Pan-cerebral sodium elevations in vascular dementia: Evidence for disturbed brain-sodium homeostasis

Vascular dementia (VaD) is the second most common cause of cognitive impairment amongst the elderly. However, there are no known disease-modifying therapies for VaD, probably due to incomplete understanding of the molecular basis of the disease. Despite the complex etiology of neurodegenerative conditions, a growing body of research now suggests the potential involvement of metal dyshomeostasis in the pathogenesis of several of the age-related dementias. However, by comparison, there remains little research investigating brain metal levels in VaD. In order to shed light on the possible involvement of metal dyshomeostasis in VaD, we employed inductively coupled plasma-mass spectrometry to quantify the levels of essential metals in post-mortem VaD brain tissue (n = 10) and age-/sex-matched controls (n = 10) from seven brain regions. We found novel evidence for elevated wet-weight cerebral sodium levels in VaD brain tissue in six out of the seven regions analyzed. Decreased cerebral-potassium levels as well as increased Na/K ratios (consistent with high tissue sodium and low potassium levels) were also observed in several brain regions. These data suggest that reduced Na+/K+-exchanging ATPase (EC 7.2.2.13) activity could contribute to the contrasting changes in sodium and potassium measured here

3,12-Diaza-6,9-diazo­nia-2,13-dioxotetra­decane bis­(perchlorate)

The crystal structure of the title diprotonated diacetyl­triethyl­ene­tetra­mine (DAT) perchorate salt, C10H24N4O2 2+·2ClO4 −, can be described as a three-dimensional assembly of alternating layers consisting of diprotonated diacetyl­triethyl­ene­tetra­mine (H2DAT)2+ strands along [100] and the anionic species ClO4 −. The (H2DAT)2+ cations in the strands are connected via N—H⋯O hydrogen bonding between the acetyl groups and the amine groups of neighbouring (H2DAT)2+ cations. Layers of (H2DAT)2+ strands and perchlorate anions are connected by a network of hydrogen bonds between the NH and NH2 groups and the O atoms of the perchlorate anion. The asymmetric unit consits of one perchlorate anion in a general position, as well as of one cation that is located on a center of inversion

Substantively Lowered Levels of Pantothenic Acid (Vitamin B5) in Several Regions of the Human Brain in Parkinson’s Disease Dementia

From MDPI via Jisc Publications RouterHistory: accepted 2021-08-23, pub-electronic 2021-08-25Publication status: PublishedFunder: Endocore Research Associates, NZ; Grant(s): 60147, 3626585; 3702766, JXU058, UOAX0815Funder: Maurice and Phyllis Paykel Trust; Grant(s): 3627036Funder: Maurice Wilkins Centre for Molecular Biodiscovery; Grant(s): 9341-3622506Funder: Oakley Mental Health Research Foundation; Grant(s): 3456030; 3627092; 3701339; 3703253; 3702870Funder: Neurological Foundation of New Zealand; Grant(s): N/AFunder: Medical Research Council; Grant(s): MR/L010445/1 and MR/L011093/1Funder: Alzheimer’s Research UK; Grant(s): ARUK-PPG2014B-7Pantothenic acid (vitamin B5) is an essential trace nutrient required for the synthesis of coenzyme A (CoA). It has previously been shown that pantothenic acid is significantly decreased in multiple brain regions in both Alzheimer’s disease (ADD) and Huntington’s disease (HD). The current investigation aimed to determine whether similar changes are also present in cases of Parkinson’s disease dementia (PDD), another age-related neurodegenerative condition, and whether such perturbations might occur in similar regions in these apparently different diseases. Brain tissue was obtained from nine confirmed cases of PDD and nine controls with a post-mortem delay of 26 h or less. Tissues were acquired from nine regions that show high, moderate, or low levels of neurodegeneration in PDD: the cerebellum, motor cortex, primary visual cortex, hippocampus, substantia nigra, middle temporal gyrus, medulla oblongata, cingulate gyrus, and pons. A targeted ultra–high performance liquid chromatography—tandem mass spectrometry (UHPLC-MS/MS) approach was used to quantify pantothenic acid in these tissues. Pantothenic acid was significantly decreased in the cerebellum (p = 0.008), substantia nigra (p = 0.02), and medulla (p = 0.008) of PDD cases. These findings mirror the significant decreases in the cerebellum of both ADD and HD cases, as well as the substantia nigra, putamen, middle frontal gyrus, and entorhinal cortex of HD cases, and motor cortex, primary visual cortex, hippocampus, middle temporal gyrus, cingulate gyrus, and entorhinal cortex of ADD cases. Taken together, these observations indicate a common but regionally selective disruption of pantothenic acid levels across PDD, ADD, and HD

Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia

From Frontiers via Jisc Publications RouterHistory: collection 2021, received 2021-05-18, accepted 2021-09-30, epub 2021-10-22Publication status: PublishedWidespread elevations in brain urea have, in recent years, been reported in certain types of age-related dementia, notably Alzheimer’s disease (AD) and Huntington’s disease (HD). Urea increases in these diseases are substantive, and approximate in magnitude to levels present in uraemic encephalopathy. In AD and HD, elevated urea levels are widespread, and not only in regions heavily affected by neurodegeneration. However, measurements of brain urea have not hitherto been reported in Parkinson’s disease dementia (PDD), a condition which shares neuropathological and symptomatic overlap with both AD and HD. Here we report measurements of tissue urea from nine neuropathologically confirmed regions of the brain in PDD and post-mortem delay (PMD)-matched controls, in regions including the cerebellum, motor cortex (MCX), sensory cortex, hippocampus (HP), substantia nigra (SN), middle temporal gyrus (MTG), medulla oblongata (MED), cingulate gyrus, and pons, by applying ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Urea concentrations were found to be substantively elevated in all nine regions, with average increases of 3–4-fold. Urea concentrations were remarkably consistent across regions in both cases and controls, with no clear distinction between regions heavily affected or less severely affected by neuronal loss in PDD. These urea elevations mirror those found in uraemic encephalopathy, where equivalent levels are generally considered to be pathogenic, and those previously reported in AD and HD. Increased urea is a widespread metabolic perturbation in brain metabolism common to PDD, AD, and HD, at levels equal to those seen in uremic encephalopathy. This presents a novel pathogenic mechanism in PDD, which is shared with two other neurodegenerative diseases

