Association between risk of dementia and very late-onset schizophrenia-like psychosis: a Swedish population-based cohort study

BACKGROUND: Although the incidence of psychotic disorders among older people is substantial, little is known about the association with subsequent dementia. We aimed to examine the rate of dementia diagnosis in individuals with very late-onset schizophrenia-like psychosis (VLOSLP) compared to those without VLOSLP. METHODS: Using Swedish population register data, we established a cohort of 15 409 participants with VLOSLP matched by age and calendar period to 154 090 individuals without VLOSLP. Participants were born between 1920 and 1949 and followed from their date of first International Classification of Diseases [ICD], Revisions 8-10 (ICD-8/9/10) non-affective psychotic disorder diagnosis after age 60 years old (or the same date for matched participants) until the end of follow-up (30th December 2011), emigration, death, or first recorded ICD-8/9/10 dementia diagnosis. RESULTS: We found a substantially higher rate of dementia in individuals with VLOSLP [hazard ratio (HR): 4.22, 95% confidence interval (95% CI) 4.05-4.41]. Median time-to-dementia-diagnosis was 75% shorter in those with VLOSLP (time ratio: 0.25, 95% CI 0.24-0.26). This association was strongest in the first year following VLOSLP diagnosis, and attenuated over time, although dementia rates remained higher in participants with VLOSLP for up to 20 years of follow-up. This association remained after accounting for potential misdiagnosis (2-year washout HR: 2.22, 95% CI 2.10-2.36), ascertainment bias (HR: 2.89, 95% CI 2.75-3.04), and differing mortality patterns between groups (subdistribution HR: 2.89, 95% CI 2.77-3.03). CONCLUSIONS: Our findings demonstrate that individuals with VLOSLP represent a high-risk group for subsequent dementia. This may be due to early prodromal changes for some individuals, highlighting the importance of ongoing symptom monitoring in people with VLOSLP

Childhood and Parental Asthma, Future Risk of Bipolar Disorder and Schizophrenia Spectrum Disorders: A Population-Based Cohort Study

BACKGROUND: Mounting evidence implicates early life and prenatal immune disturbances in the etiology of severe mental illnesses. Asthma is a common illness associated with chronic aberrant immune responses. We aimed to determine if asthma in childhood and parents is associated with bipolar and schizophrenia spectrum disorders. METHODS: A cohort study including all children born in Sweden 1973–1995 (N > 2 million) assessing associations between childhood hospitalization for asthma, parental asthma during and pre-pregnancy, and subsequent bipolar and schizophrenia spectrum disorders. RESULTS: Children with hospitalizations for asthma between 11 and 15 years had increased rates of bipolar (adjusted hazard ratio [aHR] = 1.73, 95% confidence interval [CI] = 1.21–2.47) and schizophrenia spectrum disorders (aHR = 1.62, 95% CI = 1.08–2.42). However, there was no association with asthma before aged 11. These results were supported by an analysis of siblings discordant for asthma. We found an association between both maternal and paternal asthma and bipolar disorder (aHR = 1.60, 95% CI = 1.27–2.02, and aHR = 1.44, 95% CI = 1.08–1.93, respectively), but not between parental asthma and schizophrenia spectrum disorders. CONCLUSIONS: As far as we are aware, this is the first study to find increased risk of bipolar disorder in children of individuals with asthma. Asthma admissions before aged 11 do not appear to be linked to bipolar or schizophrenia spectrum disorders. Taken together, our results do not suggest a straightforward link between asthma and severe mental illness via neurodevelopmental effects of inflammation, but potentially there is shared genetic vulnerability. This finding has implications for understanding the differential pathogenic mechanisms of bipolar and schizophrenia spectrum disorders

RS12. Sustained Late Branch Patency and Low Incidence of Persistent Type Ia Endoleaks Following Snorkel/chimney EVAR Shown in the Updated PERICLES Registry

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The Effect of 200mg/kg EGCG Oral Gavage Treatment on the Cerebellar-Dependent Behavior in a Down Syndrome Mouse Model

