Leon A. Assael, DMD

• Professor of OMFS and Surgery
• Department Chair
• Medical Director, Hospital Dentistry
• Oregon Health and Science University
• Portland, Oregon

Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration menstruation synonym order discount duphaston on line. A randomized clinical trial of 4-hydroxyphenylretinamide for high-grade squamous intraepithelial lesions of the cervix menstruation does not occur if the order duphaston without a prescription. Safety of the synthetic retinoid fenretinide: long-term results from a controlled clinical trial for the prevention of contralateral breast cancer womens health waterbury ct order duphaston 10mg on line. Pilot trial of the safety women's health menstrual problems order duphaston with a visa, tolerability menstrual ultrasound buy duphaston discount, and retinoid levels of N-(4-hydroxyphenyl) retinamide in combination with tamoxifen in patients at high risk for developing invasive breast cancer breast cancer 3 day walk michigan order duphaston 10mg on-line. Effect of the synthetic retinoid fenretinide on dark adaptation and the ocular surface. Intravitreal ranibizumab and bevacizumab in combination with full-fluence verteporfin therapy and dexamethasone for exudative age-related macular degeneration. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. Platelet-derived growth factor receptor-alpha: a novel therapeutic target in human hepatocellular cancer. The synthesis and characterization of analogs of the antimicrobial compound squalamine: 6 beta-hydroxy-3-aminosterols synthesized from hyodeoxycholic acid. Correlation of anatomic and visual outcomes in the phase 2 study of squalamine lactate ophthalmic solution 0. A phase 1 safety study of an orally available tyrosine kinase inhibitor X-82 in previously 249. Safety and effect on rod function of Acu-4429, a novel smallmolecule visual cycle modulator. Phase ii, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration. Histologic basis of variations in retinal pigment epithelium autofluorescence in eyes with geographic atrophy. Lipofuscin redistribution and loss accompanied by cytoskeletal stress in retinal pigment epithelium of eyes with age-related macular degeneration. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Association of risk factors for choroidal neovascularization in age-related macular degeneration with decreased foveolar choroidal circulation. Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse. Brimonidine blocks glutamate excitotoxicity-induced oxidative stress and preserves mitochondrial transcription factor a in ischemic retinal injury. An immunohistochemical analysis of the neuroprotective effects of memantine, hyperbaric oxygen therapy, and brimonidine after acute ischemia reperfusion injury. Brimonidine suppresses loss of retinal neurons and visual function in a murine model of optic neuritis. Evaluation of extended release brimonidine intravitreal device in normotensive rabbit eyes. Delay to treatment and visual outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration. Diagnostic accuracy of the Amsler grid and the preferential hyperacuity perimetry in the screening of patients with agerelated macular degeneration: systematic review and metaanalysis. Replacing the Amsler grid: a new method for monitoring patients with agerelated macular degeneration. Handheld shape discrimination hyperacuity test on a mobile device for remote monitoring of visual function in maculopathy. Cone-mediated multifocal electroretinogram in early age-related maculopathy and its relationships with subjective macular function tests. Self-testing of vision in age-related macula degeneration: a longitudinal pilot study using a smartphonebased rarebit test. Assessment of macular function by microperimetry in intermediate age-related macular degeneration. Impairments in dark adaptation are associated with age-related macular degeneration severity and reticular pseudodrusen. In patients with pathologic myopia, various kinds of macular lesions develop in the posterior fundus, and these are the cause of visual impairment. For example, myopic macular degeneration is the leading cause of blindness in Japan, the second most common cause in Denmark33 and in China,23 and the third cause of blindness in Latinos 40 years and older in the United States. The Blue Mountains Eye Study in Australia, which focused on a white population, reported that the prevalence of myopic retinopathy was 1. But it may be higher in East Asian populations than in white populations, and the prevalence of high myopia is probably