Hello, Listeners! For this week’s blog post, we thought that we would take a closer look at Episode 152 (LINK) and bring you back to your experiences in the biochemistry classroom. In Episode 152 of the podcast, Jay spoke with Dr. Daniel Chao and Dr. Shriji Patel about a few “journal club” topics; one of these discussed a recent article published in JAMA Ophthalmology (LINK) about the possible role of statins in decreasing risk of diabetic retinopathy. With their proven mortality benefits related to cardiovascular disease, it is tough to go through a day in clinic without encountering at least one patient currently taking a statin. That being so, let’s go over how they work!

Statins are a class of lipid-lowering medications that act as competitive HMG-CoA reductase inhibitors. As you recall, this means that the statin binds to the active site of the HMG-CoA reductase enzyme and thereby limits its function. HMG-CoA reductase is utilized in one of the first steps (the rate-limiting step, in fact) of the mevalonate pathway, which converts acetyl-CoA and acetoacetyl-CoA into Cholesterol (see image below). As a result, less cholesterol is synthesized by the liver.

Image Credit: https://en.wikipedia.org/wiki/File:HMG-CoA_reductase_pathway.svg

However, this is not where the story ends. Statins also work to increase LDL (often referred to as “bad cholesterol”) uptake. The liver extracts cholesterol from the circulation through the use of LDL receptors, which sense and take up circulating LDL. Once statins inhibit the mevalonate pathway, the liver is able to sense the resultant decrease in cholesterol synthesis and up-regulates its LDL receptors. Once in the liver, the uptaken LDL can be processed into bile salts and other products, and there is less LDL floating in circulation.

The mevalonate pathway also includes the synthesis of prenylated proteins (“prenylated” refers to the addition of a hydrophobic lipid group to a molecule). It has been hypothesized that statin-related inhibition of these syntheses is related to some of the important cardiovascular benefits of the medication, including improved endothelial and immune cell function. The evidence for this idea is founded partially in the fact that other classes of drugs that reduce LDL levels—but do not affect prenylated protein synthesis—do not show these additional benefits. However, the effect on these proteins has also been hypothesized as a cause for unwanted side effects of statins, including myopathies and elevated blood glucose.

Back to ophthalmology, it reasonable to wonder whether the benefits found against diabetic retinopathy are related to these “other” cardiovascular effects, like improved endothelial function and modulated inflammatory responses. Although the results are debated, the JUPITER (Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin) study, for example, found that statins can have cardiovascular benefit in patients independent of LDL levels (in patients with already-low levels of cholesterol) through reductions in C-reactive protein levels. Time will tell as to what the role of statins will be in diabetic retinopathy, but it is interesting to consider yet another possible role this class of drugs may play.

  -Michael Venincasa

For more information, check out: https://en.wikipedia.org/wiki/Statin

Dr. Thomas Gardner joined Jay for Episode 151 (LINK) to discuss the mechanisms of visual loss in diabetic retinopathy and the current limitations of the management of diabetic retinopathy. Today we are going to review how diabetes affects the cells of the retina and how these changes present on an exam. 

Diabetic retinopathy is a microvascular disease that occurs as a complication of diabetes mellitus. This is a disease that affects the retinal neurovascular unit, which refers to neurons, glia, and vasculature that work together to regulate normal retinal function. Throughout the course of DR, the different components of this unit can become affected. A critical feature of DR is vascular dysfunction and capillary loss, but evidence has shown that neuropathy can appear first, as some patients present with loss of color vision and contrast sensitivity before microvascular changes can be observed. Furthermore, observational studies are now showing that damage to the neuronal layer can promote microangiopathy. Glial cells are also impacted in diabetes. There is an alteration in the homeostatic function of glial cells, which impacts its ability to regulate retinal blood flow, water balance, and the maintenance of barrier function. Microglial cells are also affected in the progression of diabetes, which causes chronic and subclinical inflammation in the retina. As immune cells become activated in DR, there is enhanced leukocyte-endothelial interaction which causes leukostasis and can lead to damage of the retinal vascular endothelium and surrounding tissue. This can happen due to physical obstruction of the capillaries and through the release of pro-inflammatory cytokines, including VEGF. Lastly, diabetes also impacts the RPE, specifically disrupting photoreceptor and choroidal integrity. However, the importance of the dysfunction of this layer in the overall progression of DR remains unclear and under study.

Currently, DR is classified based on the microvascular lesions observed. In the earlier stages, there is nonproliferative diabetic retinopathy (NDPR) that then advances to proliferative diabetic retinopathy (PDR). Changes of the retina in NDPR include the appearance of intraretinal hemorrhages, microaneurysms, venous caliber abnormalities, formation of intraretinal microvascular abnormalities, cotton-wool spots from neuronal infarcts, and retinal neovascularization. As the vascular bed experiences a gradual decrease in perfusion, vessel integrity is lost, ultimately leading to occlusion or degeneration of capillaries. This causes decreased oxygenation to the retinal layer, which eventually leads to expression of proangiogenic growth factors and development of PDR. Hypoxia causes formation of new blood vessels that are fragile and can protrude into the preretinal space. Rupture of these vessels can cause vitreous hemorrhage or tractional retinal detachment. Throughout the progression of NPDR and PDR, diabetic macular edema can arise from the breakdown of the blood-retinal barrier. This breakdown causes leakage of proteins and fluid into the retina, which appears as abnormal retinal thickening and even edema of the macula. 

