Divergence of an association between depressive symptoms and a dopamine polygenic score in Caucasians and Asians.

A recent study reported a negative association between a putatively functional dopamine (DA) polygenic score, indexing higher levels of DA signaling, and depressive symptoms. We attempted to replicate this association using data from the Duke Neurogenetics Study. Our replication attempt was made in a subsample of 520 non-Hispanic Caucasian volunteers (277 women, mean age 19.78 ± 1.24 years). The DA polygenic score was based on the following five loci: rs27072 (SLC6A3/DAT1), rs4532 (DRD1), rs1800497 (DRD2/ANKK1), rs6280 (DRD3), and rs4680 (COMT). Because the discovery sample in the original study consisted mostly of Asian participants, we also conducted a post hoc analysis in a smaller subsample of Asian volunteers (N = 316, 179 women, mean age 19.61 ± 1.32 years). In the primary sample of non-Hispanic Caucasians, a linear regression analysis controlling for sex, age, socioeconomic status (SES), body mass index, genetic ancestry, and both early and recent life stress, revealed that higher DA polygenic scores were associated with higher self-reported symptoms of depression. This was in contrast to the original association of higher DA polygenic scores and lower depressive symptoms. However, the direction of the association in our Asian subsample was consistent with this original finding. Our results also suggested that compared to the Asian subsample, the non-Hispanic Caucasian subsample was characterized by higher SES, lower early and recent life stress, and lower depressive symptoms. These differences may have contributed to the observed divergence in associations. Collectively, the current findings add to evidence that specific genetic associations may differ between populations and further encourage explicit modeling of race/ethnicity in examining the polygenic nature of depressive symptoms and depression.

A genome-wide association study-derived polygenic score for interleukin-1ß is associated with hippocampal volume in two samples.

Accumulating research suggests that the pro-inflammatory cytokine interleukin-1ß (IL-1ß) has a modulatory effect on the hippocampus, a brain structure important for learning and memory as well as linked with both psychiatric and neurodegenerative disorders. Here, we used an imaging genetics strategy to test an association between an IL-1ß polygenic score and hippocampal volume in two independent samples. Our polygenic score was derived using summary statistics from a recent genome-wide association study of circulating cytokines that included IL-1ß (N = 3,309). In the first sample of 512 non-Hispanic Caucasian university students (274 women, mean age 19.78 ± 1.24 years) from the Duke Neurogenetics Study, we identified a significant positive correlation between IL-1ß polygenic scores and hippocampal volume. This positive association was successfully replicated in a second sample of 7,960 white British volunteers (4,158 women, mean age 62.63 ± 7.45 years) from the UK Biobank. Our results lend further support in humans, to the link between IL-1ß and the structure of the hippocampus.

Reward-Related Ventral Striatum Activity Buffers against the Experience of Depressive Symptoms Associated with Sleep Disturbances.

Sleep disturbances represent one risk factor for depression. Reward-related brain function, particularly the activity of the ventral striatum (VS), has been identified as a potential buffer against stress-related depression. We were therefore interested in testing whether reward-related VS activity would moderate the effect of sleep disturbances on depression in a large cohort of young adults. Data were available from 1129 university students (mean age 19.71 ± 1.25 years; 637 women) who completed a reward-related functional MRI task to assay VS activity and provided self-reports of sleep using the Pittsburgh Sleep Quality Index and symptoms of depression using a summation of the General Distress/Depression and Anhedonic Depression subscales of the Mood and Anxiety Symptoms Questionnaire-short form. Analyses revealed that as VS activity increased the association between sleep disturbances and depressive symptoms decreased. The interaction between sleep disturbances and VS activity was robust to the inclusion of sex, age, race/ethnicity, past or present clinical disorder, early and recent life stress, and anxiety symptoms, as well as the interactions between VS activity and early or recent life stress as covariates. We provide initial evidence that high reward-related VS activity may buffer against depressive symptoms associated with poor sleep. Our analyses help advance an emerging literature supporting the importance of individual differences in reward-related brain function as a potential biomarker of relative risk for depression.SIGNIFICANCE STATEMENT Sleep disturbances are a common risk factor for depression. An emerging literature suggests that reward-related activity of the ventral striatum (VS), a brain region critical for motivation and goal-directed behavior, may buffer against the effect of negative experiences on the development of depression. Using data from a large sample of 1129 university students we demonstrate that as reward-related VS activity increases, the link between sleep disturbances and depression decreases. This finding contributes to accumulating research demonstrating that reward-related brain function may be a useful biomarker of relative risk for depression in the context of negative experiences.

