Short Communication: Identification of equine corticotropin-like intermediate lobe peptide (CLIP) binding to an adrenocortipcotrophic hormone (ACTH) assay capture antibody.

A chemiluminescent immunoassay is commonly employed to measure adrenocorticotrophic hormone (ACTH) concentrations to assist pituitary pars intermedia dysfunction diagnosis. In a previous study, seasonally-dependent assay cross-reactivity to endogenous equine corticotropin-like intermediate lobe peptide (CLIP, ACTH 18-39) was suspected. The present study aimed to demonstrate binding of endogenous equine CLIP to the capture antibody of the ACTH chemiluminescent immunoassay. Liquid chromatography - mass spectrometry (LCMS) methods were optimised to identify selected ions from synthetic human ACTH, α-melanocyte stimulating hormone (α-MSH, ACTH 1-17) and CLIP. Synthetic ACTH and CLIP bound to the capture antibody of the chemiluminescent ACTH assay, but α-MSH did not. Equine endogenous CLIP was detected by LCMS in pony plasma taken in the autumn and could be eluted from the capture antibody of the ACTH chemiluminescent immunoassay. Further research is required to enable quantification of CLIP. Equine CLIP may alter measured ACTH concentrations in vivo.

Serum amyloid A and plasma fibrinogen concentrations in horses following emergency exploratory celiotomy.

BACKGROUND: Acute-phase proteins may help assess the nature and severity of lesions and outcome in horses undergoing colic surgery. OBJECTIVES: To compare serum amyloid A and plasma fibrinogen concentrations ([SAA] and [fibrinogen]) in the immediate post-operative period after exploratory celiotomy and determine their value in assessment of post-operative complications and survival to discharge. STUDY DESIGN: Observational study. METHODS: This study included horses over 1 year of age undergoing exploratory celiotomy. Surgical procedures, lesions, post-operative care, complications and survival to discharge were recorded. [SAA] and [fibrinogen] were measured prior to surgery and 5 days post-operatively. Statistical analyses included Yate's Chi-square test, linear mixed effects model, Mann-Whitney U test and logistic regression. RESULTS: Of 300 horses, 52.0% developed post-operative complications and 83.7% survived to discharge, with significantly reduced chance of survival in horses that developed post-operative complications (P<0.01). Median [SAA] at days 1, 2, 3, 4 and 5 and median [fibrinogen] at days 3, 4 and 5 were significantly different between horses that did and did not develop post-operative complications (P<0.05). Median [SAA] at days 1, 4 and 5 were significantly different between horses that did and did not survive to discharge (P<0.05). Logistic regression revealed post-operative complications to be associated with strangulating lesions (OR 2.35, 95% confidence interval [CI] 1.41-3.91, P≤0.001) and higher [fibrinogen] at admission (OR 1.21, 95% CI 1.00-1.45, P<0.05), and survival to discharge to be associated with lower [SAA] at 5 days post-operatively (OR 0.965, 95% CI 0.94-0.99, P = 0.002). MAIN LIMITATIONS: A large variety of lesions and complications prevented detailed analysis of associations between inflammatory markers, lesions and complications. CONCLUSIONS: Horses that develop post-operative complications have acute-phase responses of greater magnitudes and durations compared with those that do not develop complications. This is also seen in horses that do not survive to discharge. Measuring [SAA] daily and [fibrinogen] at admission, may help predict the development of post-operative complications.

Family-based analyses reveal novel genetic overlap between cytokine interleukin-8 and risk for suicide attempt.

