Predicting survival in malignant pleural mesothelioma using routine clinical and laboratory characteristics.

INTRODUCTION: The prognosis of malignant pleural mesothelioma (MPM) is poor, with a median survival of 8-12 months. The ability to predict prognosis in MPM would help clinicians to make informed decisions regarding treatment and identify appropriate research opportunities for patients. The aims of this study were to examine associations between clinical and pathological information gathered during routine care, and prognosis of patients with MPM, and to develop a 6-month mortality risk prediction model. METHODS: A retrospective cohort study of patients diagnosed with MPM at Queen Alexandra Hospital, Portsmouth, UK between December 2009 and September 2013. Multivariate analysis was performed on routinely available histological, clinical and laboratory data to assess the association between different factors and 6-month survival, with significant associations used to create a model to predict the risk of death within 6 months of diagnosis with MPM. RESULTS: 100 patients were included in the analysis. Variables significantly associated with patient survival in multivariate analysis were age (HR 1.31, 95% CI 1.09 to 1.56), smoking status (current smoker HR 3.42, 95% CI 1.11 to 4.20), chest pain (HR 2.14, 95% CI 1.23 to 3.72), weight loss (HR 2.13, 95% CI 1.18 to 3.72), platelet count (HR 1.05, 95% CI 1.00 to 1.10), urea (HR 2.73, 95% CI 1.31 to 5.69) and adjusted calcium (HR 1.47, 95% CI 1.10 to 1.94). The resulting risk model had a c-statistic value of 0.76. A Hosmer-Lemeshow test confirmed good calibration of the model against the original dataset. CONCLUSION: Risk of death at 6 months in patients with a confirmed diagnosis of MPM can be predicted using variables readily available in clinical practice. The risk prediction model we have developed may be used to influence treatment decisions in patients with MPM. Further validation of the model requires evaluation of its performance on a separate dataset.

Prevalence and influence of cys407* Grm2 mutation in Hannover-derived Wistar rats: mGlu2 receptor loss links to alcohol intake, risk taking and emotional behaviour.

Modulation of metabotropic glutamate 2 (mGlu2) receptor function has huge potential for treating psychiatric and neurological diseases. Development of drugs acting on mGlu2 receptors depends on the development and use of translatable animal models of disease. We report here a stop codon mutation at cysteine 407 in Grm2 (cys407*) that is common in some Wistar rats. Therefore, researchers in this field need to be aware of strains with this mutation. Our genotypic survey found widespread prevalence of the mutation in commercial Wistar strains, particularly those known as Han Wistar. Such Han Wistar rats are ideal for research into the separate roles of mGlu2 and mGlu3 receptors in CNS function. Previous investigations, unknowingly using such mGlu2 receptor-lacking rats, provide insights into the role of mGlu2 receptors in behaviour. The Grm2 mutant rats, which dominate some selectively bred lines, display characteristics of altered emotionality, impulsivity and risk-related behaviours and increased voluntary alcohol intake compared with their mGlu2 receptor-competent counterparts. In addition, the data further emphasize the potential therapeutic role of mGlu2 receptors in psychiatric and neurological disease, and indicate novel methods of studying the role of mGlu2 and mGlu3 receptors. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.

Pharmacological profiling of native group II metabotropic glutamate receptors in primary cortical neuronal cultures using a FLIPR.

