Antidiabetic drug sitagliptin blocks cyclophosphamide cerebral neurotoxicity by activating Nrf2 and suppressing redox cycle imbalance, inflammatory iNOS/NO/NF-κB response and caspase-3/Bax activation in rats.

Cyclophosphamide (CYP) is a classic DNA-interacting anticancer agent with broad application in chemotherapy. However, CYP cerebral neurotoxicity is a worrisome side effect for clinicians and patients. Strategies to mitigate the underlying oxidative inflammatory cascades and neuroapoptosis induced by CYP are urgently needed. Herein, we have repurposed an antidiabetic drug, sitagliptin (STG), for a possible abrogation of CYP-induced cerebral neurotoxicity in rats. Healthy rats were administered STG (20 mg/kg body weight) for 5 days prior to neurotoxicity induced by CYP (200 mg/kg body weight, ip) on day 5 only, and rats were sacrificed after 24 h post-CYP injection. CYP caused profound increases in the cerebral levels of nitric oxide (NO), acetylcholinesterase (AChE), malondialdehyde (MDA), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), nuclear factor-kappaB (NF-κB), inducible nitric oxide synthase (iNOS), caspase-3 and Bax protein compared to the control. Furthermore, CYP markedly depressed the activities of glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD), along with levels of reduced glutathione (GSH) and nuclear factor erythroid 2-related factor2 (Nrf2) compared to the control (p < 0.05). Interestingly, STG pretreatment inhibited the CYP-induced alterations in caspase-3, Bax, pro-inflammatory cytokines, NO, iNOS, AChE, NF-κB, and restored the cerebral antioxidant apparatus, including the Nrf2 and histopathological abrasions. Therefore, these findings show that STG could be repurposed to prevent CYP-induced cerebral toxicity in the brain.

Exogenous cryptococcal endophthalmitis in an immunocompetent patient.

We describe a case of exogenous cryptococcal endophthalmitis without central nervous system (CNS) involvement or systemic infection in an immunocompetent patient. An 82-year-old male with hypertension, hyperlipidemia, type 2 diabetes mellitus, and primary open-angle glaucoma with a history of left eye trabeculectomy presented with 3 months of worsening left eye pain and redness. Vitreous cultures resulted as Cryptococcus, prompting treatment with intravitreal amphotericin and further investigation. Systemic workup was unrevealing for an endogenous source, CNS involvement, or immunocompromising conditions. He was treated with an aggressive regimen of systemic antifungals, leading to subjective improvements in clinical exam and in vision.

"Persistence of Memory" - Multimodal imaging of delayed sympathetic ophthalmia.

Purpose: To describe a case of late post-surgical sympathetic ophthalmia documented with multimodal imaging. Observations: A 74-year-old male presented to the urgent care of the New York Eye and Ear Infirmary with blurry vision and discomfort in his left eye for three weeks. His vision was 20/50, with intraocular pressure of 13 mmHg, and slit lamp examination was significant for conjunctival congestion, 1+ anterior segment cell and flare, and diffuse keratic precipitates. His right eye was no light perception with a condensed hyphema, intraocular lens and inferonasal tube. His medical history included coronary artery bypass, prostate cancer, hyperlipidemia, and hypertension. His ocular history included blunt trauma to the right eye at age 11 with development of a traumatic macular hole and later rhegmatogenous retinal detachment at age 53, repaired with multiple vitreoretinal procedures. He developed glaucoma in the right eye and was treated with a tube shunt and ultimately transscleral cyclophotocoagulation (TSCPC) 7 years later, 13 years prior to his presentation of the left eye. Dilated fundus examination of his left eye revealed diffuse chorioretinal folds in the macula without any discrete chorioretinal lesions. Ultrasound of the right showed serous macular detachments with scleral thickening. Presumptive diagnosis of sympathetic ophthalmia was made and oral corticosteroid therapy was initiated. Subsequent SD-OCT and en-face OCT-A demonstrated Dalen-Fuchs nodules within the macula underlying areas of resolved serous detachment, after 6 weeks of oral steroids and initiation of immunomodulatory therapy (IMT). Conclusions: Sympathetic ophthalmia may rarely present with very delayed onset, and TSCPC is an uncommon inciting event. These patients may develop serous detachment, choroidal folds and inflammatory nodules identifiable on exam and multimodal imaging, which can resolve when treated appropriately. OCT-A may provide utility in monitoring response to immunosuppressive treatment in these patients.

Tesserae on Venus may preserve evidence of fluvial erosion.

