Antidepressant Exposure and DNA Methylation: Insights from a Methylome-Wide Association Study.

Importance: Understanding antidepressant mechanisms could help design more effective and tolerated treatments. Objective: Identify DNA methylation (DNAm) changes associated with antidepressant exposure. Design: Case-control methylome-wide association studies (MWAS) of antidepressant exposure were performed from blood samples collected between 2006-2011 in Generation Scotland (GS). The summary statistics were tested for enrichment in specific tissues, gene ontologies and an independent MWAS in the Netherlands Study of Depression and Anxiety (NESDA). A methylation profile score (MPS) was derived and tested for its association with antidepressant exposure in eight independent cohorts, alongside prospective data from GS. Setting: Cohorts; GS, NESDA, FTC, SHIP-Trend, FOR2107, LBC1936, MARS-UniDep, ALSPAC, E-Risk, and NTR. Participants: Participants with DNAm data and self-report/prescription derived antidepressant exposure. Main Outcomes and Measures: Whole-blood DNAm levels were assayed by the EPIC/450K Illumina array (9 studies, N exposed = 661, N unexposed = 9,575) alongside MBD-Seq in NESDA (N exposed = 398, N unexposed = 414). Antidepressant exposure was measured by self- report and/or antidepressant prescriptions. Results: The self-report MWAS (N = 16,536, N exposed = 1,508, mean age = 48, 59% female) and the prescription-derived MWAS (N = 7,951, N exposed = 861, mean age = 47, 59% female), found hypermethylation at seven and four DNAm sites (p < 9.42x10 -8 ), respectively. The top locus was cg26277237 ( KANK1, p self-report = 9.3x10 -13 , p prescription = 6.1x10 -3 ). The self-report MWAS found a differentially methylated region, mapping to DGUOK-AS1 ( p adj = 5.0x10 -3 ) alongside significant enrichment for genes expressed in the amygdala, the "synaptic vesicle membrane" gene ontology and the top 1% of CpGs from the NESDA MWAS (OR = 1.39, p < 0.042). The MPS was associated with antidepressant exposure in meta-analysed data from external cohorts (N studies = 9, N = 10,236, N exposed = 661, f3 = 0.196, p < 1x10 -4 ). Conclusions and Relevance: Antidepressant exposure is associated with changes in DNAm across different cohorts. Further investigation into these changes could inform on new targets for antidepressant treatments. 3 Key Points: Question: Is antidepressant exposure associated with differential whole blood DNA methylation?Findings: In this methylome-wide association study of 16,536 adults across Scotland, antidepressant exposure was significantly associated with hypermethylation at CpGs mapping to KANK1 and DGUOK-AS1. A methylation profile score trained on this sample was significantly associated with antidepressant exposure (pooled f3 [95%CI]=0.196 [0.105, 0.288], p < 1x10 -4 ) in a meta-analysis of external datasets. Meaning: Antidepressant exposure is associated with hypermethylation at KANK1 and DGUOK-AS1 , which have roles in mitochondrial metabolism and neurite outgrowth. If replicated in future studies, targeting these genes could inform the design of more effective and better tolerated treatments for depression.

Emotion recognition and eye tracking of static and dynamic facial affect: A comparison of individuals with and without traumatic brain injury.

Diminished social functioning is often seen after traumatic brain injury (TBI). Mechanisms contributing to these deficits are poorly understood but thought to relate to impaired ability to recognize facial expressions. Static stimuli are often used to investigate ability post-TBI, and there is less evidence using more real-life dynamic stimuli. In addition, most studies rely on behavioral responses alone. The present study investigated the performance of a TBI group and matched non-TBI group on static and dynamic tasks using eye-tracking technology alongside behavioral measures. This is the first study to use eye tracking methodology alongside behavioral measures in emotion recognition tasks in people with brain injury. Eighteen individuals with heterogeneous TBI and 18 matched non-TBI participants were recruited. Stimuli representing six core emotions (Anger, Disgust, Fear, Happy, Sad, and Surprise faces) were selected from the Amsterdam Dynamic Facial Expression Set (ADFES). Participants were instructed to identify the emotion displayed correctly whilst eye movement metrics were recorded. RESULTS: Results of analyses showed that TBI patients had First Fixation to nose for all emotion stimuli, shorter Fixation Duration and lower Fixation Count to eyes, were generally slower to classify stimuli, and less accurate than non-TBI group for the static task. Those with TBI were also less accurate at identifying Angry, Disgust, and Fear stimulus faces compared to the non-TBI group during the dynamic unfolding of an emotion. CONCLUSION: In the present study, those with TBI had atypical eye scan patterns during emotion identification in the static emotion recognition task compared to the non-TBI group and were associated with lower identification accuracy on behavioral measures in both static and dynamic tasks. Findings suggest potential disruption to oculomotor systems vital for first stage perceptual processing. Arguably, these impairments may contribute to diminished social functioning.

