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Chronically elevated circulating fatty acid levels promote lipid accumulation in nonadipose tissues and cause lipotoxicity. Adipose triglyceride lipase (ATGL) critically determines the release of fatty acids from white adipose tissue, and accumulating evidence suggests that inactivation of ATGL has beneficial effects on lipotoxicity-driven disorders including insulin resistance, steatohepatitis, and heart disease, classifying ATGL as a promising drug target. Here, we report on the development and biological characterization of the first small-molecule inhibitor of human ATGL. This inhibitor, designated NG-497, selectively inactivates human and nonhuman primate ATGL but not structurally and functionally related lipid hydrolases. We demonstrate that NG-497 abolishes lipolysis in human adipocytes in a dose-dependent and reversible manner. The combined analysis of mouse- and human-selective inhibitors, chimeric ATGL proteins, and homology models revealed detailed insights into enzyme-inhibitor interactions. NG-497 binds ATGL within a hydrophobic cavity near the active site. Therein, three amino acid residues determine inhibitor efficacy and species selectivity and thus provide the molecular scaffold for selective inhibition.

The skin is in daily contact with environmental pollutants, but the long-term effects of such exposure remain underinvestigated. Many of these toxins bind and activate the pregnane X receptor (PXR), a ligand-activated transcription factor that regulates genes central to xenobiotic metabolism. The objective of this work was to investigate the effect of constitutive activation of PXR in the basal layer of the skin to mimic repeated skin exposure to noxious molecules. We designed a transgenic mouse model that overexpresses the human PXR gene linked to the herpes simplex VP16 domain under the control of the keratin 14 promoter. We show that transgenic mice display increased transepidermal water loss and elevated skin pH, abnormal stratum corneum lipids, focal epidermal hyperplasia, activated keratinocytes expressing more thymic stromal lymphopoietin, a T helper type 2/T helper type 17 skin immune response, and increased serum IgE. Furthermore, the cutaneous barrier dysfunction precedes development of the T helper type 2/T helper type 17 inflammation in transgenic mice, thereby mirroring the time course of atopic dermatitis development in humans. Moreover, further experiments suggest increased PXR signaling in the skin of patients with atopic dermatitis when compared with healthy skin. Thus, PXR activation by environmental pollutants may compromise epidermal barrier function and favor an immune response resembling atopic dermatitis.

Mutations in the genes coding for patatin-like phospholipase domain-containing 1 (PNPLA1) and α/β-hydrolase domain-containing 5 (ABHD5), also known as comparative gene identification 58, are causative for ichthyosis, a severe skin barrier disorder. Individuals with mutations in either of these genes show a defect in epidermal ω-O-acylceramide (AcylCer) biosynthesis, suggesting that PNPLA1 and ABHD5 act in the same metabolic pathway. In this report, we identified ABHD5 as a coactivator of PNPLA1 that stimulates the esterification of ω-hydroxy ceramides with linoleic acid for AcylCer biosynthesis. ABHD5 interacts with PNPLA1 and recruits the enzyme to its putative triacylglycerol substrate onto cytosolic lipid droplets. Conversely, alleles of ABHD5 carrying point mutations associated with ichthyosis in humans failed to accelerate PNPLA1-mediated AcylCer biosynthesis. Our findings establish an important biochemical function of ABHD5 in interacting with PNPLA1 to synthesize crucial epidermal lipids, emphasizing the significance of these proteins in the formation of a functional skin permeability barrier.

Aim Current recommendations regarding the triage of patients with acute diverticulitis for inpatient or outpatient treatment are vague. We hypothesized that a significant number of patients treated as an inpatient could be managed as an outpatient. Method A retrospective cohort study was carried out of 639 patients admitted for a first episode of diverticulitis. The diagnosis of acute diverticulitis was confirmed by computed tomography (CT). The endpoints included length of stay, need for surgery, percutaneous drainage and mortality. Patients were considered to have had a minimal hospitalization, defined as survival to discharge without needing a procedure, hospitalization of ≤ 3 days and no readmission for diverticulitis within 30 days after discharge. Results Of 639 patients, 368 (57.6%) had a minimal hospitalization. Female gender and CT scan findings of free air/fluid were negatively associated with the likelihood of minimal hospitalization. The presence of an abscess