higher as well. The prevalence of myopic retinopathy is increased with advancing age in those population-based studies. Histologic studies have shown a decreased density of photoreceptors, ganglion cells, retinal pigment epithelium, and optic nerve fibers with age. Although it is reported that men have longer axial length than women,46,47 many hospital-based studies showed higher prevalence of myopic retinopathy in women than in men. In the Blue Mountains Eye Study, the prevalence of myopic retinopathy in men was 0. In the Hisayama Study, the prevalence of myopic retinopathy in men and in women was 1. The Beijing Eye Study did not report the prevalence of myopic retinopathy by sex, but the female: male ratios of the subjects with and without myopic retinopathy were 75: 57 and 570: 489, respectively. It suggests that not only greater axial length but other risk factors such as genetic factors and lifestyle risk factors may contribute to the pathogenesis of myopic retinopathy. There may be biologic mechanisms of neovascular membrane formation other than axial elongation or aging. They suggested that it is possible that eyes with a shallow staphyloma may be healthier and more metabolically active with well-perfused chorioretinal tissue and good capacity to respond to injury by neovascular ingrowth. It appears that the influence of aging and mechanical factors is rather complicated and different lesions of course may have different pathogenetic influences. In addition to the influence of biomechanical factors, aging is an important factor for the development of posterior staphyloma and subsequent myopic macular degeneration. A posterior staphyloma is rarely found in highly myopic patients younger than 40 years of age. The incidence of myopic chorioretinal atrophy increases with age, and these changes are rarely seen in persons less than 20 years old. Vurgese and Jonas reported that in axially elongated eyes, scleral thinning occurred at and posterior to the equator, being more marked closer to the posterior pole in human eyes. The architectural changes in the longitudinal fibers in pathologic myopia consist of thinning of the collagen bundles, a reduction in refringence of the bundle edges, and the loss of longitudinal fiber striations. The cross-sectional fibers demonstrate dissociation such that the individual fibers separate from one another. The more advanced examples of architectural disorganization are found in and about the regions of the posterior pole and peripapillary sclera. It has also been reported that the elastic fibers within the sclera showed a definite decrease in the number of fibers. Also, the cross-sectioned fibrils showed a marked increase in the prevalence of fissured or "star-shaped" forms. Most of the ultramicroscopic alterations seen in the myopic sclera indicate a derangement of the growth and organization of the fibrils. These aspects of development are thought to be under the control of the acidic glycosaminoglycan composition of the interfibrillar substance. It is also conceivable that this picture corresponds to abnormal fibril growth in the presence of an accentuated breakdown or catabolism of the sclera. Irregular scleral curvature was associated with the frequency of myopic macular complications. The curve of inner scleral surface is straight (arrowhead), and the optic disc is at the bottom of the posterior segment of the eye. The sclera is strongly bowed posteriorly; however, the curve is symmetric around the fovea (arrowhead), and the fovea is situated on the bottom of posterior segment of the eye. The sclera is strongly bowed posteriorly, and the most protruded point is away from the central fovea. Association between shape of sclera and myopic retinochoroidal lesions in patients with pathologic myopia. The changes subsequently affecting the choroid were essentially degenerative and atrophic. Choroidal vascular occlusions are a prominent feature of the disease, and this process appears to affect the smaller-diameter vessels initially. The choroidal vessels appear to be fewer and to have thinner walls than seen normally. There is a generalized loss of the normal connective tissue framework of the choroid with some degree of compaction of the vessels. Although the largesized choroidal vessels tend to be most resistant, these, too, may undergo occlusion in the late stages of the disease. AnimalModels Rhesus monkeys, chickens, fish, tree shrews, marmosets, and guinea-pigs have long been used as animal models of experimental myopia by inducing form-deprivation myopia by lid suture or by wearing plastic