The group II metabotropic glutamate (mGlu) receptors comprised of the mGlu2 and mGlu3 receptor subtypes have gained recognition in recent years as potential targets for psychiatric disorders, including anxiety and schizophrenia. In addition to studies already indicating which subtype mediates the anxiolytic and anti-psychotic effects observed in disease models, studies to help further define the preferred properties of selective group II mGlu receptor ligands will be essential. Comparison of the in vitro properties of these ligands to their in vivo efficacy and tolerance profiles may help provide these additional insights. We have developed a relatively high-throughput native group II mGlu receptor functional assay to aid this characterisation. We have utilised dissociated primary cortical neuronal cultures, which after 7 days in vitro have formed functional synaptic connections and display periodic and spontaneous synchronised calcium (Ca(2+)) oscillations in response to intrinsic action potential bursts. We herein demonstrate that in addition to non-selective group II mGlu receptor agonists, (2R,4R)-APDC, LY379268 and DCG-IV, a selective mGlu2 agonist, LY541850, and mGlu2 positive allosteric modulators, BINA and CBiPES, inhibit the frequency of synchronised Ca(2+) oscillations in primary cultures of rat and mouse cortical neurons. Use of cultures from wild-type, mGlu2(-/-), mGlu3(-/-) and mGlu2/3(-/-) mice allowed us to further probe the contribution of mGlu2 and mGlu3, and revealed LY541850 to be a partial mGlu2 agonist and a full mGlu3 antagonist. Overnight pre-treatment of cultures with these ligands revealed a preferred desensitisation profile after treatment with a positive allosteric modulator. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Activation of presynaptic alpha7 nicotinic receptors evokes an excitatory response in hippocampal CA3 neurones in anaesthetized rats: an in vivo iontophoretic study.

BACKGROUND AND PURPOSE: alpha7 Nicotinic receptors have been suggested to play an important role in hippocampal learning and memory. However, the direct action of this receptor subtype on hippocampal pyramidal neurones in vivo has not yet been fully investigated. The availability of selective agonists for alpha7 receptors [AR-R17779 and (R)-(-)-5'-phenylspiro[1-azabicyclo[2.2.2] octane-3,2'-(3'H)furo[2,3-b]pyridine (PSAB-OFP)] has now allowed this role to be investigated. EXPERIMENTAL APPROACH: Single-cell extracellular recordings were made from hippocampal CA3 pyramidal neurones in anaesthetized rats. The effects of nicotine, AR-R17779 and PSAB-OFP, applied either systemically or iontophoretically, were studied on the activity of these neurones. KEY RESULTS: Intravenous injection of cumulative doses of nicotine and PSAB-OFP induced dose-related, significant increases in neuronal firing in the majority of neurones tested. This excitation could be inhibited by intravenous administration of methyllycaconitine (MLA), a selective alpha7 nicotinic receptor antagonist. Furthermore, iontophoretic application of nicotine, AR-R17779 and PSAB-OFP each evoked current-dependent excitation of most CA3 pyramidal neurones studied, and this excitation was antagonized by co-iontophoretic application of MLA. In addition, the excitation induced by iontophoretic application of nicotine, AR-R17779 or PSAB-OFP was also blocked by co-iontophoretic application of either 6,7-dinitroquinoxaline-2,3-dione (DNQX) or D(2)-2-amino-5-phosphonopentanoate (D-AP5), selective N-methyl-D-aspartic acid (NMDA) and non-NMDA receptor antagonists respectively. CONCLUSIONS AND IMPLICATIONS: CA3 pyramidal neurones are modulated by activation of presynaptic alpha7 nicotinic receptors, which, at least in part, enhances glutamate release onto post-synaptic (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid and NMDA receptors on these CA3 neurones. This mechanism probably contributes to the effects of nicotine on hippocampal learning and memory.

Semisubmersible oil platforms: understudied and potentially major vectors of biofouling-mediated invasions.

Biofouling has long been recognised as a major pathway for the introduction of non-indigenous species. This study records the decapods and stomatopod crustaceans fouling a semisubmersible oil platform dry docked for hull cleaning in Jurong Port, Singapore. Of the 25 species of decapods identified, 13 were non-indigenous and represent new records to Singapore waters. Of these, the crabs Glabropilumnus seminudus and Carupa tenuipes are known to be invasive in other parts of the world. The stomatopod, Gonodactylaceus randalli, is the first mantis shrimp recorded in a biofouling community. The richness and diversity of this fouling community, consisting of many vagile species, highlights the difference between platforms and ships. With the expansion of maritime oil and gas exploration, the threat posed by an expanded fleet of semisubmersible oil platforms translocating non-indigenous fouling communities across biogeographical boundaries is very serious. Scientists, policy-makers, and stakeholders should turn their attention to this growing problem.

