Early trigeminal and sensory impairment and lysosomal dysfunction in accurate models of Wolfram syndrome.

Wolfram syndrome (WS) is a rare condition caused by homozygous or compound heterozygous mutations in the WFS1 gene primarily. It is diagnosed on the basis of early-onset diabetes mellitus and optic nerve atrophy. Patients complain of trigeminal-like migraines and show deficits in vibration sensation, but the underlying cause is unknown.

The Microphthalmia-Associated Transcription Factor (MITF) and Its Role in the Structure and Function of the Eye.

Background/objectives: The microphthalmia-associated transcription factor () has been found to play an important role in eye development, structure, and function. The gene is responsible for controlling cellular processes in a range of cell types, contributing to multiple eye development processes. In this review, we survey what is now known about the impact of on eye structure and function in retinal disorders.

Carbonic anhydrase, its inhibitors and vascular function.

It has been known for some time that Carbonic Anhydrase (CA, EC 4.2.1.

Progressive Cone-Rod Dystrophy and RPE Dysfunction in Mice.

Mutations in the mouse microphthalmia-associated transcription factor () gene affect retinal pigment epithelium (RPE) differentiation and development and can lead to hypopigmentation, microphthalmia, deafness, and blindness. For instance, an association has been established between loss-of-function mutations in the mouse gene and a variety of human retinal diseases, including Waardenburg type 2 and Tietz syndromes. Although there is evidence showing that mice with the homozygous mutation manifest microphthalmia and osteopetrosis, there are limited or no data on the effects of the heterozygous condition in the eye.

Measuring Retinal Vessel Diameter from Mouse Fluorescent Angiography Images.

It is important to study the development of retinal vasculature in retinopathies in which abnormal vessel growth can ultimately lead to vision loss. Mutations in the microphthalmia-associated transcription factor (Mitf) gene show hypopigmentation, microphthalmia, retinal degeneration, and in some cases, blindness. In vivo imaging of the mouse retina by noninvasive means is vital for eye research.

Membrane Permeability Is Required for the Vasodilatory Effect of Carbonic Anhydrase Inhibitors in Porcine Retinal Arteries.

It has been demonstrated previously that a variety of carbonic anhydrase inhibitors (CAIs) can induce vasodilation in pre-contracted retinal arteriolar segments although with different efficacy and potency. Since the CAIs tested so far are able to permeate cell membranes and inhibit both intracellular and extracellular isoforms of the enzyme, it is not clear whether extra- or intracellular isoforms or mechanisms are mediating their vasodilatory effects. By means of small wire myography, we have tested the effects of four new CAIs on wall tension in pre-contracted retinal arteriolar segments that demonstrably do not enter cell membranes but have high affinity to both cytosolic and membrane-bound isoforms of CA.

Vasodilation of Pre-contracted Porcine Retinal Arteries by Carbonic Anhydrase Inhibitors with Enhanced Lipophilicity.

Purpose: In this study, we investigated the vasodilation properties on pre-contracted retinal arteries of a restricted series of carbonic anhydrase inhibitors (CAIs) of the sulfonamide type with enhanced lipophilicity, to assess if it affects the potency of CAIs as vasodilators.

Methods: Carbonic anhydrase (CA) inhibition and kinetics of the compounds designed and synthesized for testing in this study were assessed by extracting human CA isoform proteins (hCA) from human cells expressing the isoforms of interest, and then measure the affinity of the novel compound for the hCAs by stopped-flow CO hydrase spectroscopy. Lipophilicity of compounds was measured by obtaining their octanol-water partition coefficient, expressed as calculated logP.

Mouse microphthalmia-associated transcription factor (Mitf) mutations affect the structure of the retinal vasculature.

Purpose: Mice carrying pathogenic variants in the microphthalmia transcription factor (Mitf) gene show structural and functional changes in the retina and retinal pigment epithelium. The purpose of this study was to assess the vascular changes in Mitf mice carrying pathogenic variants by determining their retinal vessel diameter.

