Omega-3 fatty acids and major depression: a Mendelian randomization study.

Omega-3 fatty acids have been implicated in the aetiology of depressive disorders, though trials supplementing omega-3 to prevent major depressive disorder (MDD) have so far been unsuccessful. Whether this association is causal remains unclear. We used two sample Mendelian randomization (MR) to investigate causality. Genetic variants associated with circulating omega-3 and omega-6 fatty acids in UK Biobank (UKBB, n = 115,078) were selected as exposures. The Psychiatric Genomics Consortium (PGC) genome-wide association studies (GWAS) of MDD (n = 430,775; cases = 116,209; controls = 314,566) and recurrent depression (rMDD, n = 80,933; cases = 17,451; controls = 62,482), were used as outcomes. Multivariable MR (MVMR) models were used to account for biologically correlated lipids, such as high- and low-density cholesterol and triglycerides, and to explore the relative importance of longer-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) using data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE, n = 8866). Genetic colocalization analyses were used to explore the presence of a shared underlying causal variant between traits. Genetically predicted total omega-3 fatty acids reduced the odds of MDD (ORIVW 0.96 per standard deviation (SD, i.e. 0.22 mmol/l) (95% CIs 0.93-0.98, p = 0.003)). The largest point estimates were observed for eicosapentaenoic acid (EPA), a long-chain omega-3 fatty acid (OREPA 0.92; 95% CI 0.88-0.96; p = 0.0002). The effect of omega-3 fatty acids was robust to MVMR models accounting for biologically correlated lipids. 'Leave-one-out' analyses highlighted the FADS gene cluster as a key driver of the effect. Colocalization analyses suggested a shared causal variant using the primary outcome sample, but genomic confounding could not be fully excluded. This study supports a role for omega-3 fatty acids, particularly EPA, in the aetiology of depression, although pleiotropic mechanisms cannot be ruled out. The findings support guidelines highlighting the importance of EPA dose and ratio for MDD and question whether targeted interventions may be superior to universal prevention trials, as modest effect sizes will limit statistical power.

Testing for causality between systematically identified risk factors and glioma: a Mendelian randomization study.

BACKGROUND: Whilst epidemiological studies have provided evidence of associations between certain risk factors and glioma onset, inferring causality has proven challenging. Using Mendelian randomization (MR), we assessed whether associations of 36 reported glioma risk factors showed evidence of a causal relationship. METHODS: We performed a systematic search of MEDLINE from inception to October 2018 to identify candidate risk factors and conducted a meta-analysis of two glioma genome-wide association studies (5739 cases and 5501 controls) to form our exposure and outcome datasets. MR analyses were performed using genetic variants to proxy for candidate risk factors. We investigated whether risk factors differed by subtype diagnosis (either glioblastoma (n = 3112) or non-glioblastoma (n = 2411)). MR estimates for each risk factor were determined using multiplicative random effects inverse-variance weighting (IVW). Sensitivity analyses investigated potential pleiotropy using MR-Egger regression, the weighted median estimator, and the mode-based estimator. To increase power, trait-specific polygenic risk scores were used to test the association of a genetically predicated increase in each risk factor with glioma onset. RESULTS: Our systematic search identified 36 risk factors that could be proxied using genetic variants. Using MR, we found evidence that four genetically predicted traits increased risk of glioma, glioblastoma or non-glioblastoma: longer leukocyte telomere length, liability to allergic disease, increased alcohol consumption and liability to childhood extreme obesity (> 3 standard deviations from the mean). Two traits decreased risk of non-glioblastoma cancers: increased low-density lipoprotein cholesterol (LDLc) and triglyceride levels. Our findings were similar across sensitivity analyses that made allowance for pleiotropy (genetic confounding). CONCLUSIONS: Our comprehensive investigation provides evidence of a causal link between both genetically predicted leukocyte telomere length, allergic disease, alcohol consumption, childhood extreme obesity, and LDLc and triglyceride levels, and glioma. The findings from our study warrant further research to uncover mechanisms that implicate these traits in glioma onset.