TC-2559 excites dopaminergic neurones in the ventral tegmental area by stimulating alpha4beta2-like nicotinic acetylcholine receptors in anaesthetised rats.

1. The in vivo effects of a selective partial agonist for neuronal nicotinic acetylcholine receptor (nAChRs) alpha4beta2 subtype, TC-2559, characterised recently in in vitro preparations, have been profiled. The brain bioavailability of TC-2559 and its effects on the spontaneous firing and bursting properties of the dopaminergic (DAergic) neurones recorded extracellularly in the ventral tegmental area (VTA) were studied following systemic administration in anaesthetised rats. 2. Cumulative doses of TC-2559 (0.021-1.36 mg kg(-1), i.v.) increased both the firing and bursting activities of VTA DA neurones. The effect of bolus doses of TC-2559 of 0.66 or 1.32 mg kg(-1), i.v., was approximately equivalent to that of 0.0665 mg kg(-1), i.v. nicotine. 3. The excitation evoked by both nicotine and TC-2559 was fully reversed by DHbetaE (0.39-0.77 mg kg(-1), i.v.), an alpha4beta2-subtype-preferring nicotinic antagonist, and application of nicotine after DHbetaE failed to evoke any excitation. MLA (0.23 mg kg(-1), i.v.), an alpha7 selective antagonist, failed to alter TC-2559-evoked excitation and bursting activities, and a novel alpha7 agonist (PSAB-OFP; 0.23 mg kg(-1), i.v.) was also without effect. 4. The present results indicated that TC-2559 fully mimics nicotine by increasing both the excitability and bursting behaviour of VTA DA neurones, effects that are predominantly due to activation of alpha4beta2-like nAChRs. 5. TC-2559 has been demonstrated to be a useful in vivo pharmacological tool for studying the alpha4beta2 subtype of nicotinic receptor.

Feeding preferences and performance of an aquatic lepidopteran on macrophytes: plant hosts as food and habitat.

Although host preferences in phytophagous insects may be generated by several factors, few studies have simultaneously examined several potential host choice determinants. In this study we tested the impact of the following potential host choice determinants on host preference of the semi-aquatic lepidopteran Munroessa gyralis (Pyralidae): growth on different host plants; protein content, polyphenolic content, toughness, and chemical extracts of different host plants; prior feeding experience; and predation pressure on the caterpillar by fishes. Two water lilies, Brasenia schreberi and Nymphaea odorata, were preferred in cafeteria-style feeding experiments over 14 other species of vascular plants. The most preferred water lily (Brasenia) also afforded the fastest growth relative to three other species on which growth was measured. Feeding preferences across species were unrelated to protein content, polyphenolic content, or toughness. Domiciles constructed by caterpillars from leaf fragments were protective from field assemblages of fishes, but domiciles made from preferred or unpreferred host species conferred no significant protection from fish in the laboratory. Caterpillars responded positively to chemical cues of water lilies, and prior feeding experience increased preference for an otherwise unpreferred water lily (Nuphar advena) within the life-span of individual caterpillars. M. gyralis is a generalist herbivore exhibiting modest preference induction and preferences for and among members of the family Nymphaeaceae. Our results suggest that relative growth rates, chemical cues, and previous feeding experience are important factors determining feeding preference. Protein content, polyphenolic content, and toughness appear less important, and the importance of fish predators remains in question. As pupation seems to occur exclusively on Nymphaea, we suggest that host use may be restricted due to life-stage-specific developmental constraints that are not apparent from the results of growth or preference assays. It is currently unknown how often specific life-stages may restrict host use, but our work suggests this as a potentially important area of inquiry.