Diabetic cardiomyopathy is associated with defective myocellular copper regulation and both defects are rectified by divalent copper chelation

BACKGROUND: Heart disease is the leading cause of death in diabetic patients, and defective copper metabolism may play important roles in the pathogenesis of diabetic cardiomyopathy (DCM). The present study sought to determine how myocardial copper status and key copper-proteins might become impaired by diabetes, and how they respond to treatment with the Cu (II)-selective chelator triethylenetetramine (TETA) in DCM. METHODS: Experiments were performed in Wistar rats with streptozotocin (STZ)-induced diabetes with or without TETA treatment. Cardiac function was analyzed in isolated-perfused working hearts, and myocardial total copper content measured by particle-induced x-ray emission spectroscopy (PIXE) coupled with Rutherford backscattering spectrometry (RBS). Quantitative expression (mRNA and protein) and/or activity of key proteins that mediate LV-tissue-copper binding and transport, were analyzed by combined RT-qPCR, western blotting, immunofluorescence microscopy, and enzyme activity assays. Statistical analysis was performed using Student’s t-tests or ANOVA and p-values of < 0.05 have been considered significant. RESULTS: Left-ventricular (LV) copper levels and function were severely depressed in rats following 16-weeks’ diabetes, but both were unexpectedly normalized 8-weeks after treatment with TETA was instituted. Localized myocardial copper deficiency was accompanied by decreased expression and increased polymerization of the copper-responsive transition-metal-binding metallothionein proteins (MT1/MT2), consistent with impaired anti-oxidant defences and elevated susceptibility to pro-oxidant stress. Levels of the high-affinity copper transporter-1 (CTR1) were depressed in diabetes, consistent with impaired membrane copper uptake, and were not modified by TETA which, contrastingly, renormalized myocardial copper and increased levels and cell-membrane localization of the low-affinity copper transporter-2 (CTR2). Diabetes also lowered indexes of intracellular (IC) copper delivery via the copper chaperone for superoxide dismutase (CCS) to its target cuproenzyme, superoxide dismutase-1 (SOD1): this pathway was rectified by TETA treatment, which normalized SOD1 activity with consequent bolstering of anti-oxidant defenses. Furthermore, diabetes depressed levels of additional intracellular copper-transporting proteins, including antioxidant-protein-1 (ATOX1) and copper-transporting-ATPase-2 (ATP7B), whereas TETA elevated copper-transporting-ATPase-1 (ATP7A). CONCLUSIONS: Myocardial copper deficiency and defective cellular copper transport/trafficking are revealed as key molecular defects underlying LV impairment in diabetes, and TETA-mediated restoration of copper regulation provides a potential new class of therapeutic molecules for DCM

Fruit crops: a summary of research, 1998

Pesticide deposition in orchards: effects of pesticide type, tree canopy, timing, cultivar, and leaf type / Franklin R. Hall, Jane A. Cooper, and David C. Ferree -- The influence of a synthetic foraging attractant, Bee-Scent™, on the number of honey bees visiting apple blossoms and on subsequent fruit production / James E. Tew and David C. Ferree -- The reliability of three traps vs. a single trap for determining population levels of codling moth in commercial northern Ohio apple orchards / Ted W. Gastier -- Evaluation of an empirical model for predicting sooty blotch and flyspeck of apples in Ohio / Michael A. Ellis, Laurence V. Madden, and L. Lee Wilson -- Influence of pesticides and water stress on photosynthesis and transpiration of apple / David C. Ferree, Franklin R. Hall, Charles R. Krause, Bruce R. Roberts, and Ross D. Brazee -- Influence of temporary bending and heading on branch development and flowering of vigorous young apple trees / David C. Ferree and John C. Schmid -- The effect of apple fruit bruising on total returns / Richard C. Funt, Ewen A. Cameron, and Nigel H. Banks -- Yield, berry quality, and economics of mechanical berry harvest in Ohio / Richard C. Funt, Thomas E. Wall, and Joseph C. Scheerens -- Monitoring flower thrips activities in strawberry fields at two Ohio locations / Roger N. Williams, M. Sean Ellis, Dan S. Fickle, and Carl M. Pelland -- Cluster thinning effects on fruit weight, juice quality, and fruit skin characteristics in 'Reliance' grapes / Yu Gao and Garth A. Cahoon -- Effects of various fungicide programs on powdery mildew control, percent berry sugar, yield, and vine vigor of 'Concord' grapes in Ohio / Michael A. Ellis, Laurence V. Madden, L. Lee Wilson, and Gregory R. Johns -- Influence of growth regulators, cropping, and number on replacement trunks of winter-injured 'Vidal Blanc' grapes / David C. Ferree, David M. Scurlock, and Rick Evans -- Effect of new herbicides on tissue-cultured black raspberry plants / Richard C. Funt, Thomas E. Wall, and B. Dale Stokes -- Investigating the relationship between vine vigor and berry set of field-grown 'Seyval Blanc' grapevines / Steven J. McArtney and David C. Ferree -- Summary of Ohio Fruit Growers Society apple cider competition, 1993-1997 / Winston Bash and Diane Mille