Reservoir computing and extreme learning machines for non-linear time-series data analysis.

Random projection architectures such as Echo state networks (ESNs) and Extreme Learning Machines (ELMs) use a network containing a randomly connected hidden layer and train only the output weights, overcoming the problems associated with the complex and computationally demanding training algorithms traditionally used to train neural networks, particularly recurrent neural networks. In this study an ESN is shown to contain an antagonistic trade-off between the amount of non-linear mapping and short-term memory it can exhibit when applied to time-series data which are highly non-linear. To overcome this trade-off a new architecture, Reservoir with Random Static Projections (R(2)SP) is investigated, that is shown to offer a significant improvement in performance. A similar approach using an ELM whose input is presented through a time delay (TD-ELM) is shown to further enhance performance where it significantly outperformed the ESN and R(2)SP as well other architectures when applied to a novel task which allows the short-term memory and non-linearity to be varied. The hard-limiting memory of the TD-ELM appears to be best suited for the data investigated in this study, although ESN-based approaches may offer improved performance when processing data which require a longer fading memory.

Using polychromatic X-radiography to examine realistic imitation firearms.

Sections 36-41 of the Violent Crimes Reduction Act (2006), which came into force in England and Wales on 1st October 2007, have placed significant restrictions on the sale and possession of 'realistic imitation firearms'. This legislation attempts to produce a definition of a 'realistic imitation' which clearly differentiates these items from other imitation firearms (which are not covered by the legislation). This paper will go a stage further by demonstrating techniques by which blank firing realistic imitation firearms which may be suitable for illegal conversion to fire live rounds may be differentiated from other less 'suitable' (but visually identical) realistic imitations. The article reports on the use of X-radiography, utilizing the bremsstrahlung of a commercial broad spectrum X-ray source, to identify the differences between alloys constituting the barrels of distinct replica and/or blank firing handguns. The resulting pseudo-signatures are transmission spectra over a range from 20 to 75 kV, taken at 1 kV intervals, which are extracted from stacks of registered, field flattened images. It is shown that it is possible to quantify differences between transmission spectra for components of different realistic imitation fire arms, and apply the results to determine the suitability of particular gun barrels from blank firing imitation firearms for illegal conversion to fire live rounds, or related illegal modifications.

Aspects of the life history of Muspicea borreli (Nematoda: Muspiceidae), parasite of the house mouse (Mus domesticus) in Australia.

Prevalence of Muspicea borreli (Nematoda) infection in wild populations of Mus domesticus in forests in southeastern New South Wales and in rural Canberra, Australia was variable, relatively low and the parasite occurred predominantly in male mice. Experimental infection of BALB/c mice occurred only via subcutaneous inoculation but was achieved using i) adults containing embryonating eggs, ii) adults containing active larvae and iii) active larvae dissected from the uterus of female worms. Experimental infection was not established using adults containing unembryonated eggs and was not established via intraperitoneal, percutaneous nor oral routes. Evidence indicates that larvae develop to the infective stage in the uterus of the adult worm, suggests that an obligate developmental phase on the host skin does not occur and that autoinfection is possible. Experimental infection predominated in males; females rarely became infected. When male BALB/c mice were inoculated subcutaneously with M. borrelia, immediately paired with an uninoculated female and permitted to breed for 90 days, infection was found in male and female offspring only of the second and subsequent litters or in the breeding female partner. Transmission to the young occurred within 21 days of birth and fifth-stage M. borrelia were found in offspring of the second and subsequent litters only after 35 or more days. However, when a male was inoculated but mating delayed for 23 days, infection was found in progeny of the first and second litters. The life cycle is direct and the prepatent period in BALB/c mice is estimated at 50-60 days. The precise mode of transmission of the parasite in breeding pairs of mice was not determined but larvae remained active for approximately an hour in balanced saline solutions (pH = 7.2) and in human saliva but died under conditions emulating free-living (tap water pH = 7.1) and stomach (pepsin solution pH = 2) environments. Transmission was not effected by transplacental, transmammary nor transseminal routes. Consequently, it is difficult not to conclude that transmission may occur via penetration of skin or mucous membranes, and allogrooming behaviour may be particularly important in this regard.