Image credit: https://www.123rf.com/photo_71633481_stock-vector-types-of-diabetic-retinopathy-non-proliferative-pre-proliferative-diabetic-retinopathy-proliferative.html

              -Amy Kloosterboer

For this week’s blog post related to Podcast Episode 150, we are going to do something different and look at one of the resources patients can use to find clinical trials and how to navigate it. ClinicalTrials.gov is a a database of trials conducted around the world that are privately and publicly funded that can be used to find trials for a condition or disease. Like Dr. Sridhar and Dr. Pennesi, it can be difficult for a patient to look up information due to the technical terminology used. Today we are going to talk about how to navigate through it, and what certain terms mean.

When first opening the website, the following screen is the first thing that you see:

Image Credit: https://clinicaltrials.gov/ct2/home

This is the simple search format they offer. The first thing that must be selected is the status of the study. Here you can select for studies that are recruiting participants or those that have not yet started to recruit participants (“recruiting and not yet recruiting studies”) or all studies, including those that are no longer recruiting, are suspended, terminated, completed or more. The next box to be filled out is that of the disease or condition of interest. For example, if you are looking for studies related to X-linked retinoschisis, this is where it can be specified. The third box allows you to narrow your search and include things like a drug name, the name of the investigator, or the NCT number which is the National Clinical Trial identifier given to each registered clinical trial. Finally, in the last box the search can be narrowed to a desired country. 

For this post, we will be looking at clinical trials related to X-linked retinoschisis. After selecting “All studies” and specifying the condition or disease as “X-linked retinoschisis”, the search returns the following widnow:

Image Credit: https://clinicaltrials.gov/ct2/home

As can be seen, all the clinical trials available for X-linked retinoschisis appear here. Each study shows the status, title, the condition they are studying, the intervention they are using, and the location.  On the left-hand side, there is a filter panel that can help narrow results. Once again, you can filter by the status of the study by selecting the options you are interested in. Next is the eligibility criteria. These are the key requirements that people who want to participate in the study must meet. Each study will have different criteria including age and sex. Following eligibility criteria, you can narrow results by study type. An interventional or clinical trial is a type of study in which the effect of an intervention or treatment is studied by assigning a participant to a group. In an observational study the participants are assessed for certain health outcomes but are not assigned to a specific intervention or treatment. The last type of study is an expanded access study, and these are ways for patients with serious diseases or conditions who can’t participate in a clinical trial to receive medical products that have not yet been approved by the FDA. You can select studies that have or do not have results, and the phase they are on. A phase 1 study is usually conducted with healthy volunteers with the goal of determining a drug’s most serious side effects and how the drug is broken down in the body and excreted. In phase 2 the focus is on whether the drug works in people with a certain condition or disease. Phase 3 aims to find more information regarding the drug’s safety and effectiveness at different dosages. The last phase is phase 4, which happens after the drug has been approved by the FDA for marketing and includes further studying the safety, efficacy, and how to best utilize this drug. Lastly, the funder type and study documents can be selected.

Once you find a trial of interest, you can learn more information by clicking on the study title. The new window will give a background information to the study and talk about what it is trying to accomplish and how, what intervention or drug they are using, and a brief section on what will be expected of the participant. It will also list the study start and end date, any inclusion and exclusion criteria that must be met in order to participate, and contact information for those interested in participating in the trial if it is still recruiting participants.

              -Amy Kloosterboer

In Episode 149 (LINK), Jay was joined by Dr. Jean-Pierre Hubschman to discuss robotic surgery and its future in the field of Ophthalmology. For this post, we thought it would be interesting to look back at how robotic surgery developed and where it stands today.

The introduction of robotics in industry began in 1951 with the first mechanical arm constructed to handle radioactive material. Ten years later, the first industrial robot was constructed for General Motors. In medicine, it was not until 1983 that a robot would be utilized to assist in a surgery. The Arhtrobot, designed in Vancouver, was used in orthopedic surgical procedures and performed over 60 arthroscopic procedures. Two years later, the PUMA 200 was used to perform a CT-guided brain biopsy (Figure 1). This was so successful, that it started being used for urological procedures at the Imperial College in London, in 1988. Two different models were used for prostate surgery that had the same limitations: the robots could be programmed based on a fixed anatomical landmark but could not be used for dynamic surgical targets.   

Figure 1: PUMA 200

Image credit: http://gelookahead.economist.com/slideshow/the-future-of-surgery/

During the 1990’s the Automated Endoscopic System for Optimal Positioning (AESOP) was built. This endoscopic camera could be controlled by the surgeon’s voice commands and was utilized for a variety of surgeries including laparoscopic cholecystectomy, hernioplasty, fundoplication, and colectomy. This robotic model was taken a step further with Zeus, a system created with arms and surgical instruments that could be controlled by the surgeon (Figure 2). Zeus was used for the first time in 1998 at the Cleveland Clinic for a fallopian tube anastomosis. In 2001 this model was used for the first transatlantic surgery, a laparoscopy performed in Strasbourg while the surgeon, Dr. Jacques Marescaux, was in New York.

