An automated micro solid phase extraction gas chromatography-mass spectrometry (µSPE-GC-MS) detection method for geosmin and 2-methylisoborneol in drinking water.

Geosmin and 2-methylisoborneol (2-MIB) are amongst the most common earthy and musty taste and odour (T&O) compounds found in drinking water. With low odour threshold detection limits below 10 ng L-1, and the complexity of raw water matrices, these two compounds provide a significant challenge for water companies globally. In this research, for the first time, a novel and fully automated micro-solid phase-extraction (µSPE) method coupled with gas chromatography (GC)-mass spectrometry (MS) has been developed for the detection of geosmin and 2-MIB for drinking water analysis. The new automated method described herein is environmentally friendly requiring low raw water sample volumes, of 25 mL, and only 50 µL of elution solvent. Our µSPE-GC-MS method exhibits excellent linearity for both compounds (R2 > 0.999) and low limits of detection of 2.0 ng L-1 and 4.3 ng L-1 for geosmin and 2-MIB, respectively. The method showed excellent recovery rates (95.1-100.1%) and good precision (RSD < 7%) in raw sample matrices. Our approach is fully automated onto a robotic workstation which can be readily integrated into a laboratory workflow for routine water analysis. Furthermore, the method has excellent potential to be incorporated within a portable system for onsite analysis.

Impacts of stigma and discrimination in the workplace on people living with psychosis.

BACKGROUND: Employment holds many benefits for people living with psychosis. However, significant barriers to employment for this cohort appear to exist, notably stigma and discrimination against people living with serious mental health conditions. We asked: Would a qualitative sample including multiple stakeholder groups reveal similar results and if so, what would be the main impacts of such stigma and discrimination? METHOD: This analysis used data from a qualitative study that had employed focus groups and interviews to investigate the employment barriers and support needs of people living with psychosis, including views of the multiple stakeholders (those living with mental health conditions, health professionals, care-givers, employments consultants and community members and employers). RESULTS: The impacts of workplace stigma and discrimination on people living with psychosis included work avoidance, reluctance to disclose mental health conditions to employers, work-related stress, and reduced longevity of employment. CONCLUSIONS: Significant impacts from such stigma and discrimination were found in this study. The findings indicate a need to provide support mechanisms and to change the culture of workplaces to improve employment opportunities and outcomes for people living with psychosis.

Optimizing real time fMRI neurofeedback for therapeutic discovery and development.

While reducing the burden of brain disorders remains a top priority of organizations like the World Health Organization and National Institutes of Health, the development of novel, safe and effective treatments for brain disorders has been slow. In this paper, we describe the state of the science for an emerging technology, real time functional magnetic resonance imaging (rtfMRI) neurofeedback, in clinical neurotherapeutics. We review the scientific potential of rtfMRI and outline research strategies to optimize the development and application of rtfMRI neurofeedback as a next generation therapeutic tool. We propose that rtfMRI can be used to address a broad range of clinical problems by improving our understanding of brain-behavior relationships in order to develop more specific and effective interventions for individuals with brain disorders. We focus on the use of rtfMRI neurofeedback as a clinical neurotherapeutic tool to drive plasticity in brain function, cognition, and behavior. Our overall goal is for rtfMRI to advance personalized assessment and intervention approaches to enhance resilience and reduce morbidity by correcting maladaptive patterns of brain function in those with brain disorders.

Orbitofrontal cortex neurofeedback produces lasting changes in contamination anxiety and resting-state connectivity.

Anxiety is a core human emotion but can become pathologically dysregulated. We used functional magnetic resonance imaging (fMRI) neurofeedback (NF) to noninvasively alter patterns of brain connectivity, as measured by resting-state fMRI, and to reduce contamination anxiety. Activity of a region of the orbitofrontal cortex associated with contamination anxiety was measured in real time and provided to subjects with significant but subclinical anxiety as a NF signal, permitting them to learn to modulate the target brain region. NF altered network connectivity of brain regions involved in anxiety regulation: subjects exhibited reduced resting-state connectivity in limbic circuitry and increased connectivity in the dorsolateral prefrontal cortex. NF has been shown to alter brain connectivity in other contexts, but it has been unclear whether these changes persist; critically, we observed changes in connectivity several days after the completion of NF training, demonstrating that such training can lead to lasting modifications of brain functional architecture. Training also increased subjects' control over contamination anxiety several days after the completion of NF training. Changes in resting-state connectivity in the target orbitofrontal region correlated with these improvements in anxiety. Matched subjects undergoing a sham feedback control task showed neither a reorganization of resting-state functional connectivity nor an improvement in anxiety. These data suggest that NF can enable enhanced control over anxiety by persistently reorganizing relevant brain networks and thus support the potential of NF as a clinically useful therapy.