A comparison of quantitative NMR and radiolabelling studies of the metabolism and excretion of Statil (3-(4-bromo-2-fluorobenzyl)-4-oxo-3H-phthalazin-1-ylacetic acid) in the rat.

The identification and quantitation of the metabolites of Statil in rat bile and urine were investigated by 1H- and 19F-NMR spectroscopy and liquid scintillation counting. Male Wistar rats received a single oral dose of 100 mg/kg of radiolabelled Statil. Statil is known to produce glucuronide conjugates which are predominantly excreted into the bile in male rats. The complex multiphasic matrix of bile has been shown to make identification of the resonances by 1H-NMR spectroscopy very difficult as Statil appeared to be micellar bound giving rise to very broad signals. This not only impaired unambiguous signal characterisation but also quantification. The partial separation by SPEC-(1)H-NMR spectroscopy enabled the disruption of the micellar matrices and hence enabled the identification of Statil predominantly as aglycone, and to a lesser extent as glucuronide conjugate. In addition, minor acyl migration products of Statil glucuronide could also be detected as they were separated during the SPEC-process. 19F-NMR spectroscopic measurements on whole bile confirmed their presence as a number of overlapped signals could be observed. The selectivity, simplicity and signal dispersion characteristic of 19F-NMR spectroscopy also enabled the calculation of dose related recoveries of Statil related material in the bile and urine samples without the need for a radiolabel. The aim of this work was to investigate the usefulness and limitations of NMR spectroscopy of intact bile and urine as a means of quantifying levels of drug metabolites. The results obtained from NMR spectroscopy are compared with those obtained using scintillation techniques. Scintillation counting yields unequivocal quantification results, provided the label is preserved in metabolites as has been the case here. In general, quantification by 19F-NMR results similar to those obtained by scintillation counting (in agreement within about 20%). However, discrepancies have been observed with very small and broad 19F-NMR signals in bile. Nevertheless, 19F-NMR spectroscopy of bile is a rapid and facile method for assessing metabolite levels of fluorinated drugs.

Life history and pathogenesis of Gallegostrongylus australis (Nematoda: Angiostrongylidae) in muridae.

Gallegostrongylus australis Spratt, Haycock & Walter, 2001 (Nematoda: Angiostrongylidae) developed in Deroceras panormitanum, Lehmannia nyctelia, L. flava and Milax gigates (Gastropoda). The first moult occurred at 18-19 days after infection (DAI) and the second moult at 28 DAI. Larvae were infective to experimental murid definitive hosts at 35 DAI. In experimentally infected Rattus fuscipes larvae moulted L3-4 at 3 DAI and L4-5 at 6-7 DAI. Patency in R.fuscipes, R. lutreolus, R. norvegicus and R. rattus occurred 27-64 DAI and duration varied from 7-392 days. Histopathological changes in the lungs of R. lutreolus and development of debilitating clinical signs, in contrast to R. fuscipes, suggests that the former host-parasite relationship may be the more recent one but other traits suggest the opposite. Patent infections were established in some wild R. rattus and some laboratory R. norvegicus but not in wild M. domesticus, laboratory M. musculus, rabbit, Oryctolagus cuniculus, and marsupial bandicoot, Isoodon macrourus.

Gallegostrongylus australis n. sp. (Nematoda: Angiostrongylidae) from Muridae in Australia, with zoogeographical considerations.

