Tear proteomic analysis of Sjogren syndrome patients with dry eye syndrome by two-dimensional-nano-liquid chromatography coupled with tandem mass spectrometry

We examined the tear film proteome of patients with Sjögren's syndrome (SS) and dry eye syndrome (group A), patients with dry eye symptoms (group B) and normal volunteers (group C). Tear samples were pooled from 8 subjects from each group and were subjected to two-dimensional-nano-liquid chromatography coupled with tandem mass spectrometry (2D-nano-LC-MS/MS). The tear breakup time for group A was significantly reduced compared with group B and C (P < 0.001). Group A (Schirmer I test, 2.13 +/- 2.38 mm/5 min) had markedly lower tear volume than group B (5.94 +/- 4.75 mm/5 min) and C (14.44 +/- 6.57 mm/5 min) (P < 0.001). Group A had significantly higher normalized tear protein content (1.8291 +/- 0.2241 mu g/mm) than group B (1.0839 +/- 0.1120 mu g/mm) (P = 0.001) and C (0.2028 +/- 0.0177 mu g/mm) (P = 0.001). The 2D-nano-LC-MS/MS analysis identified a total of 435 proteins, including 182 (54.8%),247 (74.4%) and 278 (83.7%) in group A, B, and C, respectively, with 56 (16.7%) proteins including defensin alpha 1, clusterin and lactotransferrin unique to group A. In conclusion, dry eye syndrome in SS patients is associated with an altered proteomic profile with dysregulated expression of proteins involved in a variety of important cellular process including inflammation, immunity, and oxidative stress

Evaluation of a combined index of optic nerve structure and function for glaucoma diagnosis

<p>Abstract</p> <p>Background</p> <p>The definitive diagnosis of glaucoma is currently based on congruent damage to both optic nerve structure and function. Given widespread quantitative assessment of both structure (imaging) and function (automated perimetry) in glaucoma, it should be possible to combine these quantitative data to diagnose disease. We have therefore defined and tested a new approach to glaucoma diagnosis by combining imaging and visual field data, using the anatomical organization of retinal ganglion cells.</p> <p>Methods</p> <p>Data from 1499 eyes of glaucoma suspects and 895 eyes with glaucoma were identified at a single glaucoma center. Each underwent Heidelberg Retinal Tomograph (HRT) imaging and standard automated perimetry. A new measure combining these two tests, the structure function index (SFI), was defined in 3 steps: 1) calculate the probability that each visual field point is abnormal, 2) calculate the probability of abnormality for each of the six HRT optic disc sectors, and 3) combine those probabilities with the probability that a field point and disc sector are linked by ganglion cell anatomy. The SFI was compared to the HRT and visual field using receiver operating characteristic (ROC) analysis.</p> <p>Results</p> <p>The SFI produced an area under the ROC curve (0.78) that was similar to that for both visual field mean deviation (0.78) and pattern standard deviation (0.80) and larger than that for a normalized measure of HRT rim area (0.66). The cases classified as glaucoma by the various tests were significantly non-overlapping. Based on the distribution of test values in the population with mild disease, the SFI may be better able to stratify this group while still clearly identifying those with severe disease.</p> <p>Conclusions</p> <p>The SFI reflects the traditional clinical diagnosis of glaucoma by combining optic nerve structure and function. In doing so, it identifies a different subset of patients than either visual field testing or optic nerve head imaging alone. Analysis of prospective data will allow us to determine whether the combined index of structure and function can provide an improved standard for glaucoma diagnosis.</p

Advancing clinical trials for inherited retinal diseases: Recommendations from the second monaciano symposium

Major advances in the study of inherited retinal diseases (IRDs) have placed efforts to develop treatments for these blinding conditions at the forefront of the emerging field of precision medicine. As a result, the growth of clinical trials for IRDs has increased rapidly over the past decade and is expected to further accelerate as more therapeutic possibilities emerge and qualified participants are identified. Although guided by established principles, these specialized trials, requiring analysis of novel outcome measures and endpoints in small patient populations, present multiple challenges relative to study design and ethical considerations. This position paper reviews recent accomplishments and existing challenges in clinical trials for IRDs and presents a set of recommendations aimed at rapidly advancing future progress. The goal is to stimulate discussions among researchers, funding agencies, industry, and policy makers that will further the design, conduct, and analysis of clinical trials needed to accelerate the approval of effective treatments for IRDs, while promoting advocacy and ensuring patient safety

Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease

This work was supported by a research fellowship grant from the Crohn’s and Colitis in Childhood Research Association (CICRA) and a small project grant from Crohn’s and Colitis UK (CCUK). We would like to acknowledge Professor Ian Sanderson, who helped with the initial design of this work, and provided important support throughout. We would also like to thank Dr Gary Warne for his advice and assistance in the use of the sorting by flow cytometry. We would also like to thank Dr Raj Lahiri and Professor Graham Foster for the kind gift of the primers for the ISGs (2’5’ OAS and MxA)

Development and validation of a computerized expert system for evaluation of automated visual fields from the Ischemic Optic Neuropathy Decompression Trial

BACKGROUND: The objective of this report is to describe the methods used to develop and validate a computerized system to analyze Humphrey visual fields obtained from patients with non-arteritic anterior ischemic optic neuropathy (NAION) and enrolled in the Ischemic Optic Neuropathy Decompression Trial (IONDT). The IONDT was a multicenter study that included randomized and non-randomized patients with newly diagnosed NAION in the study eye. At baseline, randomized eyes had visual acuity of 20/64 or worse and non-randomized eyes had visual acuity of better than 20/64 or were associated with patients refusing randomization. Visual fields were measured before treatment using the Humphrey Field Analyzer with the 24-2 program, foveal threshold, and size III stimulus. METHODS: We used visual fields from 189 non-IONDT eyes with NAION to develop the computerized classification system. Six neuro-ophthalmologists ("expert panel") described definitions for visual field patterns defects using 19 visual fields representing a range of pattern defect types. The expert panel then used 120 visual fields, classified using these definitions, to refine the rules, generating revised definitions for 13 visual field pattern defects and 3 levels of severity. These definitions were incorporated into a rule-based computerized classification system run on Excel(® )software. The computerized classification system was used to categorize visual field defects for an additional 95 NAION visual fields, and the expert panel was asked to independently classify the new fields and subsequently whether they agreed with the computer classification. To account for test variability over time, we derived an adjustment factor from the pooled short term fluctuation. We examined change in defects with and without adjustment in visual fields of study participants who demonstrated a visual acuity decrease within 30 days of NAION onset (progressive NAION). RESULTS: Despite an agreed upon set of rules, there was not good agreement among the expert panel when their independent visual classifications were compared. A majority did concur with the computer classification for 91 of 95 visual fields. Remaining classification discrepancies could not be resolved without modifying existing definitions. Without using the adjustment factor, visual fields of 63.6% (14/22) patients with progressive NAION and no central defect, and all (7/7) patients with a paracentral defect, worsened within 30 days of NAION onset. After applying the adjustment factor, the visual fields of the same patients with no initial central defect and 5/7 of the patients with a paracentral defect were seen to worsen. CONCLUSION: The IONDT developed a rule-based computerized system that consistently defines pattern and severity of visual fields of NAION patients for use in a research setting

Treatment with a corticotrophin releasing factor 2 receptor agonist modulates skeletal muscle mass and force production in aged and chronically ill animals

<p>Abstract</p> <p>Background</p> <p>Muscle weakness is associated with a variety of chronic disorders such as emphysema (EMP) and congestive heart failure (CHF) as well as aging. Therapies to treat muscle weakness associated with chronic disease or aging are lacking. Corticotrophin releasing factor 2 receptor (CRF2R) agonists have been shown to maintain skeletal muscle mass and force production in a variety of acute conditions that lead to skeletal muscle wasting.</p> <p>Hypothesis</p> <p>We hypothesize that treating animals with a CRF2R agonist will maintain skeletal muscle mass and force production in animals with chronic disease and in aged animals.</p> <p>Methods</p> <p>We utilized animal models of aging, CHF and EMP to evaluate the potential of CRF2R agonist treatment to maintain skeletal muscle mass and force production in aged animals and animals with CHF and EMP.</p> <p>Results</p> <p>In aged rats, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater extensor digitorum longus (EDL) force production, EDL mass, soleus mass and soleus force production compared to age matched untreated animals. In the hamster EMP model, we demonstrate that treatment with a CRF2R agonist for up to 5 months results in greater EDL force production in EMP hamsters when compared to vehicle treated EMP hamsters and greater EDL mass and force in normal hamsters when compared to vehicle treated normal hamsters. In the rat CHF model, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater EDL and soleus muscle mass and force production in CHF rats and normal rats when compared to the corresponding vehicle treated animals.</p> <p>Conclusions</p> <p>These data demonstrate that the underlying physiological conditions associated with chronic diseases such as CHF and emphysema in addition to aging do not reduce the potential of CRF2R agonists to maintain skeletal muscle mass and force production.</p