI: -0.008,0.006, p = 0.838). Exploratory analysis showed that homocysteine was however significantly associated with cortical Aß in subjects with low baseline omega-3 index (< 4.72 %) after adjustment for Apolipoprotein E ε4 status (B-coefficient 0.041, 95 % CI: 0.017,0.066, p = 0.005, n = 10), but not in subjects with a high baseline omega-3 index (B-coefficient -0.010, 95 % CI: -0.023,0.003, p = 0.132, n = 66). CONCLUSIONS: The role of n-3 PUFAs on the relationship between homocysteine and cerebral Aß warrants further investigation.

Association of Cortical ß-Amyloid with Erythrocyte Membrane Monounsaturated and Saturated Fatty Acids in Older Adults at Risk of Dementia.

OBJECTIVES: We examined the relationships between erythrocyte membrane monounsaturated fatty acids (MUFAs) and saturated fatty acids (SFAs) and cortical ß-amyloid (Aß) load in older adults reporting subjective memory complaints. DESIGN: This is a cross-sectional study using data from the Multidomain Alzheimer Preventive Trial (MAPT); a randomised controlled trial. SETTING: French community dwellers aged 70 or over reporting subjective memory complaints, but free from a diagnosis of clinical dementia. PARTICIPANTS: Participants of this study were 61 individuals from the placebo arm of the MAPT trial with data on erythrocyte membrane fatty acid levels and cortical Aß load. MEASUREMENTS: Cortical-to-cerebellar standard uptake value ratios were assessed using [18F] florbetapir positron emission tomography (PET). Fatty acids were measured in erythrocyte cell membranes using gas chromatography. Associations between erythrocyte membrane MUFAs and SFAs and cortical Aß load were explored using adjusted multiple linear regression models and were considered significant at p ≤ 0.005 (10 comparisons) after correction for multiple testing. RESULTS: We found no significant associations between fatty acids and cortical Aß load using multiple linear regression adjusted for age, sex, education, cognition, PET-scan to clinical assessment interval, PET-scan to blood collection interval and apolipoprotein E (ApoE) status. The association closest to significance was that between erythrocyte membrane stearic acid and Aß (B-coefficient 0.03, 95 % CI: 0.00,0.05, p = 0.05). This association, although statistically non-significant, appeared to be stronger amongst ApoE ε4 carriers (B-coefficient 0.04, 95 % CI: -0.01,0.09, p = 0.08) compared to ApoE ε4 non-carriers (B-coefficient 0.02, 95 % CI: -0.01,0.05, p = 0.18) in age and sex stratified analysis. CONCLUSION: Future research in the form of large longitudinal observational study is needed to validate our findings, particularly regarding the potential association of stearic acid with cortical Aß.

Cognitive Changes with Omega-3 Polyunsaturated Fatty Acids in Non-Demented Older Adults with Low Omega-3 Index.

OBJECTIVES: To investigate the changes in specific domains of cognitive function in older adults reporting subjective memory complaints with a low omega-3 index receiving omega 3 polyunsaturated fatty acid (n-3 PUFA) supplementation or placebo. DESIGN: This is a secondary exploratory analysis of the Multidomain Alzheimer Preventive Trial (MAPT) using subjects randomized to the n-3 PUFA supplementation or placebo group. SETTING: French community dwellers aged 70 or over reporting subjective memory complaints, but free from clinical dementia. PARTICIPANTS: A subgroup of MAPT subjects in the lowest quartile of omega-3 index distribution with baseline values ≤ 4.83 % (n = 183). INTERVENTION: The n-3 PUFA supplementation group consumed a daily dose of DHA (800 mg) and EPA (a maximum amount of 225 mg) for 3 years. The placebo group received identical capsules comprising liquid paraffin oil. MEASUREMENTS: Linear mixed-model repeated-measures analyses were used including baseline, 6, 12, 24 and 36-month follow-up data to assess between-group differences in the change in eight cognitive tests over 36 months. RESULTS: There was less decline on the Controlled Oral Word Association Test (COWAT) in the n-3 PUFA supplementation group compared to placebo (p = 0.009; between group mean difference over 36 months, 2.3; 95% CI, 0.6,4.0). No significant differences for any of the other cognitive tests were found, including other tests of executive functioning, although, numerically all results were in favour of the n-3 PUFA supplementation. CONCLUSIONS: We found some evidence that n-3 PUFAs might be beneficial for the maintenance of executive functioning in older adults at risk of dementia with low omega-3 index, but this exploratory finding requires further confirmation. A larger specifically designed randomised controlled trial could be merited.