Fluvial erosion is usually assumed to be absent on Venus, precluded by a high surface temperature of ~450 °C and supported by extensive uneroded volcanic flows. However, recent global circulation models suggest the possibility of Earth-like climatic conditions on Venus for much of its earlier history, prior to catastrophic runaway greenhouse warming. We observe that the stratigraphically oldest, geologically most complex units, tesserae, exhibit valley patterns morphologically similar to the patterns resulting from fluvial erosion on Earth. Given poor topographic resolution, we use an indirect technique to recognize valleys, based on the pattern of lava flooding of tesserae margins by adjacent plains volcanism. These observed valley patterns are attributed to primary geology, tectonic deformation, followed by fluvial erosion (and lesser wind erosion). This proposed fluvial erosion in tesserae provides support for climate models for a cool, wet climate on early Venus and could be an attractive research theme for future Venus missions.

Contaminating DNA in human saliva alters the detection of variants from whole genome sequencing.

Cells obtained from human saliva are commonly used as an alternative DNA source when blood is difficult or less convenient to collect. Although DNA extracted from saliva is considered to be of comparable quality to that derived from blood, recent studies have shown that non-human contaminating DNA derived from saliva can confound whole genome sequencing results. The most concerning complication is that non-human reads align to the human reference genome using standard methodology, which can critically affect the resulting variant genotypes identified in a genome. We identified clusters of anomalous variants in saliva DNA derived reads which aligned in an atypical manner. These reads had only short regions of identity to the human reference sequence, flanked by soft clipped sequence. Sequence comparisons of atypically aligning reads from eight human saliva-derived samples to RefSeq genomes revealed the majority to be of bacterial origin (63.46%). To partition the non-human reads during the alignment step, a decoy of the most prevalent bacterial genome sequences was designed and utilised. This reduced the number of atypically aligning reads when trialled on the eight saliva-derived samples by 44% and most importantly prevented the associated anomalous genotype calls. Saliva derived DNA is often contaminated by DNA from other species. This can lead to non-human reads aligning to the human reference genome using current alignment best-practices, impacting variant identification. This problem can be diminished by using a bacterial decoy in the alignment process.

RETINAL FINDINGS IN PRESUMED INFECTIOUS POSTERIOR UVEITIS AND CORRELATION WITH POLYMERASE CHAIN REACTION RESULTS.

PURPOSE: To correlate demographics, retinal lesion characteristics, and host immune status with the pathogen found on polymerase chain reaction analysis of aqueous fluid in patients with suspected infectious posterior uveitis. METHODS: Medical records of patients who underwent anterior chamber paracentesis for suspected infectious posterior uveitis and had retinal photographs between 2014 and 2016 at a single institution were reviewed. Data collection included demographics, clinical appearance of the lesions, and polymerase chain reaction results. Fundus photographs were evaluated by two masked observers for the clinical features of the retinitis. RESULTS: Twenty-eight patients were included in the study. There was substantial to almost perfect agreement on retinitis location (κ = 0.67) and number (κ = 0.76) between the masked photograph graders. Polymerase chain reaction results were positive for herpes simplex virus or varicella zoster virus in 43%, cytomegalovirus in 11%, and toxoplasmosis in 3%; 43% had negative polymerase chain reaction results. Detection of herpes simplex virus or varicella zoster virus on polymerase chain reaction of the aqueous was associated with paucifocal lesions (82%, P = 0.021) and lesions involving the peripheral retina (91%, P = 0.023), consistent with the diagnosis of acute retinal necrosis. CONCLUSION: These data suggest that the diagnosis of acute retinal necrosis can be reasonably inferred on clinical examination, providing a guide for initial empiric therapy.

Are the Current Recommendations for Chloroquine and Hydroxychloroquine Screening Appropriate?

Hydroxychloroquine and quinacrine are frequently used to treat rheumatic diseases. Ocular toxicity, although infrequent, is one of the potential side effects of antimalarial therapies. Current recommendations are unifocal in being developed by only ophthalmologists who do not treat patients for their rheumatic diseases. The data used to create the recommendations are meager and retrospective. Comanagement of patients with rheumatic disease who are exposed to antimalarial therapies requires a greater interaction between ophthalmologists and rheumatologists.

A Case of Corneal Neovascularization Misdiagnosed as Total Limbal Stem Cell Deficiency.

