Negative impact of AQP-4 channel inhibition on survival of retinal ganglion cells and glutamate metabolism after crushing optic nerve.

The purpose of this study was to determine whether inhibition of aquaporin 4 (AQP4) is neuroprotective or neurodestructive after crushing the optic nerve of rats. The left optic nerves of rats were crushed, and TGN-020 (5.0 mg/kg, crush TGN-020) or its vehicle (DMSO, crush placebo) was injected intraperitoneally just after the crushing. As controls, the left optic nerves were exposed but not touched in other rats (sham controls). The retinal damages were determined by the density of retinal ganglion cells (RGCs) and the ratio of BAX/Bcl-2 on day 7. The glutamate level in the optic nerve on day 1 after the crushing was determined. The expressions of glutamine synthetase, glutamate-aspartate transporter (GLAST), and AQP4 were determined on day 3 by immunoblotting. The effects of AQP4 inhibition on the glutamate-induced changes of AQP4 expression and on the glutamate uptake were determined for optic nerve astrocytes in culture. The results showed that the density of RGCs was 2040 ± 91.3 cells/mm(2) (n = 6) in the sham control, and it was significantly decreased to 1072 ± 134.3 cells/mm(2) after crushing the optic nerve (P < 0.0001, crush placebo, n = 7; Fisher). An intraperitoneal injection of TGN-020 led to a further significant (P = 0.02, Fisher) decrease of the density of RGCs to 743 ± 371 cells/mm(2) (crush TGN-020, n = 7). The mRNA level of BAX/Bcl-2 ratio was 0.37 ± 0.05 in the sham control (n = 6) which was significantly increased to 0.88 ± 0.10 after crushing the optic nerve (placebo crush, n = 7; P = 0.0001, Scheffe). TGN-020 also significantly increased the BAX/Bcl-2 ratio to 1.29 ± 0.4 (n = 6) from the crush placebo group (P = 0.04, Scheffe). Immunoblotting showed similar changes in the protein levels. The glutamate level in the optic nerve was significantly increased to 53.7 ± 6.0 µM/mg/protein on day 1 (n = 4) from the sham control level of 45.9 ± 3.1 µM/mg/protein (n = 4; P = 0.04, t test). TGN-020 significantly (P < 0.05, Scheffe) depressed the expression of glutamate metabolism-related proteins on day 3. Exposure of cultured optic nerve astrocytes to glutamate (1.0 mM, n = 4) significantly increased the expression of AQP4 (P < 0.001, Scheffe) that was depressed by TGN-020 (100 nM, n = 4). In addition, glutamate uptake was inhibited by TGN-020 at 10 nM or higher. These results indicate that an inhibition of AQP4 enhances the loss of RGCs and retinal damages after crushing the optic nerve. Inhibition of AQP4 impairs glutamate metabolism which may account in part for these neurodestructive events.

Change of intraocular blood flow during treatment for thyroid eye disease.

To report a sequential observational study of changes in the retinal and choroidal blood flow during medical and surgical treatments for a thyroid eye disease (TED) patient, using optical coherence tomography angiography (OCTA) and laser speckle flowgraphy (LSFG). A 28-year-old man with a history of Graves' disease diagnosed 8 months prior was presented in the active phase of TED. His clinical activity score (CAS) was 6, but without diplopia or visual loss. Intraocular pressure measurement was OD 20 mmHg and OS 24 mmHg. Thyrotropin receptor antibody (TRAb) and thyroid-stimulating antibody levels were 18.8 IU/L and 4347%. Magnetic resonance imaging revealed enlargement of both extraocular muscles and fat compartments in both orbits. The patient underwent IV pulsed steroid therapy (1 g/day, 3 days) followed by an oral prednisone for 1 month. His CAS score decreased to 4. Bilateral orbital fat decompression decreased his final CAS score to 1 in both eyes. Intraocular blood flow was measured using laser speckle flowgraphy (LSFG), and OCTA was performed. Retinal blood flow increased slightly, but choroidal blood flow showed a robust increase. Choroidal blood flow measured using both LSFG and OCTA was negatively correlated with the CAS score and TRAb. In our case report, the ocular perfusion, especially choroidal blood flow, may decrease in active TED, which may be reversed by medical and surgical treatment.