Adipocyte plasma membrane–associated protein (APMAP) has been described as an adipogenic factor in 3T3-L1 cells with unknown biochemical function; we therefore aimed to investigate the physiologic function of APMAP in vivo. We generated Apmap-knockout mice and challenged them with an obesogenic diet to investigate their metabolic phenotype. We identified a novel truncated adipocyte-specific isoform of APMAP in mice that is produced by alternative transcription. Mice lacking the full-length APMAP protein, the only isoform that is expressed in humans, have an improved metabolic phenotype upon diet-induced obesity, indicated by enhanced insulin sensitivity, preserved glucose tolerance, increased respiratory exchange ratio, decreased inflammatory marker gene expression, and reduced adipocyte size. At the molecular level, APMAP interacts with the extracellular collagen cross-linking matrix proteins lysyl oxidase–like 1 and 3. On a high-fat diet, the expression of lysyl oxidase–like 1 and 3 is strongly decreased in Apmap-knockout mice, paralleled by reduced expression of profibrotic collagens and total collagen content in epididymal white adipose tissue, indicating decreased fibrotic potential. Together, our data suggest that APMAP is a novel regulator of extracellular matrix components, and establish that APMAP is a potential target to mitigate obesity-associated insulin resistance.—Pessentheiner, A. R., Huber, K., Pelzmann, H. J., Prokesch, A., Radner, F. P. W., Wolinski, H., Lindroos-Christensen, J., Hoefler, G., Rülicke, T., Birner-Gruenberger, R., Bilban, M., Bogner-Strauss, J. G. APMAP interacts with lysyl oxidase–like proteins, and disruption of Apmap leads to beneficial visceral adipose tissue expansion.

A new generation of logarithmic reading charts has sparked interest in standardized reading performance analyses. Such reading charts have been developed according to the standards of the International Council of Ophthalmology. The print size progression in these calibrated charts is in accordance with the mathematical background of EN ISO 8596. These reading charts are: the Bailey-Lovie Word Reading Chart, the Colenbrander English Continuous Text Near Vision Cards, the Oculus Reading Probe II, the MNREAD Charts, the SKread Charts, and the RADNER Reading Charts. The test items used for these reading charts differ among the charts and are standardized to various extents. The Bailey-Lovie Charts, MNREAD Charts, SKread Charts, and RADNER Charts are also meant to measure reading speed and allow determination of further reading parameters such as reading acuity, reading speed based on reading acuity, critical print size, reading score, and logMAR/logRAD ratio. Such calibrated reading charts have already provided valuable insights into the reading performance of patients in many research studies. They are available in many languages and thus facilitate international communication about near visual performance. In the present review article, the backgrounds of these modern reading charts are presented, and their different levels of test-item standardization are discussed. Clinical research studies are mentioned, and a discussion about the immoderately high number of reading acuity notations is included. Using the logReading Acuity Determination ([logRAD] = reading acuity equivalent of logMAR) measure for research purposes would give reading acuity its own identity as a standardized reading parameter in ophthalmology.

To analyze currently available reading charts regarding print size, logarithmic print size progression, and the background of test-item standardization.For the present study, the following logarithmically scaled reading charts were investigated using a measuring microscope (iNexis VMA 2520; Nikon, Tokyo): Eschenbach, Zeiss, OCULUS, MNREAD (Minnesota Near Reading Test), Colenbrander, and RADNER. Calculations were made according to EN-ISO 8596 and the International Research Council recommendations.Modern reading charts and cards exhibit a logarithmic progression of print sizes. The RADNER reading charts comprise four different cards with standardized test items (sentence optotypes), a well-defined stop criterion, accurate letter sizes, and a high print quality. Numbers and Landolt rings are also given in the booklet. The OCULUS cards have currently been reissued according to recent standards and also exhibit a high print quality. In addition to letters, numbers, Landolt rings, and examples taken from a timetable and the telephone book, sheet music is also offered. The Colenbrander cards use short sentences of 44 characters, including spaces, and exhibit inaccuracy at smaller letter sizes, as do the MNREAD cards. The MNREAD cards use sentences of 60 characters, including spaces, and have a high print quality.Modern reading charts show that international standards can be achieved with test items similar to optotypes, by using recent technology and developing new concepts of test-item standardization. Accurate print sizes, high print quality, and a logarithmic progression should become the minimum requirements for reading charts and reading cards in ophthalmology.

