Impaired verbal memory function is related to anterior cingulate glutamate levels in schizophrenia: findings from the STRATA study.

Impaired cognition is associated with lower quality of life and poor outcomes in schizophrenia. Brain glutamate may contribute to both clinical outcomes and cognition, but these relationships are not well-understood. We studied a multicentre cohort of 85 participants with non-affective psychosis using proton magnetic resonance spectroscopy. Glutamate neurometabolites were measured in the anterior cingulate cortex (ACC). Cognition was assessed using the Brief Assessment for Cognition in Schizophrenia (BACS). Patients were categorised as antipsychotic responders or non-responders based on treatment history and current symptom severity. Inverted U-shaped associations between glutamate or Glx (glutamate + glutamine) with BACS subscale and total scores were examined with regression analyses. We then tested for an interaction effect of the antipsychotic response group on the relationship between glutamate and cognition. ACC glutamate and Glx had a positive linear association with verbal memory after adjusting for age, sex and chlorpromazine equivalent dose (glutamate, ß = 3.73, 95% CI = 1.26-6.20, P = 0.004; Glx, ß = 3.38, 95% CI = 0.84-5.91, P = 0.01). This association did not differ between good and poor antipsychotic response groups. ACC glutamate was also positively associated with total BACS score (ß = 3.12, 95% CI = 0.01-6.23, P = 0.046), but this was not significant after controlling for antipsychotic dose. Lower glutamatergic metabolites in the ACC were associated with worse verbal memory, and this relationship was independent of antipsychotic response. Further research on relationships between glutamate and cognition in antipsychotic responsive and non-responsive illness could aid the stratification of patient groups for targeted treatment interventions.

Management of functional communication, swallowing, cough and related disorders: consensus recommendations for speech and language therapy.

Communication problems (eg, dysphonia, dysfluency and language and articulation disorders), swallowing disorders (dysphagia and globus), cough and upper airway symptoms, resulting from functional neurological disorder (FND), are commonly encountered by speech and language professionals. However, there are few descriptions in the literature of the most effective practical management approaches. This consensus document aims to provide recommendations for assessment and intervention that are relevant to both adults and young people. An international panel of speech and language professionals with expertise in FND were approached to take part. Participants responded individually by email to a set of key questions regarding best practice for assessment and interventions. Next, a video conference was held in which participants discussed and debated the answers to these key questions, aiming to achieve consensus on each issue. Drafts of the collated consensus recommendations were circulated until consensus was achieved. FND should be diagnosed on the basis of positive clinical features. Speech and language therapy for FND should address illness beliefs, self-directed attention and abnormal movement patterns through a process of education, symptomatic treatment and cognitive behavioural therapy within a supportive therapeutic environment. We provide specific examples of these strategies for different symptoms. Speech and language professionals have a key role in the management of people with communication and related symptoms of FND. It is intended that these expert recommendations serve as both a practical toolkit and a starting point for further research into evidence-based treatments.

Dopamine and Glutamate in Antipsychotic-Responsive Compared With Antipsychotic-Nonresponsive Psychosis: A Multicenter Positron Emission Tomography and Magnetic Resonance Spectroscopy Study (STRATA).

The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders [R] and 44 nonresponders [NR]). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min-1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity.

Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis.

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), which is upregulated in activated microglia, is a method for investigating whether immune activation is evident in the brain of adults with schizophrenia. This study aimed to measure TSPO availability in the largest patient group to date, and to compare it between patients with recent onset (ROS) and established (ES) schizophrenia. In total, 20 ROS patients (14 male), 21 ES (13 male), and 21 healthy controls completed the study. Patients were predominantly antipsychotic-medicated. Participants underwent a PET scan using the TSPO-specific radioligand [11C](R)-PK11195. The primary outcome was binding potential (BPND) in the anterior cingulate cortex (ACC). Secondary outcomes were BPND in six other regions. Correlations were investigated between TSPO availability and symptom severity. Data showed that mean BPND was higher in older (ES and controls) compared with younger (ROS and controls) individuals, but did not significantly differ between ROS or ES and their respective age-matched controls (ACC; ANOVA main effect of diagnosis: F1,58 = 0.407, p = 0.526). Compared with controls, BPND was lower in antipsychotic-free (n = 6), but not in medicated, ROS patients. BPND in the ES group was negatively correlated with positive symptoms, and positively correlated with negative symptom score. Our data suggest ageing is associated with higher TSPO but a diagnosis of schizophrenia is not. Rather, subnormal TSPO levels in drug-free recent-onset patients may imply impaired microglial development and/or function, which is counteracted by antipsychotic treatment. The development of novel radioligands for specific immune-mechanisms is needed for further clarification.