Dietary Naringenin Preserves Insulin Sensitivity and Grip Strength and Attenuates Inflammation but Accelerates Weight Loss in a Mouse Model of Cancer Cachexia.

SCOPE: Cancer cachexia is characterized by the loss of skeletal muscle resulting in functional impairment, reduced quality of life and mortality. Naringenin, a flavonoid found in citrus fruits, improves insulin sensitivity and reduces inflammation and tumor growth in preclinical models. Therefore, the study hypothesizes that dietary supplementation of naringenin will improve insulin sensitivity, decrease inflammation, slow body weight loss, and delay tumor growth in a mouse model of cancer cachexia. METHODS AND RESULTS: Mice are fed 2 wt% dietary naringenin before and during initiation of cancer cachexia using inoculated adenocarcinoma-26 cells (C-26). Food intake, body weight, body composition, muscle function, insulin tolerance, and inflammatory status are assessed. Although naringenin-fed tumor-bearing mice exhibit reductions in body weight and food intake earlier than control diet-fed tumor-bearing mice, dietary naringenin is protective against loss of muscle strength, and attenuates the onset of insulin resistance and markers of inflammation. CONCLUSIONS: Dietary supplementation of naringenin improves multiple aspects of metabolic disturbance and inflammation during cancer cachexia progression in [C-26 tumor-bearing] mice. However, the acceleration of anorexia and weight loss is also observed. These findings emphasize the link between inflammation and insulin resistance as a basis for understanding their roles in the pathogenesis of cancer cachexia.

A Case of Giant Pituitary Adenoma Associated with a Postoperative Mental Disorder That Ultimately Resulted in Bilateral Blindness.

PURPOSE: To report the case of a patient with adrenocorticotropic hormone (ACTH)-producing pituitary adenoma who developed a mental disorder after initial surgery that kept him from undergoing scheduled follow-up visits and who ultimately had a giant recurrent tumor that resulted in blindness. CASE REPORT: A 37-year-old male presented with the primary complaint of decreased visual acuity (VA) in both eyes and visual field defects. Visual field examination revealed bitemporal hemianopia. Magnetic resonance imaging (MRI) showed a pituitary tumor of approximately 4 cm in diameter extending from the intrasellar region to the sphenoid sinus and the suprasellar region. Transnasal transsphenoidal surgery was performed. Immunostaining of tumor tissue collected intraoperatively showed ACTH-positive cells, thus leading to the diagnosis of ACTH-producing pituitary adenoma. Postoperatively, the patient reportedly developed mental disorder that possibly interfered with scheduled appointments or continuous follow-up visits for many years, so we had no postoperative data about the vision/visual filed. Seven years later, he presented with markedly decreased VA (i.e., no light perception) in both eyes. Fundus examination showed bilateral marked optic disc atrophy. MRI showed a larger than 8-cm diameter giant recurrent pituitary adenoma in the suprasellar region, for which craniotomy was performed for partial tumor resection. Preoperatively, his blood cortisol level was low, and the lesion was deemed a nonfunctioning pituitary adenoma. Postoperatively, no significant complications occurred, yet his VA was no light perception OD and light perception OS. CONCLUSIONS: Clinicians should be aware that patients with ACTH-producing pituitary adenomas may develop a mental disorder following surgery and possibly be unable to undergo scheduled follow-up, thus illustrating the importance of establishing an adequate patient follow-up system.

Gamma heavy chain disease (γ-HCD) as iatrogenic immunodeficiency- associated lymphoproliferative disorder: Possible emergent subtype of rheumatoid arthritis-associated γ-HCD.

