Phenotypic and genetic analysis of cognitive performance in Major Depressive Disorder in the Generation Scotland:Scottish Family Health Study

Abstract Lower performances in cognitive ability in individuals with Major Depressive Disorder (MDD) have been observed on multiple occasions. Understanding cognitive performance in MDD could provide a wider insight in the aetiology of MDD as a whole. Using a large, well characterised cohort (N = 7012), we tested for: differences in cognitive performance by MDD status and a gene (single SNP or polygenic score) by MDD interaction effect on cognitive performance. Linear regression was used to assess the association between cognitive performance and MDD status in a case-control, single-episode–recurrent MDD and control-recurrent MDD study design. Test scores on verbal declarative memory, executive functioning, vocabulary, and processing speed were examined. Cognitive performance measures showing a significant difference between groups were subsequently analysed for genetic associations. Those with recurrent MDD have lower processing speed versus controls and single-episode MDD (β =  −2.44, p = 3.6 × 10−04; β =  -2.86, p = 1.8 × 10−03, respectively). There were significantly higher vocabulary scores in MDD cases versus controls (β = 0.79, p = 2.0 × 10−06), and for recurrent MDD versus controls (β = 0.95, p  = 5.8 × 10−05). Observed differences could not be linked to significant single-locus associations. Polygenic scores created from a processing speed meta-analysis GWAS explained 1% of variation in processing speed performance in the single-episode versus recurrent MDD study (p = 1.7 × 10−03) and 0.5% of variation in the control versus recurrent MDD study (p = 1.6 × 10−10). Individuals with recurrent MDD showed lower processing speed and executive function while showing higher vocabulary performance. Within MDD, persons with recurrent episodes show lower processing speed and executive function scores relative to individuals experiencing a single episode

Surgical Simulator Design and Development

With the introduction of minimally invasive surgery (MIS), it became necessary to develop training methods to learn skills outside the operating room. Several training simulators have become commercially available, but fundamental research into the requirements for effective and efficient training in MIS is still lacking. Three aspects of developing a training program are investigated here: what should be trained, how it should be trained, and how to assess the results of training. In addition, studies are presented that have investigated the role of force feedback in surgical simulators. Training should be adapted to the level of behavior: skill-based, rule-based, or knowledge-based. These levels can be used to design and structure a training program. Extra motivation for training can be created by assessment. During MIS, force feedback is reduced owing to friction in the laparoscopic instruments and within the trocar. The friction characteristics vary largely among instruments and trocars. When force feedback is incorporated into training, it should include the large variation in force feedback properties as well. Training different levels of behavior requires different training methods. Although force feedback is reduced during MIS, it is needed for tissue manipulation, and therefore force application should be trained as well

Potency analysis of cellular therapies: the emerging role of molecular assays

Potency testing is an important part of the evaluation of cellular therapy products. Potency assays are quantitative measures of a product-specific biological activity that is linked to a relevant biological property and, ideally, a product's in vivo mechanism of action. Both in vivo and in vitro assays can be used for potency testing. Since there is often a limited period of time between the completion of production and the release from the laboratory for administration to the patient, in vitro assays such are flow cytometry, ELISA, and cytotoxicity are typically used. Better potency assays are needed to assess the complex and multiple functions of cellular therapy products, some of which are not well understood. Gene expression profiling using microarray technology has been widely and effectively used to assess changes of cells in response to stimuli and to classify cancers. Preliminary studies have shown that the expression of noncoding microRNA which play an important role in cellular development, differentiation, metabolism and signal transduction can distinguish different types of stem cells and leukocytes. Both gene and microRNA expression profiling have the potential to be important tools for testing the potency of cellular therapies. Potency testing, the complexities associated with potency testing of cellular therapies, and the potential role of gene and microRNA expression microarrays in potency testing of cellular therapies is discussed