BACKGROUND: Suicide is major public health concern. It is imperative to find robust biomarkers so that at-risk individuals can be identified in a timely and reliable manner. Previous work suggests mechanistic links between increased cytokines and risk for suicide, but questions remain regarding the etiology of this association, as well as the roles of sex and BMI. METHODS: Analyses were conducted using a randomly-ascertained extended-pedigree sample of 1882 Mexican-American individuals (60% female, mean age = 42.04, range = 18-97). Genetic correlations were calculated using a variance components approach between the cytokines TNF-α, IL-6 and IL-8, and Lifetime Suicide Attempt and Current Suicidal Ideation. The potentially confounding effects of sex and BMI were considered. RESULTS: 159 individuals endorse a Lifetime Suicide Attempt. IL-8 and IL-6 shared significant genetic overlap with risk for suicide attempt (ρg = 0.49, pFDR = 7.67 × 10-03; ρg = 0.53, pFDR = 0.01), but for IL-6 this was attenuated when BMI was included as a covariate (ρg = 0.37, se = 0.23, pFDR = 0.12). Suicide attempts were significantly more common in females (pFDR = 0.01) and the genetic overlap between IL-8 and risk for suicide attempt was significant in females (ρg = 0.56, pFDR = 0.01), but not in males (ρg = 0.44, pFDR = 0.30). DISCUSSION: These results demonstrate that: IL-8 shares genetic influences with risk for suicide attempt; females drove this effect; and BMI should be considered when assessing the association between IL-6 and suicide. This finding represents a significant advancement in knowledge by demonstrating that cytokine alterations are not simply a secondary manifestation of suicidal behavior, but rather, the pathophysiology of suicide attempts is, at least partly, underpinned by the same biological mechanisms responsible for regulating inflammatory response.

Validity and application of immunoturbidimetric and enzyme-linked immunosorbent assays for the measurement of adiponectin concentration in ponies.

BACKGROUND: Circulating adiponectin concentrations were lower in ponies with a history of endocrinopathic laminitis and in nonlaminitic ponies that subsequently developed laminitis. The assays used in these studies have been discontinued or are no longer valid. OBJECTIVES: (1) to determine the validity of immunoturbidimetric (IT) and enzyme linkedimmunosorbent (ELISA) assays for equine total and high molecular weight (HMW) [adiponectin] measurement and (2) to investigate the association between [adiponectin] measured using these assays and endocrinopathic laminitis. STUDY DESIGN: Method validation and cohort study. METHODS: Accuracy and precision of IT and ELISA assays for measuring total (TAC) and HMW (HMWAC) [adiponectin] were determined. Using the IT assay, the effects of anti-coagulant and storage temperature were assessed, TAC was measured in previously laminitic (PL) and never laminitic (NL) ponies (n = 6/group). Comparison with a previously validated radioimmunoassay was made in NL ponies (n = 223). Association between TAC and subsequent laminitis development in NL ponies was investigated using univariable logistic regression and ROC curve analysis. RESULTS: The IT assay was precise and demonstrated good agreement with the previously validated radioimmunoassay. TAC was significantly (P<0.01) lower in PL (mean ± s.d. 8.9 ± 2.9 µg/mL) compared to NL (24.2 ± 11.8 µg/mL) ponies and in NL ponies that developed laminitis within 12 months (median 4.8 µg/mL; IQR 2.65-13.4 µg/mL) compared to those that remained nonlaminitic (19.9 µg/mL; 9.95-31.5 µg/mL). TAC was significantly (P = 0.01) associated with laminitis occurrence within 12 months. Use of the area under the ROC curve to distinguish animals that did and did not develop laminitis showed good accuracy (0.76). None of the ELISA methods validated satisfactorily. MAIN LIMITATIONS: Laminitis risk is based on data from ponies in one region. CONCLUSIONS: The IT method is suitable for measurement of equine TAC. TAC is lower in ponies with previous or future laminitis. The ELISA methods are not suitable for measurement of equine HMWAC or TAC.

Plasma adrenocorticotropic hormone (ACTH) concentrations in ponies measured by two different assays suggests seasonal cross-reactivity or interference.