A novel allele of ASY3 is associated with greater meiotic stability in autotetraploid Arabidopsis lyrata.

In this study we performed a genotype-phenotype association analysis of meiotic stability in 10 autotetraploid Arabidopsis lyrata and A. lyrata/A. arenosa hybrid populations collected from the Wachau region and East Austrian Forealps. The aim was to determine the effect of eight meiosis genes under extreme selection upon adaptation to whole genome duplication. Individual plants were genotyped by high-throughput sequencing of the eight meiosis genes (ASY1, ASY3, PDS5b, PRD3, REC8, SMC3, ZYP1a/b) implicated in synaptonemal complex formation and phenotyped by assessing meiotic metaphase I chromosome configurations. Our results reveal that meiotic stability varied greatly (20-100%) between individual tetraploid plants and associated with segregation of a novel ASYNAPSIS3 (ASY3) allele derived from A. lyrata. The ASY3 allele that associates with meiotic stability possesses a putative in-frame tandem duplication (TD) of a serine-rich region upstream of the coiled-coil domain that appears to have arisen at sites of DNA microhomology. The frequency of multivalents observed in plants homozygous for the ASY3 TD haplotype was significantly lower than in plants heterozygous for ASY3 TD/ND (non-duplicated) haplotypes. The chiasma distribution was significantly altered in the stable plants compared to the unstable plants with a shift from proximal and interstitial to predominantly distal locations. The number of HEI10 foci at pachytene that mark class I crossovers was significantly reduced in a plant homozygous for ASY3 TD compared to a plant heterozygous for ASY3 ND/TD. Fifty-eight alleles of the 8 meiosis genes were identified from the 10 populations analysed, demonstrating dynamic population variability at these loci. Widespread chimerism between alleles originating from A. lyrata/A. arenosa and diploid/tetraploids indicates that this group of rapidly evolving genes may provide precise adaptive control over meiotic recombination in the tetraploids, the very process that gave rise to them.

Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology.

These updated guidelines from the British Association for Psychopharmacology replace the original version published in 2011. They address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting was held in 2017, involving experts in schizophrenia and its treatment. They were asked to review key areas and consider the strength of the evidence on the risk-benefit balance of pharmacological interventions and the clinical implications, with an emphasis on meta-analyses, systematic reviews and randomised controlled trials where available, plus updates on current clinical practice. The guidelines cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. It is hoped that the practice recommendations presented will support clinical decision making for practitioners, serve as a source of information for patients and carers, and inform quality improvement.

Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study.

BACKGROUND: Major depressive disorder is associated with raised peripheral inflammatory markers. Mounting evidence also suggests that inflammation is involved in suicidal behavior. However, the involvement of inflammation in the brains of individuals with depression, and its association with suicidal ideation, needs further clarification. Translocator protein (TSPO), which is upregulated in activated glia (predominantly microglia), can be measured as an indication of neuroinflammation in vivo using positron emission tomography and TSPO-specific radioligands. METHODS: We used [11C](R)-PK11195 positron emission tomography to compare TSPO availability in the anterior cingulate cortex (ACC), prefrontal cortex, and insula between 14 medication-free patients in a major depressive episode of at least moderate severity and 13 matched healthy control subjects. In a post hoc analysis, we also compared TSPO availability between patients with and without suicidal thoughts. RESULTS: Multivariate analysis of variance indicated significantly higher TSPO in patients compared with control subjects (p = .005). The elevation was of large effect size and significant in the ACC (p = .022, Cohen's d = 0.95), with smaller nonsignificant elevations in the prefrontal cortex (p = .342, Cohen's d = 0.38) and insula (p = .466, Cohen's d = 0.29). TSPO was not elevated in patients without suicidal thinking but was significantly increased in those with suicidal thoughts compared with those without, most robustly in the ACC (p = .008) and insula (p = .023). CONCLUSIONS: We confirm evidence for increased TSPO availability, suggestive of predominantly microglial activation, in the ACC during a moderate to severe major depressive episode. Our findings provide further incentive for evaluating anti-inflammatory therapies in major depressive disorder.

The use of biodegradable (SX-ELLA) oesophageal stents to treat dysphagia due to benign and malignant oesophageal disease.