Optimal CT windowing on low-monoenergetic images using a simplex algorithm-based approach for abdominal inflammatory processes.

BACKGROUND: OBJECTIVES: To determine optimal window settings for conspicuity of abdominal inflammatory processes on 50 keV low-monoenergetic images derived from dual-energy spectral CT (DECT). METHODS: A retrospective study of 30 patients with clinically proven pancreatitis (15/30) or pyelonephritis (15/30) with inflammatory lesions visible on DECT scans were selected to serve as reference populations. 50 keV low-monoenergetic images in the portal venous phase were iteratively evaluated by 6 abdominal radiologists in twenty-one different windows (7-350HU center; 120-580HU width), selected using a simplex optimization algorithm. Each reader graded the conspicuity of the parenchymal hypodense lesions and image background quality. Three-dimensional contour maps expressing the relationship between overall reader grade and window center and width were constructed and used to find the ideal window for inflammatory pancreatic and renal processes and the image background quality. Finally, 15 appendicitis cases were reviewed on optimal pancreas and kidney windows and the manufacturer recommended conventional abdominal window settings for conventional imaging. RESULTS: Convergence to optimal windowing was achieved based upon a total of 3,780 reads (21 window settings × 6 readers × 15 cases for pancreas and kidney). Highest conspicuity grade (>4.5 ± 0.0) for pancreas inflammatory lesions was seen at 116HU/430HU, whereas hypodense pyelonephritis had highest conspicuity at 290HU/570HU. This rendered an ideal "compromise" window (>4 ± 0.2) of 150HU/450HU which differed substantially from conventional manufacturer recommended settings of 50HU/380HU (2.1 ± 1.0, p = 0.00001). Appendix mucosal enhancement was best visualized at manufacturer settings. CONCLUSIONS: Optimal visualization of inflammatory processes in abdominal organs on 50 keV low-monoenergetic images may require tailored refinement of window settings.

Dual-energy CT in acute cholecystitis- features predicting culture-positive bile and outcome.

PURPOSE: Low mono-energetic CT has been shown to improve visualization of acute abdominal inflammatory processes. We aimed to determine its utility in patients with acute cholecystitis and potential added value in clinical decision making. METHODS: Sixty-seven consecutive patients with radiological signs of cholecystitis on contrast-enhanced dual-layer CT imaging were retrospectively identified over a four-year period (2/17-8/21). A ranked Likert scale was created for imaging findings present in acute cholecystitis, including gallbladder mucosal integrity and enhancement and pericholecystic liver parenchymal enhancement. These rankings were correlated with laboratory data, followed by sensitivity, specificity, and odds-ratios calculations. RESULTS: Mucosal integrity and pericholecystic liver enhancement were better seen on low-energetic images by unanimous consensus. Presence of pericholecystic liver enhancement and poorer mucosal wall integrity correlated with positive bile cultures (sensitivity: 93.8 % and 96.9 %, specificity: 37.5 and 50.0 %; odds-ratio: 9.0[1.1-68.1 95 %CI] and 31.0 [2.7-350.7 95 %CI], p = 0.017 and p ≤ 0.001) in patients undergoing cholecystostomy (n = 40/67). Moreover, binary regression modeling showed that the strongest predictor variable for bile culture positivity was the score for pericholecystic liver enhancement (Exp(B) = 0.6, P = 0.022). By contrast, other laboratory markers and other imaging findings (such as GB wall thickness) showed lower sensitivities (76-82 %), specificities (16-21 %) and odds ratios (0.2-4.4) for the prediction of infected bile. CONCLUSIONS: Pericholecystic liver enhancement and gallbladder wall integrity are better visualized on low-DECT images. These findings also potentially predict bile culture positivity in patients with cholecystitis, which may influence clinical management including the need for intervention.