Gallegostrongylus australis n. sp. (Nematoda: Angiostrongylidae) is described from subpleural nodules in the lungs of Rattus fuscipes, R. lutreolus and Mus domesticus in Australia. It is distinguished from G. andersoni occurring in gerbillids in West Africa by the shorter lengths of spicules and gubernaculum, and from G. ibicensis occurring in microtids and murids in Spain by the greater lengths of spicules and gubernaculum and the shorter distances from vulva and from anus to the caudal extremity of females. The parasite has been found only in 16 of 4,227 (prevalence 0.38%) animals representing at least 28 species of native and three species of introduced murid rodents throughout Australia. The genus Gallegostrongylus may be an old one, possibly originating in rats. By rafting and/or human activities the parasite appears to have been distributed around the world where it has encountered suitable intermediate hosts and available niches for colonisation of new definitive hosts. Consequently, morphologically similar but biologically distinct species have evolved in rodent hosts in West Africa, the western Mediterranean, and Australia.

Mitochondrial DNA polymorphism within and among species of Capillaria sensu lato from Australian marsupials and rodents.

The nucleotide variation in a mitochondrial DNA (mtDNA) fragment within and among species of Capillaria sensu lato from Australian marsupials and rodents was analyzed using a mutation scanning/sequencing approach. The fragment of the cytochrome c oxidase subunit I (COI) was amplified by PCR from parasite DNA, and analysed by single-strand conformation polymorphism (SSCP) and sequencing. There was no significant variation in SSCP profiles within a morphospecies from a particular host species, but significant variation existed among morphospecies originating from different host species. The same morphospecies was found to occur in 1-3 tissue habitats within one host individual or within different individuals of a particular species of host from the same or different geographical areas, and morphospecies appeared to be relatively host specific at the generic level. The results indicated that the species of Capillaria sensu lato examined, although highly variable in their host and tissue specificity, may exhibit the greatest degree of specificity at the level of host genus.

Examination of the metabolic status of rat air pouch inflammatory exudate by high field proton NMR spectroscopy.

High field proton (1H) NMR spectroscopy was employed to investigate the metabolic status of rat air pouch inflammatory exudates obtained subsequent to the induction of inflammation with carrageenan, and the 1H NMR profiles of these fluids were compared and contrasted with those of inflammatory human synovial fluid, rat plasma and human serum. The characteristic biochemical features obtained from 1H NMR analysis of these exudates consisted of (1) substantially elevated levels of lactate (11.40+/-1.46x10-3 mol dm-3 for samples collected at a time point of 24 h post induction) with little or no NMR-detectable glucose, data consistent with a hypoxic environment and consequent anaerobic metabolism in the inflamed air pouch, and (2) high levels of the ketone body 3-d-hydroxybutyrate, providing evidence for an increased utilization of fats for energy by lymphocytes, the predominant leucocytes present in this environment. These phenomena represent a pathological extreme of the abnormal metabolic status of inflammatory human synovial fluids.

The effects of atropisomerism and porphyrin deformation on 57Fe shieldings in superstructured hemoprotein models.

57Fe NMR chemical shifts of superstructured heme model compounds have been found to be extremely sensitive to atropisomerism and deformation (ruffling) of the porphyrin geometry.

High resolution 1H NMR investigations of the reactivities of alpha-keto acid anions with hydrogen peroxide.

The chemical reactivity of various alpha-keto acid anions (beta-hydroxypyruvate, beta-phenylpyruvate, 2-ketobutyrate and 2-ketoglutarate) with hydrogen peroxide (H2O2) was investigated at physiological pH (7.4) and a temperature of 25 degrees C. The initial concentration of the alpha-keto acid anions was kept constant at 1.00 mM whilst that of added H2O2 was varied from 0.25 to 1.00 mM, and the rate and extent of these reactions was evaluated using 1H NMR spectroscopy. At all H2O2 concentrations utilised, the order of reactivity of the alpha-keto acid anions was beta-hydroxypyruvate > beta-phenylpyruvate > 2-ketobutyrate > 2-ketoglutarate. The results obtained are in agreement with a proposed mechanism for these reactions, involving nucleophilic attack of the mono-deprotonated peroxide species (HO2-) at the C-2 carbonyl group carbon centre. The antioxidant capacity of such alpha-keto acids is discussed in terms of their potential use as therapeutic agents in clinical conditions where H2O2 has been shown to play a critical role in the disease process, i.e., those involving 'oxidative stress'.

