Angle-closure glaucoma (ACG) is a subset of glaucoma affecting 16 million people. Although 4 million people are bilaterally blind from ACG, the causative molecular mechanisms of ACG remain to be ...defined. High intraocular pressure induces glaucoma in ACG. High intraocular pressure traditionally was suggested to result from the iris blocking or closing the angle of the eye, thereby limiting aqueous humor drainage. Eyes from individuals with ACG often have a modestly decreased axial length, shallow anterior chamber and relatively large lens, features that predispose to angle closure. Here we show that genetic alteration of a previously unidentified serine protease (PRSS56) alters axial length and causes a mouse phenotype resembling ACG. Mutations affecting this protease also cause a severe decrease of axial length in individuals with posterior microphthalmia. Together, these data suggest that alterations of this serine protease may contribute to a spectrum of human ocular conditions including reduced ocular size and ACG.
Some pathological manifestations of diabetes in the eye include retinopathy, cataracts and elevated intraocular pressure (IOP). Loss of retinal ganglion cells (RGCs) in non-proliferative stages of ...diabetic retinopathy and small increases in IOP in diabetic patients has raised the possibility that diabetes affects the development and progression of ocular hypertension and glaucoma. The Ins2Akita mutation is known to cause diabetes and retinopathy on a C57BL/6J (B6) background by as early as 3 months of age. Here, the impact of the Akita mutation on glaucoma was assessed using DBA/2J (D2) mice, a widely used mouse model of ocular hypertension induced glaucoma. In D2.Ins2Akita/+ mice, the contribution of diabetes to vascular permeability, IOP elevation, RGC loss, and glaucoma development was assessed. D2.Ins2Akita/+ mice developed a severe diabetic nephropathy and early mortality between 6-8 months of age. This agrees with previous reports showing that the D2 background is more susceptible to diabetes than the B6 background. In addition, D2.Ins2Akita/+ mice had vascular leakage, astrocyte reactivity and a significant increase in IOP. However no RGC loss and no anterograde axonal transport dysfunction were found at 8.5 months of age. Therefore, our data show that despite severe diabetes and an increased IOP compared to controls, RGCs do not lose axon transport or degenerate. This may be due to a DBA/2J-specific genetic modifier(s) that could provide novel and important avenues for developing new therapies for diabetic retinopathy and possibly glaucoma.
Glaucoma is an age-related neurodegenerative disorder involving the loss of retinal ganglion cells (RGCs), which results in blindness. Studies in animal models have shown that activation of ...inflammatory processes occurs early in the disease. In particular, the complement cascade is activated very early in DBA/2J mice, a widely used mouse model of glaucoma. A comprehensive analysis of the role of the complement cascade in DBA/2J glaucoma has not been possible because DBA/2J mice are naturally deficient in complement component 5 (C5, also known as hemolytic complement, Hc), a key mediator of the downstream processes of the complement cascade, including the formation of the membrane attack complex.
To assess the role of C5 in DBA/2J glaucoma, we backcrossed a functional C5 gene from strain C57BL/6J to strain DBA/2J for at least 10 generations. The prevalence and severity of glaucoma was evaluated using ocular examinations, IOP measurements, and assessments of optic nerve damage and RGC degeneration. To understand how C5 affects glaucoma, C5 expression was assessed in the retinas and optic nerves of C5-sufficient DBA/2J mice, using immunofluorescence.
C5-sufficient DBA/2J mice developed a more severe glaucoma at an earlier age than standard DBA/2J mice, which are therefore protected by C5 deficiency. Components of the membrane attack complex were found to be deposited at sites of axonal injury in the optic nerve head and associated with RGC soma in the retina.
C5 plays an important role in glaucoma, with its deficiency lessening disease severity. These results highlight the importance of fully understanding the role of the complement cascade in neurodegenerative diseases. Inhibiting C5 may be beneficial as a therapy for human glaucoma.