Point prevalence and clinical course of proteinuria in dogs with idiopathic non-erosive immune-mediated polyarthritis.

OBJECTIVES: To describe the point prevalence and clinical course of proteinuria in dogs diagnosed with idiopathic non-erosive immune-mediated polyarthritis. MATERIALS AND METHODS: Cases presenting to a single referral centre with a diagnosis of idiopathic non-erosive immune-mediated polyarthritis were retrospectively recruited from January 2009 to August 2018. Data including signalment, urinalysis, clinicopathological results, cytology from arthrocentesis, treatment and long-term follow-up were analysed. Dogs were defined as: non-proteinuric (UPC <0.2), borderline proteinuric (UPC 0.2-0.5) or overtly proteinuric (UPC >0.5). RESULTS: Fifty-eight dogs met the inclusion criteria. Twenty-two dogs were overtly proteinuric (38%), eight dogs were borderline proteinuric (14%) and 28 dogs were non-proteinuric (48%). Repeated urinalysis was performed in nine of 12 dogs with UPC greater than 2.0. The UPC decreased in all nine dogs, with the UPC decreasing to less than 0.5 in 44% of dogs. A greater than 50% decrease in UPC was noted in 44% of dogs, despite seven of nine (77%) receiving prednisolone as either monotherapy or in conjunction with an adjunctive immunosuppressive medication. CLINICAL SIGNIFICANCE: Proteinuria was common in this cohort of dogs diagnosed with primary idiopathic non-erosive immune-mediated polyarthritis. The use of prednisolone does not appear to be contraindicated in proteinuric dogs with idiopathic non-erosive immune-mediated polyarthritis.

Systematic review of wastewater surveillance of antimicrobial resistance in human populations.

OBJECTIVES: We systematically reviewed studies using wastewater for AMR surveillance in human populations, to determine: (i) evidence of concordance between wastewater-human AMR prevalence estimates, and (ii) methodological approaches which optimised identifying such an association, and which could be recommended as standard. We used Lin's concordance correlation coefficient (CCC) to quantify concordance between AMR prevalence estimates in wastewater and human compartments (where CCC = 1 reflects perfect concordance), and logistic regression to identify study features (e.g. sampling methods) associated with high agreement studies (defined as >70% of within-study wastewater-human AMR prevalence comparisons within ±10%). RESULTS: Of 8,867 records and 441 full-text methods reviewed, 33 studies were included. AMR prevalence data was extractable from 24 studies conducting phenotypic-only (n = 7), genotypic-only (n = 1) or combined (n = 16) AMR detection. Overall concordance of wastewater-human AMR prevalence estimates was reasonably high for both phenotypic (CCC = 0.85 [95% CI 0.8-0.89]) and genotypic approaches (CCC = 0.88 (95% CI 0.84-0.9)) despite diverse study designs, bacterial species investigated and phenotypic/genotypic targets. No significant relationships between methodological approaches and high agreement studies were identified using logistic regression; however, this was limited by inconsistent reporting of study features, significant heterogeneity in approaches and limited sample size. Based on a secondary, descriptive synthesis, studies conducting composite sampling of wastewater influent, longitudinal sampling >12 months, and time-/location-matched sampling of wastewater and human compartments generally had higher agreement. CONCLUSION: Wastewater-based surveillance of AMR appears promising, with high overall concordance between wastewater and human AMR prevalence estimates in studies irrespective of heterogenous approaches. However, our review suggests future work would benefit from: time-/location-matched sampling of wastewater and human populations, composite sampling of influent, and sampling >12 months for longitudinal studies. Further research and clear and consistent reporting of study methods is required to identify optimal practice.