Tumour cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance.

Fibroblast growth factor receptors (FGFRs) can act as driving oncoproteins in certain cancers, making them attractive drug targets. Here we have characterized tumour cell responses to two new inhibitors of FGFR1-3, AZ12908010 and the clinical candidate AZD4547, making comparisons with the well-characterized FGFR inhibitor PD173074. In a panel of 16 human tumour cell lines, the anti-proliferative activity of AZ12908010 or AZD4547 was strongly linked to the presence of deregulated FGFR signalling, indicating that addiction to deregulated FGFRs provides a therapeutic opportunity for selective intervention. Acquired resistance to targeted tyrosine kinase inhibitors is a growing problem in the clinic but has not yet been explored for FGFR inhibitors. To assess how FGFR-dependent tumour cells adapt to long-term FGFR inhibition, we generated a derivative of the KMS-11 myeloma cell line (FGFR(Y373C)) with acquired resistance to AZ12908010 (KMS-11R cells). Basal phosphorylated FGFR and FGFR-dependent downstream signalling were constitutively elevated and refractory to drug in KMS-11R cells. Sequencing of FGFR3 in KMS-11R cells revealed the presence of a heterozygous mutation at the gatekeeper residue, encoding FGFR3(V555M); consistent with this, KMS-11R cells were cross-resistant to AZD4547 and PD173074. These results define the selectivity and efficacy of two new FGFR inhibitors and identify a secondary gatekeeper mutation as a mechanism of acquired resistance to FGFR inhibitors that should be anticipated as clinical evaluation proceeds.

Transcranial magnetic stimulation and connectivity mapping: tools for studying the neural bases of brain disorders.

There has been an increasing emphasis on characterizing pathophysiology underlying psychiatric and neurological disorders in terms of altered neural connectivity and network dynamics. Transcranial magnetic stimulation (TMS) provides a unique opportunity for investigating connectivity in the human brain. TMS allows researchers and clinicians to directly stimulate cortical regions accessible to electromagnetic coils positioned on the scalp. The induced activation can then propagate through long-range connections to other brain areas. Thus, by identifying distal regions activated during TMS, researchers can infer connectivity patterns in the healthy human brain and can examine how those patterns may be disrupted in patients with different brain disorders. Conversely, connectivity maps derived using neuroimaging methods can identify components of a dysfunctional network. Nodes in this dysfunctional network accessible as targets for TMS by virtue of their proximity to the scalp may then permit TMS-induced alterations of components of the network not directly accessible to TMS via propagated effects. Thus TMS can provide a portal for accessing and altering neural dynamics in networks that are widely distributed anatomically. Finally, when long-term modulation of network dynamics is induced by trains of repetitive TMS, changes in functional connectivity patterns can be studied in parallel with changes in patient symptoms. These correlational data can elucidate neural mechanisms underlying illness and recovery. In this review, we focus on the application of these approaches to the study of psychiatric and neurological illnesses.

Minimum and optimum light requirements for laryngoscopy in paediatric anaesthesia: a manikin study.

Direct laryngoscopy is performed regularly in paediatric anaesthetic practice for the purpose of intubating a patient's trachea. A minimum illumination of 700 lux at a distance of 20 mm has been suggested in a draft standard for laryngoscopes from the International Organization for Standardization. We investigated the minimum and optimum illumination required by anaesthetists during laryngoscopy. Fifty anaesthetists were recruited to perform laryngoscopy on a child manikin with a selection of laryngoscope blades and bulbs attached to a variable voltage supply. There was a large variation in the illumination range of different bulb and blade combinations. We demonstrated a large interindividual variability between anaesthetists for illumination requirements during laryngoscopy. Anaesthetists can see the larynx at very low light levels, but optimum illumination was significantly greater than minimum illumination. Two of the six combinations could produce more than 700 lux. In all, 78% and 54% of anaesthetists considered 700 lux too bright with a halogen and xenon bulb, respectively. Our study suggests that the proposed standard of 700 lux may possibly be too bright.

Evaluation of the Basic Airway Model, a novel mask ventilation training manikin.

The Basic Airway Model is an airway manikin designed for training in mask ventilation. We investigated the ability of the Basic Airway Model to provide varying levels of difficulty for mask ventilation. Volunteers with three levels of experience (novice, intermediate and expert) attempted to ventilate the manikin at three levels of difficulty: easy, intermediate and difficult. The distribution of frequencies of successful ventilation by different groups at the three levels of difficulty were statistically significant (p < 0.0001). The median (IQR (range)) degree of difficulty was 3 (2-5 (1-7)), 4 (3-5.3 (2-7)) and 6 (5-7 (3-9)) for easy, intermediate and difficult settings, respectively. We conclude that the Basic Airway Model can provide different levels of difficulty for mask ventilation training.