While all forms of glaucoma are characterized by a specific pattern of retinal ganglion cell death, they are clinically divided into several distinct subclasses, including normal tension glaucoma, ...primary open angle glaucoma, congenital glaucoma, and secondary glaucoma. For each type of glaucoma there are likely numerous molecular pathways that control susceptibility to the disease. Given this complexity, a single animal model will never precisely model all aspects of all the different types of human glaucoma. Therefore, multiple animal models have been utilized to study glaucoma but more are needed. Because of the powerful genetic tools available to use in the laboratory mouse, it has proven to be a highly useful mammalian system for studying the pathophysiology of human disease. The similarity between human and mouse eyes coupled with the ability to use a combination of advanced cell biological and genetic tools in mice have led to a large increase in the number of studies using mice to model specific glaucoma phenotypes. Over the last decade, numerous new mouse models and genetic tools have emerged, providing important insight into the cell biology and genetics of glaucoma. In this review, we describe available mouse genetic models that can be used to study glaucoma-relevant disease/pathobiology. Furthermore, we discuss how these models have been used to gain insights into ocular hypertension (a major risk factor for glaucoma) and glaucomatous retinal ganglion cell death. Finally, the potential for developing new mouse models and using advanced genetic tools and resources for studying glaucoma are discussed.
•Mice can be used to model specific glaucoma-relevant phenotypes.•Mice are a valuable tool to determine the molecular mechanisms underlying glaucoma phenotypes.•Mice are a valuable tool to probe the cell biology underlying findings from human genetic studies.•Mice can be used to find new genes and molecular pathways that contribute to human glaucoma.
The soft modelling of the skin tones in Vermeer’s
Girl with a Pearl Earring
(Mauritshuis) has been remarked upon by art historians, and is their main argument to date this painting to c. 1665. This ...paper describes the materials and techniques Vermeer used to accomplish the smooth flesh tones and facial features of the
Girl
, which were investigated as part of the 2018
Girl in the Spotlight
research project. It combines macroscopic X-ray fluorescence imaging (MA-XRF), reflectance imaging spectroscopy (RIS), and 3D digital microscopy. Vermeer built up the face, beginning with distinct areas of light and dark. He then smoothly blended the final layers to create almost seamless transitions. The combination of advanced imaging techniques highlighted that Vermeer built the soft contour around her face by leaving a ‘gap’ between the background and the skin. It also revealed details that were otherwise not visible with the naked eye, such as the eyelashes. Macroscopic imaging was complemented by the study of paint cross-sections using: light microscopy, SEM–EDX, FIB-STEM, synchrotron radiation µ-XRPD and FTIR–ATR. Vermeer intentionally used different qualities or grades of lead white in the flesh paints, showing different hydrocerussite/cerussite ratios and particle sizes. Lead isotope analysis showed that the geographic source of lead, from which the different types of lead white were manufactured, was the same: the region of Peak District of Derbyshire, UK. Finally, cross-section analysis identified the formation of new lead species in the paints: lead soaps and palmierite (K
2
Pb(SO
4
)
2
), associated with the red lake.
Worldwide there is a shortage of available organs for patients requiring transplants. However, some countries such as France, Italy and Spain have had greater success by allowing donations from ...patients with unexpected and unrecoverable circulatory arrest who arrive in the ED. Significant advances in the surgical approach to organ recovery from donation after circulatory death (DCD) led to the establishment of a pilot programme for uncontrolled DCD in the ED of the Royal Infirmary of Edinburgh. This paper describes the programme and discusses the lessons learnt.
It is now clear that cytokines function as powerful regulators of glial cell function in the central nervous system (CNS), either inhibiting or promoting their contribution to CNS pathology. Although ...these interactions are complex, the availability of animals with targeted deletions of these genes and/or their receptors, as well as transgenic mice in which cytokine expression has been targeted to specific cell types, and the availability of purified populations of glia that can be studied in vitro, has provided a wealth of interesting and frequently surprising data relevant to this activity. A particular feature of many of these studies is that it is the nature of the receptor that is expressed, rather than the cytokine itself, that regulates the functional properties of these cytokines. Because cytokine receptors are themselves modulated by cytokines, it becomes evident that the effects of these cytokines may change dramatically depending upon the cytokine milieu present in the immediate environment. An additional exciting aspect of these studies is the previously underappreciated role of these factors in repair to the CNS. In this review, we focus on current information that has helped to define the role of cytokines in regulating glial cell function as it relates to the properties of microglia and astrocytes.
Objective
This study evaluated weight changes after cessation of the 10‐year intensive lifestyle intervention (ILI) in the Look AHEAD (Action for Health in Diabetes) study. It was hypothesized that ...ILI participants would be more likely to gain weight during the 2‐year observational period following termination of weight‐loss–maintenance counseling than would participants in the diabetes support and education (DSE) control group.