poster abstractTrisomy 21 (Ts21) causes deficits in motor and cognitive ability that are hallmark phenotypes in Down syndrome (DS). The Ts65Dn mouse model of DS has about 50% of the orthologous genes that are triplicated from human chromosome 21, including the Dual specificity tyrosinephosphorylation-regulated kinase 1A (Dyrk1A) gene. Three copies of Dyrk1A have been implicated in the motor and cognitive deficits and altered cerebellar structure and function may contribute these impairments in Ts65Dn mice. Epigallocatechin 3-gallate (EGCG) is a catechin found in green tea and an inhibitor of Dyrk1A activity. We hypothesize that a 200mg/kg EGCG treatment given by oral gavage will inhibit Dyrk1A activity in the cerebellum of Ts65Dn mice and rescue deficits in motor coordination while performing the balance beam task. Evidence of improvement in this task would be observed as a reduction of paw slips as the animal traverses across beams of varying widths. In previous studies, EGCG treatment was placed in the animal’s water to be consumed but EGCG rapidly degrades in solution and it is difficult to control treatment doses via treatment in drinking water, due to each animal’s consumption behavior. This study utilized a daily oral gavage treatment of EGCG to control the dose and limits loss due to degradation. Results to date indicate that the Ts65Dn mice show deficits on the balance beam task relative to the euploid mice, particularly at the narrowest beam width used. The EGCG treatment does not appear to improve the performance of the Ts65Dn mice, though the lack of observed effects of EGCG may be due to the relatively low numbers of Ts65Dn-EGCG treated mice that have completed testing so far. One notable trend is that we will continue to test additional mice to gain sufficient power to determine conclusively whether EGCG improves motor coordination performance in Ts65Dn mice

Collected world experience about the performance of the snorkel/chimney endovascular technique in the treatment of complex aortic pathologies: The PERICLES registry

Objectives: We sought to analyze the collected worldwide experience with use of snorkel/chimney endovascular aneurysm repair (EVAR) for complex abdominal aneurysm treatment. Background: EVAR has largely replaced open surgery worldwide for anatomically suitable aortic aneurysms. Lack of availability of fenestrated and branched devices has encouraged an alternative strategy utilizing parallel or snorkel/chimney grafts (ch-EVAR). Methods: Clinical and radiographic information was retrospectively reviewed and analyzed on 517 patients treated by ch-EVAR from 2008 from 2014 by prearranged defined and documented protocols. Results: A total of 119 patients in US centers and 398 in European centers were treated during the study period. US centers preferentially used Zenith stent-grafts (54.2%) and European centers Endurant stent-grafts (62.2%) for the main body component. Overall 898 chimney grafts (49.2% balloon expandable, 39.6% self-expanding covered stents, and 11.2% balloon expandable bare metal stents) were placed in 692 renal arteries, 156 superior mesenteric arteries (SMA), and 50 celiac arteries. At a mean follow-up of 17.1 months (range: 1-70 months), primary patency was 94%, with secondary patency of 95.3%. Overall survival of patients in this high-risk cohort for open repair at latest follow-up was 79%. Conclusions: This global experience represents the largest series in the ch-EVAR literature and demonstrates comparable outcomes to those in published reports of branched/fenestrated devices, suggesting the appropriateness of broader applicability and the need for continued careful surveillance. These results support ch-EVAR as a valid off-the-shelf and immediately available alternative in the treatment of complex abdominal EVAR and provide impetus for the standardization of these techniques in the future

The Incidence of Nonaffective, Nonorganic Psychotic Disorders in Older People: A Population-based Cohort Study of 3 Million People in Sweden

BACKGROUND: There are limited data on the epidemiology of very late-onset schizophrenia-like psychosis (VLOSLP) and how this relates to potential risk factors including migration, sensory impairment, traumatic life events, and social isolation. METHODS: We followed up a cohort of 3 007 378 people living in Sweden, born 1920-1949, from their 60th birthday (earliest: January 15, 1980) until December 30 2011, emigration, death, or first recorded diagnosis of nonaffective psychosis. We examined VLOSLP incidence by age, sex, region of origin, income, partner or child death, birth period, and sensory impairments. RESULTS: We identified 14 977 cases and an overall incidence of 37.7 per 100 000 person-years at-risk (95% CI = 37.1-38.3), with evidence that rates increased more sharply with age for women (likelihood ratio test: χ2(6) = 31.56, P < .001). After adjustment for confounders, rates of VLOSLP were higher among migrants from Africa (hazard ratio [HR] = 2.0, 95% CI = 1.4-2.7), North America (HR = 1.4, 95% CI = 1.0-1.9, P = .04), Europe (HR = 1.3, 95% CI = 1.2-1.4), Russian-Baltic regions (HR = 1.6, 95% CI = 1.4-1.9), and Finland (HR = 1.6, 95% CI = 1.5-1.7). VLOSLP risk was highest for those in the lowest income quartile (HR = 3.1, 95% CI = 2.9-3.3). Rates were raised in those whose partner died 2 years before cohort exit (HR = 1.1, 95% CI = 1.0-1.3, P = .02) or whose child died in infancy (HR = 1.2, 95% CI = 1.0-1.4, P = .05), those without a partner (HR = 1.9, 95% CI = 1.8-1.9) or children (HR = 2.4, 95% CI = 2.3-2.5), and those whose child had a psychotic disorder (HR = 2.4, 95% CI = 2.2-2.6). INTERPRETATION: We identified a substantial burden of psychosis incidence in old age, with a higher preponderance in women and most migrant groups. Life course exposure to environmental factors including markers of deprivation, isolation, and adversity were associated with VLOSLP risk

