The Controversy of Chronotherapy: Emerging Evidence regarding Bedtime Dosing of Antihypertensive Medications in Non-Arteritic Anterior Ischemic Optic Neuropathy.

"Blindness upon awakening" occurs in a significant proportion of patients with non-arteritic anterior ischemic optic neuropathy (NAION). This observation has led to a notion that nocturnal hypotension is a significant contributor and, perhaps, the final insult in a multifactorial process leading to the development of NAION, as has been proposed in other ischemic events like strokes, myocardial infarction, and ischemic rest pain. An extension of this concept has led to the recommendation that patients who have experienced NAION avoid taking blood pressure medications at bedtime. However, mounting evidence in the cardiology literature suggests that nocturnal hypertension is associated with increased risk of cardiovascular morbidity. In two prospective blood pressure monitoring studies in 1994 and 1999, Hayreh observed an extreme dipping pattern in nocturnal systolic blood pressure in NAION patients compared to reported normal values. Yet, two subsequent ambulatory blood pressure studies found either normal or non-dipping patterns in NAION patients. The majority of clinical trials published since 1976 that have studied nocturnal administration of antihypertensives have reported enhanced blood pressure control and reduced cardiovascular risk. Most notably, the large, prospective 2020 Hygia Chronotherapy Trial reported a statistically-significant beneficial effect of nocturnal antihypertensive dosing on cardiovascular outcomes and mortality. The controversy regarding nocturnal hypotension and NAION is of increasing relevance as there is new evidence to suggest a beneficial effect of nocturnal antihypertensive dosing in cardiovascular risk. This new information should prompt a re-evaluation of the relevant risk-to-benefit of reducing the risk of NAION on one hand, and the potential increase of cardiovascular risk on the other. Definitive resolution of this question would require a prospective, randomized control study with input from both cardiology and ophthalmology.

Neuro-oculo-cutaneous cavernous hemangiomas: a CCM1 mutation-associated phakomatosis.

Evaluation for intracranial lesions in a patient with retinal cavernous hemangiomas is vital for early recognition of this heritable and potentially life-threatening disease. We report a case of a highly penetrant but variably expressed form of cerebral cavernous malformation syndrome with cerebral, cutaneous, and retinal cavernomas in a family found to harbor a nonsense mutation of the CCM1 gene.

Clinical Implications of Direct Immunofluorescence Findings in Patients With Ocular Mucous Membrane Pemphigoid.

PURPOSE: To examine the clinical implications of positive or negative direct immunofluorescence biopsies (DIF) in patients with clinically typical ocular mucous membrane pemphigoid (MMP). DESIGN: Retrospective cohort study. METHODS: The study population was patients with clinically typical ocular MMP disease with documented DIF results who were followed for at least 1 year at the Duke University multidisciplinary ocular MMP clinic. Data were collected by chart review and included patient demographics, clinical examination findings, and history of autoimmune disease and/or malignancy, as well as topical, systemic, and surgical treatments received. Main outcome measures included MMP Disease Area Index, Foster stages, proportion legally blind, duration of follow-up, and use of systemic immunosuppression and ocular procedures in treatment. RESULTS: In multivariable analysis restricted to 55 patients, patients with negative and positive biopsies were similar in the outcome measures; however, positive-biopsy patients were more likely to be treated with systemic immunosuppression and were followed for longer at our clinic. Patients with isolated ocular disease were also more likely to have negative biopsies compared to those who also had extraocular disease. Patients who had conjunctival biopsies were more likely to have a negative direct immunofluorescence result than patients with biopsies from other sites. CONCLUSIONS: We encourage clinicians and patients to consider treatment with systemic immunosuppression even in the absence of diagnosis confirmation by DIF. Furthermore, this study supports current standard of care to pursue a nonocular biopsy of normal-appearing, perilesional skin or oral mucosa when possible.

Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit.

Although the roles of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling in KRAS-driven tumorigenesis are well established, KRAS activates additional pathways required for tumor maintenance, the inhibition of which are likely to be necessary for effective KRAS-directed therapy. Here, we show that the IκB kinase (IKK)-related kinases Tank-binding kinase-1 (TBK1) and IKKε promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and interleukin (IL)-6 and identify CYT387 as a potent JAK/TBK1/IKKε inhibitor. CYT387 treatment ablates RAS-associated cytokine signaling and impairs Kras-driven murine lung cancer growth. Combined CYT387 treatment and MAPK pathway inhibition induces regression of aggressive murine lung adenocarcinomas driven by Kras mutation and p53 loss. These observations reveal that TBK1/IKKε promote tumor survival by activating CCL5 and IL-6 and identify concurrent inhibition of TBK1/IKKε, Janus-activated kinase (JAK), and MEK signaling as an effective approach to inhibit the actions of oncogenic KRAS.