Impact of short-term dietary modification on postprandial oxidative stress

<p>Abstract</p> <p>Background</p> <p>We have recently reported that short-term (21-day) dietary modification in accordance with a stringent vegan diet (i.e., a Daniel Fast) lowers blood lipids as well as biomarkers of oxidative stress. However, this work only involved measurements obtained in a fasted state. In the present study, we determined the postprandial response to a high-fat milkshake with regards to blood triglycerides (TAG), biomarkers of oxidative stress, and hemodynamic variables before and following a 21-day Daniel Fast.</p> <p>Methods</p> <p>Twenty-two subjects (10 men and 12 women; aged 35 ± 3 years) completed a 21-day Daniel Fast. To induce oxidative stress, a milkshake (fat = 0.8 g·kg^-1; carbohydrate = 1.0 g·kg^-1; protein = 0.25 g·kg^-1) was consumed by subjects on day one and day 22 in a rested and 12-hour fasted state. Before and at 2 and 4 h after consumption of the milkshake, heart rate (HR) and blood pressure were measured. Blood samples were also collected at these times and analyzed for TAG, malondialdehyde (MDA), hydrogen peroxide (H₂O₂), advanced oxidation protein products (AOPP), nitrate/nitrite (NOx), and Trolox Equivalent Antioxidant Capacity (TEAC).</p> <p>Results</p> <p>A time effect was noted for HR (<it>p </it>= 0.006), with values higher at 2 hr post intake of the milkshake as compared to pre intake (<it>p </it>< 0.05). Diastolic blood pressure was lower post fast as compared to pre fast (<it>p </it>= 0.02), and a trend for lower systolic blood pressure was noted (<it>p </it>= 0.07). Time effects were noted for TAG (<it>p </it>= 0.001), MDA (<it>p </it>< 0.0001), H₂O₂(<it>p </it>< 0.0001), AOPP (<it>p </it>< 0.0001), and TEAC (<it>p </it>< 0.0001); all concentrations were higher at 2 h and 4 h post intake compared to pre intake, except for TEAC, which was lower at these times (<it>p </it>< 0.05). A condition effect was noted for NOx (<it>p </it>= 0.02), which was higher post fast as compared to pre fast. No pre/post fast × time interactions were noted (<it>p </it>> 0.05), with the area under the curve from pre to post fast reduced only slightly for TAG (11%), MDA (11%), H₂O₂(8%), and AOPP (12%), with a 37% increase noted for NOx.</p> <p>Conclusion</p> <p>Partaking in a 21-day Daniel Fast does not result in a statistically significant reduction in postprandial oxidative stress. It is possible that a longer time course of adherence to the Daniel Fast eating plan may be needed to observe significant findings.</p

Put My Skills to Use? Understanding the Joint Effect of Job Security and Skill Utilization on Job Satisfaction Between Skilled Migrants and Australian Born Workers in Australia

The topic of skilled migrants has gained importance in the past decade as they are increasingly becoming one of the main drivers for labor supply in developed countries like Australia. Although there is research on skilled migrants, most have been studied from the perspectives of (un)employment, wage and over-education. Some evidence suggests that skilled migrants are often less satisfied with their job compared to their local counterparts, yet little is known about why these differences exist. Using a nationally representative sample of Australian workers, we examine how two important job characteristics, job security and skill utilization, exert their differential interaction effect on job satisfaction for skilled migrants and Australian born workers. We found a differential moderation effect between job security and skill utilization for skilled migrants and Australian born workers. For skilled migrants, high job security did not lead to positive reaction (i.e., job satisfaction), as this effect was dependent on their skill utilization; while such moderation effect was not present for Australian born workers. This study highlights the need to take a more fine-tuned approach by understanding target sample groups (e.g., skilled migrants) when study the relationship between key job characteristics and job satisfaction. Furthermore, it highlights the importance for organizations to revisit their human resource management strategies and policies to recognize the needs for enhancing skill utilization for skilled migrants

