IMPORTANCE Acetazolamide is commonly used to treat idiopathic intracranial hypertension (IIH), but there is insufficient information to establish an evidence base for its use. OBJECTIVE To determine whether acetazolamide is beneficial in improving vision when added to a low-sodium weight reduction diet in patients with IIH and mild visual loss. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-masked, placebo-controlled study of acetazolamide in 165 participants with IIH and mild visual loss who received a low-sodium weight-reduction diet. Participants were enrolled at 38 academic and private practice sites in North America from March 2010 to November 2012 and followed up for 6 months (last visit in June 2013). All participants met the modified Dandy criteria for IIH and had a perimetric mean deviation (PMD) between −2 dB and −7 dB. The mean age was 29 years and all but 4 participants were women. INTERVENTIONS Low-sodium weight-reduction diet plus the maximally tolerated dosage or acetazolamide (up to 4 g/d) or matching placebo for 6 months. MAIN OUTCOMES AND MEASURES The planned primary outcome variable was the change in PMD from baseline to month 6 in the most affected eye, as measured by Humphrey Field Analyzer. Perimetric mean deviation is a measure of global visual field loss (mean deviation from age-corrected normal values), with a range of 2 to −32 dB; larger negative values indicate greater vision loss. Secondary outcome variables included changes in papilledema grade, quality of life (Visual Function Questionnaire 25 [VFQ-25] and 36-Item Short Form Health Survey), headache disability, and weight at month 6. RESULTS The mean improvement in PMD was greater with acetazolamide (1.43 dB, from −3.53 dB at baseline to −2.10 dB at month 6; n = 86) than with placebo (0.71 dB, from −3.53 dB to −2.82 dB;n = 79); the difference was 0.71 dB (95% CI, 0 to 1.43 dB; P= .050). Mean improvements in papilledema grade (acetazolamide: −1.31, from 2.76 to 1.45; placebo: −0.61, from 2.76 to 2.15; treatment effect, −0.70; 95% CI, −0.99 to −0.41; P < .001) and vision-related quality of life as measured by the National Eye Institute VFQ-25 (acetazolamide: 8.33, from 82.97 to 91.30; placebo: 1.98, from 82.97 to 84.95; treatment effect, 6.35; 95% CI, 2.22 to 10.47; P = .003) and its 10-item neuro-ophthalmic supplement (acetazolamide: 9.82, from 75.45 to 85.27; placebo: 1.59, from 75.45 to 77.04; treatment effect, 8.23; 95% CI, 3.89 to 12.56; P < .001) were also observed with acetazolamide. Participants assigned to acetazolamide also experienced a reduction in weight (acetazolamide: −7.50 kg, from 107.72 kg to 100.22 kg; placebo: −3.45 kg, from 107.72 kg to 104.27 kg; treatment effect, −4.05 kg, 95% CI, −6.27 to −1.83 kg; P < .001). CONCLUSIONS AND RELEVANCE In patients with IIH and mild visual loss, the use of acetazolamide with a low-sodium weight-reduction diet compared with diet alone resulted in modest improvement in visual field function. The clinical importance of this improvement remains to be d...

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Fibroblasts represent a dynamic population of cells, exhibiting functional heterogeneity within and among tissues. Fibroblast heterogeneity also results from phenotypic differences and may arise from activation or differentiation processes taking place in the cells. We previously reported that human fibroblasts were heterogeneous with respect to surface Thy-1 expression and that separation into Thy-1 ؉ and Thy-1 ؊ subsets resulted in functionally distinct subpopulations, leading to the concept of fibroblast subset specialization. In this report we investigated whether Thy-1 ؉ and/or Thy-1 ؊ fibroblasts were capable of differentiating into myofibroblasts or lipofibroblasts. Fibroblast subsets were used from human myometrium and orbit to test this hypothesis. Only Thy-1 ؉ human myometrial and orbital fibroblasts were capable of myofibroblast differentiation after treatment with TGF␤ or platelet concentrate supernatant, assessed by ␣ smooth muscle actin expression. Interestingly, only Thy-1 ؊ , but not Thy-1 ؉ subsets differentiated to lipofibroblasts, as determined by the accumulation of cytoplasmic lipid droplets after treatment with 15-deoxy-⌬ 12 , 14 -PGJ 2 or ciglitazone. We propose that fibroblast Thy-1 display predetermines lineage to a contractile or lipid-like phenotype in the human myometrium and orbit. This additional distinction between Thy-1 ؉ and Thy-1