BACKGROUND: Biodegradable (BD) oesophageal stents have been available commercially only since 2008 and previous published research is limited. Our aim was to review the use of BD stents to treat dysphagia in benign or malignant oesophageal strictures. METHODS: Patients were identified from a prospective interventional radiological database. BD stents were inserted radiologically under fluoroscopic control. RESULTS: Between July 2008 and February 2011, 25 attempts at placing SX-ELLA biodegradable oesophageal stents were made in 17 males and five females, with a median age of 69 (range = 54-80) years. Two patients required more than one BD stent. Indications were benign strictures (n = 7) and oesophageal cancer (n = 17). One attempt was unsuccessful for a technical success rate of 96% with no immediate complications. Clinical success rate was 76%. Median dysphagia score before stent insertion was 3 (range = 2-4) compared to 2 (range = 0-3) after stent insertion (p = 0.0001). CONCLUSION: BD stents provide good dysphagia relief for the life time of the stent. They may help avoid the use of feeding tubes in patients having radical chemoradiotherapy or awaiting oesophagectomy. They do not require removal or interfere with radiotherapy planning via imaging. However, the reintervention rate is high after the stent dissolves.

Progesterone receptor gene variants and risk of endometrial cancer.

Prolonged excessive estrogen exposure unopposed by progesterone is widely accepted to be a risk factor for endometrial cancer development. The physiological function of progesterone is dependent upon the presence of its receptor [progesterone receptor (PGR)] and several studies have reported single nucleotide polymorphisms (SNPs) in the PGR gene to be associated with endometrial cancer risk. We sought to confirm the associations with endometrial cancer risk previously reported for four different PGR polymorphisms. A maximum of 2888 endometrial cancer cases and 4483 female control subjects from up to three studies were genotyped for four PGR polymorphisms (rs1042838, rs10895068, rs11224561 and rs471767). Logistic regression with adjustment for age, study, ethnicity and body mass index was performed to calculate odds ratios (ORs) and associated 95% confidence intervals (CIs) and P-values. Of the four SNPs investigated, only rs11224561 in the 3' region of the PGR gene was found to be significantly associated with endometrial cancer risk. The A allele of the rs11224561 SNP was associated with increased risk of endometrial cancer (OR per allele 1.31; 95% CI 1.12-1.53, P = 0.001, adjusted for age and study), an effect of the same magnitude and direction as reported previously. We have validated the endometrial cancer risk association with a tagSNP in the 3' untranslated region of PGR previously reported in an Asian population. Replication studies will be required to refine the risk estimate and to establish if this, or a correlated SNP, is the underlying causative variant.

Common polymorphisms in ERCC2 (Xeroderma pigmentosum D) are not associated with breast cancer risk.

A substantial proportion of the familial risk of breast cancer may be due to genetic variants, each contributing a small effect. The protein encoded by ERCC2 is a key enzyme involved in nucleotide excision repair, in which gene defects could lead to cancer prone syndromes such as Xeroderma pigmentosum D. We have examined the association between single nucleotide polymorphisms in the ERCC2 gene and the incidence of invasive breast cancer in three case-control series, with a maximum of 3,634 patients and of 3,340 controls. None of the three single nucleotide polymorphisms were significantly associated with the incidence of breast cancer.

Playing with fire: images of fire on toy packaging.

Despite prevention efforts designed to teach children that fire is not a toy, each year hundreds of children, primarily male, are injured while playing with fire. Mass-produced toys and games shape children's behaviors, and the fire images on toy packaging may send the message that fire is fun rather than dangerous. The purpose of this study was to determine the frequency of male fire-related injuries at our burn center and to investigate the use of fire images in toy packaging. An aisle-by-aisle search was conducted at a national toy store. Toys with fire images on their packaging were identified. Target gender and the setting in which the fire was displayed also were recorded. Only toys with clearly visible flames on their packaging were included. We reviewed our TRACS database from April 1997 to May 1999 for fire-related injuries to children admitted to our institution as a result of playing with fire. Review of toy stores revealed 404 toys with packaging containing fire images. Of these, 97% (393 of 404) were targeted to males. Video games were the leading category of flame-related packaging (208 of 404), followed by toy car/truck displays (84 of 404). Packaging for girls' toys had safe and contained settings, whereas boys' toys used settings that were uncontrolled and associated with speed and weapons. A total of 59 children, 52 males and 7 females, with a mean age of 10 +/- 0.6 years and mean TBSA burn of 12.3 +/- 2.1% were admitted to our facility with fire-related injuries during the study interval. Children imitate life with toys and use play to experiment with new behavior. Boys are receiving a powerful, consistent message from images of fire on toy packaging. These advertisements may help to contribute to the higher incidence of fire-related injuries in boys.