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Rationale: Major Depressive Disorder (MDD) significantly impairs the quality of life for those affected. While the exact causes of MDD are not fully understood, the deficit of monoamines, especially serotonin and noradrenaline, is widely accepted. Resistance to long-term treatments and adverse effects are often observed, highlighting the need for new pharmacological therapies. Synthetic organic compounds containing selenium have exhibited pharmacological properties, including potential antidepressant effects., Objective: To evaluate the antidepressant-like effect of N-(3-((3-(trifluoromethyl)phenyl)selenyl)prop-2-yn-1-yl) benzamide (CF 3 SePB) in mice and the involvement of the serotonergic and noradrenergic systems., Methods: Male Swiss mice were treated with CF 3 SePB (1-50 mg/kg, i.g.) and 30 min later the forced swimming test (FST) or tail suspension test (TST) was performed. To investigate the involvement of the serotonergic and noradrenergic systems in the antidepressant-like effect of CF 3 SePB, mice were pre-treated with p-CPA (a 5-HT depletor, 100 mg/kg, i.p.) or the receptor antagonists WAY100635 (0.1 mg/kg, s.c., a 5-HT 1A receptor antagonist), ketanserin (1 mg/kg, i.p., a 5-HT 2A/2C receptor antagonist), ondansetron (1 mg/kg, i.p., a 5-HT 3 receptor antagonist), GR110838 (0.1 mg/kg, i.p., a 5-HT 4 receptor antagonist), prazosin (1 mg/kg, i.p., an α 1 -adrenergic receptor antagonist), yohimbine (1 mg/kg, i.p., an α 2 -adrenergic receptor antagonist) and propranolol (2 mg/kg, i.p., a non-selective beta-adrenergic receptor antagonist) at specific times before CF 3 SePB (50 mg/kg, i.g.), and after 30 min of CF 3 SePB administration the FST was performed., Results: CF 3 SePB showed an antidepressant-like effect in both FST and TST and this effect was related to the modulation of the serotonergic system, specially the 5-HT 1A and 5-HT 3 receptors. None of the noradrenergic antagonists prevented the antidepressant-like effect of CF 3 SePB. The compound exhibited a low potential for inducing acute toxicity in adult female Swiss mice., Conclusion: This study pointed a new compound with antidepressant-like effect, and it could be considered for the development of new antidepressants., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

1-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with an antidepressant-like effect in mice by regulation of the serotonergic system. This study investigated the involvement of dopaminergic and noradrenergic systems in the antidepressant-like action of MeSeI. For this purpose, Swiss male mice were pretreated with different antagonists, after 15 min, the MeSeI was administrated by intragastric (i.g.) via; after 30 min, the mouse behavior was assessed in the forced swimming test (FST). The action of MeSeI on the activity of monoamine oxidase (MAO) was determined. The pretreatment of mice with haloperidol (0.05 mg/kg, intraperitoneally, i.p.; non-selective dopamine receptor antagonist), sulpiride (50 mg/kg, i.p.; D 2 receptor antagonist), yohimbine (1 mg/kg, i.p.; α 2 receptor antagonist), and propranolol (2 mg/kg, i.p.; non-selective β receptor antagonist), inhibited the anti-immobility action of MeSeI (50 mg/kg, i.g.) in the FST. This blocking effect was not observed when SCH23390 (0.01 mg/kg, i.p.; D 1 receptor antagonist), and prazosin (1 mg/kg, i.p.; α 1 receptor antagonist) were administered. The coadministration of subeffective doses of bupropion (3 mg/kg. i.g.; dopamine and noradrenaline reuptake inhibitor) and MeSeI (0.5 mg/kg. i.g.) reduced the immobility time in the FST. Furthermore, MeSeI inhibited MAO-A and B activities in vitro and ex vivo tests. These results suggest that MeSeI exerts its antidepressant-like effect via regulation of the D 2 , α 2 , and β 1 receptors and the inhibition of MAO-A and B activities. Molecular docking investigations corroborated these results. This study provides comprehensive insights into the antidepressant-like mechanism of MeSeI in mice, suggesting its potential as a novel antidepressant candidate., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive molecules produced naturally by the body and by external factors. When these species are generated in excessive amounts, they can lead to oxidative stress, which in turn can cause cellular and tissue damage. This damage is known to contribute to the aging process and is associated with age-related conditions, including cardiovascular and neurodegenerative diseases. In recent years, there has been an increased interest in the development of compounds with antioxidant potential to assist in the