Complex chronic conditions among children born to women with schizophrenia.

PURPOSE: Maternal schizophrenia is linked to complications in offspring near the time of birth. Whether there is also a higher future risk of the child having a complex chronic condition (CCC) - a pediatric condition affecting any bodily system expected to last at least 12 months that is severe enough to require specialty care and/or a period of hospitalization - is not known. METHODS: In this population-based health administrative data cohort study (Ontario, Canada, 1995-2018), the risk for CCC was compared in 5066 children of women with schizophrenia (the exposed) vs. 2,939,320 unexposed children. Adjusted hazard ratios (aHR) were generated for occurrence of any CCC, by CCC category, and stratified by child sex, and child prematurity. RESULTS: CCC was more frequent in the exposed (7.7 per 1000 person-years [268 children]) than unexposed (4.2 per 100 person-years [124,452 children]) - an aHR of 1.25 (95% CI 1.10-1.41). aHRs were notably higher in 5 of 9 CCC categories: neuromuscular (1.73, 1.28-2.33), cardiovascular (1.94, 1.64-2.29), respiratory (1.83, 1.32-2.54), hematology/immunodeficiency (2.24, 1.24-4.05) and other congenital or genetic defect (1.59, 1.16-2.17). The aHR for CCC was more pronounced among boys (1.32, 1.13-1.55) than girls (1.16, 0.96-1.40), and of similar magnitude in term (1.22, 1.05-1.42) and preterm infants (1.18, 0.95-1.46). CONCLUSIONS: The risk for a CCC appears to be higher in children born to women with schizophrenia. This finding introduces opportunities for targeted preconception counselling, optimization of maternal risk factors, and intervention to support a vulnerable parent population who will experience unique challenges caring for a child with CCCs.

Serological markers of gluten sensitivity in Border terriers with gall bladder mucocoeles.

OBJECTIVES: To evaluate serological markers of gluten sensitivity in conjunction with cholecystokinin measurement in Border terriers with gall bladder mucocoeles. MATERIALS AND METHODS: Medical records from two referral hospitals were obtained between 2011 and 2019 to identify Border terriers with gall bladder mucocoeles, non-Border terriers with gall bladder mucocoeles and control Border terriers with non-biliary diseases. Enzyme-linked immunosorbent assays were performed on stored fasted serum samples for anti-gliadin IgG, anti-canine transglutaminase-2-IgA autoantibodies and cholecystokinin. Statistical analysis was performed using the Kruskall-Wallis test to identify differences between the groups. RESULTS: Fifteen Border terriers with gall bladder mucocoeles, 17 non-Border terriers with gall bladder mucocoeles and 14 control Border terriers with non-biliary diseases were recruited. Median transglutaminase-2-IgA autoantibodies in Border terriers with gall bladder mucocoeles was 0.73 (range: 0.18 to 1.67), which was significantly greater than in control Border terriers at 0.41 (0.07 to 1.14). Median cholecystokinin concentration in Border terriers with gall bladder mucocoeles was 13 pg/mL (6 to 45 pg/mL), which was significantly lower than in control Border terriers at 103 pg/mL (9 to 397 pg/mL). There was no difference in the anti-gliadin IgG between these groups. There was no difference observed in the non-Border terriers with gall bladder mucocoeles with either of the other groups. CLINICAL SIGNIFICANCE: Reduced cholecystokinin and increased transglutaminase-2-IgA autoantibodies was detected in Border terriers with gall bladder mucocoeles; which is in part homologous to gall bladder disease identified in human coeliac disease. The results suggest an immunological disease with impaired cholecystokinin release may be affecting gall bladder motility and possibly contributing to mucocoele formation in Border terriers.

