Tau positron emission tomography,cerebrospinal fluid and plasma biomarkers of neurodegeneration,and neurocognitive testing: an exploratory study of participants with myotonic dystrophy type 1

Journal of Neurology - To investigate Tau pathology using multimodal biomarkers of neurodegeneration and neurocognition in participants with myotonic dystrophy type 1 (DM1). We recruited twelve...     

Catecholamines and their <Emphasis Type="Italic">O</Emphasis>-methylated metabolites in vitreous humor in hypothermia cases

Purpose

The aim of this study was to assess the diagnostic value of catecholamines and their O-methylated metabolites in vitreous humor samples in identifying antemortem cold exposure and fatal hypothermia in the forensic casework.

Methods

A total of 80 autopsy cases (40 hypothermia fatalities and 40 cases in which hypothermia as the main or contributory cause of death was excluded) were selected for this study. Catecholamines and their O-methylated metabolites were measured in urine and vitreous humor samples collected at autopsy.

Results

Urine catecholamine and their O-methylated metabolite concentrations were significantly higher in hypothermia-related deaths. On the other hand, measurements in vitreous humor samples did not reveal statistically significant differences between hypothermia-related deaths and controls.

Conclusions

Globally considered, our findings seem to suggest that, contrary to urine catecholamines and their O-methylated metabolites, vitreous levels of these compounds appear to be of limited value in characterizing human antemortem stress reactions due to cold exposure and can hardly be used in the forensic setting to support the diagnosis of hypothermia.

     

Mitochondrial genome architecture in non‐alcoholic fatty liver disease

Non‐alcoholic fatty liver disease (NAFLD) is associated with mitochondrial dysfunction, a decreased liver mitochondrial DNA (mtDNA) content, and impaired energy metabolism. To understand the clinical implications of mtDNA diversity in the biology of NAFLD, we applied deep‐coverage whole sequencing of the liver mitochondrial genomes. We used a multistage study design, including a discovery phase, a phenotype‐oriented study to assess the mutational burden in patients with steatohepatitis at different stages of liver fibrosis, and a replication study to validate findings in loci of interest. We also assessed the potential protein‐level impact of the observed mutations. To determine whether the observed changes are tissue‐specific, we compared the liver and the corresponding peripheral blood entire mitochondrial genomes. The nuclear genes POLG and POLG2 (mitochondrial DNA polymerase‐γ) were also sequenced. We observed that the liver mtDNA of patients with NAFLD harbours complex genomes with a significantly higher mutational (1.28‐fold) rate and degree of heteroplasmy than in controls. The analysis of liver mitochondrial genomes of patients with different degrees of fibrosis revealed that the disease severity is associated with an overall 1.4‐fold increase in mutation rate, including mutations in genes of the oxidative phosphorylation (OXPHOS) chain. Significant differences in gene and protein expression patterns were observed in association with the cumulative number of OXPHOS polymorphic sites. We observed a high degree of homology (～98%) between the blood and liver mitochondrial genomes. A missense POLG p.Gln1236His variant was associated with liver mtDNA copy number. In conclusion, we have demonstrated that OXPHOS genes contain the highest number of hotspot positions associated with a more severe phenotype. The variability of the mitochondrial genomes probably originates from a common germline source; hence, it may explain a fraction of the ‘missing heritability’ of NAFLD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Validity of model approximations for receptor-ligand kinetics in nuclear medicine

An appropriate mathematical model is required for quantitative analysis of high affinity radioligands as direct or surrogate probes to measure receptor distribution, affinity, concentration, binding potential, and endogenous or exogenous ligand occupancy levels. For studies with positron emission tomography (PET) or single photon emission computed tomography (SPECT), the receptor-ligand compartment model has been well established and widely used. This pharmacokinetic model is represented mathematically by a set of nonlinear ordinary differential equations. Variations of models for PET and SPECT account for radioactive decay differently. These are not equivalent and entail assumptions or approximations that may be not appreciated. In this study, a general form of the model is presented and compared with others with various approximations, which are valid only under specific conditions. The various approximate formulations were analytically compared to the exact model to identify the terms that were neglected in the approximate formulations. The extent to which the approximations impact the model solutions was assessed by computer simulations based on numerical solutions to each set of equations. Specifically, each model formulation was tested using three simulated injection protocols representing a typical PET experiment, a typical SPECT experiment, and an extreme experiment where both the injected activity and the specific activity were very high. No significant differences were found among the output of the three model formulations when the PET and SPECT injection protocols were tested. The only conditions that produced significant differences occurred when the specific activity and the administered activity were simultaneously very high. These conditions, however, have little practical relevance to experimentally achievable conditions due to radiation dose and specific activity of radiopharmaceuticals     