treatment of disorders related to oxidative stress. In this way, compounds containing sulfur (S) and/or selenium (Se) have been considered promising due to the relevant role of these elements in the biosynthesis of antioxidant enzymes and essential proteins with physiological functions. In this context, studies involving heterocyclic nuclei have significantly increased, notably highlighting the indolizine nucleus, given that compounds containing this nucleus have been demonstrating considerable pharmacological properties. Thus, the objective of this research was to evaluate the in vitro antioxidant activity of eight S- and Se-derivatives containing indolizine nucleus and different substituents. The in vitro assays 1,1-diphenyl-2-picryl-hydrazil (DPPH) scavenger activity, ferric ion (Fe 3+ ) reducing antioxidant power (FRAP), thiobarbituric acid reactive species (TBARS), and protein carbonylation (PC) were used to access the antioxidant profile of the compounds. Our findings demonstrated that all the compounds showed FRAP activity and reduced the levels of TBARS and PC in mouse brains homogenates. Some compounds were also capable of acting as DPPH scavengers. In conclusion, the present study demonstrated that eight novel organochalcogen compounds exhibit antioxidant activity., Competing Interests: Eder João Lenardão is an Academic Editor for PeerJ., (©2024 Schossler Garcia et al.)

Pain has a negative impact on public health, reducing quality of life. Unfortunately, current treatments are not fully effective and have adverse effects. Therefore, there is a need to develop new analgesic compounds. Due to promising results regarding the antinociceptive effect of N-(3-(phenylselanyl)prop-2-in-1-yl)benzamide (SePB), this study aimed to evaluate the participation of the dopaminergic and noradrenergic systems in this effect in mice, as well as its toxicity. To this, the antagonists sulpiride (D 2 /D 3 receptor antagonist, 5 mg/kg), SCH-23390 (D 1 receptor antagonist, 0.05 mg/kg), prazosin (α 1 adrenergic receptor antagonist, 0.15 mg/kg), yohimbine (α 2 -adrenergic receptors, 0.15 mg/kg) and propranolol (non-selective β-adrenergic antagonist, 10 mg/kg) were administered intraperitoneally to mice 15 min before SePB (10 mg/kg, intragastrically), except for propranolol (20 min). After 26 min of SePB administration, the open field test was performed for 4 min to assess locomotor activity, followed by the tail immersion test to measure the nociceptive response. For the toxicity test, animals received a high dose of 300 mg/kg of SePB. SePB showed an increase in the latency for nociceptive response in the tail immersion test, and this effect was prevented by SCH-23390, yohimbine and propranolol, indicating the involvement of D 1 , α 2 and β-adrenergic receptors in the antinociceptive mechanism of the SePB effect. No changes were observed in the open field test, and the toxicity assessment suggested that SePB has low potential to induce toxicity. These findings contribute to understanding SePB's mechanism of action, with a focus on the development of new alternatives for pain treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Major depressive disorder (MDD) is a psychiatric disorder that affects a large portion of the population, with dysregulation of the serotonergic system, which is deeply involved in both the pathophysiology of MDD and mechanism of action of many antidepressants. Current pharmacological therapies do not meet the neurobiological needs of all depressed individuals, making the development of new antidepressants necessary. In recent decades, compounds containing triazoles have become promising due to their range of biological activities, including antidepressant activity. In this study, we evaluated the antidepressant-like effect of a hybrid containing triazole and acetophenone, 1-(2-(4-(4-ethylphenyl)-1 H -1,2,3-triazol-1-yl)phenyl)ethan-1-one (ETAP) (0.5-5 mg/kg), in the forced swimming test (FST) and tail suspension test (TST) in mice, as well as the involvement of the serotonergic system in this effect. Our findings demonstrated that ETAP exhibited an antidepressant-like effect from the dose of 1 mg/kg and that this effect is modulated by 5-HT 2A/2C and 5-HT 4 receptors. We also demonstrated that this effect may be related to inhibition of monoamine oxidase A activity in the hippocampus. Additionally, we evaluated the in silico pharmacokinetic profile of ETAP, which predicted its penetration into the central nervous system. ETAP exhibited a low potential for toxicity at a high dose, making this molecule interesting for the development of a new therapeutic strategy for MDD.