Gamma heavy chain disease (γ-HCD) is a rare B-cell neoplasm that produces a truncated immunoglobulin γ-heavy chain lacking the light chain. The clinical features of γ-HCD are heterogeneous, resembling different types of B-cell lymphomas. Although rheumatoid arthritis (RA) is one of the common underlying diseases of γ-HCD, the therapeutic modality for RA has changed greatly in recent years; therefore, γ-HCD as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) should be taken into consideration. Here, we report such a γ-HCD case. A 69-year-old female was admitted because of fever, multiple lymph node swelling in the abdominal cavity, and peritoneal effusion. She had been treated using methotrexate for RA for 14 years, and using infliximab and adalimumab for Crohn's disease for one year. The serum concentration of IgG was 3,525 mg/dL, which was revealed to be monoclonal IgG lacking the light chain by rocket immunoselection assay. CD19+/CD20-/smκ-/smλ- large abnormal lymphocytes were observed in the peritoneal fluid, which were demonstrated to be clonal B-cells by PCR examination. Discontinuation of methotrexate did not improve her condition and she died of pneumonia. Many abnormal lymphocytes positive for IgG and EBER but negative for the light chain were found on immunohistological examination of necropsy specimens from the spleen and bone marrow.

C-reactive protein may be useful to differentiate idiopathic orbital inflammation and orbital cellulitis in cases with acute eyelid erythema and edema.

PURPOSE: Idiopathic orbital inflammation (IOI) and orbital cellulitis can present similar clinical features, and the diagnoses of these two disorders are sometimes confused. The purpose of the present study was to determine whether or not inflammatory markers in the blood can be useful to differentiate between IOI and orbital cellulitis in cases with acute eyelid erythema and edema. SUBJECTS AND METHODS: In this retrospective single-institute study, we reviewed the medical records spanning the past 10 years at the Department of Ophthalmology, Osaka Medical College Hospital, Takatsuki, Osaka, Japan, and found 45 cases, with patients >15 years of age, with presumed IOI. Their blood samples were obtained within 5 days after the onset of IOI. Of those cases, 15 patients (10 males, 5 females, mean age of 56.9 years; range 38-76 years) presented acute eyelid erythema and edema, and were initially misdiagnosed as orbital cellulitis. Thus, inflammatory markers in the blood (ie, white blood cells [WBCs] and C-reactive protein [CRP]) of those 15 patients were analyzed with 17 patients (10 males, 7 females) having orbital cellulitis. The receiver operating characteristic curve analysis was performed to determine the optimal cut-off values. RESULTS: The mean ± standard error (SE) levels of the WBC were 6.80±0.70×103/µL in the IOI patients, and 8.54±0.91×103/µL in the orbital cellulitis patients, and no significant differences were observed (P=0.15, Student's t-test). However, the mean ± SE levels of CRP were 1.04±0.43 mg/dL in the IOI patients, yet were significantly increased to 4.65±1.21 mg/dL in the orbital cellulitis patients (P=0.01, Student's t-test). The area under the curve value was 0.80 and the optimal cut-off value was 0.43 for orbital cellulitis, with sensitivity and specificity being 82% and 73%, respectively. CONCLUSION: The findings of this study indicate that CRP may be useful in distinguishing patients with idiopathic orbital inflammation from those with orbital cellulitis.

Convergent strabismus fixus after bilateral abducens nerve palsies due to aneurysms: A case report.

RATIONALE: Convergent strabismus fixus is an ocular motor abnormality in which the eye is fixed in adduction. This condition is mostly associated with high myopia and is caused by a displacement of the extraocular muscles. We report a nonmyopic woman with convergent strabismus fixus due to aneurysms. PATIENT CONCERNS: A 79-year-old woman complained of progressive worsening of esotropia about 50 years prior to her visit. Neuroimaging showed that the eye was not dislocated, and the extraocular muscles were not displaced. However, aneurysms were found bilaterally from the intracavernous carotid arteries and the location was on both abducens nerves. DIAGNOSES: Chronic bilateral abducens nerve palsies due to aneurysms. INTERVENTIONS: Endovascular treatment was successfully performed for the aneurysms. OUTCOMES: Convergent strabismus fixus still remained. LESSONS: Chronic abducens nerve palsies may develop to nonmyopic convergent strabismus fixus without displacement of extraocular muscles, and mass lesions in the brain including aneurysms should be ruled out when orbital MRI cannot explain the condition.

Complete Recovery from Blindness in Case of Compressive Optic Neuropathy due to Unruptured Anterior Cerebral Artery Aneurysm.