Increased methylation at an unexplored glucocorticoid responsive element within exon 1D of NR3C1 gene is related to anxious-depressive disorders and decreased hippocampal connectivity

Among the major psychiatric disorders, anxious-depressive disorders stand out as one of the more prevalent and more frequently associated with hypothalamic-pituitary-adrenal (HPA) axis abnormalities. Methylation at the exon 1_F of the glucocorticoid receptor gene NR3C1 has been associated with both early stress exposure and risk for developing a psychiatric disorder; however, other NR3C1 promoter regions have been underexplored. Exon 1_D emerges as a suggestive new target in stress-related disorders epigenetically sensitive to early adversity. After assessment of 48 monozygotic twin pairs (n=96 subjects) informative for lifetime history of anxious-depressive disorders, they were classified as concordant, discordant or healthy in function of whether both, one or neither twin in each pair had a lifetime diagnosis of anxious-depressive disorders. DNA for epigenetic analysis was extracted from peripheral blood. Exon 1_F and exon 1_D CpG-specific methylation was analysed by means of pyrosequencing technology. Functional magnetic resonance imaging was available for 54 subjects (n=27 twin pairs). Exon 1_D CpG-specific methylation within a glucocorticoid responsive element (GRE) was correlated with familial burden of anxious-depressive disorders (r=0.35, z=2.26, p=0.02). Right hippocampal connectivity was significantly associated with CpG-specific GRE methylation (β=?2.33, t=?2.85, p=0.01). Exon 1_F was uniformly hypomethylated across all subgroups of the present sample. GRE hypermethylation at exon 1_D of the NR3C1 gene in monozygotic twins concordant for anxious-depressive disorders suggests this region plays a role in increasing vulnerability to psychosocial stress, partly mediated by altered hippocampal connectivity.     

Quality of life and stability of tooth color change at three months after dental bleaching

Purpose

Intracoronary bleaching is a minimally invasive, alternative treatment that addresses aesthetic concerns related to non-vital teeth discoloration. However, to the best of our knowledge, no studies have assessed the psychosocial impacts of such procedures on patients’ aesthetic perceptions. The aim of this study was to evaluate aesthetic perceptions and the psychosocial impact of patients up to 3 months after their teeth had been bleached with hydrogen peroxide (35%) and carbamide peroxide (37%) using the walking bleach technique.

Methods

The patients were randomly divided into two groups according to the bleaching agent used: G1?=?hydrogen peroxide 35% (n?=?25) and G2?=?carbamide peroxide 37% (n?=?25). Non-vital bleaching was performed in four sessions. Color was objectively (ΔE) and subjectively (ΔSGU) evaluated. Aesthetic perception and psychosocial factors were evaluated before, 1 week and 1 month after the bleaching using the Oral Health Impact Profile (OHIP) and Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ) questionnaires.

Results

The color change (ΔE) values at 1 month were G1?=?16.80?±?6.07 and G2?=?14.09?±?4.83. These values remained stable until the third month after treatment (p?>?0.05). There was a decrease in the values of OHIP-aesthetics and PIDAQ after treatment versus baseline (p?<?0.05). This status was maintained through the third month after treatment.

Conclusions

Both agents were highly effective and had a positive impact on the aesthetic perception and psychosocial impact of patients, values that also remained stable over time. Non-vital bleaching yields positive and stable impacts on aesthetic perception and psychosocial factors. ClinicalTrials.gov identifier NCT02718183.

     

ASO Visual Abstract: Repeat Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Cancers with Peritoneal Metastasis—A 30-year Institutional Experience

Annals of Surgical Oncology -     

Non-invasive high-speed blinking kinematics characterization

Graefe's Archive for Clinical and Experimental Ophthalmology - The objective of this study was to analyze the differences in blinking kinematics of spontaneous and voluntary blinks using for...