Towards third generation matrix metalloproteinase inhibitors for cancer therapy

The failure of matrix metalloproteinase (MMP) inhibitor drug clinical trials in cancer was partly due to the inadvertent inhibition of MMP antitargets that counterbalanced the benefits of MMP target inhibition. We explore how MMP inhibitor drugs might be developed to achieve potent selectivity for validated MMP targets yet therapeutically spare MMP antitargets that are critical in host protection

A survey of owners' perceptions of fear of fireworks in a sample of dogs and cats in New Zealand

AIMS: To establish reliable information regarding the behavioural responses of dogs and cats to fireworks in New Zealand; record interventions used by owners, and their perceived efficacies; and establish the prevalence of firework-related injury, and quantify owners' attitudes towards fireworks. METHODS: A questionnaire targeting dog and cat owners was distributed via the Auckland Society for the Prevention of Cruelty to Animals (SPCA) Animals Voice magazine and 25 veterinary clinics. The questionnaire covered demographics of animals, fear of fireworks, severity of the fear, and behaviours exhibited. Also included were treatments tried, source and perceived efficacy, prevalence of injury, and owners' attitudes towards the sale of fireworks for private use. RESULTS: From a total of 8,966 questionnaires distributed, 1,007 valid questionnaires were returned, representing 3,527 animals. Of these 1,635 (46%) animals displayed a level of fear of fireworks recognisable to their owners. Owners of dogs identified a significantly higher fear response than owners of cats but the duration of these fear responses did not differ between species. Fear of fireworks frequently resulted in dogs exhibiting active fear behaviours, whereas cats were more likely to exhibit hiding and cowering behaviours. A significantly increased severity and duration of fear response over time in dogs and cats was associated with owners who comforted them when they displayed a fearful response. Only 141/890 (15.8%) of owners sought professional treatment from a veterinarian, animal behaviourist or animal trainer for their animals, with variable efficacy. Six percent (51/923) of animals had received physical injuries from fireworks. The majority (837/1,007; 83%) of respondents, regardless of whether they owned a fearful animal or not, supported a ban on the sale of fireworks for private use. CONCLUSIONS: The results provide valuable information that is, as yet, unsubstantiated in New Zealand, although potential biases exist due to the non-random selection of respondents. Differences between dogs and cats were likely due to differing responses to fear-provoking stimuli between the species. Owner-reported increase in fearful response over time for comforted animals may indicate a negative impact on the longer-term psychological welfare of their animal. CLINICAL RELEVANCE: The greater the awareness of effective treatment plans for animals that suffer from a fear of fireworks, the greater the possibility that this fear can be reduced. Wider dissemination of effective owner behaviour and treatment programmes for firework fears is needed to improve levels of professional treatment for dogs and cats

Chlorpromazine for schizophrenia: a Cochrane systematic review of 50 years of randomised controlled trials

BACKGROUND: Chlorpromazine (CPZ) remains one of the most common drugs used for people with schizophrenia worldwide, and a benchmark against which other treatments can be evaluated. Quantitative reviews are rare; this one evaluates the effects of chlorpromazine in the treatment of schizophrenia in comparison with placebo. METHODS: We sought all relevant randomised controlled trials (RCT) comparing chlorpromazine to placebo by electronic and reference searching, and by contacting trial authors and the pharmaceutical industry. Data were extracted from selected trials and, where possible, synthesised and random effects relative risk (RR), the number needed to treat (NNT) and their 95% confidence intervals (CI) calculated. RESULTS: Fifty RCTs from 1955–2000 were included with 5276 people randomised to CPZ or placebo. They constitute 2008 person-years spent in trials. Meta-analysis of these trials showed that chlorpromazine promotes a global improvement (n = 1121, 13 RCTs, RR 0.76 CI 0.7 to 0.9, NNT 7 CI 5 to 10), although a considerable placebo response is also seen. People allocated to chlorpromazine tended not to leave trials early in both the short (n = 945, 16 RCTs, RR 0.74 CI 0.5 to 1.1) and medium term (n = 1861, 25 RCTs, RR 0.79 CI 0.6 to 1.1). There were, however, many adverse effects. Chlorpromazine is sedating (n = 1242, 18 RCTs, RR 2.3 CI 1.7 to 3.1, NNH 6 CI 5 to 8), increases a person's chances of experiencing acute movement disorders, Parkinsonism and causes low blood pressure with dizziness and dry mouth. CONCLUSION: It is understandable why the World Health Organization (WHO) have endorsed and included chlorpromazine in their list of essential drugs for use in schizophrenia. Low- and middle-income countries may have more complete evidence upon which to base their practice compared with richer nations using recent innovations

Are lay people good at recognising the symptoms of schizophrenia?