Minimum and optimum light output of Macintosh size 3 laryngoscopy blades: a manikin study.

Illumination provided by laryngoscope blades varies widely. It is not known what the optimum level of illumination should be during laryngoscopy. So far, no published standards exist for light intensity provided by laryngoscopes. Fifty anaesthetists were recruited to perform laryngoscopy on a manikin with three different laryngoscopes attached to a variable voltage supply. Anaesthetists were asked to find the minimum and optimum level of light they would wish to have for intubation. This study demonstrated that anaesthetists can see the larynx at very low light levels. The optimum level was significantly greater than the minimum level. The vacuum bulb laryngoscopes provides a significant lower light output than halogen and xenon laryngoscopes. There is a large variation in illumination requirements amongst anaesthetists which may make setting standards difficult. A brighter laryngoscope, as suggested by some manufacturers, may not necessarily be a better one.

Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder.

In the search for the biological causes of schizophrenia and bipolar disorder, glutamate neurotransmission has emerged as one of a number of candidate processes and pathways where underlying gene deficits may be present. The analysis of chromosomal rearrangements in individuals diagnosed with neuropsychiatric disorders is an established route to candidate gene identification in both Mendelian and complex disorders. Here we describe a set of genes disrupted by, or proximal to, chromosomal breakpoints (2p12, 2q31.3, 2q21.2, 11q23.3 and 11q24.2) in a patient where chronic schizophrenia coexists with mild learning disability (US: mental retardation). Of these disrupted genes, the most promising candidate is a member of the kainate-type ionotropic glutamate receptor family, GRIK4 (KA1). A subsequent systematic case-control association study on GRIK4 assessed its contribution to psychiatric illness in the karyotypically normal population. This identified two discrete regions of disease risk within the GRIK4 locus: three single single nucleotide polymorphism (SNP) markers with a corresponding underlying haplotype associated with susceptibility to schizophrenia (P=0.0005, odds ratio (OR) of 1.453, 95% CI 1.182-1.787) and two single SNP markers and a haplotype associated with a protective effect against bipolar disorder (P=0.0002, OR of 0.624, 95% CI 0.485-0.802). After permutation analysis to correct for multiple testing, schizophrenia and bipolar disorder haplotypes remained significant (P=0.0430, s.e. 0.0064 and P=0.0190, s.e. 0.0043, respectively). We propose that these convergent cytogenetic and genetic findings provide molecular evidence for common aetiologies for different psychiatric conditions and further support the 'glutamate hypothesis' of psychotic illness.

The pressure required to force liquid through breathing system filters.

Liquid in the form of sputum and condensation may be forced through a breathing system filter if sufficient pressure is applied to the filter layer, with the potential for cross-infection. Twenty-three different breathing system filters (12 adult, 11 paediatric) were assessed to determine the pressure causing liquid penetration. Five samples of each were tested by connecting the ventilator end of a breathing system filter to a water-filled U-tube and reservoir. The reservoir was positioned so that the water surface was level with the filter layer and raised until liquid appeared through the filter layer on the patient side and the water-column height recorded. There were substantial differences in performance between models. Liquid penetration occurred at lower pressures for adult electrostatic than adult pleated filters: median [IQR] 1.18 [1.08- 1.32] and 8.04 [4.27-12.80] kPa, respectively, p < 0.0001. Liquid penetration occurred at similar pressures in paediatric electrostatic filters (0.98 [0.74-1.32] kPa) compared to adult electrostatic filters.

Dopa decarboxylase genotypes may influence age at onset of schizophrenia.

Several lines of evidence implicate dopa decarboxylase (DDC) with schizophrenia. By analysis of two putative functional DDC variants in 173 schizophrenic patients and 204 controls we tested the hypotheses that DDC is involved in: (1) predisposition to schizophrenia; and (2) modulation of age at disease onset. No association was observed with schizophrenia as a whole, whereas an association between DDC genotypes and age at disease onset was suggested in males (P = 0.03). This association was most pronounced in relation to genotypes of haplotypes comprising both variants, suggesting an additive model where one variant mediates early and the other late onset. Accordingly, the haplotype-based genotypes could be assigned into three groups by their possible relative effect on age at onset: an "early", "neutral" and "late" group. Dividing the male schizophrenics into four groups with increasing age at onset, the "early" genotypes were seen to decrease in frequency from 51.5% to 16.7% while the "late" genotypes increased from 12.1% to 33.3% (P = 0.02). The difference in mean age at onset between male patients with "early" genotypes vs patients with "late" genotypes was close to 5 years (95% CI: 0.7-8.8). Thus, DDC may possibly act as a modulator of age at onset in male schizophrenics.