BACKGROUND: Analysis of plasma adrenocorticotropic hormone concentration [ACTH] aids diagnosis of pituitary pars intermedia dysfunction (PPID). Comparisons of the validated chemiluminescent-immunoassay (CI) and immunofluorescent (IF) assays are limited. OBJECTIVES: To compare the results of [ACTH] analysis by CI and IF methods of samples collected in autumn and spring and assess cross-reactivity. STUDY DESIGN: Method comparison. METHODS: Plasma from nonlaminitic ponies was analysed concurrently using the IF and CI methods in autumn and the following spring. Diagnostic thresholds for the IF method were derived using ROC curves and Youden indices to correspond with CI thresholds. Assay specificity was assessed using commercially available ACTH fragments and degradation products of endogenous ACTH. RESULTS: CI and IF methods yielded different results (P<0.001); mean differences (CI-IF), (95% confidence intervals): Autumn (n=99) 38.6 (30.6-46.5) pg/ml, Spring (n=88) 5.1 (3.9-6.3) pg/ml. The association between CI and IF results differed in autumn and spring, consistent with seasonally dependent cross-reactivity or interference. Good (κ=0.66-0.74) agreement was obtained for binary interpretation in spring between IF and CI using thresholds of >24 and >29 pg/ml respectively and in autumn between IF and CI using thresholds of >27 and >47 pg/ml respectively or >33 and >77 pg/ml respectively. Of 88 ponies with both spring and autumn samples, 56 (64%) exceeded a published autumn CI threshold (>47 pg/ml), of which 39 (70%) were below the equivalent threshold (<29 pg/ml) the following spring without treatment. The CI assay showed apparent increases in [ACTH] following addition of CLIP (ACTH 18-39). Degradation of ACTH during storage affected the assays differently. MAIN LIMITATIONS: Limited numbers of PPID cases were included. Immunoreactivity of commercially available peptides may differ from their endogenous equivalents. CONCLUSIONS: The methods yielded different absolute values but the agreement for binary classification was good. An altered pituitary secretome in autumn that affects apparent [ACTH] values is likely. The Summary is available in Spanish - see Supporting information.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

Developing preference-based measures for diabetes: DHP-3D and DHP-5D.

AIMS: The aim of this study was to develop two diabetes-specific preference-based measures [the Diabetes Health Profile-3 Dimension (DHP-3D) and the Diabetes Health Profile-5 Dimension (DHP-5D)] for use in the calculation of Quality Adjusted Life Years, a key outcome in economic evaluation. These measures were based on the non-preference-based instrument the Diabetes Health Profile. METHODS: For DHP-3D, psychometric and Rasch analyses were used to develop a health state classification system based on the Diabetes Health Profile-18 (DHP-18). The DHP-5D added two dimensions to the DHP-3D to extend the range of impacts measured. Each classification system was valued by 150 general public respondents in the United Kingdom using Time Trade Off (TTO). Multivariate regression was used to estimate utility value sets. The matched dimensions across each measure were compared using z-score tests. RESULTS: The DHP-3D included three dimensions defined as mood, eating and social limitations, and the DHP-5D added dimensions defined as hypoglycaemic attacks and vitality. For both, the random effects generalized least squares regression model produced consistent value sets, with the DHP-3D and DHP-5D ranging from 0.983 (best state) to 0.717 (worst state), and 0.979 to 0.618 respectively. The addition of the two extra dimensions leads to significant differences for the more severe levels of each matched dimension. CONCLUSIONS: We have developed two diabetes-specific preference-based measures that, subject to psychometric assessment, can be used to provide condition-specific utility values to complement generic utilities from more widely validated measures such as the EuroQol-5 Dimension.

The lipidome in major depressive disorder: Shared genetic influence for ether-phosphatidylcholines, a plasma-based phenotype related to inflammation, and disease risk.

