Qunatification of Metabolites in MR Spectroscopic Imaging using Machine Learning

Magnetic Resonance Spectroscopic Imaging (MRSI) is a clinical imaging modality for measuring tissue metabolite levels in-vivo. An accurate estimation of spectral parameters allows for better assessment of spectral quality and metabolite concentration levels. The current gold standard quantification method is the LCModel - a commercial fitting tool. However, this fails for spectra having poor signal-to-noise ratio (SNR) or a large number of artifacts. This paper introduces a framework based on random forest regression for accurate estimation of the output parameters of a model based analysis of MR spectroscopy data. The goal of our proposed framework is to learn the spectral features from a training set comprising of different variations of both simulated and in-vivo brain spectra and then use this learning for the subsequent metabolite quantification. Experiments involve training and testing on simulated and in-vivo human brain spectra. We estimate parameters such as concentration of metabolites and compare our results with that from the LCModel

Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing:a population-based study

Background<p></p> Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia.<p></p> Methods<p></p> We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls.<p></p> Results<p></p> Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls.<p></p> Conclusions<p></p> We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis

Subtle changes in the flavour and texture of a drink enhance expectations of satiety

Background: The consumption of liquid calories has been implicated in the development of obesity and weight gain. Energy-containing drinks are often reported to have a weak satiety value: one explanation for this is that because of their fluid texture they are not expected to have much nutritional value. It is important to consider what features of these drinks can be manipulated to enhance their expected satiety value. Two studies investigated the perception of subtle changes in a drink’s viscosity, and the extent to which thick texture and creamy flavour contribute to the generation of satiety expectations. Participants in the first study rated the sensory characteristics of 16 fruit yogurt drinks of increasing viscosity. In study two, a new set of participants evaluated eight versions of the fruit yogurt drink, which varied in thick texture, creamy flavour and energy content, for sensory and hedonic characteristics and satiety expectations. Results: In study one, participants were able to perceive small changes in drink viscosity that were strongly related to the actual viscosity of the drinks. In study two, the thick versions of the drink were expected to be more filling and have a greater expected satiety value, independent of the drink’s actual energy content. A creamy flavour enhanced the extent to which the drink was expected to be filling, but did not affect its expected satiety. Conclusions: These results indicate that subtle manipulations of texture and creamy flavour can increase expectations that a fruit yogurt drink will be filling and suppress hunger, irrespective of the drink’s energy content. A thicker texture enhanced expectations of satiety to a greater extent than a creamier flavour, and may be one way to improve the anticipated satiating value of energy-containing beverages

Evidence for a role of TRIB3 in the regulation of megakaryocytopoiesis

Megakaryocytopoiesis is a complex differentiation process driven by the hormone thrombopoietin by which haematopoietic progenitor cells give rise to megakaryocytes, the giant bone marrow cells that in turn break down to form blood platelets. The Tribbles Pseudokinase 3 gene (TRIB3) encodes a pleiotropic protein increasingly implicated in the regulation of cellular differentiation programmes. Previous studies have hinted that TRIB3 could be also involved in megakaryocytopoiesis but its role in this process has so far not been investigated. Using cellular model systems of haematopoietic lineage differentiation here we demonstrate that TRIB3 is a negative modulator of megakaryocytopoiesis. We found that in primary cultures derived from human haematopoietic progenitor cells, thrombopoietin-induced megakaryocytic differentiation led to a time and dosedependent decrease in TRIB3 mRNA levels. In the haematopoietic cell line UT7/mpl, silencing of TRIB3 increased basal and thrombopoietin-stimulated megakaryocyte antigen expression, as well as basal levels of ERK1/2 phosphorylation. In primary haematopoietic cell cultures, silencing of TRIB3 facilitated megakaryocyte differentiation. In contrast, over-expression of TRIB3 in these cells inhibited the differentiation process. The in-vitro identification of TRIB3 as a negative regulator of megakaryocytopoiesis suggests that in-vivo this gene could be important for the regulation of platelet production

Adenoviral vector-mediated expression of a gene encoding secreted, EpCAM-targeted carboxylesterase-2 sensitises colon cancer spheroids to CPT-11

CPT-11 (irinotecan or 7-ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) is an anticancer agent in use for the treatment of colon cancer. In order to be fully active, CPT-11 needs to be converted into SN-38 (7-ethyl-10-hydroxycamptothecin) by the enzyme carboxylesterase (CE). In humans, only a minority of CPT-11 is converted to SN-38. To increase the antitumour effect of CPT-11 by gene-directed enzyme prodrug therapy, we constructed a replication-deficient adenoviral vector Ad.C28-sCE2 containing a fusion gene encoding a secreted form of human liver CE2 targeted to the surface antigen epithelial cell adhesion molecule (EpCAM) that is highly expressed on most colon carcinoma cells. By targeting CE2 to EpCAM, the enzyme should accumulate specifically in tumours and leakage into the circulation should be minimised. Ad.C28-sCE2-transduced colon carcinoma cells expressed and secreted active CE that bound specifically to EpCAM-expressing cells. In sections of three-dimensional colon carcinoma spheroids transduced with Ad.C28-sCE2, it was shown that C28-sCE2 was capable of binding untransduced cells. Most importantly, treatment of these spheroids with nontoxic concentrations of CPT-11 resulted in growth inhibition comparable to treatment with SN-38. Therefore, Ad.C28-sCE2 holds promise in gene therapy approaches for the treatment of colon carcinoma

Is the prevalence of psychiatric disorders associated with urbanization?