Cutaneous and systemic mycoses from infection with Lecanicillium spp. in captive Guthega skinks (Liopholis guthega).

BACKGROUND: Guthega skinks have been listed as critically endangered and are considered particularly vulnerable to extinction because of their isolation and restricted distribution. There is no information on their captive husbandry, or the diseases that affect them. CASE REPORT: Cutaneous and systemic mycosis from infection with Lecanicillium spp. was diagnosed in a captive colony of Guthega skinks (Liopholis guthega). Infection resulted in the death of five lizards. Diagnosis of infection was confirmed using a combination of histopathology, fungal culture and DNA sequencing from all affected animals. An additional four similarly affected individuals were successfully treated with a combination of voriconazole (10 mg/kg PO once daily) and shallow baths of benzalkonium chloride and polyhexamethylene biguanide hydrochloride (F10) (1 : 250, 20 min once daily). This is the first report of Lecanicillium spp. infection in reptiles.

The effect of chemotherapy on health-related quality of life in mesothelioma: results from the SWAMP trial.

BACKGROUND: The effect of chemotherapy on health-related quality of life (HRQoL) in malignant pleural mesothelioma (MPM) is poorly understood. Patient-individualised prognostication and prediction of treatment response from chemotherapy is useful but little evidence exists to guide practice. METHOD: Consecutive patients with MPM who were fit for first-line chemotherapy with pemetrexed and cisplatin\carboplatin were recruited and followed up for a minimum of 12 months. This study focussed on the HRQoL outcomes of these patients using the EQ-5D, EORTC QLQ-C30 and LC13. RESULTS: Seventy-three patients were recruited of which 58 received chemotherapy and 15 opted for best supportive care (BSC). Compliance with HRQoL questionnaires was 98% at baseline. The chemotherapy group maintained HRQoL compared with the BSC group whose overall HRQoL fell (P=0.006) with worsening dyspnoea and pain. The impact of chemotherapy was irrespective of histological subtype although those with non-epithelioid disease had worse HRQoL at later time points (P=0.012). Additionally, those with a falling mesothelin or improvement on modified-RECIST CT at early follow-up had a better HRQoL at 16 weeks. CONCLUSIONS: HRQoL was maintained following chemotherapy compared with a self-selected BSC group. Once chemotherapy is initiated, a falling mesothelin or improved RECIST CT findings infer a quality-of-life advantage.

The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication.

BACKGROUND: Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care. METHODS: Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil-lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months. FINDINGS: Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR<4 was an independent predictor of better OS (median survival 453 (IQR 272-576) days vs NLR⩾4, 257 (IQR 147-490), P=0.002). Although baseline serum mesothelin did not predict OS, a falling level at 8 weeks significantly predicted longer time to progression (TTP) (P<0.001). INTERPRETATION: Neutrophil-lymphocyte ratio and baseline TGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients' treatment response.

Clusterin regulates ß-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway.

Although the mechanism of Aß action in the pathogenesis of Alzheimer's disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aß neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aß/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aß toxicity and DKK1 upregulation and, conversely, Aß increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1. To further elucidate how the clusterin-dependent induction of Dkk1 by Aß mediates neurotoxicity, we measured the effects of Aß and Dkk1 protein on whole-genome expression in primary neurons, finding a common pathway suggestive of activation of wnt-planar cell polarity (PCP)-c-Jun N-terminal kinase (JNK) signalling leading to the induction of genes including EGR1 (early growth response-1), NAB2 (Ngfi-A-binding protein-2) and KLF10 (Krüppel-like factor-10) that, when individually silenced, protected against Aß neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aß-induced pathway and resulted in age-dependent increases in tau phosphorylation in hippocampus and cognitive impairment. Furthermore, we show that this Dkk1/wnt-PCP-JNK pathway is active in an Aß-based mouse model of AD and in AD brain, but not in a tau-based mouse model or in frontotemporal dementia brain. Thus, we have identified a pathway whereby Aß induces a clusterin/p53/Dkk1/wnt-PCP-JNK pathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, thereby providing new mechanistic insights into the action of Aß in neurodegenerative diseases.