BACKGROUND: The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies have implicated lipidomic changes across numerous psychiatric disorders. In particular, there is growing evidence that the concentrations of several classes of lipids are altered in those diagnosed with MDD. However, for lipidomic abnormalities to be considered potential treatment targets for MDD (rather than secondary manifestations of the disease), a shared etiology between lipid concentrations and MDD should be demonstrated. METHODS: In a sample of 567 individuals from 37 extended pedigrees (average size 13.57 people, range=3-80), we used mass spectrometry lipidomic measures to evaluate the genetic overlap between twenty-three biologically distinct lipid classes and a dimensional scale of MDD. RESULTS: We found that the lipid class with the largest endophenotype ranking value (ERV, a standardized parametric measure of pleiotropy) were ether-phosphodatidylcholines (alkylphosphatidylcholine, PC(O) and alkenylphosphatidylcholine, PC(P) subclasses). Furthermore, we examined the cluster structure of the twenty-five species within the top-ranked lipid class, and the relationship of those clusters with MDD. This analysis revealed that species containing arachidonic acid generally exhibited the greatest degree of genetic overlap with MDD. CONCLUSIONS: This study is the first to demonstrate a shared genetic etiology between MDD and ether-phosphatidylcholine species containing arachidonic acid, an omega-6 fatty acid that is a precursor to inflammatory mediators, such as prostaglandins. The study highlights the potential utility of the well-characterized linoleic/arachidonic acid inflammation pathway as a diagnostic marker and/or treatment target for MDD.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Use of the oral sugar test in ponies when performed with or without prior fasting.

BACKGROUND: It is recommended that the oral sugar test (OST) for insulin dysregulation (ID) be performed after an overnight fast, but fasting is impractical in ponies kept solely at pasture. There are few data on OST repeatability and reliability in ponies. OBJECTIVES: To report 1) whether OST results obtained in the morning after an overnight fast or without fasting in the afternoon (FASTING/FED) can be used interchangeably, 2) time of highest insulin concentration Tmax [insulin], repeatability and reliability of insulin response to the OST when FASTING or FED and 3) dichotomous agreement (ID/normal) within a small sample when FASTING or FED. STUDY DESIGN: Method comparison study. METHODS: Oral sugar tests were performed on four occasions in 10 adult native British ponies, twice FASTING and twice FED. Insulin concentrations were measured by radioimmunoassay at 0-120 min (T0,30,60,75,90,120 ). Differences between FASTING and FED results were assessed using mixed effects models. Indices of repeatability and reliability were calculated; dichotomous agreement was reported using kappa statistics. RESULTS: Serum [insulin] was significantly (P≤0.05) higher at T60 -T90 with prior fasting (estimated differences [95% confidence intervals]): T60 : 23.5 µiu/ml (8.7-38.4 µiu/ml), T75 : 27.1 µiu/ml (12.3-41.8 µiu/ml), T90 : 15.1 (0.36-29.9 µiu/ml). Most frequently, Tmax [ins] occurred at T30 . At any single time point, within-subject coefficients of variation were: FASTING: 40% and FED: 31%. The 95% limits for repeatability were FASTING: 29-340%, FED: 41-240%. Test reliabilities were FASTING: 0.70 and FED: 0.67. For dichotomous interpretation similar results (kappa = 0.7) were obtained using cut-offs of [Insulin] >60 µiu/ml at T60 or T90 for FASTING and [Insulin] >51 µiu/ml at T30 or T60 for FED samples. MAIN LIMITATIONS: Oral sugar tests were performed on a small number of animals on one pasture during one season (spring). CONCLUSIONS: Clinicians should beware of interpreting changes in absolute OST results owing to poor repeatability. When stabling is unavailable, OSTs of ponies at pasture may yield similar dichotomous results without prior fasting.

Effect of a national urgent care telephone triage service on population perceptions of urgent care provision: controlled before and after study.

