Objective quantification of vitreous haze on optical coherence tomography scans: no evidence for relationship between uveitis and inflammation in multiple sclerosis

BACKGROUND AND PURPOSE: The occurrence of intermediate uveitis, which is characterized by the presence of vitreous haze (VH), in patients with multiple sclerosis (MS) may be a sign of coexistent inflammatory central nervous system (CNS) disease activity. Using an automated algorithm to quantify VH on optical coherence tomography (OCT) scans, the aim was to investigate whether VH in MS patients is associated with signs of inflammatory CNS disease activity. METHODS: Vitreous haze was quantified on OCT macular volume scans of 290 MS patients and 85 healthy controls (HCs). The relationship between VH and clinical, retinal OCT and magnetic resonance imaging parameters of inflammatory disease activity was investigated using generalized estimating equations. RESULTS: Mean VH scores did not differ between patients and HCs (P = 0.629). Six patients (2.1%) showed values higher than the highest of the controls by HCs. VH scores did not differ between the different disease types or between eyes with and without a history of optic neuritis (P = 0.132). VH was not associated with inner nuclear layer volume on OCT (P = 0.233), cerebral T2 lesion load on magnetic resonance imaging (P = 0.416) or the development of new relapses (P = 0.205). CONCLUSION: In this study, OCT-based automated VH estimation did not detect increased vitreous inflammation in MS patients compared to HCs and did not find an association with CNS inflammatory burden

Directing the Aggregation of Native Polythiophene during in Situ Polymerization

The performance of semiconducting polymers strongly depends on their intra- and intermolecular electronic interactions. Therefore, the morphology and particularly crystallinity and crystal structure play a crucial role in enabling a sufficient overlap between the orbitals of neighboring polymers. A new solution-based in situ polymerization for the fabrication of native polythiophene thin films is presented, which exploits the film formation process to influence the polymer crystal structure in the resulting thin films. The synthesis of the insoluble polythiophene is based on an oxidative reaction in which the oxidizing agent, iron(III) p-toluenesulfonate (FeTos), initially oxidizes the monomers to enable the polymer chain growth and secondly the final polymers, thereby chemically doping the polythiophene. To exploit the fact that the doped polythiophene has a different crystal packing structure compared to the undoped polythiophene, we investigate the structural effect of this inherent doping process by varying the amounts of FeTos in the reaction mixture, creating polythiophene thin films with different degrees of doping. The structural investigation performed by means of grazing incidence wide-angle X-ray scattering (GIWAXS) suggests that the strongly doped polymer chains aggregate in a $π$-stacked manner in the film formation process. Moreover, this π-stacking can be maintained after the removal of the dopant molecules. GIWAXS measurements, molecular dynamics simulations, and spectroscopic analysis suggest the presence of polythiophene in a novel and stable crystal structure with an enhanced intermolecular interaction

Exploring Vitreous Haze as a Potential Biomarker for Accelerated Glymphatic Outflow and Neurodegeneration in Multiple Sclerosis: A Cross-Sectional Study

Background: The glymphatic system removes neurodegenerative debris. The ocular glymphatic outflow is from the eye to the proximal optic nerve. In multiple sclerosis (MS), atrophy of the optic nerve increases the glymphatic outflow space. Here, we tested whether vitreous haze (VH) can provide novel insights into the relationship between neurodegeneration and the ocular glymphatic system in MS. Methods: This cross-sectional study comprised 315 persons with MS and 87 healthy controls (HCs). VH was quantified from optical coherence tomography (OCT) volume scans. Neurodegeneration was determined on three-dimensional T1 (3DT1) MRI, lesion detection on fluid-attenuated inversion (FLAIR), and layer thickness on OCT. Generalized estimating equations, corrected for age, were used to analyze associations between VH and metrics for neurodegeneration, demographics, and clinical scales. Group differences were determined between mild, moderate, and severe disability. Results: On the group level, VH scores were comparable between MS and control (p = 0.629). In MS, VH scores declined with disease duration (β = −0.009, p = 0.004) and age (β = −0.007, p = 0.001). There was no relation between VH scores and higher age in HCs. In MS patients, VH was related to normalized gray (NGMV, β = 0.001, p = 0.011) and white matter volume (NWMV, β = 0.001, p = 0.003), macular ganglion cell–inner plexiform layer thickness (mGCIPL, β = 0.006, p < 0.001), and peripapillary retinal nerve fiber layer thickness (pRNFL, β = 0.004, p = 0.008). VH was significantly lower in severe compared to mild disability (mean difference −28.86%, p = 0.058). Conclusions: There is a correlation between VH on OCT and disease duration, more severe disability and lower brain volumes in MS. Biologically, these relationships suggest accelerated glymphatic clearance with disease-related atrophy