Figure 2: Zeus robotic surgical system. a. surgeon console, b. robotic arms.

Image credit https://link.springer.com/article/10.1007%2Fs00268-016-3543-9

Around the same time the da Vinci system was designed. First used in 1997 for a robotic-assisted cholecystectomy in Brussels, Belgium this model gained popularity and in 2000 the FDA approved it for abdominal surgeries. This model overcame many of the previous robots’ limitations. It could now replicate exactly what a human arm could do. The system consists of three parts: a Vision System that includes a high-definition 3D endoscope and large viewing monitor, a Patientside Cart with the robotic arms controlled by the surgeon, and the Surgeon Console from where he or she performs the surgery. Throughout the years this system has been upgraded. Most notably, in 2002 the robot consisted of three operating arms. In 2006 the new model gave better handling and increased range of motion, allowing for a bigger surgical field. Finally, in 2009 the imaging system was upgraded, and a second surgeon’s console was added to allow less experienced surgeons to train. While robotic surgery is now commonly being used in many different fields of medicine—including neurosurgery, GI, urology, orthopedic surgery and more—it is still in its infancy in ophthalmology. As technology progresses, robotics are expected to be introduced more into ophthalmic practice. As discussed in this episode, the two areas that are expected to first see the use of robotics will be vitreoretinal and cataract surgeries.

Figure 3: da Vinci Surgical System.

Image credit: https://www.davincisurgery.com/da-vinci-surgery/da-vinci-surgical-system/

Typical optical setup of single point OCT. Scanning the light beam on the sample enables non-invasive cross-sectional imaging up to 3 mm in depth with micrometer resolution. Image Credit: https://en.wikipedia.org/wiki/Optical_coherence_tomography#Theory

Medicine is constantly progressing, in part due to technological advances of today’s digital age. In ophthalmology, one of the most important recent technological advances has been the development of optical coherence tomography, or OCT. Within the past ~25 years OCT has risen to be ubiquitous in the field, with applications in nearly all sub-specialties and for countless clinical purposes. Given our recent Podcast Episode’s (link - http://www.retinapodcast.com/episodes/2019/1/6/episode-148-january-2019-retinal-physician-review-including-digital-imaging-in-vr-surgery-surgery-in-rop-eyes-vkh-achromatopsia) discussion on the growing use of intraoperative OCT, for today’s Lessons from our Pupils blog post, we wanted to take a look at the history of OCT and to cover some basics of the science behind it.

Optical coherence tomography – the name itself gives the reader a good idea about the principles at play. Optical, in the world of physics, suggests involvement of the visible portion of the electromagnetic spectrum. Coherence refers to the state in which two waves are in sync (called “in-phase”) with each other. And finally, tomography refers to imaging through slices (“sectioning”). We could assume that OCT, then, should involve the use of two waves of light (and whether or not they are in-phase) to image a slice of an object.

At this point, we should probably wrap up this blog post, since we already went over all there is to know about OCT! For those who would like to keep reading, let’s dive into some more specifics. As you would expect with the word “coherence,” OCT requires the comparison of two different waves of light, produced by a beam splitter inside the machine. One beam travels to a “reference mirror” while the other beam travels to the sample you are trying to image. When the beams of light return to the device, they are merged together in a beam reducer and analyzed using a photo detector. Depending on how in-phase or out-of-phase the two beams of light are when they return to be merged, the computer can assign different intensities to that portion of the sample, which is then repeated thousands and thousands of times to create the final image.

The specifics of this process, however, varies based on OCT type. There exist two “domains” for analyzing coherence: the time domain (TD), and the frequency domain (FD). In the time domain, the time it takes for the beam of light to travel to the reference mirror and back to the photo collector (the “reference arm pathlength” is altered through movement of the reference mirror; this allows “scanning” different depths of your tissue sample. In the frequency domain, different frequencies of light (which penetrate to different depths of the tissue sample) are included in each beam, and these frequencies are detected in parallel using spectrally-separated detectors; this allows for much greater speed of analysis, since the reference mirror does not need to be moved for different sample depths to be analyzed. While the initial TD-OCT systems could perform 400 axial scans (A-scans) per second (low due to the need to move the reference mirror), use of the FD for Spectral Domain OCT (SD-OCT) can be performed at ~300,000 A-scans/second (though most clinical systems operate at rates below this). Since we can acquire images so much more quickly, we are now able to perform three-dimensional scans of tissue.

Although you may not deal with the physics behind OCT in your daily clinic, it is always nice to learn a little bit about what goes into the technology that we use. We hope that you enjoyed reading about OCT and we are excited to see just how far this technology will go, both in the field of ophthalmology and beyond.

- Michael Venincasa

For more information, you may be interested in: 

Invest Ophthalmol Vis Sci. 2011 Apr; 52(5): 2425–2436. doi: 10.1167/iovs.10-6312

https://en.wikipedia.org/wiki/Optical_coherence_tomography#Theory