It is not common for an isolated visual symptom to be the first indication of an aneurysm compressing the optic nerve. The compression can lead to blindness, and a recovery from the blindness is rare. We report a female with a left painless optic neuropathy caused by an unruptured anterior cerebral artery aneurysm. The patient had a temporal hemianopic visual field defect, which progressed to blindness in the left eye, while the right visual function was not affected. A coil embolization of the aneurysm completely restored her visual acuity to 20/20. These findings suggest that aneurysmal lesions should be ruled out in case of unilateral optic neuropathy with hemianopic visual field defects and progressive visual loss.

Protective effect of P7C3 on retinal ganglion cells from optic nerve injury.

PURPOSE: To determine whether P7C3-A20, a proneurogenic neuroprotective agent, can protect the retinal ganglion cells (RGCs) of rats from optic nerve crushing. METHODS: The left optic nerve of 67 rats was crushed, and 5.0 mg/kg/day of P7C3-A20 (crush-P7C3) or its vehicle (crush-placebo) was injected intraperitoneally for 3 days from one day prior to the crushing. The protective effects were determined by the number of Tuj-1-stained RGCs and by the ratio of the mRNA levels of BAX/Bcl-2 on day 7. The levels of NAD and NAD-related genes were also determined. RESULTS: The density of RGCs was 2009.4 ± 57.7 cells/mm2 in the sham controls; it was significantly lower in the crush-placebo group at 979.7 ± 144.3 cells/mm2 (P < 0.0001). The neuroprotective effects of P7C3-A20 was demonstrated by the significantly higher density of 1266.0 ± 193.1 cells/mm2 than in the crush-placebo group (P = 0.01, Scheffe). After crushing the optic nerve the BAX/Bcl-2 ratio was higher in the optic nerves and retina, application of P7C3-A20 significantly reduced this ratio. P7C3-A20 significantly increased the NAD level in the untouched optic nerves from 1.36 ± 0.05 to 1.59 ± 0.10 nmol/mg protein (P = 0.02, t test). Crushing the optic nerve decreased the level to 1.27 ± 0.21 nmol/mg protein and P7C3-A20 preserved the level at 1.43 ± 0.10 nmol/mg protein. Crushing the optic nerve decreased the mRNA levels of Nampt and Sirt-1 in the optic nerves, while P7C3-A20 significantly restored the levels. CONCLUSIONS: P7C3-A20 can protect RGCs from optic nerve crushing possibly through preserving the NAD levels in the optic nerves.

Two Cases of Proliferative Diabetic Retinopathy with Marked Sheathing of the Retinal Arteries following Vitrectomy.

PURPOSE: The aim of this paper was to report 2 patients (3 eyes) with proliferative diabetic retinopathy (PDR) who showed marked sheathing of the retinal arterioles that was ultimately attributed to calcification following vitrectomy. CASES: Case 1 involved a 65-year-old female with PDR who underwent bilateral vitrectomy for traction retinal detachment. Postoperatively, bilateral retinal redetachment (reRD) was observed. Sheathing of the retinal arterioles was observed at the same time, yet was not apparent preoperatively. Case 2 involved a 71-year-old female with PDR who underwent vitrectomy for vitreous hemorrhage. Postoperatively, reRD was observed, and fundus findings showed sheathing of the retinal arterioles. In both patients, silicone oil tamponade and retinopexy were performed at reoperation, but sheathing of the retinal arterioles persisted postoperatively. Fluorescein fundus angiography showed that retinal blood flow was maintained, and no vessel leakage occurred. In addition, no sheathing of the retinal veins was observed. Optical coherence tomography (OCT) showed a higher intensity for retinal arterioles with sheathing than for normal retinal arterioles. CONCLUSION: Vessel sheathing in our 2 patients (3 eyes) differed from the sheathing seen in vasculitis. Based on the hyperintensity on OCT, this sheathing may have been due to retinal artery calcification induced by hypoxia and inflammation associated with reRD.

A comparison of sex steroid concentration levels in the vitreous and serum of patients with vitreoretinal diseases.