The Alexander technique: its application in midwifery and the results of preliminary research into Parkinson's.

This article outlines the origins and theory of the Alexander Technique and how it is learnt. Recent research is listed and a description given of main presenting symptoms and medical problems of pupils coming for lessons. The paper also describes how the Alexander Technique is used by women in pregnancy and childbirth and explains why it is beneficial. The final section describes Parkinson's research results, mainly from a preliminary study designed some years ago to test a methodology for a randomized controlled trial.

A theoretical investigation of reference frames for the planning of speech movements.

Does the speech motor control system use invariant vocal tract shape targets when producing vowels and semivowels? A 4-part theoretical treatment favoring models whose only invariant targets are regions in auditory perceptual space over models that posit invariant constriction targets is presented. Auditory target regions are hypothesized to arise during development as an emergent property of neural map formation in the auditory system. Furthermore, speech movements are planned as trajectories in auditory perceptual space. These trajectories are then mapped into articulator movements through a neural mapping that allows motor equivalent variability in constriction locations and degrees when needed. These hypotheses are illustrated using computer simulations of the DIVA model of speech acquisition and production. Finally, several difficult challenges to proponents of constriction theories based on this theoretical treatment are posed.

A method of testing the compliance of 15 and 22 mm conical connectors on heat and moisture exchangers to ISO 5356-1:1987.

Heat and moisture exchangers (HMEs) are used to warm and humidify the gas delivered to patients during anaesthesia and in intensive care. Typically, HMEs are connected between the tracheal tube or catheter mount and the breathing system. This point of connection has been identified as having a high risk of disconnection. To reduce the possibility of disconnection, the International Standard for HMEs specifies that the connectors on an HME shall comply with ISO 5356-1: 1987, the International Standard for cones and sockets. A simple method is described to test whether or not the connectors comply with this standard. This method is used when evaluating HMEs for the Medical Devices Agency (MDA). Results are quoted from the MDA series Evaluation. The majority of connectors tested were found to comply with the standard. The test method is also suitable for testing conical connectors on other devices.

Distribution of Fungal Spores and Fractal Diversity of Quadrats on Membrane Filters †.

In standard practice, estimations of populations of fungal spores on gridded membrane filter discs are made from spore loads in arbitrarily selected groups or rows of grids (quadrats). We used the resting spores of Synchytrium endobioticum to examine actual/expected spore ratio. The ratios showed unacceptable divergences, and are characterized by an aggregated spore distribution. The fractal diversity index of the quadrats is inversely related the loga of the population numbers. The analysis gives values for the appropriate spore number per quadrat and the quadrat pattern to yield the best actual/expected ratio.

The relationship between perimenstrual depressive mood and depressive illness.

In a study of 144 women, mainly self-designated PMS sufferers, the premenstrual depression experienced was, apart from its shorter duration, quantitatively and qualitatively similar to major depressive disorder for a substantial proportion of subjects. The associations with previous history of depression were complex: the severity of premenstrual depression was related to previous history of postnatal depression, whereas its duration (i.e., whether it persisted through longer) was related to a history of treatment with antidepressants. Two independent dimensions are proposed. (i) A menstrual cycle-related factor which in vulnerable women can results in severe and disabling premenstrual dysphoria, and which may be aetiologically related to a subgroup of postnatal depression. (ii) In a minority of women a more general propensity for depressive illness evidence as a tendency for any premenstrual depression to be prolonged.

Should all pregnant women be screened for hepatitis B?

To assess the sensitivity of historical risk factors for identification for hepatitis B surface antigen (HBsAg)-positive parturients, 4399 pregnant women were consecutively screened for HBsAg. Information regarding risk for hepatitis B infection was obtained from each HBsAg-positive parturient. Twenty-three HBsAg-positive subjects were identified (5.2/1000 deliveries). The HBsAg carrier rate (18/2231, or 8.1/1000 deliveries) was significantly higher in women of black, Asian, or Hispanic origin than in the remaining ethnic groups (non-Hispanic whites plus all others, 5/2168, or 2.3/1000 deliveries) (chi square, 5.95; p = 0.016). Risk factors for identification of HBsAg-positive women were present in 10 of 22 asymptomatic subjects (sensitivity, 45%; 95% confidence interval, 24% to 68%). Much of the information required to assess one of these risk factors, previous infection, involved detailed questioning and is unlikely to be obtained in the context of conventional obstetrical care. Routine maternal HBsAg screening programs may be needed if transmission of hepatitis B from mother to infant is to be prevented.