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Alfredo A Sadun

Publications and source records attributed to Alfredo A Sadun.

11 recordsLinked to original sources
PubMed2003

Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy.

PURPOSE: To conduct systematic epidemiologic, neuro-ophthalmologic, psychophysical, and mitochondrial DNA (mtDNA) genetic examinations on a newly identified pedigree with Leber hereditary optic neuropathy (LHON). DESIGN: Observational population cohort study. METHODS: A prospective investigation of an entire Brazilian LHON family. SETTING: A field investigation by an international team conducted in a remote part of Brazil. STUDY POPULATION: We evaluated 265 (both eyes) of the 328 living family members of this LHON pedigree. Only members of this pedigree were studied. Those entering the pedigree as spouses were used as controls. OBSERVATION PROCEDURES: We conducted epidemiologic interviews emphasizing possible environmental risk factors, comprehensive neuro-ophthalmologic examinations, psychophysical tests, Humphrey visual field studies, fundus photography, and blood testing for mitochondrial genetic analysis. RESULTS: We reconstructed a seven-generation maternal lineage descended from a common ancestor dating to the 1870s. All maternally related family members were invariably homoplasmic 11778 with a haplogroup J mtDNA, 33 being affected, of which 22 are still living. With each subsequent generation, there was a progressive decrease of penetrance, and only males were affected in the last two generations. A significant exposure (greater than 95% confidence intervals) to a variety of environmental risk factors characterized the affected individuals, with smoking as the most common (P <.01). Both affected and carriers (95% confidence intervals) presented with a significantly lower incidence of hypertension and high cholesterol compared with the control group (P <.05). CONCLUSIONS: Almost 95% of a 328-living-member pedigree with LHON 11778/J haplogroup was comprehensively studied. Our initial results indicate the strong influence of environmental risk factors. The remarkably reduced incidence of cardiovascular risk in the maternal lineage is discussed. Further genetic analysis may reveal a role for the nuclear genome.

Adolescent↗
PubMed2003

Interleukin-6 in retinal ischemia reperfusion injury in rats.

PURPOSE: To study the role of interleukin (IL)-6 after retinal ischemia-reperfusion (I/R) injury in rats. METHODS: Intraocular pressure of adult male Lewis albino rats was raised to create retinal ischemia for 1 hour. Retinal reperfusion was reestablished, and the animals were killed at various time points after the injury. Their eyes were enucleated and processed for immunohistochemistry to detect IL-6 and ED-1 (a marker of microglial/phagocytic cells), enzyme-linked immunosorbent assay (ELISA) of IL-6 protein, and semiquantitative real-time RT-PCR for IL-6 mRNA. The neuroprotective effect of IL-6 was evaluated by giving intravitreal injections of 150 or 300 ng rat recombinant IL-6 to eyes immediately after I/R injury and counting cresyl violet-stained retinal ganglion cell layer cells (RGCLCs) and fluorochrome-labeled retinal ganglion cells (RGCs) on flat preparations of retinas at 7 days. RESULTS: IL-6-positive cells appeared after I/R injury in the inner plexiform layer (IPL) and the inner nuclear layer (INL). Their numbers were significantly higher 18 hours after the injury, and most of these cells were also ED-1 positive. ELISA showed noticeable increases in endogenous retinal IL-6 protein levels 8 hours after I/R injury. Semiquantitative real-time RT-PCR showed significant increases in endogenous retinal IL-6 mRNA levels between 2 and 18 hours. Exogenously added IL-6 prevented between 50% and 70% of RGC loss after I/R injury. CONCLUSIONS: IL-6 is upregulated after retinal I/R injury, and its expression by microglia/phagocytic cells may protect RGC layer neurons from I/R injury. Exogenously added IL-6 protects the inner retina after I/R injury.

Animals↗
PubMed2002

First application of extremely high-resolution magnetic resonance imaging to study microscopic features of normal and LHON human optic nerve.