Glucocorticoid receptor phosphorylation in mouse L-cells

This paper summarizes our observations on the phosphorylation state of untransformed and transformed glucocorticoid receptors isolated from 32P-labeled L-cells. The 300-350-kDa 9S untransformed murine glucocorticoid receptor complex is composed of a 100-kDa steroid-binding phosphoprotein and one or possibly two units of the 90-kDa heat shock protein (hsp90), which is also a phosphoprotein. Transformation of this complex to the 4S DNA-binding state is accompanied by dissociation of hsp90. When receptors in cytosol are transformed by heating at 25[deg]C, there is no gross change in the degree of phosphorylation of the steroid-binding protein. Both receptors that are bound to DNA after transformation under cell-free conditions and receptors that are located in the nucleus of cells incubated at 37[deg]C in the presence of glucocorticoid are labeled with 32P. The results of experiments in which the 32P-labeled receptor was submitted to limited proteolysis suggest that the 16-kDa DNA-binding domain is phosphorylated and that the 28-kDa steroid-binding domain is not.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26917/1/0000483.pd

TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial

Background: Experimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm. Methods/Design: Telmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis. We aim to randomly assign 300 participants with small abdominal aortic aneurysm to either 40 mg of telmisartan or identical placebo and follow patients over 2 years. The primary endpoint will be abdominal aortic aneurysm growth as measured by 1) maximum infra-renal aortic volume on computed tomographic angiography, 2) maximum orthogonal diameter on computed tomographic angiography, and 3) maximum diameter on ultrasound. Secondary endpoints include change in resting brachial blood pressure, abdominal aortic aneurysm biomarker profile and health-related quality of life. TEDY is an international collaboration conducted from major vascular centres in Australia, the United States and the Netherlands. Discussion: Currently, no medication has been convincingly demonstrated to limit abdominal aortic aneurysm progression. TEDY will examine the potential of a promising treatment strategy for patients with small abdominal aortic aneurysms. Trial registration: Australian and Leiden study centres: Australian New Zealand Clinical Trials Registry ACTRN12611000931976, registered on 30 August 2011; Stanford study centre: clinicaltrials.gov NCT01683084, registered on 5 September 2012

Deficits in a Radial-Arm Maze Spatial Pattern Separation Task and Cell Proliferation in a Mouse Model for Down Syndrome

poster abstractDown syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in an array of phenotypes including intellectual disability. Ts65Dn mice have three copies of ~50% of the genes on Hsa21 and display many phenotypes associated with DS, including cognitive deficits. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including CNS development. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have shown that a three-week EGCG treatment normalizes skeletal abnormalities in Ts65Dn mice, yet did not rescue deficits in the Morris water maze spatial learning task or novel object recognition. The current study investigated deficits in a radial arm maze pattern separation task in Ts65Dn mice. Pattern separation requires differentiation between similar memories acquired during learning; distinguishing between these similar memories is thought to depend on distinctive encoding in the hippocampus. Pattern separation has been linked to functional activity of newly generated granule cells in the dentate gyrus. Recent studies in Ts65Dn mice have reported significant reductions in adult hippocampal neurogenesis, and after EGCG treatment, enhanced hippocampal neurogenesis. Thus, it was hypothesized that Ts65Dn mice would be impaired in the pattern separation task, and that EGCG would alleviate the pattern separation deficits seen in trisomic mice, in association with increased adult hippocampal neurogenesis. Beginning on postnatal day 75, mice were trained on a radial arm maze-delayed non-matching-to-place pattern separation task. Euploid mice performed significantly better over training than Ts65Dn mice, including better performance at each of the three separations. EGCG did not significantly alleviate the pattern separation deficits in Ts65Dn mice. The euploid controls had significantly more BrdU labeled cells than Ts65Dn mice, however, EGCG does not appear to increase proliferation of the hippocampal neuroprogenitor cells

Background and Proposed Design for a Metformin Abdominal Aortic Aneurysm Suppression Trial

Abdominal aortic aneurysm (AAA) may lead to rupture and death if left untreated. While endovascular or surgical repair is generally recommended for AAA greater than 5–5.5 cm, the vast majority of aneurysms detected by screening modalities are smaller than this threshold. Once discovered, there would be a significant potential benefit in suppressing the growth of these small aneurysms in order to obviate the need for repair and mitigate rupture risk. Patients with diabetes, in particular those taking the oral hypoglycaemic medication metformin, have been shown to have lower incidence, growth rate, and rupture risk of AAA. Metformin therefore represents a widely available, non-toxic, potential inhibitor of AAA growth, but thus far no prospective clinical studies have evaluated this. Here, we present the background, rationale, and design for a randomised, double-blind, placebo-controlled clinical trial of metformin for growth suppression in patients with small AAA