Proton-Binding Sites of Acid-Sensing Ion Channel 1

Acid-sensing ion channels (ASICs) are proton-gated cation channels that exist throughout the mammalian central and peripheral nervous systems. ASIC1 is the most abundant of all the ASICs and is likely to modulate synaptic transmission. Identifying the proton-binding sites of ASCI1 is required to elucidate its pH-sensing mechanism. By using the crystal structure of ASIC1, the protonation states of each titratable site of ASIC1 were calculated by solving the Poisson-Boltzmann equation under conditions wherein the protonation states of all these sites are simultaneously in equilibrium. Four acidic-acidic residue pairs—Asp238-Asp350, Glu220-Asp408, Glu239-Asp346, and Glu80-Glu417—were found to be highly protonated. In particular, the Glu80-Glu417 pair in the inner pore was completely protonated and possessed 2 H+, implying its possible importance as a proton-binding site. The pKa of Glu239, which forms a pair with a possible pH-sensing site Asp346, differs among each homo-trimer subunit due to the different H-bond pattern of Thr237 in the different protein conformations of the subunits. His74 possessed a pKa of ≈6–7. Conservation of His74 in the proton-sensitive ASIC3 that lacks a residue corresponding to Asp346 may suggest its possible pH-sensing role in proton-sensitive ASICs

Retinal inner nuclear layer volume reflects inflammatory disease activity in multiple sclerosis; a longitudinal OCT study.

BACKGROUNG: The association of peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness with neurodegeneration in multiple sclerosis (MS) is well established. The relationship of the adjoining inner nuclear layer (INL) with inflammatory disease activity is less well understood. OBJECTIVE: The objective of this paper is to investigate the relationship of INL volume changes with inflammatory disease activity in MS. METHODS: In this longitudinal, multi-centre study, optical coherence tomography (OCT) and clinical data (disability status, relapses and MS optic neuritis (MSON)) were collected in 785 patients with MS (68.3% female) and 92 healthy controls (63.4% female) from 11 MS centres between 2010 and 2017 and pooled retrospectively. Data on pRNFL, GCIPL and INL were obtained at each centre. RESULTS: There was a significant increase in INL volume in eyes with new MSON during the study (N = 61/1562, β = 0.01 mm(3), p < .001). Clinical relapses (other than MSON) were significantly associated with increased INL volume (β = 0.005, p = .025). INL volume was independent of disease progression (β = 0.002 mm(3), p = .474). CONCLUSION: Our data demonstrate that an increase in INL volume is associated with MSON and the occurrence of clinical relapses. Therefore, INL volume changes may be useful as an outcome marker for inflammatory disease activity in MSON and MS treatment trials

High Salt Intake Down-Regulates Colonic Mineralocorticoid Receptors, Epithelial Sodium Channels and 11β-Hydroxysteroid Dehydrogenase Type 2

Besides the kidneys, the gastrointestinal tract is the principal organ responsible for sodium homeostasis. For sodium transport across the cell membranes the epithelial sodium channel (ENaC) is of pivotal relevance. The ENaC is mainly regulated by mineralocorticoid receptor mediated actions. The MR activation by endogenous 11β-hydroxy-glucocorticoids is modulated by the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Here we present evidence for intestinal segment specific 11β-HSD2 expression and hypothesize that a high salt intake and/or uninephrectomy (UNX) affects colonic 11β-HSD2, MR and ENaC expression. The 11β-HSD2 activity was measured by means of 3H-corticosterone conversion into 3H-11-dehydrocorticosterone in Sprague Dawley rats on a normal and high salt diet. The activity increased steadily from the ileum to the distal colon by a factor of about 3, an observation in line with the relevance of the distal colon for sodium handling. High salt intake diminished mRNA and protein of 11β-HSD2 by about 50% (p<0.001) and reduced the expression of the MR (p<0.01). The functionally relevant ENaC-β and ENaC-γ expression, a measure of mineralocorticoid action, diminished by more than 50% by high salt intake (p<0.001). The observed changes were present in rats with and without UNX. Thus, colonic epithelial cells appear to contribute to the protective armamentarium of the mammalian body against salt overload, a mechanism not modulated by UNX

Association of polymorphisms in HCN4 with mood disorders and obsessive compulsive disorder