goggles. In comparison with emmetropic eyes (top), the choroid is extremely thinned in eyes with pathologic myopia (bottom). Large choroidal vessels sporadically remain and indent the overlying retinal pigmented epithelium. In the posterior fundus (left), lacquer cracks are observed to course as linear streaks. Electron microscopic photograph at the area of lacquer cracks shows a disruption of choriocapillaris (right). The chicken has the classic vertebrate sclera, consisting of a layer of cartilage surrounded by layers of fibrous connective tissue, whereas in most mammals, including primates and rodents, the cartilage has been lost. Based on the benefit of having similar scleral components, mice have commonly been used as experimental myopia,72,73 although there is some drawback that the induced myopia is not as severe as in the chickens because mice are not "visual animals. In addition to an excessive elongation of the posterior chamber, the Lpr2-deficient eye had normal intraocular pressure and developed chorioretinal atrophy and staphyloma resembling human pathologic myopia. This result is interesting because it suggests that lacquer cracks are purely caused by mechanical stretching of the globe and less affected by aging. Downregulation of zebrafish lumican gene expression manifested ocular enlargement resembling axial myopia due to disruption of the collagen fibril arrangement in the sclera and resulted in scleral thinning. Veth and colleagues79 have used zebrafish to identify a genetically complex, recessive mutant that shows risk factors for glaucoma including adultonset severe myopia, elevated intraocular pressure, and progressive retinal ganglion cell pathology. Positional cloning and analysis of a noncomplementing allele indicated that nonsense mutations in low-density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotype. PosteriorStaphyloma A posterior staphyloma is an outward protrusion of all layers of the posterior eye globe and is considered a hallmark lesion of pathologic myopia. Until recently there has not been a uniformly accepted definition of a posterior staphyloma; thus, it has been common for authors to refer to abnormalities in the posterior pole of myopic eyes, even those that do not involve an outpouching, as being "staphylomas. A posterior staphyloma is not common in children with pathologic myopia, and the incidence of staphyloma is significantly higher in older patients (96. According to the main path of natural progression, five categories were proposed (category 0, no macular lesions; category 1, tessellated fundus; category 2, diffuse chorioretinal atrophy; category 3, patchy chorioretinal atrophy; category 4, macular atrophy). The eyes with lesions more severe than or equal to category 2 or with "plus lesions" are considered "pathologic myopia. Wide-field fundus photo (left) shows diffuse chorioretinal atrophy in the posterior fundus. Proposed classification of posterior staphylomas based on analyses of eye shape by threedimensional magnetic resonance imaging. Proposed classification of posterior staphylomas based on analyses of eye shape by three-dimensional magnetic resonance imaging. In the top row, diffuse chorioretinal atrophy (left), patchy chorioretinal atrophy (middle), and lacquer cracks (right). Lacquer cracks are more easily detected by fluorescein angiography, fundus autofluorescence imaging, and indocyanine green angiography. According to Tokoro, there is diffuse chorioretinal atrophy and patchy chorioretinal atrophy. Due to the disappearance of most of the choroid, only large choroidal vessels sporadically remain. Patchy chorioretinal atrophy is observed as grayish-white and well-defined chorioretinal atrophy. At 5 and 10 years after onset, however, visual acuity dropped to 20/200 or less in 89% and 96%, respectively. Fluorescein angiogram (top right) shows choroidal filling defect in the area of patchy atrophy. Fifteen years later, the width of lacquer cracks has widened and has progressed to patchy atrophy (right). In fluorescein angiogram (A), the lesions are observed as radial hypofluorescence. In fundus autofluorescence (B), the lesions are seen as a mixture of hyper- and hypoautofluorescence. The patients in the intravitreal aflibercept group gained significantly more vision at week 24 and 48 than those in the sham injection group. Although the mechanism of the development of this condition is not fully clear, the glial cells such as astrocytes, which exist abundantly around the retinal vessels, can migrate and proliferate through the paravascular lamellar holes.

