Iron deficiency in parkinsonism : region-specific iron dysregulation in Parkinson's disease and multiple system atrophy

Alpha synuclein pathology is widespread and found in diverse cell types in multiple system atrophy (MSA) as compared to Parkinson's disease (PD). The reason for this differential distribution is unknown. Regional differences in the distribution of iron are associated with neurodegenerative diseases, and here we characterize the relationship between iron homeostasis proteins and regional concentration, distribution and form of iron in MSA and PD. In PD substantia nigra, tissue iron and expression of the iron export protein ferroportin increased, while the iron storage protein ferritin expression was unchanged. In the basis pontis of MSA cases, increased total iron concentration coupled with a disproportionate increase in ferritin in dysmorphic microglia and a reduction in ferroportin expression. This is supported by isothermal remanent magnetisation evidence consistent with elevated concentrations of ferritin-bound iron in MSA basis pontis. Conventional opinion holds that excess iron is involved in neurodegeneration. Our data support that this may be the case in PD. While region-specific changes in iron are evident in both PD and MSA, the mechanisms of iron dysregulation appear quite distinct, with a failure to export iron from the MSA basis pontis coupling with significant intracellular accumulation of ferritin iron. This pattern also occurs, to a lesser extent, in the MSA putamen. Despite the excess tissue iron, the manner of iron dysregulation in MSA is reminiscent of changes in anemia of chronic disease, and our preliminary data, coupled with the widespread pathology and involvement of multiple cell types, may evidence a deficit in bioavailabile iron

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic

Mammal responses to global changes in human activity vary by trophic group and landscape

Wildlife must adapt to human presence to survive in the Anthropocene, so it is critical to understand species responses to humans in different contexts. We used camera trapping as a lens to view mammal responses to changes in human activity during the COVID-19 pandemic. Across 163 species sampled in 102 projects around the world, changes in the amount and timing of animal activity varied widely. Under higher human activity, mammals were less active in undeveloped areas but unexpectedly more active in developed areas while exhibiting greater nocturnality. Carnivores were most sensitive, showing the strongest decreases in activity and greatest increases in nocturnality. Wildlife managers must consider how habituation and uneven sensitivity across species may cause fundamental differences in human–wildlife interactions along gradients of human influence.Peer reviewe

Investigation of the relationship between iron and high field MRI in healthy and Alzheimer's disease tissue

It has been proposed that increased tissue iron concentration, which has been observed in certain regions of the brain in individuals with Alzheimer’s Disease (AD), could provide a marker for diagnosis through detection with MRI. This is investigated in this thesis using high field MRI to examine post mortem human brain tissue. It is shown here that by using data from multiple brain regions discriminant analysis can successfully differentiate between AD and control samples, even when no statistically significant differences are observed in individual brain regions. A unique set of complementary techniques was used to investigate iron content, R2 and R2* of tissue samples from the caudate nucleus, putamen, globus pallidus substantia nigra, amygdala and pons, from a set of three control and AD cases. The particulate iron content of the samples was investigated by SQUID magnetometry and was followed by iron quantification. A trend of increased particulate and total iron concentration was observed in the AD tissue compared to control, however this did not reach statistical significance in any brain region. High resolution MRI relaxometry at 9.4 T was carried out on tissue from the caudate nucleus, putamen, globus pallidus and substantia nigra using a custom design Bruker micro-imaging MicWB40 probe. As part of the work towards this PhD the probe was tested, and MRI relaxometry protocols optimised for high resolution (86 x 86 μm in plane, 150 μm slice thickness) mapping of tissue samples with high iron concentration. Again, no statistically significant differences were observed between AD and control tissue. However, discriminant analysis of these data (particulate or total iron or R2 or R2*) from multiple brain regions achieved differentiation between control and AD cases with 100% sensitivity and specificity for this small sample set. This demonstrates the potential clinical usefulness of MRI of measurements of non-haem brain iron to aid in disease diagnosis. Synchrotron X-ray fluorescence (SXRF) mapping of 30 μm thick sections, cut from the MRI samples, showed the relative concentration distribution of iron, copper and zinc in one AD and control sample from each brain region. Each metal was shown to have a distinct distribution. In particular, the inhomogeneity of iron concentration within individual brain regions, such as the putamen, was demonstrated. This may explain the wide variation in iron concentration reported in the literature for the same brain regions, and highlights the importance of close anatomical matching of samples when making comparisons. The ability of high resolution SXRF mapping to investigate the metal content within individual cells was demonstrated and used to show an increase in iron in individual AD neurons, in addition to the surrounding grey and white matter tissue. Spatially matched SXRF and MRI maps were used to demonstrate a strong, statistically significant linear relationship between tissue iron concentration and R2, R2* and R2’ at 9.4 T. The gradient of the linear relationship between iron and R2, agrees extremely well with the predicted gradient at this field, where the prediction was made by Vymazal et al. (1996) using MRI relaxometry at 0.05 to 1.5 T. To the best of my knowledge, this is the first time that this relationship has been quantified at 9.4 T, or at any field above 7 T. MRI at 14.1 T was carried out on low iron concentration regions (the pons and amygdala). Matched SXRF and R2* maps did not show a strong linear relationship between iron and R2*. The iron concentration in these regions is less than 50 μg/g and it was concluded that in tissue with low iron content, other tissue properties - such as water content - are dominating the value of R2*. This result was replicated with data measured at 9.4 T, when only tissue with an iron concentration of less than 50 μg/g was considered