The purpose of this study was to compare steroid hormone concentration levels in the vitreous and serum of vitreoretinal disease patients to elucidate the possibility of neurosteroid production in the retina. Serum and vitreous samples were collected from vitrectomy patients, and estradiol (E2) and testosterone (T) concentrations were measured using electro-chemiluminescence immunoassay. We measured E2 in epiretinal membrane (ERM, n = 14), macular hole (MH, n = 18), proliferative diabetic retinopathy (PDR, n = 20), and retinal detachment (RD, n = 19) cases, and T in ERM (n = 14), MH (n = 17), PDR (n = 13), and RD (n = 17) cases. No statistically significant age differences existed among the groups. Mean respective E2 concentrations (pg/ml) in the male/female vitreous were ERM: 6.67±4.04/18.82±7.10, MH: 10.3±7.02/17.00±4.8, PDR: 4.2±3.05/15.83±3.46, and RD: 10.00±4.58/16.06±4.57, while those in serum were ERM: 31.67±5.51/5.82±1.08, MH: 21.00±8.89/7.53±3.2, PDR: 29.20±7.07/12.75±10.62, and RD: 24.33±6.51/7.5±4.42. E2 concentrations were significantly higher (P<0.001) in the male serum than vitreous, yet significantly higher in the female vitreous than serum. Mean respective T concentrations (ng/ml) in the male/female vitreous were ERM: 0.15±0.03/0.15±0.01, MH: 0.15±0.01/0.15±0.01, PDR: 0.15±0.03/0.16±0.12, and RD: 0.14±0.01/0.17±0.08, while those in serum were ERM: 4.54±1.46/0.16±0.01, MH: 8.04±2.29/0.16±0.10, PDR: 5.14±1.54/0.22±0.11, and RD: 3.24±0.75/0.17±0.10. T concentrations were high in the male serum, yet extremely low in the male and female vitreous and female serum. High concentrations of E2 were found in the vitreous, and women, in particular, exhibited significantly higher concentrations in the vitreous than in the serum. This finding suggests the possibility that in vitreoretinal disease cases, the synthesis of E2 is increased locally only in female eyes.

A Case of Hydranencephaly in Which Ophthalmic Examinations Were Performed.

PURPOSE: We performed ophthalmic examinations, including optical coherence tomography (OCT), on a case diagnosed with hydranencephaly. CASE REPORT: This case involved a female infant born at the gestational age of 35 weeks and 4 days, with the birth weight of 2,152 g, who was one of monochorionic diamniotic twins, and the identical twin died in utero at the gestational age of 24 weeks. After that, examination by fetal echo indicated that she had microcephaly and ventriculomegaly. Postnatal magnetic resonance imaging (MRI) of her head indicated microcephaly and significant enlargement of the lateral ventricle on both sides, with no obvious signs of elevated intracranial pressure. The brain parenchyma of both sides of the frontal lobe, parietal lobe, and occipital lobe had marked thinning, yet that of the temporal lobe, basal ganglia, thalamus, brain stem, and cerebellum had been maintained. Moreover, no obvious hematoma or neoplastic lesions were observed. Ophthalmic examinations indicated that both of her eyes had slight light reflex, attributed to optic nerve atrophy. Examination by use of a hand-held OCT system indicated a layered structure of the retina and thinning of the ganglion cell layer. Flicker electroretinogram (ERG) examination by use of a hand-held ERG system indicated an almost normal wave. However, no clear visual reaction was observed when she was 10 months old. CONCLUSION: Our findings in this case of hydranencephaly revealed that even though the outer layer functions of the patient's retina were maintained, extensive damage to her cerebral cortex resulted in poor visual function.

Clinical course of focal choroidal excavation in Vogt-Koyanagi-Harada disease.

We describe focal choroidal excavation (FCE) in a case of Vogt-Koyanagi-Harada (VKH) disease and compare the findings with different chorioretinal conditions. A 55-year-old man was diagnosed with VKH based on panuveitis and exudative retinal detachments. Spectral-domain optical coherence tomography demonstrated a dome-shaped protrusion with a nonconforming pattern at the fovea, which had been detected as a conforming pattern 1 year before the onset. The FCE pattern returned into a conforming pattern following corticosteroid therapy. These findings suggest that the natively existent FCE could be affected by pathophysiological changes of VKH as well as other chorioretinal conditions.