Medical hypothesis discovery and innovation in ophthalmology

Editorial/ No abstract

Apoptosis, or programmed cell death, is an integral component of developmental biology, embryology, and anatomy. All eukaryotic cells possess the molecular machinery necessary to execute apoptosis. However, dysregulated apoptosis in the form of too much or too little cell death results in diseases such as Alzheimer’s disease, autoimmune disorders, and cancer. It is postulated that apoptosis of the photoreceptors in the retina plays a vital role in mediating vision, and evidence is presented here to support this hypothesis. However, the precise mechanisms that regulate this cell death in photoreceptors have yet to be fully elucidated.

Aging is the common denominator and the highest risk factor for macular degeneration and Alzheimers Disease (AD). Important pathological hallmarks common to both diseases are the presence of amyloid β (Aβ) in the senile plaques of the AD brain and in the drusen of age-related macular degeneration (AMD) patients, oxidative stress, and apoptotic cell death. Data suggest that a common pathogenic mechanism might exist between AMD and AD. Brain and eye depend on redox electrons from pyridinic and flavinic nucleotides to produce ATP, and reactive oxygen intermediates (ROI). Disorganization of mitochondrial structure and decline in mitochondrial oxidative phosphorylation (OXPHOS) functioning, as well as hypometabolism and alterations in mitochondrial DNA are aging features. Because ROI damage and mitochondrial dysregulation are prominent in AMD and AD and their relationship to the redox state is unclear we addressed a new hypothesis according to which the interaction of melatonin vs Aβ are intertwined to balance of the intra- and extra-mitochondrial energy production. This balance would be impaired by the ageing process and environmental/genetic factors, ultimately leading to AD and /or AMD.

In the United States, 20,000 patients each year lose their sight from diabetic retinopathy. The cause has been attributed to a failure of control of glucose levels. Recent studies have challenged this, and have suggested that there is no evidence for a consistent glycemic threshold in various populations relating to the incidence of retinopathy. The Ehrlichia have been recently suggested as having a role in diabetes.  The action of this obligate parasitic bacterium which often affects the cells involved in immunity has the potential of affecting various tissues randomly.    This includes self-reactive T or B cells which may be erroneously altered or released from the marrow because of infection of marrow precursors by an Ehrlichia. The discovery of a gene obtained by molecular methodology from a leukemia patient, has given us a tool to identify by molecular methods, the presence of this gene and assumed bacterium in the blood of patients with various syndromes that includes diabetes. Because of the inconsistent evidence of a uniform glycemic threshold in retinopathy and the failure of its control, this hypothesis raises the question of something else that might be causing this damage.  The suspected bacterium in diabetes may have as a significant side effect of its infection of the immune system, specifically the site of action of damage to the small vessels of the retina which could lead to what is regularly described in retinopathy; further, and that may include damage to other vessels seen in peripheral and coronary arteries. The availability of a molecular test in whole blood specimens from diabetics suggests a survey for the gene of the bacterium described in diabetic patients and matched controls.  Such an investigation could lead to other therapies directed against the bacterium's presence in the marrow if discovered, and strategies to eliminate the harmful self-reactive T or B cells, if found in diabetes.

The etiology of reticular macular disease (RMD), a sub-phenotype of age-related macular degeneration (AMD), is controversial and has not been clarified. RMD is suspected to be a multifactorial, complex disease with genetic, environmental, and systemic factors playing an important role in its origin. Findings from combinations of different imaging modalities suggest that the pattern that characterizes this condition is associated with an alteration of the choriocapillaris blood flow. If the choroid is indeed affected in RMD, the possible linkage with inflammatory or other systemic diseases could be better supported.

Letter/ No abstract