To develop 28 short sentence optotypes for the English version of the Radner Reading Charts that are as comparable as possible in number and length of words, as well as in difficulty and syntactical construction. Thirty-four English sentences were constructed following the method used for other Radner Reading Charts to obtain “sentence optotypes” with comparable structure and the same lexical and grammatical difficulty. Best comparable sentences were statistically selected and standardized in 50 volunteers. Reading speed and the number of errors were determined. Validity was analyzed with a 124-word long 4th-grade paragraph of the Florida Comprehensive Assessment Test®. Computerized measurements of reading parameters were performed with the RADNER Reading Device (RAD-RD©; in conjunction with a PC and microphone). The mean reading speed obtained with the 28 selected short sentences was 201.53 ± 35.88 words per minute (wpm), as compared to 215.01 ± 30.37 wpm for the long paragraph. The mean reading times were 4.30 ± 0.79 s and 35.26 ± 4.85 s, respectively. The mean number of reading errors was 0.11 ± 0.34. The correlation between the short sentences and the long paragraph was high (r = 0.76; p

In in vitro and in vivo studies, episclerally sutured radio-opaque markers were evaluated as localizers for better determination of the clinical tumour volume prior to stereotactic radio-therapy of uveal melanoma. Four different types of markers were studied in vitro: tantalum marker, 2.5 mm in diameter; ring-shaped markers custom-designed in polymethyl methacrylate (PMMA), 2.6 mm and 3.0 mm in diameter; and barium-impregnated silicone rubber spheres, 2 mm in diameter. In vivo PMMA markers 3.0 mm in diameter and barium-impregnated silicone rubber spheres 2 mm in diameter were used. The best results were obtained with the barium-impregnated silicone rubber spheres both in vitro and in vivo. For the CT-delineation of selected uveal melanomas with either a flat discoid shape or flat tumour extensions or when adjacent serous retinal detachment is present, small episclerally sutured barium-impregnated silicone rubber spheres are useful as localizers for determining the clinical tumour volume.

A thorough understanding of intraocular pressure homeostasis is the biological foundation for the development of new strategies to treat patients with elevated intraocular pressure or glaucoma. However, investigations on the physiology of intraocular pressure homeostasis are also important to gain more comprehensive insights into the pathogenesis of glaucoma and other diseases with associated alterations of intraocular pressure. The present review intends to give alternative insights into the biological and physical aspects of intraocular pressure regulation. The pressure-volume as well as the hydraulic model of intraocular pressure and also the relationship between ciliary blood flow and aqueous humor production, which has moved into the centre of interest because of its possible clinical relevance for glaucoma patients, will be explained. The authors Have attempted to interrelate the different aspects of intraocular pressure genesis and regulation in a comprehensive but understandable way.

A chart for measuring visual acuity is a better functional test than the routine distance visual acuity testing with single optotypes. The characteristics of a good reading chart are: logarithmically diminishing print size, simultaneous measurement of reading acuity and reading speed, and the calculation of one score for reading acuity corrected for the number of reading errors. The original German-language Radner Reading Chart meets all these requirements, and above all emphasizes the principle of 'sentence optotypes' i.e. highly standardized sentences, because sentence complexity also influences reading performance. Sentence optotypes were created in the Dutch language and tested according to Radner's strict principles. The most equally matched sentence optotypes in terms of reading speed and number of reading errors were selected for the introduction and printing of the first Dutch version of the Radner Reading Chart. The Dutch Radner Reading Chart is precise and practical and therefore useful for research and daily practice.

A pilot study of human neural retinal transplantation was undertaken to investigate three major issues: whether a safe surgical procedure could be devised for transplantation of neural retinal tissue into the subretinal space, whether the transplant would be accepted in the subretinal space, and whether an improvement in vision could be achieved.Eight patients with bare light perception (LP) vision due to retinitis pigmentosa (RP) and one patient with bare LP vision due to advanced neovascular age-related macular degeneration (AMD) received subretinal transplants of human fetal retinal microaggregate suspensions without postoperative systemic immunosuppression. The patient with AMD also received a fetal retinal sheet transplant. The ages of the patients ranged from 31 to 94 years (median, 55 years). The pre- and postoperative evaluations included visual function testing, detailed fundus examinations, fundus photography, fluorescein angiography, macular perimetry using a scanning laser ophthalmoscope (SLO), and full field and focal electroretinograms (ERGs).Three of the eight RP patients demonstrated possible improved light sensitivity during the initial months of follow-up. However, visual improvement disappeared between 3 and 13 months of follow-up. After transplantation, no subject showed any changes in the ERG recordings or SLO macular perimetry relative to their preoperative baseline. No patient experienced a retinal detachment, infection, or extensive bleeding. None of the patients developed retinal vasculitis or intraocular inflammation. In one RP patient, fluorescein angiography and fundus photography documented the formation and maturation of new host retinal vessels in the area of the transplant.Transplantation of fetal retinal photoreceptor suspensions into the subretinal space was achieved safely in nine subjects. Although a definite positive effect on visual function could not be demonstrated, the apparent high tolerance for graft tissue is promising for future efforts in the field of neural retinal transplantation.