Lack of Chemokine Signaling through CXCR5 Causes Increased Mortality, Ventricular Dilatation and Deranged Matrix during Cardiac Pressure Overload

RATIONALE: Inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF. OBJECTIVE: We sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF. METHODS AND RESULTS: Mice harboring a systemic knockout of the CXCR5 (CXCR5(-/-)) displayed increased mortality during a follow-up of 80 days after aortic banding (AB). Following three weeks of AB, CXCR5(-/-) developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5(-/-) compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5(-/-) mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment. CONCLUSIONS: Lack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly

Intra-tumoural microvessel density in human solid tumours

Over the last decade assessment of angiogenesis has emerged as a potentially useful biological prognostic and predictive factor in human solid tumours. With the development of highly specific endothelial markers that can be assessed in histological archival specimens, several quantitative studies have been performed in various solid tumours. The majority of published studies have shown a positive correlation between intra-tumoural microvessel density, a measure of tumour angiogenesis, and prognosis in solid tumours. A minority of studies have not demonstrated an association and this may be attributed to significant differences in the methodologies employed for sample selection, immunostaining techniques, vessel counting and statistical analysis, although a number of biological differences may account for the discrepancy. In this review we evaluate the quantification of angiogenesis by immunohistochemistry, the relationship between tumour vascularity and metastasis, and the clinicopathological studies correlating intra-tumoral microvessel density with prognosis and response to anti-cancer therapy. In view of the extensive nature of this retrospective body of data, comparative studies are needed to identify the optimum technique and endothelial antigens (activated or pan-endothelial antigens) but subsequently prospective studies that allocate treatment on the basis of microvessel density are required

Prognostic factors in prostate cancer

Prognostic factors in organ confined prostate cancer will reflect survival after surgical radical prostatectomy. Gleason score, tumour volume, surgical margins and Ki-67 index have the most significant prognosticators. Also the origins from the transitional zone, p53 status in cancer tissue, stage, and aneuploidy have shown prognostic significance. Progression-associated features include Gleason score, stage, and capsular invasion, but PSA is also highly significant. Progression can also be predicted with biological markers (E-cadherin, microvessel density, and aneuploidy) with high level of significance. Other prognostic features of clinical or PSA-associated progression include age, IGF-1, p27, and Ki-67. In patients who were treated with radiotherapy the survival was potentially predictable with age, race and p53, but available research on other markers is limited. The most significant published survival-associated prognosticators of prostate cancer with extension outside prostate are microvessel density and total blood PSA. However, survival can potentially be predicted by other markers like androgen receptor, and Ki-67-positive cell fraction. In advanced prostate cancer nuclear morphometry and Gleason score are the most highly significant progression-associated prognosticators. In conclusion, Gleason score, capsular invasion, blood PSA, stage, and aneuploidy are the best markers of progression in organ confined disease. Other biological markers are less important. In advanced disease Gleason score and nuclear morphometry can be used as predictors of progression. Compound prognostic factors based on combinations of single prognosticators, or on gene expression profiles (tested by DNA arrays) are promising, but clinically relevant data is still lacking

Rodent models of focal cerebral ischemia: procedural pitfalls and translational problems

Rodent models of focal cerebral ischemia are essential tools in experimental stroke research. They have added tremendously to our understanding of injury mechanisms in stroke and have helped to identify potential therapeutic targets. A plethora of substances, however, in particular an overwhelming number of putative neuroprotective agents, have been shown to be effective in preclinical stroke research, but have failed in clinical trials. A lot of factors may have contributed to this failure of translation from bench to bedside. Often, deficits in the quality of experimental stroke research seem to be involved. In this article, we review the commonest rodent models of focal cerebral ischemia - middle cerebral artery occlusion, photothrombosis, and embolic stroke models - with their respective advantages and problems, and we address the issue of quality in preclinical stroke modeling as well as potential reasons for translational failure