OBJECTIVE: To measure the effect of an urgent care telephone service NHS 111 on population perceptions of urgent care. DESIGN: Controlled before and after population survey, using quota sampling to identify 2000 respondents reflective of the age/sex profile of the general population. SETTING: England. 4 areas where NHS 111 was introduced, and 3 control areas where NHS 111 had yet to be introduced. PARTICIPANTS: 28 071 members of the general population, including 2237 recent users of urgent care. INTERVENTION: NHS 111 offers advice to members of the general population seeking urgent care, recommending the best service to use or self-management. Policymakers introduced NHS 111 to improve access to urgent care. OUTCOMES MEASURES: The primary outcome was change in satisfaction with recent urgent care use 9 months after the launch of NHS 111. Secondary outcomes were change in satisfaction with urgent care generally and with the national health service. RESULTS: The overall response rate was 28% (28 071/100 408). 8% (2237/28 071) had used urgent care in the previous 3 months. Of the 652 recent users of urgent care in the NHS 111 intervention areas, 9% (60/652) reported calling NHS 111 in the 'after' period. There was no evidence that the introduction of NHS 111 was associated with a changed perception of recent urgent care. For example, the percentage rating their experience as excellent remained at 43% (OR 0.97, 95% CI 0.69 to 1.37). Similarly, there was no change in population perceptions of urgent care generally (1.06, 95% CI 0.95 to 1.17) or the NHS (0.94, 95% CI 0.85 to 1.05) following the introduction of NHS 111. CONCLUSIONS: A new telephone triage service did not improve perceptions of urgent care or the health service. This could be explained by the small amount of NHS 111 activity in a large emergency and urgent care system.

Genome-wide significant loci for addiction and anxiety.

BACKGROUND: Psychiatric comorbidity is common among individuals with addictive disorders, with patients frequently suffering from anxiety disorders. While the genetic architecture of comorbid addictive and anxiety disorders remains unclear, elucidating the genes involved could provide important insights into the underlying etiology. METHODS: Here we examine a sample of 1284 Mexican-Americans from randomly selected extended pedigrees. Variance decomposition methods were used to examine the role of genetics in addiction phenotypes (lifetime history of alcohol dependence, drug dependence or chronic smoking) and various forms of clinically relevant anxiety. Genome-wide univariate and bivariate linkage scans were conducted to localize the chromosomal regions influencing these traits. RESULTS: Addiction phenotypes and anxiety were shown to be heritable and univariate genome-wide linkage scans revealed significant quantitative trait loci for drug dependence (14q13.2-q21.2, LOD=3.322) and a broad anxiety phenotype (12q24.32-q24.33, LOD=2.918). Significant positive genetic correlations were observed between anxiety and each of the addiction subtypes (ρg=0.550-0.655) and further investigation with bivariate linkage analyses identified significant pleiotropic signals for alcohol dependence-anxiety (9q33.1-q33.2, LOD=3.054) and drug dependence-anxiety (18p11.23-p11.22, LOD=3.425). CONCLUSIONS: This study confirms the shared genetic underpinnings of addiction and anxiety and identifies genomic loci involved in the etiology of these comorbid disorders. The linkage signal for anxiety on 12q24 spans the location of TMEM132D, an emerging gene of interest from previous GWAS of anxiety traits, whilst the bivariate linkage signal identified for anxiety-alcohol on 9q33 peak coincides with a region where rare CNVs have been associated with psychiatric disorders. Other signals identified implicate novel regions of the genome in addiction genetics.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

A database survey of equine tumours in the United Kingdom.

REASONS FOR PERFORMING STUDY: Survey data on equine tumours are sparse compared with other species and may have changed over time. OBJECTIVES: To describe the most frequently diagnosed equine tumours recorded by a diagnostic pathology laboratory over 29 years, to identify background factors associated with tumour type, and to identify any changes in the tumours diagnosed or the background of cases submitted during the study period. STUDY DESIGN: Observational; cross-sectional analysis of records of a diagnostic pathology laboratory. METHODS: The records of all neoplastic equine histology submissions to the University of Bristol (January 1982-December 2010) were accessed from a database, and a list of diagnoses compiled. The 6 most commonly diagnosed tumour types were analysed using logistic regression to identify background factors associated with tumour type. The overall population of equine tumour submissions and the relative frequency of diagnosis of the most common tumour types were compared between decades. RESULTS: There were 964 cases included. The most frequently diagnosed tumours were: sarcoid (24% cases), squamous cell carcinoma (SCC) (19%), lymphoma (14%), melanoma (6%), gonadal stromal tumour (6%) and mast cell tumour (MCT) (4%). With sarcoid, Thoroughbred/Thoroughbred cross and gelding as reference categories: increasing age was significantly associated with the odds of each of the other tumour types, mares were at reduced risk of SCC, Arab/Arab cross had a higher risk of MCT, Cob/Cob cross had an increased risk of SCC and MCT, and ponies had an increased risk of melanoma. The mean age of submissions increased in each successive decade and the breed composition became broader. Sarcoids and lymphoma formed a smaller proportion of diagnoses in later decades. CONCLUSIONS: The types of tumours submitted to this laboratory have changed over the last 3 decades. Current data inform clinicians and researchers and further studies are warranted to follow trends.