Objectives In many countries, the total rate of psychiatric disorders tends to be higher in urban areas than in rural areas. The relevance of this phenomenon is that it may help in identifying environmental factors that are important in the pathogenesis of mental disorders. Moreover, urban preponderance suggests that the allocation of funds and services should take urbanization levels into account. Method The Netherlands Mental Health Survey and Incidence Study (NEMESIS) used the Composite International Diagnostic Interview (CIDI) to determine the prevalence of DSM-III-R disorders in a sample of 7,076 people aged 18–64. The sample was representative of the population as a whole. The study population was assigned to five urbanization categories defined at the level of municipalities. The association between urbanization and 12-month prevalence rates of psychiatric disorders was studied using logistic regression taking several confounders into account. Results The prevalence of psychiatric disorders gradually increased over five levels of urbanization. This pattern remained after adjustment for a range of confounders. Comorbidity rates also increased with level of urbanization. Conclusion This study confirms that psychiatric disorders are more common and more complex in more urbanized areas. This should be reflected in service allocation and may help in identifying environmental factors of importance for the aetiology of mental disorders. j Key words population survey – psychiatric epidemiology – mental disorders – urbanizatio

Molecular characterisation of protist parasites in human-habituated mountain gorillas (Gorilla beringei beringei), humans and livestock, from Bwindi impenetrable National Park, Uganda

Over 60 % of human emerging infectious diseases are zoonotic, and there is growing evidence of the zooanthroponotic transmission of diseases from humans to livestock and wildlife species, with major implications for public health, economics, and conservation. Zooanthroponoses are of relevance to critically endangered species; amongst these is the mountain gorilla (Gorilla beringei beringei) of Uganda. Here, we assess the occurrence of Cryptosporidium, Cyclospora, Giardia, and Entamoeba infecting mountain gorillas in the Bwindi Impenetrable National Park (BINP), Uganda, using molecular methods. We also assess the occurrence of these parasites in humans and livestock species living in overlapping/adjacent geographical regions

Lipase-catalysed acylation of starch and determination of the degree of substitution by methanolysis and GC

Background: Natural polysaccharides such as starch are becoming increasingly interesting as renewable starting materials for the synthesis of biodegradable polymers using chemical or enzymatic methods. Given the complexity of polysaccharides, the analysis of reaction products is challenging. Results: Esterification of starch with fatty acids has traditionally been monitored by saponification and back-titration, but in our experience this method is unreliable. Here we report a novel GC-based method for the fast and reliable quantitative determination of esterification. The method was used to monitor the enzymatic esterification of different starches with decanoic acid, using lipase from Thermomyces lanuginosus. The reaction showed a pronounced optimal water content of 1.25 mL per g starch, where a degree of substitution (DS) of 0.018 was obtained. Incomplete gelatinization probably accounts for lower conversion with less water. Conclusions: Lipase-catalysed esterification of starch is feasible in aqueous gel systems, but attention to analytical methods is important to obtain correct DS values

The effect of acute exercise on glycogen synthesis rate in obese subjects studied by 13C MRS

In obesity, insulin-stimulated glucose uptake in skeletal muscle is decreased. We investigated whether the stimulatory effect of acute exercise on glucose uptake and subsequent glycogen synthesis was normal. The study was performed on 18 healthy volunteers, 9 obese (BMI = 32.6 ± 1.2 kg/m2, mean ± SEM) and 9 lean (BMI = 22.0 ± 0.9 kg/m2), matched for age and gender. All participants underwent a euglycemic hyperinsulinemic clamp, showing reduced glucose uptake in the obese group (P = 0.01), during which they performed a short intense local exercise (single-legged toe lifting). Dynamic glucose incorporation into glycogen in the gastrocnemius muscle before and after exercise was assessed by 13C magnetic resonance spectroscopy combined with infusion of [1-13C]glucose. Blood flow was measured to investigate its potential contribution to glucose uptake. Before exercise, glycogen synthesis rate tended to be lower in obese subjects compared with lean (78 ± 14 vs. 132 ± 24 μmol/kg muscle/min; P = 0.07). Exercise induced highly significant rises in glycogen synthesis rates in both groups, but the increase in obese subjects was reduced compared with lean (112 ± 15 vs. 186 ± 27 μmol/kg muscle/min; P = 0.03), although the relative increase was similar (184 ± 35 vs. 202 ± 51%; P = 0.78). After exercise, blood flow increased equally in both groups, without a temporal relationship with the rate of glycogen synthesis. In conclusion, this study shows a stimulatory effect of a short bout of acute exercise on insulin-induced glycogen synthesis rate that is reduced in absolute values but similar in percentages in obese subjects. These results suggest a shared pathway between insulin- and exercise-induced glucose uptake and subsequent glycogen synthesis