Thyroid eye disease (TED) is an inflammatory condition of the orbit closely associated with Graves’ disease. During the course of TED, fibrosis can develop around the extraocular muscles, and excess extracellular matrix and fat accumulates in the periorbital space. This dramatic remodeling results in protrusion of the eye, also known as exophthalmos. Current treatments are sometimes effective in alleviating the symptoms of the disease, but there remains a demand for treatments that prevent or reverse the pathological alterations of orbital tissues. Such treatments may become available as a result of research aimed at understanding the mechanism by which Graves’ disease leads to specific remodeling of orbital tissues. Recent findings have uncovered the importance of intercellular communication between autoreactive T cells and orbital fibroblasts. When orbital fibroblasts are activated, possibly by Graves’ disease–related autoantibodies, they release T cell chemoattractants, initiating an interaction in which these cells activate each other. These interactions ultimately result in fibroblasts expressing extracellular matrix molecules, proliferating and differentiating into myofibroblasts or lipofibroblasts. Although the mechanisms underlying these processes are not completely understood, several currently available therapeutic strategies might interrupt the signaling between B and T cells and fibroblasts, thereby treating the clinical manifestations of TED.

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The differentiation of preadipocyte fibroblasts to adipocytes is a crucial process to many disease states including obesity, cardiovascular, and autoimmune diseases. In Graves' disease, the orbit of the eye can become severely inflamed and infiltrated with T lymphocytes as part of the autoimmune process. The orbital fibroblasts convert to fat-like cells causing the eye to protrude, which is disfiguring and can lead to blindness. Recently, the transcription factor peroxisome proliferator activated receptor (PPAR)-gamma and its natural (15d-PGJ2) and synthetic (thiazolidinedione-type) PPAR-gamma agonists have been shown to be crucial to the in vitro differentiation of preadipocyte fibroblasts to adipocytes. We show herein several novel findings. First, that activated T lymphocytes from Graves' patients drive the differentiation of PPAR-gamma-expressing orbital fibroblasts to adipocytes. Second, this adipogenic differentiation is blocked by nonselective small molecule cyclooxygenase (Cox)-1/Cox-2 inhibitors and by Cox-2 selective inhibitors. Third, activated, but not naïve, human T cells highly express Cox-2 and synthesize prostaglandin D2 and related prostaglandins that are PPAR-gamma ligands. These provocative new findings provide evidence for how activated T lymphocytes, through production of PPAR-gamma ligands, profoundly influence human fibroblast differentiation to adipocytes. They also suggest the possibility that, in addition to the orbit, T lymphocytes influence the deposition of fat in other tissues.

The results suggest that T cells and orbital fibroblasts participate in an antigen-dependent positive feedback loop in which presentation of autoantigens by fibroblasts via MHC class II and CD40-CD40L signaling results in T-cell activation. These activated T cells stimulate fibroblast proliferation, leading to fibroblast-associated diseases in GO. Thus, therapies that interfere with CD40-CD40L signaling, antigen expression by fibroblasts, or T-cell function may be effective in preventing progression of GO symptoms.

The tumor microenvironment comprises many cell types including infiltrating immune cells such as lymphocytes, endothelial cells and a complex stroma consisting mainly of fibroblasts. Fibroblasts are heterogeneous and consist of Thy-1+ and Thy-1- subsets that define different biosynthetic and differentiation potential. They produce mediators linked to carcinogenesis and metastasis, including Cox-2 and PGE2, both of which are also increased in most cancers. This review will highlight the emerging role of the complex fibroblastic stroma in establishing a microenvironment supporting malignant transformation, tumor growth and attenuation of host anti-tumor immune responses.