Identifying clinically relevant prognostic subgroups of postmenopausal women with node-positive hormone receptor-positive early-stage breast cancer treated with endocrine therapy: a combined analysis of ABCSG-8 and ATAC using the PAM50 risk of recurrence score and intrinsic subtype.

BACKGROUND: In the adjuvant treatment of hormone receptor-positive (HR+) breast cancer, variables like tumour size, grade and nodal status have great impact on therapy decisions. As most node-positive patients with HR+ breast cancer currently receive adjuvant chemotherapy improved methods for characterization of individuals' metastasis risk are needed to reduce overtreatment. PATIENTS AND METHODS: Tissue specimens from node-positive patients of the ABCSG-8 and ATAC trials who received adjuvant tamoxifen and/or anastrozole were included in this study. Analysing RNA from paraffin blocks using the PAM50 test, the primary objective was to evaluate the prognostic information of the risk of recurrence (ROR) score added to combined clinical standard variables in patients with one positive node (1N+) and in patients with two or three positive nodes (2-3N+), using log-likelihood ratio tests. RESULTS: At a median follow-up of 9.6 years, distant metastases occurred in 97 (18%) of 543 node-positive patients. In a multivariate analysis, the PAM50-derived ROR score provided reliable prognostic information in addition to and beyond established clinical factors for 1N+ (P < 0.0001) and 2-3N+ patients (P = 0.0002). Ten-year distant recurrence risk was significantly increased in the high-risk compared with the low-risk group derived from ROR score for 1N+ [25.5%, 95% confidence interval (CI) 17.5% to 36.1%versus 6.6%, 95% CI 3.3% to 12.8%] and compared with the combined low/intermediate risk group for 2-3N+ patients (33.7%, 95% CI 25.5% to 43.8% versus 12.5%, 95% CI 6.6% to 22.8%). Additionally, the luminal A intrinsic subtype (IS) exhibited significantly lower risk of distant recurrence compared with the luminal B subtype in 1N+ and 2-3N+ patients. CONCLUSION: PAM50 ROR score and IS can identify node-positive patient subgroups with limited risk of metastasis after endocrine therapy, for whom adjuvant chemotherapy can be spared. The PAM50 test is a valuable tool in determining treatment of node-positive early-stage breast cancer patients.

Suspected acorn toxicity in nine horses.

REASONS FOR PERFORMING STUDY: Acorn toxicity has been anecdotally reported to cause fatal colitis and colic in horses but reports in the scientific literature are sparse. OBJECTIVES: This study reports the diagnosis, treatment, prognosis and outcome of 9 cases with suspected acorn toxicity admitted to 2 referral hospitals. STUDY DESIGN: Retrospective case series. METHODS: Case records from 2004 to 2013 were reviewed. Horses were included in the study if they met 3 of 4 criteria: exposure to acorns; clinical and laboratory data suggesting alimentary or renal dysfunction; acorn husks in the faeces or gastrointestinal tract; and necropsy and histopathological findings consistent with acorn toxicity. Data collected included case history, clinical presentation, clinicopathological data, ultrasonographic findings, case progression, and necropsy and histopathological findings. RESULTS: Nine horses met the inclusion criteria. Five cases presenting with haemorrhagic diarrhoea deteriorated rapidly and were subjected to euthanasia or died. Four cases showed signs of colic with gas distension, displacement of the large colon and diarrhoea. Three of these (33%) survived with medical management, the fourth was subjected to euthanasia. Post mortem examination of 6 cases demonstrated submucosal oedema of the large intestine and caecum (n = 6), acute tubular nephrosis (n = 6), diffuse necrohaemorrhagic and ulcerative typhlocolitis and enteritis (n = 4), and small intestinal oedema (n = 3). CONCLUSIONS: Acorn ingestion may be associated with typhylocolitis leading to diarrhoea, colic and acute renal tubular nephrosis. Recovery is possible in mildly affected cases; more severe cases show hypovolaemia, intractable pain, renal dysfunction and cardiovascular failure, and often succumb to the disease process. Disease is only seen in a small proportion of the population exposed to acorns and there seems to be an increased occurrence in certain years. Further investigation into factors predisposing to disease is required, but limiting exposure to acorns in the autumn seems prudent.