These deposits have been found as early as age 19 women's health xmas kekse cheap duphaston 10mg visa, and their prevalence progressively increases with age57 such that they are present in all eyes age 40 and older women's health center hershey pa buy duphaston 10mg overnight delivery. However pregnancy 8 weeks symptoms order duphaston 10mg otc, they are more commonly seen in the elastic layer in eyes from middle-aged persons womens health evergreen order duphaston 10 mg free shipping. Hydraulic conductivity is the measurement of the bulk flow of fluid through a test membrane in response to applied pressure women's health lincoln ne order 10mg duphaston with mastercard. The decrease in conductivity is greatest in the first four decades of life breast cancer organization duphaston 10 mg cheap,61,62 and then it continues to decline at a slower rate with increasing age. Clearly, further studies are required, as only a limited number of younger eyes have been examined. Age-RelatedMacularChangesasSeen onFundusImaging the structural changes noted with normal aging, as described in the previous sections, do correlate with observations made on clinical imaging performed in living persons. Each of these observations may correlate with loss of centrally located ganglion cells that occur with age. The choroidal vascular pattern has become more prominent in the fovea consistent with nongeographic atrophy. Histopathologic studies are critical to advance our understanding of the disease processes, while clinical studies provide more limited information about mechanisms of the disease processes but are essential to the understanding of clinical disease evolution. This was referred to as the basal linear deposit, and it proved a useful histologic marker for the stage of the disease. However, another layer could also be demonstrated, lying external to the basement membrane. Green and Enger76 suggested retaining the term basal laminar deposit for the material internal to the basement membrane, but resurrecting the term basal linear deposit for the diffuse layer of vesicular and granular material on the external aspect. This article will use the acronyms BlamD for basal laminar deposit and BlinD for basal linear deposit and refer to both of them generically as basal deposits, as proposed by Curcio and Millican. The arteriolar filling begins in the subfoveal region in radial fashion toward the peripheral fundus. The dye fills rapidly, and the arterioles run in a fine, tortuous, and multibranching fashion throughout the time course. Aging changes of the choroidal dye filling pattern in indocyanine green angiography of normal subjects. BlamD can be demonstrated consistently by the seventh decade43 but has been found even in the fifth decade. Early form of basal laminar deposit is seen as continuous, blue-staining layer beneath the retinal pigment epithelium. Unstained spaces (right arrow) would correspond to membranous debris on electron microscopy. With electron microscopy the BlamD is seen to consist of three phenotypes: fibrillar, polymerized, and amorphous. Photoreceptors disappear, and external limiting membrane terminates on BlamD (methylene blue and basic fuscin; x500). The two forms of the BlamD are seen: the blue-staining, early form (long arrow) and, on its inner surface, nodular collections of the late hyalinized form (arrowheads). Epithelial component remains atop BlamD (bottom), which in turn overlies an artifactually empty soft druse. Persistent BlamD divides subretinal fibrocellular scar in the subretinal space from fibrovascular scar (fv. The druse is covered by late, amorphous BlamD (short arrow) and has dystrophic calcification. These collections are referred to as "basal mounds" and may account for the drusen-like dots noted clinically. Since these deposits are focal accentuations of a continuous layer of debris, their margins are ill defined and they readily become confluent. It is into this plane that choroidal new vessels grow; a neovascular membrane was present nearby. The arrow points to a small basal mound of similar appearance, lying above the druse. These findings have corresponded to foci of hyperpigmentation on clinical examination or on fundus photographs. These cells in turn become filled with lipofuscin and round off, losing their ability to phagocytose. As the dead cells are discarded, nearby viable cells migrate and increase in surface area. Finally, neighboring cells can no longer stretch to fill the gap and atrophy results. Hyperpigmentation therefore precedes hypopigmentation, and this in turn is the prelude to the development of patches of atrophy. The subretinal drusenoid deposit is well formed, with overlying photoreceptors that are deflected or shortened. It includes an apical cap of material, distinct from outer segments in both staining density and size. Both retinal pigment epithelia underlying the deposit and overlying the druse are minimally disturbed. In contrast, the soft druse has membranous debris of simpler shapes, mostly spheres, and heterogeneous sizes. Much of the druse contents are missing, consistent with the known physical fragility of these lesions. The spectrum of drusen, how drusen evolve, and the histopathologic and imaging characteristics of drusen will be detailed in this section. Circle C0 is used to differentiate small from medium drusen, circle C1 is used to differentiate medium from large drusen, and circle C2 indicates the minimum area on which to base a definition of geographic atrophy. The diagonal lines facilitate locating the central point and estimating size of lesions. An international classification and grading system for age-related maculopathy and age-related macular degeneration. Drusen size is estimated by comparing the shortest diameter of a druse to the width of a major retinal vein as it crosses the edge of the optic disc. Concentrating on the morphology of drusen, both its borders and its central substance, drusen can be broadly divided into hard and soft categories, with soft drusen being further subdivided into soft indistinct or