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

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

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

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

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 &lt; 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

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