Resistant Starch Type 2 from Wheat Reduces Postprandial Glycemic Response with Concurrent Alterations in Gut Microbiota Composition.

The majority of research on the physiological effects of dietary resistant starch type 2 (RS2) has focused on sources derived from high-amylose maize. In this study, we conduct a double-blind, randomized, placebo-controlled, crossover trial investigating the effects of RS2 from wheat on glycemic response, an important indicator of metabolic health, and the gut microbiota. Overall, consumption of RS2-enriched wheat rolls for one week resulted in reduced postprandial glucose and insulin responses relative to conventional wheat when participants were provided with a standard breakfast meal containing the respective treatment rolls (RS2-enriched or conventional wheat). This was accompanied by an increase in the proportions of bacterial taxa Ruminococcus and Gemmiger in the fecal contents, reflecting the composition in the distal intestine. Additionally, fasting breath hydrogen and methane were increased during RS2-enriched wheat consumption. However, although changes in fecal short-chain fatty acid (SCFA) concentrations were not significant between control and RS-enriched wheat roll consumption, butyrate and total SCFAs were positively correlated with relative abundance of Faecalibacterium, Ruminoccocus, Roseburia, and Barnesiellaceae. These effects show that RS2-enriched wheat consumption results in a reduction in postprandial glycemia, altered gut microbial composition, and increased fermentation activity relative to wild-type wheat

Diffusion weighted and dynamic contrast enhanced MRI as an imaging biomarker for stereotactic ablative body radiotherapy (SABR) of primary renal cell carcinoma.

PURPOSE:To explore the utility of diffusion and perfusion changes in primary renal cell carcinoma (RCC) after stereotactic ablative body radiotherapy (SABR) as an early biomarker of treatment response, using diffusion weighted (DWI) and dynamic contrast enhanced (DCE) MRI. METHODS:Patients enrolled in a prospective pilot clinical trial received SABR for primary RCC, and had DWI and DCE MRI scheduled at baseline, 14 days and 70 days after SABR. Tumours <5cm diameter received a single fraction of 26 Gy and larger tumours received three fractions of 14 Gy. Apparent diffusion coefficient (ADC) maps were computed from DWI data and parametric and pharmacokinetic maps were fitted to the DCE data. Tumour volumes were contoured and statistics extracted. Spearman's rank correlation coefficients were computed between MRI parameter changes versus the percentage tumour volume change from CT at 6, 12 and 24 months and the last follow-up relative to baseline CT. RESULTS:Twelve patients were eligible for DWI analysis, and a subset of ten patients for DCE MRI analysis. DCE MRI from the second follow-up MRI scan showed correlations between the change in percentage voxels with washout contrast enhancement behaviour and the change in tumour volume (ρ = 0.84, p = 0.004 at 12 month CT, ρ = 0.81, p = 0.02 at 24 month CT, and ρ = 0.89, p = 0.001 at last follow-up CT). The change in mean initial rate of enhancement and mean Ktrans at the second follow-up MRI scan were positively correlated with percent tumour volume change at the 12 month CT onwards (ρ = 0.65, p = 0.05 and ρ = 0.66, p = 0.04 at 12 month CT respectively). Changes in ADC kurtosis from histogram analysis at the first follow-up MRI scan also showed positive correlations with the percentage tumour volume change (ρ = 0.66, p = 0.02 at 12 month CT, ρ = 0.69, p = 0.02 at last follow-up CT), but these results are possibly confounded by inflammation. CONCLUSION:DWI and DCE MRI parameters show potential as early response biomarkers after SABR for primary RCC. Further prospective validation using larger patient cohorts is warranted

Interspecific aggresion between Black Redstart \kur{Phoenicurus ochruros} and Common Redstart \kur{Phoenicurus phoenicurus}: Do only neighbours fight?