soft distinct based on further characterization of the sharpness of the drusen borders. Soft drusen may converge or become confluent with one another and demonstrate heterogeneity in size and shape. Hard drusen tend to be small and have a sharp or distinct appearance throughout the deposit, and they tend to exist individually from one another. As drusen size and morphology are highly correlated with one another, current drusen descriptions have largely shifted to inclusion of size alone, as this can be derived with more objectivity than describing drusen morphology. The extent or severity of macular involvement may be assessed by noting drusen number or the total macular area occupied by drusen. Drusen number may be described as minimal or nonextensive under the following conditions: when there are fewer than five and the largest druse present is small; when there are fewer than 20 and the most advanced druse present is soft, indistinct, and extensive soft distinct drusen are not present; or when there are fewer than 65 soft distinct drusen in the absence of extensive soft indistinct drusen on macular examination. Moderate or extensive drusen are present when the number of drusen within these drusen subtypes is exceeded. Area occupied by drusen is largely reserved for research purposes, as it requires study of fundus photographs with the assistance of templates that depict a spectrum of area sizes to estimate the total drusen area. In addition, the contents of soft drusen are easily lost during histopathologic processing, and thus all the constituents of these drusen may not have been identified. Discordance between the descriptions of ultrastructure of drusen and assumptions about drusen composition based on clinical descriptions also exists. For example, drusen of each of the four ultrastructural phenotypes described by Hageman could occur clinically in a range of drusen sizes that would appear small to large with ophthalmoscopy. One can argue that any existing classification system may not be widely generalizable to clinical findings. Therefore, in the following sections, these prior classification schemes may be referenced, but the distinction, especially between differing soft drusen types under these classification systems,76,78,81 will be deemphasized in this discussion. Some drusen may grow larger in diameter, taller in height, and coalesce while others may spontaneously regress. They are difficult to see in lightly pigmented fundi, but use of red-free light may facilitate identification. Another common pattern for this type of drusen is a wide band outside the vascular arcades that continues nasal to the disc, with sparing of the posterior pole. Toward the equator they assume a linear arrangement in relation to a polygonal pattern of hyperpigmented lines, giving rise to reticular (honeycomb) degeneration of the pigment epithelium. By following a number of patients with small, hard drusen over time, Sarks and coworkers described the process by which these drusen may fuse to form large drusen, which they termed "pseudosoft" drusen. Initially small, hard drusen that form in a cluster may remain as discrete deposits on ophthalmoscopy, even if they appear to touch one another. Different histologic classification systems for drusen have been described,76,78,81,102 with some relying solely on ultrastructural classification of the drusen,102 others combining clinicopathologic correlations and more global assessments of the histologic features of the maculas,76,78 and others combining historical changes on clinical exam and imaging with histopathologic assessment. Red arrowheads show large druse with no apparent calcification on color photographs and examination. This nomenclature was based on clinicopathologic data (detailed below) from a limited number of eyes with these features that had been followed for many years. They appear to evolve from progressive confluence of existing soft drusen often retaining a scalloped outline representing the borders of the original individual druse before they merged. The basal laminar deposit (BlamD) lies internal to the BsM, and typical drusen lie external. The BlamD exists in an early, striated form (shown in blue) and late amorphous form (shown in brown). As overlying hyperpigmentation and hypopigmentation develop, often in the form of a radiating pigment figure, the contents become whiter and more inspissated. Hyperpigmentation and hypopigmentation often develop over the surface of the druse. Groups of mainly small, hard drusen associated with hyperpigmentation are seen at the fovea. Large, soft, confluent drusen appear to be located temporal to the fovea, but in red-free light (C), and particularly on fluorescein angiography (B), the soft drusen can be seen to consist of closely packed clusters of small, hard drusen. The druse was located just superior to the foveal center and vision remained unaffected. Drusen patterns predisposing to geographic atrophy of the retinal pigment epithelium. Numerous soft, yellow drusen of solid appearance in the right eye of a 72-year-old man. This eye developed a hemorrhagic disciform lesion shortly before the patient died at age 75. The left eye had similar drusen and also proved to contain an early active neovascular membrane. Many of the surrounding soft drusen have spontaneously resolved as well, many without overt signs of nongeographic atrophy in their place. Hyalinized drusen form anterior to these changes, and as they grow they become hemispherical or almost globular. On electron microscopy, greater electron density is noted at the borders and less in the center. Fluorescein angiograms of the right eye of a man at age 55 (A), 58 (B), and 61 (C). In the inner macula they form clusters in which the individual drusen are more difficult to distinguish owing to confluence and breakdown. The more central clusters have become completely homogeneous on fluorescein angiography. Visual acuity remained 20/20, although the patient had been aware of some deterioration.

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