LVAD Outflow Graft Role in Pump Thrombosis.

Left ventricular assist devices are (LVAD) used for circulatory support in patients with end-stage heart failure. Hemolysis/pump dysfunction is a well-known complication of this therapy with various etiologic causes. A small proportion of these complications are caused by outflow graft obstructions; this complication has received little attention in the scientific literature. Herein, we provide a comprehensive overview of the role of the LVAD outflow graft obstruction and its treatment options.

The use of an inexpensive processing aid device (the Mouse PAD) to facilitate rodent tissue banking.

The generation of an experimental animal model often requires considerable investment of both time and money. Typically, investigators are interested in specific organs and when experimental animals are euthanized, tissues that are not the focus of the research project are discarded. However, the remaining tissues from these animals could provide valuable scientific information if efficient, error-proof and economical approaches to collect and biobank them were available. We have developed a device that, when incorporated into our tissue processing workflow, allows for high-throughput collection and processing of multiple rodent organ systems. This device, the mouse Processing Aid Device, or mouse PAD, helps to standardize organ collection and increase its efficiency.

Genetic Risk for Rheumatoid Arthritis is Associated with Increased Striatal Volume in Healthy Young Adults.

Rheumatoid arthritis (RA), an autoimmune disease, has recently been associated with increased striatal volume and decreased intracranial volume (ICV) in longstanding patients. As inflammation has been shown to precede the clinical diagnosis of RA and it is a known moderator of neuro- and gliogenesis, we were interested in testing whether these brain morphological changes appear before the clinical onset of disease in healthy young adult volunteers, as a function of relative genetic risk for RA. Genetic and structural MRI data were available for 516 healthy non-Hispanic Caucasian university students (275 women, mean age 19.78 ± 1.24 years). Polygenic risk scores were computed for each individual based on a genome-wide association study of RA, so that higher scores indicated higher risk. Striatal volume (sum of caudate, putamen, and nucleus accumbens volumes) and ICV were derived for each individual from high-resolution T1-weighted images. After controlling for sex, age, genetic components of ethnicity, socioeconomic status, and depressive symptoms, we found that higher RA polygenic risk scores were associated with increased striatal volume, but not decreased ICV. Our findings suggest that increased striatal volume may be linked to processes that precede disease onset, such as inflammation, while decreased ICV may relate to disease progression.

A normothermic ex vivo organ perfusion delivery method for cardiac transplantation gene therapy.

Clinically, both percutaneous and surgical approaches to deliver viral vectors to the heart either have resulted in therapeutically inadequate levels of transgene expression or have raised safety concerns associated with extra-cardiac delivery. Recent developments in the field of normothermic ex vivo cardiac perfusion storage have now created opportunities to overcome these limitations and safety concerns of cardiac gene therapy. This study examined the feasibility of ex vivo perfusion as an approach to deliver a viral vector to a donor heart during storage and the resulting bio distribution and expression levels of the transgene in the recipient post-transplant. The influence of components (proprietary solution, donor blood, and ex vivo circuitry tubing and oxygenators) of the Organ Care System (OC) (TransMedics, Inc., Andover MA) on viral vector transduction was examined using a cell-based luciferase assay. Our ex vivo perfusion strategy, optimized for efficient Adenoviral vector transduction, was utilized to deliver 5 × 1013 total viral particles of an Adenoviral firefly luciferase vector with a cytomegalovirus (CMV) promotor to porcine donor hearts prior to heterotopic implantation. We have evaluated the overall levels of expression, protein activity, as well as the bio distribution of the firefly luciferase protein in a series of three heart transplants at a five-day post-transplant endpoint. The perfusion solution and the ex vivo circuitry did not influence viral vector transduction, but the serum or plasma fractions of the donor blood significantly inhibited viral vector transduction. Thus, subsequent gene delivery experiments to the explanted porcine heart utilized an autologous blood recovery approach to remove undesired plasma or serum components of the donor blood prior to its placement into the circuit. Enzymatic assessment of luciferase activity in tissues (native heart, allograft, liver etc.) obtained post-transplant day five revealed wide-spread and robust luciferase activity in all regions of the allograft (right and left atria, right and left ventricles, coronary arteries) compared to the native recipient heart. Importantly, luciferase activity in recipient heart, liver, lung, spleen, or psoas muscle was within background levels. Similar to luciferase activity, the luciferase protein expression in the allograft appeared uniform and robust across all areas of the myocardium as well as in the coronary arteries. Importantly, despite high copy number of vector genomic DNA in transplanted heart tissue, there was no evidence of vector DNA in either the recipient's native heart or liver. Overall we demonstrate a simple protocol to achieve substantial, global gene delivery and expression isolated to the cardiac allograft. This introduces a novel method of viral vector delivery that opens the opportunity for biological modification of the allograft prior to implantation that may improve post-transplant outcomes.