Identification of a predominant cognitive phenotype in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment occurs frequently in multiple sclerosis (MS). However, the prevalence and clinical characteristics of cognitive MS phenotype are not well established. The aim of the study was to characterize the clinical course and neurocognitive impairment of patients with MS meeting an Expanded Disability Status Scale (EDSS)-defined cognitive phenotype. METHODS: A total of 2302 patients from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) study were studied. Predominant cognitive MS phenotype was defined as EDSS Cerebral Functional System (FS) subscore ≥3 and remaining EDSS FS subscores ≤2 on at least one clinical visit. Demographic/clinical characteristics, phenotype stability and neurocognitive domain impairment of these subjects were assessed. RESULTS: A total of 60 of 2302 (2.6%) patients (age 52.8 ± 10.8 years, 68% female, 82% relapsing MS) met criteria for phenotype designation. A total of 29 of 60 (48%) were designated within 10 years of their presenting MS symptom. The mean cohort annualized relapse rate was 0.38 and EDSS score at last clinical assessment was 3.2 ± 1.3. Cognitive phenotype status was poorly sustained, with only 27% of subjects maintaining Cerebral FS score ≥2 throughout all follow-up. However, predominant cognitive phenotype subjects with clinical neuropsychiatric testing [n = 39/60 (65%)] frequently had cognitive impairment (1.5 SD below mean) in ≥1 domain [n = 30/39 (77%) of subjects] affecting memory, attention/executive function and processing speed. A total of 11 of 39 (28%) patients had severe-range cognitive impairment (3.0 SD below mean). Cognitive phenotype designation was associated with low rate of employment at last clinical assessment. CONCLUSION: Predominant cognitive MS phenotype is rare, although an EDSS-based definition identifies patients with multidomain cognitive impairment and may serve as a practical screen for identification of patients who might warrant close monitoring of neurocognitive status.

Gall bladder mucoceles in Border terriers.

BACKGROUND: Gall bladder mucoceles (GBM) are a leading cause of biliary disease in dogs with several breeds, including the Shetland Sheepdog, American Cocker Spaniel, Chihuahua, Pomeranian, and Miniature Schnauzer apparently predisposed. OBJECTIVE: To determine risk factors, clinical features, and response to treatment of GBM in Border terriers (BT). ANIMALS: Medical records of 99 dogs (including 51 BT) with an ultrasonographic (±histopathologic) diagnosis of GBM from three referral centers in the United Kingdom were collected. A control group of 87 similar-aged BT with no ultrasonographic evidence of gall bladder disease was selected for comparison. METHOD: Retrospective case-control study. Odds ratios were calculated to establish breed predisposition. Signalment, presence of endocrine disease, clinicopathologic results, and outcome were compared between the BT, other breeds, and control BTs. RESULTS: The odds of identifying a GBM in a BT in this hospital population was 85 times that of all other breeds (95% confidence interval 56.9-126.8). BT had similar clinical signs and clinicopathologic changes to other breeds with GBM. There was no evidence that endocrinopathies were associated with GBM in BT. CLINICAL SIGNIFICANCE: A robust breed predisposition to GBM is established for the BT.

Effects of short- and long-term exposure of silver nanoparticles and silver ions to Nitrosomonas europaea biofilms and planktonic cells.

The increasing use of silver nanoparticles (AgNPs) in consumer products, and their resulting influx into wastewater, may pose a threat to biological nutrient removal in wastewater treatment plants. Planktonic ammonia-oxidizing bacteria (AOB), which convert ammonia to nitrite in the first step of nitrification, are highly sensitive to AgNPs and their released silver ions (Ag+), but the sensitivity of AOB biofilms to AgNPs and Ag+ is less clear. This study demonstrated that biofilms of Nitrosomonas europaea, a model AOB, were more resistant to both short-term and long-term exposure to AgNP and Ag+ than planktonic cells. The increased resistance of N. europaea biofilms was attributed primarily to the increased biomass and slower growth rates present in the biofilm. Similar inhibition mechanisms were observed for AgNPs and Ag+ in both planktonic cells and biofilms with enzymatic inhibition observed at lower concentrations and cell lysis observed at higher concentrations. Long-term continuous exposure to AgNPs lowered the inhibitory concentration by 1-2 orders of magnitude below that required by short-term exposures. Although the total AgNP load was similar between the short and long-term exposure scenarios, the long-term exposure resulted in an order of magnitude more silver being associated in the biofilms and is the primary reason for the increased sensitivity observed. This suggests that short-term batch toxicity assays may greatly underestimate the sensitivity of biofilm treatment systems to long-term exposures of low concentrations of AgNPs and Ag+.

Legionella indianapolisensis sp. nov., isolated from a patient with pulmonary abscess.