Molecular mechanisms of the bleaching actions associated with commercially-available whitening oral health care products.

An increased public awareness in dental aesthetics has resulted in the wide availability of techniques of tooth bleaching, both in the dental chair and at home. This article reviews the aetiology of tooth discolouration both at the clinical and the molecular level, together with methods of alleviating such discolouration. Much of the therapeutic and aesthetic actions of commercially-available tooth whiteners, gels, oral rinses and other dentifrices are predominantly dependent on their ability to act as oxidants. A novel method of evaluating these aspects of dentifrice activity is also described: high resolution proton nuclear magnetic resonance (NMR) spectroscopy is a virtually non-invasive, multi component bioanalytical technique that can be employed to study oxidation/reduction reactions at the molecular level and is utilised here to investigate the mechanisms of action of a newly developed dentifrice (Ultrawhite Opal, Janina International). Such methodology also offers much potential for studies concerning the numerous chemical reactions occurring within the oral environment.

Generation of substance P carbamate in neutral aqueous solution. Relevance to inflammatory joint diseases.

High-field proton (1H) nuclear magnetic resonance (NMR) spectroscopy has been employed to evaluate the formation of substance P carbamate in aqueous solution. Equilibration of substance P with physiologically relevant concentrations of bicarbonate (2.50 x 10(-2) mol.dm-3) at pH 7.00 generated a new multiplet signal centred at 4.13 ppm in its NMR spectrum, characteristic of the alpha-proton of peptide carbamate species. High-field 1H NMR spectroscopy also demonstrated that the model dipeptide, Arg-Gly, formed a carbamate in neutral aqueous solutions containing 2.50 x 10(-2) mol.dm-3 HCO3-. The physiological significance of these results is discussed in view of the central roles of vasoactive neuropeptides in human joint diseases and the hypercapnic environment of the inflamed rheumatoid joint.

High resolution proton NMR investigations of rat blood plasma. Assignment of resonances for the molecularly mobile carbohydrate side-chains of 'acute-phase' glycoproteins.

An intense broad resonance at 2.14 ppm present in high field (400, 500 and 600 MHz) Hahn spin-echo 1H-NMR spectra of rat blood plasma, but absent from those of human blood plasma is attributable to the presence of terminal O-acetylsialate sugars in the molecularly mobile carbohydrate side-chains of 'acute-phase' glycoproteins (predominantly alpha 1-acid glycoprotein). The presence of such alternative acetylsugars in the carbohydrate side-chains of rat plasma glycoproteins are of much physiological and experimental significance in view of the regular use of these animals in model systems of human inflammatory conditions.

Oxidative damage to hyaluronate and glucose in synovial fluid during exercise of the inflamed rheumatoid joint. Detection of abnormal low-molecular-mass metabolites by proton-n.m.r. spectroscopy.

Proton Hahn spin-echo n.m.r. spectroscopy was employed to detect abnormal metabolites present in rheumatoid synovial fluid that are derived from the deleterious generation of reactive oxygen radical species during exercise of the inflamed rheumatoid joint. A resonance attributable to a low-molecular-mass N-acetylglucosamine-containing oligosaccharide formed by the oxygen-radical-mediated depolymerization of synovial-fluid hyaluronate was clearly demonstrable when subjects with inflammatory joint disease were exercised. Moreover, formate, which may be derived from the attack of OH.radical on synovial-fluid carbohydrates, was also readily detectable in these samples. gamma-Radiolysis of rheumatoid synovial fluid samples and aqueous solutions of hyaluronate also gave rise to the production of the low-molecular-mass hyaluronate-derived oligosaccharide species and markedly elevated concentrations of (non-protein-bound) formate in the biological fluids. As expected, corresponding spectra of gamma-irradiated blood serum samples obtained from normal volunteers did not contain the signal attributable to the low-molecular-mass oligosaccharide species, but the formate resonance (barely detectable in non-irradiated normal serum samples) became clearly visible. Additionally, a curious increase in the effective concentration of non-protein-bound low-molecular-mass metabolites such as acetate, citrate, lactate and glutamine was observed after gamma-radiolysis of all biological fluids studied. The hyaluronate-derived low-molecular-mass oligosaccharide species and formate are suggested as novel markers of reactive oxygen radical activity in the inflamed rheumatoid joint during exercise-induced hypoxic/reperfusion injury.