©2013 Erritty, Wydell. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Aim: The aim of this study was to explore the general public’s perception of schizophrenia symptoms and the need to seekhelp for symptoms. The recognition (or ‘labelling’) of schizophrenia symptoms, help-seeking behaviours and public awareness of schizophrenia have been suggested as potentially important factors relating to untreated psychosis. Method: Participants were asked to rate to what extent they believe vignettes describing classic symptoms (positive and negative) of schizophrenia indicate mental illness. They were also asked if the individuals depicted in the vignettes required help or treatment and asked to suggest what kind of help or treatment. Results: Only three positive symptoms (i.e., Hallucinatory behaviour, Unusual thought content and Suspiciousness) of schizophrenia were reasonably well perceived (above 70%) as indicating mental illness more than the other positive or negative symptoms. Even when the participants recognised that the symptoms indicated mental illness, not everyone recommended professional help. Conclusion: There may be a need to improve public awareness of schizophrenia and psychosis symptoms, particularly regarding an awareness of the importance of early intervention for psychosis

A Metabolite Specific 3D Stack-of-Spiral bSSFP Sequence for Improved Lactate Imaging in Hyperpolarized [1-13^{13}C]Pyruvate Studies on a 3T Clinical Scanner

Purpose: The balanced steady-state free precession sequence has been previously explored to improve the efficient use of non-recoverable hyperpolarized $^{13}$C magnetization, but suffers from poor spectral selectivity and long acquisition time. The purpose of this study was to develop a novel metabolite-specific 3D bSSFP ("MS-3DSSFP") sequence with stack-of-spiral readouts for improved lactate imaging in hyperpolarized [1-$^{13}$C]pyruvate studies on a clinical 3T scanner. Methods: Simulations were performed to evaluate the spectral response of the MS-3DSSFP sequence. Thermal $^{13}$C phantom experiments were performed to validate the MS-3DSSFP sequence. In vivo hyperpolarized [1-$^{13}$C]pyruvate studies were performed to compare the MS-3DSSFP sequence with metabolite specific gradient echo ("MS-GRE") sequences for lactate imaging. Results: Simulations, phantom and in vivo studies demonstrate that the MS-3DSSFP sequence achieved spectrally selective excitation on lactate while minimally perturbing other metabolites. Compared with MS-GRE sequences, the MS-3DSSFP sequence showed approximately a 2.5-fold SNR improvement for lactate imaging in rat kidneys, prostate tumors in a mouse model and human kidneys. Conclusions: Improved lactate imaging using the MS-3DSSFP sequence in hyperpolarized [1-$^{13}$C]pyruvate studies was demonstrated in animals and humans. The MS-3DSSFP sequence could be applied for other clinical applications such as in the brain or adapted for imaging other metabolites such as pyruvate and bicarbonate

Assessment for learning : a model for the development of a child’s self competence in the early years of education

In recent years policy documents, curricula and other educational initiatives have promoted a pedagogy founded on the concept of independent learning. This is broadly defined as ‘having the belief in yourself to think through learning activities, problems or challenges, make decisions about your learning and act upon those decisions (Blandford and Knowles, 2009:336). The central role of Assessment for Learning (AfL) in this process is often overlooked in practice. By considering the findings from a small scale research study this article addresses the central role of the teacher /practitioner in developing effective AfL in the early years classroom (3-5 years)

Pleiotropic functions of the tumor- and metastasis-suppressing Matrix Metalloproteinase-8 in mammary cancer in MMTV-PyMT transgenic mice

Matrix metalloproteinase-8 (MMP-8; neutrophil collagenase) is an important regulator of innate immunity which has onco-suppressive actions in numerous tumor types

Where There Is No Health Research: What Can Be Done to Fill the Global Gaps in Health Research?

As part of a cluster of articles leading up to the 2012 World Health Report and critically reflecting on the theme of “no health without research," Martin McKee and colleagues examine the question of what to do to build capacity in the many countries around the world where health research is virtually non-existent

Genetics of the Hippocampal Transcriptome in Mouse: A Systematic Survey and Online Neurogenomics Resource

Differences in gene expression in the CNS influence behavior and disease susceptibility. To systematically explore the role of normal variation in expression on hippocampal structure and function, we generated an online microarray database for a diverse panel of strains of mice, including most common inbred strains and numerous recombinant inbred lines (www.genenetwork.org). Using this resource, coexpression networks for families of genes can be generated rapidly to test causal models related to function. The data set is optimized for quantitative trait locus (QTL) mapping and was used to identify over 5500 QTLs that modulate mRNA levels. We describe a wide variety of analyses and novel synthetic approaches that take advantage of this resource, and demonstrate how both the data and associated tools can be applied to the study of gene regulation in the hippocampus and relations to structure and function