Methods: Mice examined in this study were: B6-Mitf (n = 6), B6-Mitf /Mitf (n = 6) and C57BL/6J wild type mice (n = 6), all 3 months old.

Molecular genetics of inherited retinal degenerations in Icelandic patients.

The study objective was to delineate the genetics of inherited retinal degenerations (IRDs) in Iceland, a small nation of 364.000 and a genetic isolate. Benefits include delineating novel pathogenic genetic variants and defining genetically homogenous patients as potential investigative molecular therapy candidates.

Mechanisms of Ion Transport Across the Mouse Retinal Pigment Epithelium Measured In Vitro.

Purpose: To examine ion transport across the mouse retinal pigment epithelium (RPE), measured by the short-circuit current (ISC) and transepithelial resistance (TER).

Methods: Sheets of RPE from mice (C57BL6/J) with retina, choroid, and sclera attached were mounted in Ussing chambers (0.031-cm2 aperture) and Krebs solution.

Mitf Links Neuronal Activity and Long-Term Homeostatic Intrinsic Plasticity.

Neuroplasticity forms the basis for neuronal circuit complexity and differences between otherwise similar circuits. We show that the microphthalmia-associated transcription factor () plays a central role in intrinsic plasticity of olfactory bulb (OB) projection neurons. Mitral and tufted (M/T) neurons from mutant mice are hyperexcitable, have a reduced A-type potassium current (I) and exhibit reduced expression of , which encodes a potassium voltage-gated channel subunit (Kv4.

The microphthalmia-associated transcription factor (Mitf) gene and its role in regulating eye function.

Mutations in the microphthalmia-associated transcription factor (Mitf) gene can cause retinal pigment epithelium (RPE) and retinal dysfunction and degeneration. We examined retinal and RPE structure and function in 3 month old mice homo- or heterozygous or compound heterozygous for different Mitf mutations (Mitf, Mitf/Mitf, Mitf and Mitf/Mitf) which all have normal eye size with apparently normal eye pigmentation. Here we show that their vision and retinal structures are differentially affected.

Retinal oximetry: Metabolic imaging for diseases of the retina and brain.

Retinal oximetry imaging of retinal blood vessels measures oxygen saturation of hemoglobin. The imaging technology is non-invasive and reproducible with remarkably low variability on test-retest studies and in healthy cohorts. Pathophysiological principles and novel biomarkers in several retinal diseases have been discovered, as well as possible applications for systemic and brain disease.

Carbonic Anhydrase Inhibitors of Different Structures Dilate Pre-Contracted Porcine Retinal Arteries.

Carbonic anhydrase inhibitors (CAIs), such as dorzolamide (DZA), are used as anti-glaucoma drugs to lower intraocular pressure, but it has been found that some of these drugs act as vasodilators of retinal arteries. The exact mechanism behind the vasodilatory effect is not yet clear. Here we have addressed the issue by using small vessel myography to examine the effect of CAIs of the sulfonamide and coumarin type on the wall tension in isolated segments of porcine retinal arteries.

Retinal Oximetry Discovers Novel Biomarkers in Retinal and Brain Diseases.

Purpose: Biomarkers for several eye and brain diseases are reviewed, where retinal oximetry may help confirm diagnosis or measure severity of disease. These include diabetic retinopathy, central retinal vein occlusion (CRVO), retinitis pigmentosa, glaucoma, and Alzheimer's disease.

Methods: Retinal oximetry is based on spectrophotometric fundus imaging and measures oxygen saturation in retinal arterioles and venules in a noninvasive, quick, safe manner.

Retinal A2A and A3 adenosine receptors modulate the components of the rat electroretinogram.

Adenosine is a neuromodulator present in various areas of the central nervous system, including the retina. Adenosine may serve a neuroprotective role in the retina, based on electroretinogram (ERG) recordings from the rat retina. Our purpose was to assess the role of A2A and A3 adenosine receptors in the generation and modulation of the rat ERG.

