High-content screening assay-based discovery of paullones as novel podocyte-protective agents.

Podocyte dysfunction and loss is an early event and a hallmark of proteinuric kidney diseases. A podocyte's normal function is maintained via its unique cellular architecture that relies on an intracellular network of filaments, including filamentous actin (F-actin) and microtubules, that provides mechanical support. Damage to this filamentous network leads to changes in cellular morphology and results in podocyte injury, dysfunction, and death. Conversely, stabilization of this network protects podocytes and ameliorates proteinuria. This suggests that stabilization of podocyte architecture via its filamentous network could be a key therapeutic strategy for proteinuric kidney diseases. However, development of podocyte-directed therapeutics, especially those that target the cell's filamentous network, is still lacking, partly because of unavailability of appropriate cellular assays for use in a drug discovery environment. Here, we describe a new high-content screening-based methodology and its implementation on podocytes to identify paullone derivatives as a novel group of podocyte-protective compounds. We find that three compounds, i.e., kenpaullone, 1-azakenpaullone, and alsterpaullone, dose dependently protect podocytes from puromycin aminonucleoside (PAN)-mediated injury in vitro by reducing PAN-induced changes in both the filamentous actin and microtubules, with alsterpaullone providing maximal protection. Mechanistic studies further show that alsterpaullone suppressed PAN-induced activation of signaling downstream of GSK3ß and p38 mitogen-activated protein kinase. In vivo it reduced ADR-induced glomerular injury in a zebrafish model. Together, these results identify paullone derivatives as novel podocyte-protective agents for future therapeutic development.

Multifocal Serpiginoid Choroiditis Due to Mycobacterium Mageritense following Laparoscopic Hysterectomy in an Immunocompetent Host.

PURPOSE: To report nontubercular choroiditis, caused by Mycobacterium mageritense isolated using MALDI-TOF MS, following laparoscopic hysterectomy in an immunocompetent patient. CASE REPORT: A 42-year-old female presented with gradual, painless diminution of vision in the right eye for six weeks. She had undergone laparoscopic hysterectomy two months back. BCVA was 2/60 OD. Clinical presentation and imaging all pointed to a diagnosis of serpiginous-like choroiditis. Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) had led to isolation of Mycobacterium mageritense. Patient was treated with systemic antibiotics. At 3 months follow up, BCVA improved to 6/60; fundus showed healed choroiditis and chorioretinal thinning. CONCLUSION: Atypical mycobacterial infections associated with laparoscopic surgeries can rarely lead to debilitating systemic bacteremia resulting in profound visual impairment. The importance of timely diagnosis using specific and sophisticated methods such as MALDI-TOF MS as well as maintaining aseptic precautions perioperatively during major surgeries cannot be overemphasized.

Central retinal vein occlusion post ChAdOx1 nCoV-19 vaccination - can it be explained by the two-hit hypothesis?

PURPOSE: To report a case of central retinal vein occlusion (CRVO) seven days following the first dose of ChAdOx1 nCoV-19 vaccine and propose a hypothesis for the possible underlying pathogenesis. OBSERVATION: A 31-year-old male presented with CRVO with cystoid macular edema, one week after receiving his first ChAdOx1 nCoV-19 vaccine dose. Apart from mild hyperhomocysteinemia, no major thrombophilic or systemic risk factors were found. Anti-platelet factor 4 antibodies, specific for vaccine-induced immune thrombotic thrombocytopenia, were also negative. However, he tested strongly positive (> 250 U/mL) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG spike antibodies, 2 weeks post the first dose - suggestive of a prior subclinical infection. CONCLUSION: COVID-19 is known to be associated with an altered host one-carbon metabolism resulting in hyperhomocysteinemia. We hypothesize that a prior subclinical infection with COVID-19, the first hit, may have led to hyperhomocysteinemia in our patient and vaccination must have been the second hit that triggered the thrombotic event. Further studies, including correlation of thrombotic complications with IgG antibody titres post-vaccination, are essential in order to better understand the pathogenesis of such events.

Regression of choroidal metastasis from breast carcinoma with palbociclib.

BACKGROUND: Uveal metastasis is reported to be the most common intraocular malignancy. The most common site of origin of ocular metastases in females is the breast. In some cases, uveal metastatic lesions respond to systemic chemotherapy. We report a case of a patient who developed choroidal metastasis, while on endocrine therapy with selective estrogen receptor modulator (SERM), tamoxifen, for estrogen receptor (ER) positive, progesterone receptor (PR) positive and (human epidermal growth factor receptor 2) HER2 negative primary breast carcinoma, which then regressed following systemic chemotherapy with palbociclib. CASE DESCRIPTION: An 83-year-old female, with a history of modified radical mastectomy, chemotherapy and radiation therapy for infiltrating duct carcinoma of the breast, presented with a choroidal metastatic lesion in the left eye along with liver and lung metastases, 3 years after the primary carcinoma was treated. At the time of presentation, she was on tamoxifen. The choroidal tumor showed regression after the introduction of palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. CONCLUSION: This report highlights the use of palbociclib, in the palliative treatment of choroidal metastasis from primary breast cancer. The use of chemotherapy for choroidal metastasis can help avoid external beam radiation therapy and its concurrent side effects. Although there are a few reports involving the use of palbociclib for metastatic breast carcinoma, all of those have been in conjunction with and/or following non-response to other treatment modalities. Ours is the first report wherein palbociclib has been used as the first-line palliative chemotherapy and helped in regression of choroidal metastasis.

Presumed bilateral diffuse uveal melanocytic proliferation - A case report and review of literature.

Purpose: To describe a case of presumed bilateral diffuse uveal melanocytic proliferation (BDUMP) associated with renal cell carcinoma (RCC) and provide an updated review of literature. Observations: A 58-year-old man, with a history of radical nephrectomy for RCC 8 years ago, presented with gradual diminution of vision. Based on multimodal imaging and detailed systemic evaluation, a diagnosis of presumed BDUMP and metastatic RCC was made. He was started on sunitinib malate as palliative chemotherapy. However, he refused plasmapheresis for BDUMP. The patient rapidly developed bilateral exudative retinal detachment. Subsequently, he progressed to bilateral neovascular glaucoma secondary to closed funnel retinal detachment. Eventually, he was lost to follow up after 13 months. Conclusions & Importance: BDUMP portends an underlying advanced systemic malignancy. Studies have not conclusively proven any definite treatment for BDUMP and survival is generally poor. Ocular side effects of palliative targeted chemotherapy for the primary malignancy, such as sunitinib, should be borne in mind.

Relapsing neuromyelitis optica in an adolescent girl.

Early differentiation of neuromyelitis optica spectrum disorder (NMO-SD) from multiple sclerosis (MS) is of paramount importance as NMO-SD (especially relapsing variant) has more severe morbidity than MS. We describe a case of an adolescent girl who presented with repeated episodes of optic neuritis over a period of 4 years with normal brain MRI scans. She was treated initially as relapsing remitting MS, before showing clinical evidence of transverse myelitis (TM), and eventually being diagnosed as NMO-SD. Pulse intravenous methyl prednisolone along with immunosuppressive therapy led to remission of her disease. However, delay in diagnosis as NMO-SD led to visual disability in the left eye. Therefore, in young patients with recurrent optic neuritis and normal brain MRI, it may be prudent to get spinal MRI done to look for TM, even when asymptomatic. In addition, we should keep a low threshold for requesting aquaporin-4 antibody testing in these patients.