Genome-Wide Analyses of Working-Memory Ability: A Review.

Working memory, a theoretical construct from the field of cognitive psychology, is crucial to everyday life. It refers to the ability to temporarily store and manipulate task-relevant information. The identification of genes for working memory might shed light on the molecular mechanisms of this important cognitive ability and-given the genetic overlap between, for example, schizophrenia risk and working-memory ability-might also reveal important candidate genes for psychiatric illness. A number of genome-wide searches for genes that influence working memory have been conducted in recent years. Interestingly, the results of those searches converge on the mediating role of neuronal excitability in working-memory performance, such that the role of each gene highlighted by genome-wide methods plays a part in ion channel formation and/or dopaminergic signaling in the brain, with either direct or indirect influence on dopamine levels in the prefrontal cortex. This result dovetails with animal models of working memory that highlight the role of dynamic network connectivity, as mediated by dopaminergic signaling, in the dorsolateral prefrontal cortex. Future work, which aims to characterize functional variants influencing working-memory ability, might choose to focus on those genes highlighted in the present review and also those networks in which the genes fall. Confirming gene associations and highlighting functional characterization of those associations might have implications for the understanding of normal variation in working-memory ability and also for the development of drugs for mental illness.

Plasma fructosamine concentrations in horses with pituitary pars intermedia dysfunction with and without laminitis.

REASONS FOR PERFORMING STUDY: Plasma fructosamine concentration ([fructosamine]) is believed to reflect medium term, average blood glucose concentration and in a previous study was higher in horses with active laminitis than in normal horses. Pituitary pars intermedia dysfunction (PPID) is associated with hyperglycaemia and laminitis. OBJECTIVES: To test the hypotheses that: [fructosamine] is higher in PPID cases than normal animals; furthermore, that within cases of PPID [fructosamine] is higher in those with active laminitis than nonlaminitic cases and in cases that have been affected by active laminitis in the preceding year than those that have not. STUDY DESIGN: Observational, case-control/cross-sectional study. METHODS: [Fructosamine] was measured in cases of PPID (n = 46) and normal animals (n = 139). A normal range was calculated; values were compared between the 2 groups and within the PPID group, between cases with and without active laminitis and between cases that had and had not been affected by active laminitis in the preceding year. RESULTS: In normal animals mean [fructosamine] was 248.7 µmol/l; the normal range (mean ± 2 s.d.) was 195.5-301.9 µmol/l. Plasma [fructosamine] was not higher in PPID cases than in normal animals. In PPID cases, [fructosamine] was significantly (P = 0.006) higher in cases with active laminitis (mean ± s.d. 261.2 ± 39.2 µmol/l) compared with those without active laminitis (234.5 ± 32.9 µmol/), but [fructosamine] was not higher in cases that had been affected by active laminitis in the preceding year than those that had not. CONCLUSIONS: In horses affected by PPID, [fructosamine] is higher in cases with active laminitis than in cases without active laminitis. POTENTIAL RELEVANCE: Clinical use of [fructosamine] is limited due to overlap with the normal range. Further studies into glucose and protein metabolism in cases of PPID are warranted.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.