Methods
Look AHEAD was a randomized controlled trial that compared the effects of ILI and DSE on cardiovascular morbidity and mortality in participants with overweight/obesity and type 2 diabetes. Look AHEAD was converted to an observational study in September 2012.
Results
Two years after the end of the intervention (EOI), ILI and DSE participants lost a mean (SE) of 1.2 (0.2) kg and 1.8 (0.2) kg, respectively (P = 0.003). In addition, 31% of ILI and 23.9% of DSE participants gained ≥ 2% (P < 0.001) of EOI weight, whereas 36.3% and 45.9% of the respective groups lost ≥ 2% of EOI weight (P = 0.001). Two years after the EOI, ILI participants reported greater use of weight‐control behaviors than DSE participants.
Conclusions
Both groups lost weight during the 2‐year follow‐up period, but more ILI than DSE participants gained ≥ 2% of EOI weight. Further understanding is needed of factors that affected long‐term weight change in both groups.
IL-11 Regulates Autoimmune Demyelination Gurfein, Blake T; Zhang, Yueting; Lopez, Carolina B ...
The Journal of immunology (1950),
10/2009, Letnik:
183, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Current therapies for the autoimmune demyelinating disease multiple sclerosis (MS) target inflammation, but do not directly address neuroprotection or lesion repair. Cytokines of the gp130 family ...regulate survival and differentiation of both neural and immune cells, and we recently identified expression of the family member IL-11 in active MS plaques. In this study, we show that IL-11 regulates the clinical course and neuropathology of experimental autoimmune encephalomyelitis, a demyelinating model that mimics many of the clinical and pathologic features of MS. Importantly, the effects of IL-11 are achieved via a combination of immunoregulation and direct neuroprotection. IL-11R-alpha-null (IL-11Ralpha(-/-)) mice displayed a significant increase in clinical severity and neuropathology of experimental autoimmune encephalomyelitis compared with wild-type littermates. Inflammation, demyelination, and oligodendrocyte and neuronal loss were all exacerbated in IL-11Ra(-/-) animals. Conversely, wild-type mice treated with IL-11 displayed milder clinical signs and neuropathology than vehicle-treated controls. In cocultures of murine myelin oligodendrocyte glycoprotein(35-55)-specific CD4+ T lymphocytes and CD11c+ APCs, IL-11 treatment resulted in a significant decrease in T cell-derived effector cytokine production. This effect was generated via modulation of CD11c+ APC-mediated lymphocyte activation, and was associated with a decrease in the size of the CD11c+ cell population. Conversely, IL-11 strongly reduced apoptosis and potentiated mitosis in primary cultures of mouse oligodendrocyte progenitors. Collectively, these data reveal that IL-11 regulates inflammatory demyelination via a unique combination of immunoregulation and neuroprotection. IL-11 signaling may represent a therapeutic avenue to restrict CNS inflammation and potentiate oligodendrocyte survival in autoimmune demyelinating disease.
Mechanisms that regulate oligodendrocyte survival and myelin formation are an intense focus of research into myelin repair in the lesions of multiple sclerosis (MS). Although demyelination and ...oligodendrocyte loss are pathological hallmarks of the disease, increased oligodendrocyte numbers and remyelination are frequently observed in early lesions, but these diminish as the disease course progresses. In the current study, we used a microarray-based approach to investigate genes regulating repair in MS lesions, and identified interleukin-11 (IL-11) as an astrocyte-derived factor that potentiates oligodendrocyte survival and maturation, and myelin formation. IL-11 was induced in human astrocyte cultures by the cytokines IL-1beta and TGFbeta1, which are both prominently expressed in MS plaques. In MS tissue samples, IL-11 was expressed by reactive astrocytes, with expression particularly localized at the myelinated border of both active and silent lesions. Its receptor, IL-11R alpha, was expressed by oligodendrocytes. In experiments in human cultures in vitro, IL-11R alpha localized to immature oligodendrocytes, and its expression decreased during maturation. In cultures treated with IL-11, we observed a significant increase in oligodendrocyte number, and this was associated with enhanced oligodendrocyte survival and maturation. Importantly, we also found that IL-11 treatment was associated with significantly increased myelin formation in rodent CNS cocultures. These data are the first to implicate IL-11 in oligodendrocyte viability, maturation, and myelination. We suggest that this pathway may represent a potential therapeutic target for oligodendrocyte protection and remyelination in MS.
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