Comparison of fixed-ratio versus variable-ratio regular and NPH semisynthetic human insulin in insulin-requiring diabetic patients.

The efficacy and safety of a fixed combination of semisynthetic human insulin (Novolin) providing a 70:30 ratio of NPH to regular insulin versus a varying ratio of semisynthetic human insulin, regular and NPH (control group), were compared in adult insulin-dependent and noninsulin-dependent diabetic patients whose glycemic control had been stable on customized split-mix regimens of animal insulin. Seventy-eight patients were enrolled, of whom 72 were evaluated for efficacy of the respective regimens. Although the baseline fasting serum glucose concentrations were significantly higher in the fixed-ratio group than in the control group, mean serum glucose and glycosylated hemoglobin values throughout the 12 weeks of experimental treatment were not significantly different between groups. The mean serum glucose and glycosylated hemoglobin values in the fixed-ratio group also did not differ significantly from baseline; however, statistically significant increases were observed in the control group at weeks 4 and 8, but not at week 12. Total daily insulin dosages were comparable between the two groups, and body weight did not change significantly in either group. At the end of the study, the investigators judged 90% of the patients in the fixed-ratio group and 88% of the patients in the control group to be either improved or unchanged with respect to glycemic control. The frequency of hypoglycemic episodes and other clinical events did not change significantly from baseline in either group or differ significantly between the two groups at any time. The results of this study suggest that stable diabetic patients receiving animal insulin can safely be transferred to semisynthetic human insulin and that the majority of patients can maintain acceptable glycemic control with a fixed 70:30 ratio of NPH to regular semisynthetic human insulin.

NPH human insulin: does it work in a once-a-day regimen?

A clinical transfer trial was conducted to ascertain whether semisynthetic human NPH insulin has a full 24-hour duration of therapeutic effect comparable to that of NPH insulin from animal sources. Diabetic patients requiring insulin and stabilized on a once-a-day (QD) regimen of animal NPH insulin were enrolled and entered a two-week run-in period during which the constancy of their insulin requirements and the stability of their glycemic control were assessed. At the end of the run-in phase, baseline measurements were made of fasting blood glucose (FBG), hemoglobin A1 C, C-peptide, and insulin antibodies. Patients then were transferred to a QD regimen of semisynthetic human NPH insulin (Novolin N) in the same dose as the animal insulin. Glycemic control was reassessed after 1, 4, and 8 weeks of therapy, and a global assessment of overall glycemic control was made at the conclusion of the study. Efficacy variables were analyzed for 39 patients. Most had non-insulin-dependent diabetes mellitus (NIDDM) and most were transferred from mixed beef/pork insulin. Six (15%) patients required significant adjustments in insulin dose or regimen; the remaining 85% completed the eight weeks of treatment with minimal changes in insulin dose. Mean values for FBG and hemoglobin A1 C did not change significantly between baseline and the end of the study. The only statistically significant change was an increase in mean body weight (P less than or equal to 0.01). Results of the investigators' global assessments showed that 74% of the patients had unchanged or improved control of glycemia after transferring to semisynthetic human NPH insulin. The average frequency of hypoglycemic events was not significantly changed.(ABSTRACT TRUNCATED AT 250 WORDS)