Retinal vessel oxygen saturation and vessel diameter in retinitis pigmentosa.

Purpose: To assess retinal vessel oxygen saturation and retinal vessel diameter in retinitis pigmentosa.

Methods: A retinal oximeter (Oxymap ehf., Reykjavik, Iceland) was used to measure retinal vessel oxygen saturation and vessel diameter in ten patients with retinitis pigmentosa (RP) (mean age 49 years, range 23-71 years).

Lysosomal alkalinization, lipid oxidation, and reduced phagosome clearance triggered by activation of the P2X7 receptor.

Lysosomal enzymes function optimally at low pH; as accumulation of waste material contributes to cell aging and disease, dysregulation of lysosomal pH may represent an early step in several pathologies. Here, we demonstrate that stimulation of the P2X7 receptor (P2X7R) for ATP alkalinizes lysosomes in cultured human retinal pigmented epithelial (RPE) cells and impairs lysosomal function. P2X7R stimulation did not kill RPE cells but alkalinized lysosomes by 0.

Dynamic conservation of forest genetic resources in 33 European countries.

Dynamic conservation of forest genetic resources (FGR) means maintaining the genetic diversity of trees within an evolutionary process and allowing generation turnover in the forest. We assessed the network of forests areas managed for the dynamic conservation of FGR (conservation units) across Europe (33 countries). On the basis of information available in the European Information System on FGR (EUFGIS Portal), species distribution maps, and environmental stratification of the continent, we developed ecogeographic indicators, a marginality index, and demographic indicators to assess and monitor forest conservation efforts.

The A3 adenosine receptor attenuates the calcium rise triggered by NMDA receptors in retinal ganglion cells.

The A(3) adenosine receptor is emerging as an important regulator of neuronal signaling, and in some situations receptor stimulation can limit excitability. As the NMDA receptor frequently contributes to neuronal excitability, this study examined whether A(3) receptor activation could alter the calcium rise accompanying NMDA receptor stimulation. Calcium levels were determined from fura-2 imaging of isolated rat retinal ganglion cells as these neurons possess both receptor types.

Glaucoma filtration surgery and retinal oxygen saturation.

Purpose: Glaucoma may involve disturbances in retinal oxygenation and blood flow. The purpose of this study was to measure the effect of glaucoma filtration surgery on retinal vessel oxygen saturation.

Methods: A noninvasive spectrophotometric retinal oximeter was used to measure hemoglobin oxygen saturation in retinal arterioles and venules before and after glaucoma filtration surgery.

Dorzolamide-timolol combination and retinal vessel oxygen saturation in patients with glaucoma or ocular hypertension.

Aims: To examine whether the addition of dorzolamide to timolol monotherapy influences oxygen saturation in the human retina.

Methods: Non-invasive spectrophotometric retinal oximetry was used to measure oxygen saturation in retinal vessels. Twenty patients with open-angle glaucoma (11) and ocular hypertension (9) were recruited.

Oxygen saturation in human retinal vessels is higher in dark than in light.

Purpose: Animal studies have indicated that retinal oxygen consumption is greater in dark than light. In this study, oxygen saturation is measured in retinal vessels of healthy humans during dark and light.

Methods: The oximeter consists of a fundus camera, a beam splitter, a digital camera and software, which calculates hemoglobin oxygen saturation in the retinal vessels.

GABA agonists fail to protect the retina from ischemia-reperfusion injury.

The purpose of this study was to test the hypothesis that ischemia/reperfusion injury in the rat retina may be ameliorated by reducing retinal metabolism with either hypothermia or inhibitory GABA agonists. The intraocular pressure of each right eye in rats was raised to 130 mm Hg for 60 min with the left eye serving as normal control. The rats were divided into four groups in terms of drug and hypothermia treatment: (1) Untreated ischemia, (2) Hypothermia, (3) Baclofen/midazolam and (4) Baclofen/muscimol.