BACKGROUND: To date, at least 50 species of Legionella have been described. These organisms are ubiquitous in nature and have been isolated from diverse ecological environments, including man-made structures such as cooling towers and spas. Legionellae have also been isolated from human and veterinary clinical specimens, and their roles in disease are well-established. This report describes the isolation of a novel Legionella species from a respiratory specimen from a patient with influenza and suspected pulmonary embolus. CASE: A 68-year-old male presented to an Indianapolis-area hospital with pulmonary disease; upon workup, he was found to have influenza A. Bronchoalveolar lavage fluid was also submitted for conventional bacterial culture and Legionella culture. The patient was prescribed a broad-spectrum antibiotic and recovered. RESULTS: A Legionella-like bacterium was isolated on buffered charcoal yeast extract agar, and mass spectrometry and comparative 16S rRNA gene sequencing inconclusively identified the isolate as a Legionella sp. Further analysis of the 16S rRNA gene confirmed the strain to be a new species, related to Legionella hackeliae. Physiochemical and morphological testing were used to confirm the discovery of a novel species, Legionella indianapolisensis sp. nov., type strain SMNF-IS.

New IR imaging modalities for cancer detection and for intra-cell chemical mapping with a sub-diffraction mid-IR s-SNOM.

We present two new modalities for generating chemical maps. Both are mid-IR based and aimed at the biomedical community, but they differ substantially in their technological readiness. The first, so-called "Digistain", is a technologically mature "locked down" way of acquiring diffraction-limited chemical images of human cancer biopsy tissue. Although it is less flexible than conventional methods of acquiring IR images, this is an intentional, and key, design feature. It allows it to be used, on a routine basis, by clinical personnel themselves. It is in the process of a full clinical evaluation and the philosophy behind the approach is discussed. The second modality is a very new, probe-based "s-SNOM", which we are developing in conjunction with a new family of tunable "Quantum Cascade Laser" (QCL) diode lasers. Although in its infancy, this instrument can already deliver ultra-detailed chemical images whose spatial resolutions beat the normal diffraction limit by a factor of ∼1000. This is easily enough to generate chemical maps of the insides of single cells for the first time, and a range of new possible scientific applications are explored.

A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants.

BACKGROUND: Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design. METHODS: In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years. RESULTS: We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses. CONCLUSIONS: AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine.

The cooking task: making a meal of executive functions.

Current standardized neuropsychological tests may fail to accurately capture real-world executive deficits. We developed a computer-based Cooking Task (CT) assessment of executive functions and trialed the measure with a normative group before use with a head-injured population. Forty-six participants completed the computerized CT and subtests from standardized neuropsychological tasks, including the Tower and Sorting Tests of executive function from the Delis-Kaplan Executive Function System (D-KEFS) and the Cambridge prospective memory test (CAMPROMPT), in order to examine whether standardized executive function tasks, predicted performance on measurement indices from the CT. Findings showed that verbal comprehension, rule detection and prospective memory contributed to measures of prospective planning accuracy and strategy implementation of the CT. Results also showed that functions necessary for cooking efficacy differ as an effect of task demands (difficulty levels). Performance on rule detection, strategy implementation and flexible thinking executive function measures contributed to accuracy on the CT. These findings raise questions about the functions captured by present standardized tasks particularly at varying levels of difficulty and during dual-task performance. Our preliminary findings also indicate that CT measures can effectively distinguish between executive function and Full Scale IQ abilities. Results of the present study indicate that the CT shows promise as an ecologically valid measure of executive function for future use with a head-injured population and indexes selective executive function's captured by standardized tests.

Association of Socioeconomic Position and Demographic Characteristics with Cardiovascular Disease Risk Factors and Healthcare Access among Adults Living in Pohnpei, Federated States of Micronesia.