Increasing doxorubicin activity against breast cancer cells using PPARγ-ligands and by exploiting circadian rhythms.

BACKGROUND AND PURPOSE: Doxorubicin is effective against breast cancer, but its major side effect is cardiotoxicity. The aim of this study was to determine whether the efficacy of doxorubicin on cancer cells could be increased in combination with PPARγ agonists or chrono-optimization by exploiting the diurnal cycle. EXPERIMENTAL APPROACH: We determined cell toxicity using MCF-7 cancer cells, neonatal rat cardiac myocytes and fibroblasts in this study. KEY RESULTS: Doxorubicin damages the contractile filaments of cardiac myocytes and affects cardiac fibroblasts by significantly inhibiting collagen production and proliferation at the level of the cell cycle. Cyclin D1 protein levels decreased significantly following doxorubicin treatment indicative of a G1/S arrest. PPARγ agonists with doxorubicin increased the toxicity to MCF-7 cancer cells without affecting cardiac cells. Rosiglitazone and ciglitazone both enhanced anti-cancer activity when combined with doxorubicin (e.g. 50% cell death for doxorubicin at 0.1 µM compared to 80% cell death when combined with rosiglitazone). Thus, the therapeutic dose of doxorubicin could be reduced by 20-fold through combination with the PPARγ agonists, thereby reducing adverse effects on the heart. The presence of melatonin also significantly increased doxorubicin toxicity, in cardiac fibroblasts (1 µM melatonin) but not in MCF-7 cells. CONCLUSIONS AND IMPLICATIONS: Our data show, for the first time, that circadian rhythms play an important role in doxorubicin toxicity in the myocardium; doxorubicin should be administered mid-morning, when circulating levels of melatonin are low, and in combination with rosiglitazone to increase therapeutic efficacy in cancer cells while reducing the toxic effects on the heart.

Haematological alterations in Rattus norvegicus (Wistar) experimentally infected with Echinostoma paraensei (Trematoda: Echinostomatidae).

Laboratory rats (Rattus norvegicus) were infected with Echinostoma paraensei (Trematoda: Echinostomatidae). The rodents received 150 metacercariae each and blood samples were collected weekly until the fifth week of infection. The blood samples were analyzed for determination of haematocrit, total red blood cells with their dimensions, haemoglobin and haematimetric index (mean corpuscular volume, MCV; mean corpuscular haemoglobin, MCH; and mean corpuscular haemoglobin concentration, MCHC) and platelets. Red blood cells, haematocrit and haemoglobin in the first week had significantly lower levels than those of uninfected (control) rats, suggesting the development of normocytic and normocromic anaemia with anisocytic alteration. The number of eosinophils did not increase significantly among the groups. We concluded that E. paraensei produces haematological alterations in R. norvegicus, causing regenerative anaemia. This system can therefore be a useful model to study the direct and indirect effects of gastrointestinal infections.

VEGF and sVEGFR-1 in malignant pleural effusions: association with survival and pleurodesis outcomes.

VEGF is a key mediator of tumour growth and metastasis and is considered central to the formation of exudative pleural effusions. This study examined the relationship between levels of VEGF and its soluble receptor, sVEGFR-1 in the pleural fluid and plasma of patients with malignant pleural effusions and their association with pleurodesis outcomes and survival. 103 patients with malignant pleural effusions were recruited at their first presentation. Follow-up was to 6 months or death. Survival and pleurodesis outcomes were robustly ascertained. VEGF and sVEGFR-1 were measured in pleural fluid and plasma by ELISA. VEGF and sVEGFR-1 were present in significantly higher concentrations in pleural fluid than plasma. There was no significant correlation between mediators within or between sample types. There was no association between baseline pleural fluid VEGF or sVEGFR-1 levels and pleurodesis failure. In both sample types, survival was inversely associated with sVEGFR-1 and within the non-small cell lung cancer sub-group (n=26), a highly significant association between increased pleural fluid VEGF and sVEGFR-1 and reduced survival was demonstrated (p=0.02 and 0.004 respectively). In conclusion, we have shown for the first time that sVEGFR-1 can be reproducibly measured in pleural fluid from malignant effusions. High levels at presentation in those with non-small cell carcinoma are strongly associated with poor outcomes.