Deficient Liver Biosynthesis of Docosahexaenoic Acid Correlates with Cognitive Impairment in Alzheimer's Disease

Reduced brain levels of docosahexaenoic acid (C22:6n-3), a neurotrophic and neuroprotective fatty acid, may contribute to cognitive decline in Alzheimer's disease. Here, we investigated whether the liver enzyme system that provides docosahexaenoic acid to the brain is dysfunctional in this disease. Docosahexaenoic acid levels were reduced in temporal cortex, mid-frontal cortex and cerebellum of subjects with Alzheimer's disease, compared to control subjects (P = 0.007). Mini Mental State Examination (MMSE) scores positively correlated with docosahexaenoic/α-linolenic ratios in temporal cortex (P = 0.005) and mid-frontal cortex (P = 0.018), but not cerebellum. Similarly, liver docosahexaenoic acid content was lower in Alzheimer's disease patients than control subjects (P = 0.011). Liver docosahexaenoic/α-linolenic ratios correlated positively with MMSE scores (r = 0.78; P<0.0001), and negatively with global deterioration scale grades (P = 0.013). Docosahexaenoic acid precursors, including tetracosahexaenoic acid (C24:6n-3), were elevated in liver of Alzheimer's disease patients (P = 0.041), whereas expression of peroxisomal d-bifunctional protein, which catalyzes the conversion of tetracosahexaenoic acid into docosahexaenoic acid, was reduced (P = 0.048). Other genes involved in docosahexaenoic acid metabolism were not affected. The results indicate that a deficit in d-bifunctional protein activity impairs docosahexaenoic acid biosynthesis in liver of Alzheimer's disease patients, lessening the flux of this neuroprotective fatty acid to the brain

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

A microstructure sensitive modeling approach for fatigue life prediction considering the residual stress effect from heat treatment

A multiscale numerical method to study the high cycle fatigue (HCF) and very high cycle fatigue (VHCF) properties of bearing steels is proposed in this study. The method is based on the microstructur sensitive modeling approach resulting from the integrated computational materials ensfgineming concept, and further consider the effect of residual stress generated from the prior heat treatment processes. The microstructure features, including the grain size and shape distribution and inclusion size and shape description, are represented by the representative volume element (RVE) models. The matrix mechanical response to the cyclic loading is described by the crystal plasticity (CP) model. The CP material parameter set is calibrated inversely based on the strain controlled low cycle fatigue tests. The results show that the residual stresses, especially those around the inclusion, have a great effect on the fatigue properties, which provides the key factor to give the correct prediction of the fatigue crack initiation site. (C) 2018 The Authors. Published by Elsevier B.V. Peer-review under responsibility of the ECF22 organizers.Peer reviewe

Palliative venting gastrostomy in malignant intestinal obstruction

This retrospective clinical study reports on the experience of palliative venting gastrostomy (PVG) in an integrated acute teaching hospital and hospice-based palliative care service over a seven-year period (1989-97). PVG was performed for 51 patients with refractory nausea and vomiting resulting from varying degrees and levels of persisting or intermittent malignant bowel obstruction. There were 32 females and 19 males; the mean age was 61 years (range 25-86 years). All patients had advanced and incurable cancer with intra-abdominal spread, originating from the following primary sites: colon and rectum (27), ovary (16), breast (2), pancreas (2), and other (4). The venting gastrostomy tube was inserted endoscopically by a railroading technique in 46 patients (using a 16- to 20-French Dobhoff PEG tube), at open laparotomy in four cases and under radiological (abdominal computerized tomography) control in one case. Endoscopic insertion was attempted and abandoned for technical reasons in a further two cases. The median survival of all 51 patients from the time of gastrostomy insertion was 17 days (range 1-190). In 47/51 (92%), the symptoms of nausea and vomiting were relieved by the procedure, and these patients experienced restoration of some level of oral soft food and fluid intake. Twenty patients were discharged home, and six died at home. In a small group of highly selected patients, for whom pharmacological measures failed to palliate the effects of malignant bowel obstruction, PVG was shown to be a safe and effective means of abolishing or substantially improving vomiting. Provided that the intervention is appropriate to the given clinical situation and acceptable to the patient, it should be considered