Background. The burden of cardiovascular disease (CVD) is increasing in low-to-middle income countries. We examined how socioeconomic and demographic characteristics may be associated with CVD risk factors and healthcare access in such countries. Methods. We extracted data from the World Health Organization's STEPwise approach to surveillance 2002 cross-sectional dataset from Pohnpei, Federated States of Micronesia (FSM). We used these data to estimate associations for socioeconomic position (education, income, and employment) and demographics (age, sex, and urban/rural) with CVD risk factors and with healthcare access, among a sample of 1638 adults (25-64 years). Results. In general, we found significantly higher proportions of daily tobacco use among men than women and respondents reporting primary-level education (<9 years) than among those with postsecondary education (>12 years). Results also revealed significant positive associations between paid employment and waist circumference and systolic blood pressure. Healthcare access did not differ significantly by socioeconomic position. Women reported significantly higher mean waist circumference than men. Conclusion. Our results suggest that socioeconomic position and demographic characteristics impact CVD risk factors and healthcare access in FSM. This understanding may help decision-makers tailor population-level policies and programs. The 2002 Pohnpei data provides a baseline; subsequent population health surveillance data might define trends.

Preoperative immunonutrition and its effect on postoperative outcomes in well-nourished and malnourished gastrointestinal surgery patients: a randomised controlled trial.

BACKGROUND/OBJECTIVES: Invasive procedures such as surgery cause immunosuppression, leading to increased risk of complications, infections and extended hospital stay. Emerging research around immune-enhancing nutrition supplements and their ability to reduce postoperative complications and reduce treatment costs is promising. This randomised controlled trial aims to examine the effect of preoperative immunonutrition supplementation on length of hospital stay (LOS), complications and treatment costs in both well-nourished and malnourished gastrointestinal surgery patients. SUBJECTS/METHODS: Ninety-five patients undergoing elective upper and lower gastrointestinal surgery were recruited. The treatment group (n=46) received a commercial immuno-enhancing supplement 5 days preoperatively. The control group (n=49) received no supplements. The primary outcome measure was LOS, and secondary outcome measures included complications and cost. RESULTS: A nonsignificant trend towards a shorter LOS within the treatment group was observed (7.1 ± 4.1 compared with 8.8 ± 6.5 days; P=0.11). For malnourished patients, this trend was greater with hospital stay reduced by 4 days (8.3 ± 3.5 vs 12.3 ± 9.5 days; P=0.21). Complications and unplanned intensive care admission rates were very low in both the groups. The average admission cost was reduced by AUD1576 in the treatment group compared with the control group (P=0.37). CONCLUSIONS: Preoperative immunonutrition therapy in gastrointestinal surgery has the potential to reduce the LOS and cost, with greater treatment benefit seen in malnourished patients; however, there is a need for additional research with greater patient numbers.

Ovarian mass causing paradoxical MI and leg ischaemia.

Paradoxical embolus through a patent foramen ovale is a well-reported phenomenon. Clinical consequences include stroke, intestinal infarction, lower limb ischaemia, and even acute myocardial infarction (MI), via embolisation to the coronary arteries. We present a case of acute MI, cardiogenic shock, and cardiac arrest caused not by this mechanism, but by embolisation of thrombotic material to the aortic root with transient complete occlusion of the left main stem (LMS) coronary artery. During percutaneous coronary intervention to treat this occlusion the thrombus became lodged at the aortic bifurcation causing lower limb ischaemia. Despite successful treatment of this via bilateral groin exploration and thromboembolectomy the patient became increasingly acidotic and an abdominal and pelvic CT scan was performed. This revealed the source of the thrombus to be the patient's congested and compressed pelvic veins which were the result of a large, previously undiagnosed ovarian malignancy with metastatic spread. Although very unusual we feel this case highlights an important differential in the diagnosis of anterolateral MI and images similar to those presented here are previously unreported in the literature.

Heat-related injury in lambs.

The broad spectrum of heat-related injury (HRI) and its associated lesions is well described in the human literature, with rare reports of similar findings in farm animals. In the current case series, lesions from 4 of 8 lambs that presented with clinical signs of heat stress are reported. Gross lesions at necropsy consisted of acute renal swelling and pallor in 2 of 4 lambs, muscle pallor in 2 of 4 lambs, and chronic bronchointerstitial pneumonia in each of the 4 lambs. Histological lesions considered heat-related included acute renal tubular necrosis, pigment casts, tubular epithelial regeneration, multifocal myocyte degeneration, necrosis, and dropout with histiocytic influx and regeneration. Chronic, bronchointerstitial pneumonia, present in each lamb, was considered a condition predisposing to HRI. Compatibility between observed lesions and those reported in human beings with injury secondary to elevated body temperatures established a diagnosis of HRI in these animals. Diagnostic pathologists should consider HRI in lambs with histological evidence of renal tubular necrosis and/or rhabdomyolysis and even in cases where the clinical picture is strongly suggestive but lesions are not demonstrable.