PURPOSE: To apply new methods in magnetic resonance imaging (MRI) in resolving the histoarchitecture of the human optic nerve obtained from normal individuals and a Leber's hereditary optic neuropathy (LHON) case. DESIGN: Small case series--clinicopathologic correlation. METHOD: Three optic nerves were obtained from two normal subjects, aged 69 and 70, and a LHON/3460 patient, aged 75. The posterior pole of the eye with attached optic nerves was fixed in buffered paraformaldehyde and placed into a 10-mm quartz tube. Images were acquired in a Bruker AMX500 12 Tesla microimaging system. The three-dimensional data were acquired with 512 x 256 x 256 points, yielding a final isotopic resolution of 30 microm. RESULTS: The sclera, choroids, and retina were easily distinguished. The nerve fiber layer was seen to enter the optic disc and traverse the lamina cribrosa (LC). The resolution of the image of the optic nerve head was such that the LC was visualized as multiple stacked plates. The fibers emerged from glial columns in the LC as distinct fascicles and could be made out to change appearance as they became myelinated and expanded in the more posterior nerve. The ophthalmic artery and vein were visualized, as were the optic nerve arachnoid and dural sheaths. In the Leber's case, the LC plates seemed collapsed or compressed. The axonal bundles were atrophic and the pial-collagen septae markedly thickened. The entire nerve had shrunk, creating space under the arachnoid, down and around the central ophthalmic artery and vein. CONCLUSIONS: These results demonstrate the feasibility of using extremely high-resolution magnetic resonance imaging (microMRI) to examine the three-dimensional (30 microm) images of the human optic nerve. Several atrophic lesions, normally visible only by histopathologic examination, were visualized in the Leber's optic nerve. microMRI may eventually permit the in vivo visualization of lesions in or about the optic nerve.

Aged↗
PubMed2002

Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies.

Selective degeneration of the smallest fibers (papillo-macular bundle) of the human optic nerve occurs in a large number of optic neuropathies characterized primarily by loss of central vision. The pathophysiology that underlies this peculiar pattern of cell involvement probably reflects different forms of genetic and acquired mitochondrial dysfunction. Maternally inherited Leber's hereditary optic neuropathy (LHON), dominant optic atrophy (Kjer disease), the optic atrophy of Leigh's syndrome, Friedreich ataxia and a variety of other conditions are examples of inherited mitochondrial disorders with different etiologies. Tobacco-alcohol amblyopia (TAA), the Cuban epidemic of optic neuropathy (CEON) and other dietary (Vitamins B, folate deficiencies) optic neuropathies, as well as toxic optic neuropathies such as due to chloramphenicol, ethambutol, or more rarely to carbon monoxide, methanol and cyanide are probably all related forms of acquired mitochondrial dysfunction. Biochemical and cellular studies in LHON point to a partial defect of respiratory chain function that may generate either an ATP synthesis defect and/or a chronic increase of oxidative stress. Histopathological studies in LHON cases and a rat model mimicking CEON revealed a selective loss of retinal ganglion cells (RGCs) and the corresponding axons, particularly in the temporal-central part of the optic nerve. Anatomical peculiarities of optic nerve axons, such as the asymmetric pattern of myelination, may have functional implications on energy dependence and distribution of mitochondrial populations in the different sections of the nerve. Histological evidence suggests impaired axonal transport of mitochondria in LHON and in the CEON-like rat model, indicating a possible common pathophysiology for this category of optic neuropathies. Histological evidence of myelin pathology in LHON also suggests a role for oxidative stress, possibly affecting the oligodendrocytes of the optic nerves.

Animals↗
PubMed2002

Perioperative risk factors for posterior ischemic optic neuropathy.