Replication in Imaging Genetics: The Case of Threat-Related Amygdala Reactivity.

BACKGROUND: Low replication rates are a concern in most, if not all, scientific disciplines. In psychiatric genetics specifically, targeting intermediate brain phenotypes, which are more closely associated with putative genetic effects, was touted as a strategy leading to increased power and replicability. In the current study, we attempted to replicate previously published associations between single nucleotide polymorphisms and threat-related amygdala reactivity, which represents a robust brain phenotype not only implicated in the pathophysiology of multiple disorders, but also used as a biomarker of future risk. METHODS: We conducted a literature search for published associations between single nucleotide polymorphisms and threat-related amygdala reactivity and found 37 unique findings. Our replication sample consisted of 1117 young adult volunteers (629 women, mean age 19.72 ± 1.25 years) for whom both genetic and functional magnetic resonance imaging data were available. RESULTS: Of the 37 unique associations identified, only three replicated as previously reported. When exploratory analyses were conducted with different model parameters compared to the original findings, significant associations were identified for 28 additional studies: eight of these were for a different contrast/laterality; five for a different gender and/or race/ethnicity; and 15 in the opposite direction and for a different contrast, laterality, gender, and/or race/ethnicity. No significant associations, regardless of model parameters, were detected for six studies. Notably, none of the significant associations survived correction for multiple comparisons. CONCLUSIONS: We discuss these patterns of poor replication with regard to the general strategy of targeting intermediate brain phenotypes in genetic association studies and the growing importance of advancing the replicability of imaging genetics findings.

Elevated Neutrophil Gelatinase Lipocalin Levels Are Associated With Increased Oxidative Stress in Hemodialysis Patients.

BACKGROUND: Administration of intravenous iron is an essential treatment of anemia in hemodialysis patients, but it may lead to oxidative stress and increased morbidity and mortality. There is evidence that neutrophil gelatinase-associated lipocalin (NGAL) is protective against oxidative stress and thus the aim of the present study was to investigate the relationship between plasma NGAL and advanced oxidative protein products (AOPP) in hemodialysis patients treated with intravenous iron. METHODS: In a prospective study, 47 hemodialysis patients (mean age 63 years, SD = 13.6; 40% women) were enrolled from two separate hospitals. Oxidative stress was induced by an intravenous administration of 100 mg iron saccharate 0.5 h after the start of dialysis. Blood samples were drawn at the beginning of the dialysis, 0.5 h after iron administration and at the end of dialysis. NGAL levels were measured from the first blood sample, AOPP levels were measured from all blood samples. RESULTS: Our results showed that higher NGAL and AOPP levels at the beginning of the dialysis, prior to iron administration, significantly predicted higher levels of AOPP toward the end of dialysis, (ß = 0.355, SE = 0.054, P = 0.035; ß = 0.297, SE = 0.159, P = 0.043, respectively). CONCLUSIONS: Our results suggest that higher level of NGAL is a risk factor for oxidative stress, as measured by AOPP levels, in dialysis patients receiving intravenous iron. Our findings could identify dialysis patients who are at higher risk from iron supplementation via measurement of NGAL levels.