PURPOSE: To report a case of corneal neovascularization misdiagnosed as total limbal stem cell deficiency (LSCD). METHODS: This is a case report of a 61-year-old woman who has a history of bilateral idiopathic scleritis, keratitis, and uveitis for more than 20 years. She was diagnosed with total LSCD in her left eye based on clinical presentation alone and was confirmed as a candidate for limbal transplantation at several major tertiary eye care centers in the United States. After referral to the Stein Eye Institute, in vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (AS-OCT) were performed to clarify the diagnosis. RESULTS: Slit-lamp examination of the left eye revealed 360-degree severe thinning at the limbus and peripheral corneal pannus and neovascularization that spared the central cornea, a smooth epithelium without fluorescein staining at the central cornea, an uneven surface, and pooling of fluorescein at the peripheral cornea accompanied by minimal fluorescein staining of the sectoral peripheral epithelium. IVCM showed that epithelial cells in the central cornea exhibited a corneal phenotype and that the morphology of the epithelium in all limbal regions except the nasal limbus was normal. Epithelial cellular density and thickness were within the normal range. AS-OCT showed severe thinning in the limbus and a normal epithelial layer in the cornea and limbus. Based on the findings of IVCM and AS-OCT, we concluded that the patient had minimal LSCD, and limbal stem cell transplantation was not recommended. CONCLUSIONS: Clinical presentation alone is insufficient to correctly diagnose LSCD in complex cases. Additional diagnostic tests, such as IVCM, are necessary to confirm the diagnosis before any surgical intervention.

Intercuneiform and Lisfranc Fracture-Dislocation Due to Seizure: A Case Report.

Cuneiform dislocation associated with Lisfranc injury is a very rare injury. Dislocation over the midfoot due to a seizure has not been previously reported in published studies. A 35-year-old female presented with an intercuneiform dislocation and Lisfranc fracture-dislocation after a generalized seizure. Immediate close reduction of the dorsally dislocated cuneiforms was performed, followed by definitive treatment to restore the foot arches. A proposed underlying pathophysiology of dislocation due to seizure in terms of the biomechanics is discussed. The purpose of our report was to present the unusual etiology of this form of cuneiform dislocation and Lisfranc joint complex injury.

CHIKUNGUNYA-ASSOCIATED UVEITIS AND EXUDATIVE RETINAL DETACHMENT: A CASE REPORT.

PURPOSE: To report the first known case of bilateral granulomatous panuveitis secondary to chikungunya fever in the United States, acquired by a U.S. citizen traveling from an endemic region. METHODS: Case report. RESULTS: A 47-year-old woman presented with 10 days of bilateral decreased vision and photophobia concurrent with a febrile illness contracted while visiting the Dominican Republic. She presented with bilateral granulomatous panuveitis and exudative retinal detachments. Extensive workup was negative with the exception of positive chikungunya virus immunoglobulin G and immunoglobulin M titers. Initially, she responded to corticosteroid treatment but developed recurrent inflammation 3 months after completing the initial treatment. Immunomodulatory therapy was initiated at the time of recurrence, and with immunomodulatory therapy alone her inflammation has been controlled for 6 months. CONCLUSION: The prevalence of chikungunya fever-related uveitis is increasing with the recent epidemics throughout the Americas. Inflammation can occur during the febrile illness or months later and can manifest in a variety of ways. Posterior segment inflammation is more commonly a delayed presentation. Previous reports suggest that chikungunya fever-related uveitis responds well to corticosteroid therapy. This is the first reported case of recurrent inflammation. Given the wide variety of presentations, chikungunya fever-related uveitis should be included in the differential diagnosis of all at-risk patients presenting with acute ocular inflammation, particularly those traveling from endemic regions.

Panuveitis With Exudative Retinal Detachments After Vaccination Against Human Papilloma Virus.

A 20-year-old white woman presented with bilateral acute visual loss (visual acuity: 20/60), panuveitis, and exudative retinal detachments 3 weeks after a second dose of quadrivalent human papillomavirus (HPV4) vaccine. She was treated with oral prednisolone for 6 weeks and responded rapidly. By week 4, vision had normalized and clinical signs resolved. Uveitis after HPV4 vaccination has been reported in two cases. Although the differential diagnosis includes Harada disease, temporal correlation with HPV4 and definitive response to a short course of treatment implicate the vaccine in this case. Vaccine-induced uveitis is rare and difficult to distinguish from coincidental autoimmune disease.

Spontaneous Dissociation of Fluocinolone Acetonide Sustained Release Implant (Retisert) with Dislocation into the Anterior Chamber.

PURPOSE: To report two cases of spontaneous Retisert implant dissociation with dislocation of the medication reservoir into the anterior chamber. DESIGN AND METHODS: Case reports. RESULTS: Two patients with chronic, noninfectious uveitis following Retisert implantation between 6 and 7 years prior presented with a complaint of a "white spot" in their right eyes. Both patients had previous pars plana vitrectomies. Anterior segment examination revealed a dislocated medication reservoir of the Retisert implant in the inferior portion of anterior chamber with associated reservoir-corneal endothelial touch and stromal edema. The reservoirs were subsequently retrieved via a pars plana approach and removed from the anterior chamber through a corneal incision. CONCLUSIONS: Spontaneous dissociation of the Retisert implant with dislocation of the medication reservoir into the anterior chamber can be a late complication of Retisert implantation. Eye care professionals and patients should be aware of this complication, particularly with long-term intraocular retention of this device.