BACKGROUND: Infarction of the optic nerve posterior to the lamina cribrosa, called posterior ischemic optic neuropathy (PION), is a condition that can result in profound bilateral blindness. Cases of PION treated at this institution and those described in the literature were analyzed to identify clinical features that profile those individuals at risk of PION in an attempt to identify major contributing factors that could be addressed prophylactically to enable effective prevention. STUDY DESIGN: Salient clinical features in seven cases of PION diagnosed at the Doheny Eye Institute between 1989 and 1998 are compared with 46 cases of PION reported in the literature. RESULTS: In the Doheny series there were six men and one woman aged 12 to 66 years (mean, 47 years). Five patients were status-post spine surgery, one was status-post knee surgery, and one had a bleeding stomach ulcer. Vision loss was simultaneously bilateral in six of seven patients (85.7%) and was apparent immediately after surgery. There were no abnormal retinal or choroidal findings including diabetic retinopathy, in any of the patients. Notable contributing factors were blood loss in all seven patients, ranging from 2,000 to 16,000 mL, with a drop in hematocrit of 9.5% to 19% (mean, 14%), and intraoperative systemic hypotension in all patients. Facial edema was a factor in three of six spine surgery patients (50%). Patients reported in the literature had a mean age of 50 years and were also predominantly men (34 of 46, 74%) who underwent spine surgery (30 of 46, 65.2%). CONCLUSIONS: Middle-aged men undergoing spine surgery with prolonged intraoperative hypotension and postoperative anemia and facial swelling are at risk of developing PION from hypovolemic hypotension. Avoiding or immediately correcting these contributory factors can reduce the incidence of PION.

Adolescent↗
PubMed2002

A very large Brazilian pedigree with 11778 Leber's hereditary optic neuropathy.

PURPOSE: We conducted extensive epidemiological, neuro-ophthalmological, psychophysical, and blood examinations on a newly discovered, very large pedigree with molecular analysis showing mtDNA mutation for Leber's hereditary optic neuropathy (LHON). METHODS: Four patients representing four index cases from a remote area of Brazil were sent to Sao Paulo, where complete ophthalmological examinations strongly suggested LHON. Molecular analysis of their blood demonstrated that they were LHON, homoplasmic 11778, J-haplogroup. They had an extensive family that all lived in one rural area in Brazil. To investigate this family, we drew on a number of international experts to form a team that traveled to Brazil. This field team also included several members of the Federal University of Sao Paulo, and together we evaluated 273 of the 295 family members that were still alive. We conducted epidemiological interviews emphasizing possible environmental risk factors, comprehensive neuro-ophthalmological examinations, psychophysical tests, Humphrey visual field studies, fundus photography, and blood testing for both mitochondrial genetic analysis and nuclear gene linkage analysis. RESULTS: The person representing the first-generation case immigrated from Verona, Italy, to Colatina. Subsequent generations demonstrated penetrance rates of 71%, 60%, 34%, 15%, and 9%. The percentages of males were 60%, 50%, 64%, 100%, and 100%. Age at onset varied from 10 to 64 years, and current visual acuities varied from LP to 20/400. CONCLUSIONS: Almost 95% of a nearly 300-member pedigree with LHON 11778 were comprehensively studied. Analysis of environmental risk factors and a nuclear modifying factor from this group may help address the perplexing mystery of LHON: Why do only some of the genetically affected individuals manifest the disease? This fully described database may also provide an excellent opportunity for future clinical trials of any purported neuroprotective agent.

Adolescent↗
PubMedDate not supplied

The eye as metronome of the body.

Vision is much more than just resolving small objects. In fact, the eye sends visual information to the brain that is not consciously perceived. One such pathway entails visual information to the hypothalamus. The retinohypothalamic tract (RHT) mediates light entrainment of circadian rhythms. Retinofugal fibers project to several nuclei of the hypothalamus. These and further projections to the pineal via the sympathetic system provide the anatomical substrate for the neuro-endocrine control of diurnal and longer rhythms. Without the influence of light and dark, many rhythms desynchronize and exhibit free-running periods of approximately 24.2-24.9 hours in humans. This review will demonstrate the mechanism by which the RHT synchronizes circadian rhythms and the importance of preserving light perception in those persons with impending visual loss.

Animals↗