Hyperpolarization activated cyclic nucleotide-gated (HCN) potassium channels are implicated in the control of neuronal excitability and are expressed widely in the brain. HCN4 is expressed in brain regions relevant to mood and anxiety disorders including specific thalamic nuclei, the basolateral amygdala, and the midbrain dopamine system. We therefore examined the association of HCN4 with a group of mood and anxiety disorders. We genotyped nine tag SNPs in the HCN4 gene using Sequenom iPLEX Gold technology in 285 Caucasian patients with DSM-IV mood disorders and/or obsessive compulsive disorder and 384 Caucasian controls. HCN4 polymorphisms were analyzed using single marker and haplotype-based association methods. Three SNPs showed nominal association in our population (rs12905211, rs3859014, rs498005). SNP rs12905211 maintained significance after Bonferroni correction, with allele T and haplotype CTC overrepresented in cases. These findings suggest HCN4 as a genetic susceptibility factor for mood and anxiety disorders; however, these results will require replication using a larger sample

BMP axis in cancer cachexia

BACKGROUND Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although cancer cachexia is responsible for about 25% of cancer deaths, no effective therapies are available, and the underlying mechanisms have not been fully elucidated. Its occurrence complicates patients’ management, reduces tolerance to treatments and negatively affects patient quality of life. Muscle wasting, mainly due to increased protein breakdown rates, is one of the most prominent features of cachexia. Blocking muscle loss in cachexia mouse models dramatically prolongs survival even of animals in which tumor growth is not inhibited. Recent observations showed that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is a master regulator of muscle homeostasis. BMP-Smad1/5/8 axis negatively regulates a novel ubiquitin ligase (MUSA1) required for muscle loss induced by denervation. MATERIALS AND METHODS First aim of the present work was to test if alterations of the BMP signaling pathway occur in cancer-induced muscle wasting in patients. For this purpose we checked the state of activation of the BMP pathway in muscle of cachectic vs non–cachectic patients affected by colon, pancreatic and esophagus cancer and in control subjects. We checked by Western Blot the phosphorylation levels of Smad1/5/8 and of Smad3 and by quantitative Real-Time PCR (qRT-PCR) the expression levels of different atrophy-related genes The second aim was to evaluate the degree of muscle atrophy and distribution of muscle fibers in patients and control subjects using morphometric and immunohistochemical analyses. We also performed analysis on distribution of NCAM positive muscle fibers to assess the effect of denervation on muscle tropism. RESULTS From December 2014 we collected 95 rectus abdominis muscle biopsies of cancer patients and 11 from control subjects. In line with the results we obtained in C26 mice model (a well-established cancer cachexia experimental model) Smad1/5/8 phosphorylation, readout of the state of activation of the BMP pathway, was nearly completely abrogated in the muscles of cancer cachectic patients compared to cancer non-cachectic ones. Interestingly, the level of phosphorylation of Smad3 was not significantly affected suggesting specific effects of cancer growth on BMP pathway. The expression levels of different atrophy-related genes including MUSA1 were induced in the cachectic muscles. Interestingly, several BMP related genes are also changing the expression during cancer growth. We also found a correlation between suppression of BMP pathway, expression of atrophy related genes and Noggin, known to block BMP pathway. Morphometric analysis shown that patients with cancer cachexia have smaller myofiber diameter (in particular fast type fibers) in comparison to age-matched controls. In skeletal muscle from cancer patients (either cachectic or non-cachectic) we detected a prevalence of flat shaped, angulated and severely atrophic myofibers (i.e. morphological features of denervated myofibers), big fiber-type grouping (i.e. typical hallmark of denervation/reinnervation events) and numerous NCAM positive myofibers (i.e. specific marker of denervation). CONCLUSIONS These findings are consistent with the hypothesis that BMP inhibition is permissive to cachexia onset. Since the reactivation of the BMP-dependent signaling and MUSA1 suppression was sufficient to prevent tumor-induced muscle atrophy in our C26 mouse model (data not shown), the present data suggest that the BMP axis can be an effective target for therapeutic approaches to counteract cachexia also in cancer patients. The results of morphometric and immunohistochemical studies collected till now may suggest that denervation contributes to myofiber atrophy in cancer cachexia

The consumer scam: an agency-theoretic approach

Despite the extensive body of literature that aims to explain the phenomenon of consumer scams, the structure of information in scam relationships remains relatively understudied. The purpose of this article is to develop an agency-theoretical approach to the study of information in perpetrator-victim interactions. Drawing a distinction between failures of observation and failures of judgement in the pre-contract phase, we introduce a typology and a set of propositions that explain the severity of adverse selection problems in three classes of scam relationships. Our analysis provides a novel, systematic explanation of the structure of information that facilitates scam victimisation, while also enabling critical scrutiny of a core assumption in agency theory regarding contract design. We highlight the role of scam perpetrators as agents who have access to private information and exercise considerable control over the terms and design of scam relationships. Focusing on the consumer scam context, we question a theoretical assumption, largely taken for granted in the agency literature, that contact design is necessarily in the purview of the uninformed principal