Core muscle activity during suspension exercises.

OBJECTIVES: Suspension exercise has been advocated as an effective means to improve core stability among healthy individuals and those with musculoskeletal complaints. However, the activity of core muscles during suspension exercises has not been reported. In this study, we investigated the level of activation of core muscles during suspension exercises within young and healthy adults. DESIGN: The study was conducted in a controlled laboratory setting. METHODS: Surface electromyographic (sEMG) activity of core muscles (rectus abdominis, external oblique, internal oblique/transversus abdominis, and superficial lumbar multifidus) during four suspension workouts (hip abduction in plank, hamstring curl, chest press, and 45° row) was investigated. Muscle activity during a 5-s hold period of the workouts was measured by sEMG and normalized to the individual's maximal voluntary isometric contraction (MVIC). RESULTS: Different levels of muscle activation were observed during the hip abduction in plank, hamstring curl, and chest press. Hip abduction in plank generated the highest activation of most abdominal muscles. The 45° row exercise generated the lowest muscle activation. CONCLUSIONS: Among the four workouts investigated, the hip abduction in plank with suspension was found to have the strongest potential strengthening effect on core muscles. Also, suspension training was found to generate relatively high levels of core muscle activation when compared with that among previous studies of core exercises on stable and unstable support surfaces.

Fundus image diagnostic agreement in uveitis utilizing free and open source software.

OBJECTIVE: To assess the adequacy of image agreement regarding uveitis based on color fundus and fluorescein angiography images alone, and to use free and open source applications to conduct an image agreement study. DESIGN: Cross-sectional agreement study. PARTICIPANTS: Baseline fundus and fluorescein images of patients with panuveitis, posterior, or intermediate uveitis enrolled in the Multi-center Uveitis Steroid Treatment (MUST) trial. METHODS: Three fellowship-trained specialists in uveitis independently reviewed patient images using ClearCanvas™ and responded using Epi Info™. The diagnoses of the 3 reviewers were compared with the MUST clinician as a gold standard. A rank transformation adjusted for the possible variation in number of responses per patient. Chance-corrected interobserver agreement among the 3 reviewers was estimated with the ι coefficient. Confidence interval (CI) and SE were bootstrapped. RESULTS: Agreement between the diagnoses of the respondents and the baseline MUST clinician's diagnosis was poor across all diagnostic categories, ι = 0.09 (95% CI, 0.07-0.11). The agreement among respondents alone also was poor, ι = 0.11 ± 0.02 (95% CI, 0.08-0.13). The specialists requested more patient historical and clinical information to make a diagnosis on all patients. CONCLUSIONS: The role in distinguishing the multiple conditions in uveitis appears to be limited when based on fundus imaging alone. Future studies should investigate different categories of clinical data to supplement image data. Freely available applications have excellent utility in ophthalmic imaging agreement studies.

Polychromatic angiography for the assessment of VEGF-induced BRB dysfunction in the rabbit retina.

PURPOSE: To determine the utility of polychromatic angiography (PCA) in the assessment of VEGF-induced blood retinal barrier (BRB) dysfunction in rabbits. METHODS: Twenty-six eyes of 24 Dutch Belted rabbits were injected intravitreally with 1.25 µg (group A, n = 5), 10 µg (group C, n = 7), or 4 µg (group B, n = 6; group D, n = 4; and group E, n = 4) of VEGF on day 0. Groups D and E were also injected intravitreally with 1.25 µg and 12.5 µg bevacizumab, respectively, on day 2. On days 0, 2, 4, 7, 11, and 14, PCA was performed using a contrast agent mixture composed of fluorescein sodium, indocyanine green, PCM102, and PCM107 and imaged with a modified fundus camera. PCA scores were based on detected leaking fluorophores. RESULTS: On day 7, there was a statistically significant difference between PCA scores of group A (0.6 ± 0.89) and both groups B (2.67 ± 1.37, P = 0.0154) and C (3.33 ± 0.52, P = 0.00085). There was also a statistically significant difference between groups B and E (PCA score 0.75 ± 0.96, P = 0.032) on day 7. On day 11, there was statistically significant difference between group C (1.80 ± 1.1) and both groups A (0, P = 0.021) and B (0.33 ± 0.52, P = 0.037). CONCLUSIONS: A differential response to both increasing VEGF dose and administration of bevacizumab could be discerned using the PCA. PCA allowed stratification of VEGF-induced BRB dysfunction and inhibitory effects of bevacizumab therapy in the rabbit retina.