Reading acuity as well as reading speed are good predictors of everyday visual function. As visual acuity tests are poor predictors of the real-world function, performance-based tests, e.g., reading speed measurements, can be used for the determination of visual function. Thus, a German reading chart was developed in order to evaluate reading acuity as well as reading speed.Print size is defined as the height of a lower case x and progresses logarithmically from one phrase to another (factor: 1.25). Reading acuity is determined in LogRAD (Reading Acuity Determination). 32 short German phrases were created, comparable concerning grammatical difficulty as well as in number (n = 14), length and position of words. The reading speed parameters measured with a stop-watch in 160 persons (aged: Phi = 21a +/- 3.8a) were calculated in words per minute (w/min). Out of the 32 phrases the 24 most similar ones were selected statistically and used for the reading charts (Radner Reading Charts). With these reading charts a reading acuity score (LogRAD-score) can be calculated considering reading errors in words of different length. Reading speed can be determined at the same time. Reading acuity (LogRAD-Score) was measured in 32 normal eyes of 16 students and compared to the angular visual acuity (LogMAR).The mean reading speed of the test persons was 211.8 +/- 34.1 w/min. 24 phrases fulfilled the test item criteria for the reading chart: mean +/- 0.25 x SD. The reliability analyses yielded an overall Cronbach's alpha coefficient of 0.98! The mean visual acuity measured in 32 eyes was -0.115 +/- 0.097 LogMAR and the mean reading acuity score was +0.026 +/- 0.091 LogRAD. The mean difference was +0.104 +/- 0.066 and the correlation between LogMAR and LogRAD was good (r = 0.59).With these reading charts it is for the first time possible to simultaneously determine reading acuity as well as reading speed in German. The high reliability of the 24 phrases and the high correlation between LogMAR and LogRAD leads us to expect a good reproducibility of the reading acuity evaluations. For the "Radner Reading Charts" we have shown that print size is the main reason for changes of reading speed.

The present case report describes primary orbital immunocytoma (IgM-kappa) mimicking Hodgkin's disease of the diffuse, lymphocyte predominance type by expressing Hodgkin simulating cells as well as Reed-Sternberg simulating cells (both: H-RS cells).The patient (87a; male) was admitted to hospital with increasing left upper eyelid protrusion. Computed tomography revealed an unspecific accumulation of soft tissue within the orbit. A biopsy was taken. Light microscopical sections were stained with PAS, Giemsa and haematoxylin-eosin. Immunohistochemistry was performed following standard procedures.By means of light microscopy, Hodgkin's disease of the diffuse, lymphocyte predominance type was indicated. This initial diagnosis was mainly based on morphological criteria, e.g. the presence of H-RS-like cells. Since staging work-up produced no evidence of systemic disease, immunohistochemistry was performed. It revealed that the misleading cells were H-RS simulating cells. Finally, the diagnosis made was that of immunocytoma (IgM-kappa); stage I EA.The diagnosis of Hodgkin's disease of the diffuse, lymphocyte predominance type is normally based on morphological criteria. However, in very rare cases immunocytomas simulate this variant of Hodgkin's disease by expressing misleading H-RS simulating cells. Thus, immunohistochemical investigations should generally be included in the criteria for the diagnosis of Hodgkin's disease of the diffuse, lymphocyte predominance type. As far as we are aware, primary immunocytoma mimicking this variant of Hodgkin's disease within the orbit has never been reported.

Many retinal diseases can be treated either with laser treatment or with vitreo-retinal surgery. However, in some of these cases a severe visual loss cannot be avoided and visual rehabilitation has to be initiated. Visual rehabilitation is initially performed by fitting low vision aids. With low vision aids the patients ability to read can be restored as well as many other needs of every days life e.g. reading bus numbers, street names, bank notes or letters. In analogy with the higher life expectancy in the middle european countries the incidence of age related maculopathy will increase in the next years. Thus, the need for visual rehabilitation will increase as well.