Investigating the 'latent' deficit hypothesis: age at time of head injury, implicit and executive functions and behavioral insight.

This study investigated the 'latent deficit' hypothesis in two groups of head-injured patients with predominantly frontal lesions, those injured prior to steep morphological and corresponding functional maturational periods for frontal networks (28 years. The latent deficit hypothesis proposes that early injuries produce enduring cognitive deficits manifest later in the lifespan with graver consequences for behavior than adult injuries, particularly after frontal pathology (Eslinger, Grattan, Damasio & Damasio, 1992). Implicit and executive deficits both contribute to behavioral insight after frontal head injury (Barker, Andrade, Romanowski, Morton, & Wasti, 2006). On the basis of morphological and behavioral data, we hypothesized that early injury would confer greater vulnerability to impairment on tasks associated with frontal regions than later injury. Patients completed experimental tasks of implicit cognition, executive function measures and the DEX measure of behavioral insight (Behavioral Assessment of the Dysexecutive Syndrome: Wilson, Alderman, Burgess, Emslie, & Evans, 1996). The Early Injury group were more impaired on implicit cognition tasks compared to controls that Late Injury patients. There were no marked group differences on most executive function measures. Executive ability only contributed to behavioral awareness in the Early Injury Group. Findings showed that age at injury moderates the relationship between executive and implicit cognition and behavioral insight and that early injuries result in long-standing deficits to functions associated with frontal regions partially supporting the latent deficit hypothesis.

Case report: reconstruction of the distal tibia with porous tantalum spacer after resection for giant cell tumor.

Treatment options for giant cell tumors of the distal tibia include curettage and cement packing, curettage and bone grafting, or resection and reconstruction for aggressive tumors. Curettage of aggressive tumors often leads to severe bone loss requiring reconstruction. Allograft and autograft may be effective options for reconstruction, but each is associated with drawbacks including the possibility of infection and collapse. We present a case of giant cell tumor of the distal tibia treated with curettage and arthrodesis using a porous tantalum spacer. Complete removal of the tumor and successful arthrodesis of the ankle were accomplished using the spacer. The patient returned to pain-free walking along with eradication of the giant cell tumor. We believe porous tantalum spacers are a reasonable option for reconstructing the distal tibia after curettage of a giant cell tumor with extensive bone loss.

Sustained effect of the aromatase inhibitors anastrozole and letrozole on endometrial thickness in patients with endometrial hyperplasia and endometrial carcinoma.

OBJECTIVE: To investigate whether there may be a role for aromatase inhibitors (AIs) in the treatment of endometrial hyperplasia (EH) and endometrial adenocarcinoma (EA) in postmenopausal women, a retrospective study on the effect of aromatase inhibitors (anastrozole or letrozole) was conducted for 16 patients who were not amenable to surgical treatment. MAIN OUTCOME MEASURE: Resolution of endometrial thickening measured by transvaginal ultrasound at 3-month intervals; the response of metastases was assessed by standard oncological criteria. RESULTS: In all, 16 patients were studied. The BMI of 13 of the 16 patients was known and ranged from 20.7 to 47.7 (mean 34.5) kg/m(2). During treatment with AIs, mean endometrial thickness in the eight patients with EH decreased progressively by 81.7% from 14.7 mm at the start of treatment to 2.7 mm following 36 months of treatment. A greater original mean endometrial thickness of 17 mm was seen in the four patients with localised EA, this fell progressively by 67.1% to 5.6 mm following 36 months of treatment. No responses were seen in four patients with metastatic disease. CONCLUSION: Our results indicate that treatment of EH with anastrozole or letrozole can reduce endometrial thickness as seen ultrasonically, and that in some cases AI treatment can reduce endometrial thickness in patients with localised EA. We found no evidence to indicate that AI treatment prevents disease progression in patients with metastatic EA. Further investigations will be necessary to validate our findings from this small retrospective study and to compare AI inhibitor treatment with topical progestogen therapy.