Background Chemical imaging of the human brain has great potential for diagnostic and monitoring purposes. The heterogeneity of human brain iron distribution, and alterations to this distribution in Alzheimer’s disease, indicate iron as a potential endogenous marker. The influence of iron on certain magnetic resonance imaging (MRI) parameters increases with magnetic field, but is under-explored in human brain tissues above 7 T. New Method Magnetic resonance microscopy at 9.4 T is used to calculate parametric images of chemically-unfixed post-mortem tissue from Alzheimer’s cases (n = 3) and healthy controls (n = 2). Iron-rich regions including caudate nucleus, putamen, globus pallidus and substantia nigra are analysed prior to imaging of total iron distribution with synchrotron X-ray fluorescence mapping. Iron fluorescence calibration is achieved with adjacent tissue blocks, analysed by inductively coupled plasma mass spectrometry or graphite furnace atomic absorption spectroscopy. Results Correlated MR images and fluorescence maps indicate linear dependence of R2, R2* and R2’ on iron at 9.4 T, for both disease and control, as follows: [R2(s−1) = 0.072[Fe] + 20]; [R2*(s−1) = 0.34[Fe] + 37]; [R2’(s−1) = 0.26[Fe] + 16] for Fe in μg/g tissue (wet weight). Comparison with Existing Methods This method permits simultaneous non-destructive imaging of most bioavailable elements. Iron is the focus of the present study as it offers strong scope for clinical evaluation; the approach may be used more widely to evaluate the impact of chemical elements on clinical imaging parameters. Conclusion The results at 9.4 T are in excellent quantitative agreement with predictions from experiments performed at lower magnetic fields

High field magnetic resonance microscopy of the human hippocampus in Alzheimer's disease : quantitative imaging and correlation with iron

We report R2 and R2* in human hippocampus from five unfixed post-mortem Alzheimer's disease (AD) and three age-matched control cases. Formalin-fixed tissues from opposing hemispheres in a matched AD and control were included for comparison. Imaging was performed in a 600 MHz (14 T) vertical bore magnet at MR microscopy resolution to obtain R2 and R2* (62 μm × 62 μm in-plane, 80 μm slice thickness), and R1 at 250 μm isotropic resolution. R1, R2 and R2* maps were computed for individual slices in each case, and used to compare subfields between AD and controls. The magnitudes of R2 and R2* changed very little between AD and control, but their variances in the Cornu Ammonis and dentate gyrus were significantly higher in AD compared for controls (p < 0.001). To investigate the relationship between tissue iron and MRI parameters, each tissue block was cryosectioned at 30 μm in the imaging plane, and iron distribution was mapped using synchrotron microfocus X-ray fluorescence spectroscopy. A positive correlation of R2 and R2* with iron was demonstrated. While studies with fixed tissues are more straightforward to conduct, fixation can alter iron status in tissues, making measurement of unfixed tissue relevant. To our knowledge, these data represent an advance in quantitative imaging of hippocampal subfields in unfixed tissue, and the methods facilitate direct analysis of the relationship between MRI parameters and iron. The significantly increased variance in AD compared for controls warrants investigation at lower fields and in-vivo, to determine if this parameter is clinically relevant

Concentration of various trace elements in the rat retina and their distribution in different structures

Inductively coupled plasma mass spectrometry (ICP-MS) was used to quantify the total amount of trace elements in retina from adult male Sprague-Dawley rats (n = 6). Concentration of trace elements within individual retinal areas in frozen sections of the fellow eye was established with the use of two methodologies: (1) particle-induced X-ray emission (PIXE) in combination with 3D depth profiling with Rutherford backscattering spectrometry (RBS) and (2) synchrotron X-ray fluorescence (SXRF) microscopy. The most abundant metal in the retina was zinc, followed by iron and copper. Nickel, manganese, chromium, cobalt, selenium and cadmium were present in very small amounts. The PIXE and SXRF analysis yielded a non-homogenous pattern distribution of metals in the retina. Relatively high levels of zinc were found in the inner part of the photoreceptor inner segments (RIS)/outer limiting membrane (OLM), inner nuclear layer and plexiform layers. Iron was found to accumulate in the retinal pigment epithelium/choroid layer and RIS/OLM. Copper in turn, was localised primarily in the RIS/OLM and plexiform layers. The trace elements iron, copper, and zinc exist in different amounts and locations in the rat retina