Rationale: Depression is a mental disorder that affects approximately 280 million people worldwide. In the search for new treatments for mood disorders, compounds containing selenium and indolizine derivatives show promising results., Objectives and Methods: To evaluate the antidepressant-like effect of 1-(phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) (0.5-50 mg/kg, intragastric-i.g.) on the tail suspension test (TST) and the forced swim test (FST) in adult male Swiss mice and to elucidate the role of the serotonergic system in this effect through pharmacological and in silico approaches, as well to evaluate acute oral toxicity at a high dose (300 mg/kg)., Results: MeSeI administered 30 min before the FST and the TST reduced immobility time at doses from 1 mg/kg and at 50 mg/kg and increased the latency time for the first episode of immobility, demonstrating an antidepressant-like effect. In the open field test (OFT), MeSeI did not change the locomotor activity. The antidepressant-like effect of MeSeI (50 mg/kg, i.g.) was prevented by the pre-treatment with p-chlorophenylalanine (p-CPA), a selective tryptophan hydroxylase inhibitor (100 mg/kg, intraperitoneally-i.p. for 4 days), with ketanserin, a 5-HT 2A/2C receptor antagonist (1 mg/kg, i.p.), and with GR113808, a 5-HT 4 receptor antagonist (0.1 mg/kg, i.p.), but not with WAY100635, a selective 5-HT 1A receptor antagonist (0.1 mg/kg, subcutaneous-s.c.) and ondansetron, a 5-HT 3 receptor antagonist (1 mg/kg, i.p.). MeSeI showed a binding affinity with 5-HT 2A , 5 -HT 2C , and 5-HT 4 receptors by molecular docking. MeSeI (300 mg/kg, i.g.) demonstrated low potential to cause acute toxicity in adult female Swiss mice., Conclusion: In summary, MeSeI exhibits an antidepressant-like effect mediated by the serotonergic system and could be considered for the development of new treatment strategies for depression., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background Preclinical studies suggest that imatinib resistance in gastrointestinal stromal tumor (GIST) can be mediated by MAP-kinase activation via fibroblast growth factor (FGF) signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib, was cytotoxic and superior to imatinib therapy alone. In FGF-dependent GIST, the combination of BGJ398 and imatinib may provide a mechanism to overcome imatinib resistance. Methods This phase Ib study of BGJ398 and imatinib was performed in patients with imatinib refractory advanced GIST. A standard 3 + 3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Two treatment schedules were evaluated incorporating imatinib 400 mg daily in combination with (A) BGJ398 daily 3 weeks on, 1 week off or (B) BGJ398 daily 1 week on, 3 weeks off. Results 16 patients enrolled. The median age was 54 years (range: 44-77), 81% were male, and the median number of lines of prior therapy was 4 [range: 2-6, 13 patients had ≥3 prior therapies]. 12 patients received treatment on schedule A [BGJ398 dose range: 25 - 75 mg]: 2 patients experienced dose limiting toxicities (DLT) (n = 1, myocardial infarction & grade (G)4 CPK elevation; n = 1, G3 ALT elevation) on schedule A (BGJ398 75 mg), significant hyperphosphatemia, an on-target effect, was not observed, implying the maximum tolerated dose was below the therapeutic dose. Following protocol amendment, 4 patients enrolled on schedule B [BGJ398 dose range: 75 - 100 mg]: no DLTs were observed. The most common treatment related adverse events occurring in >15% of patients included CPK elevation (50%), lipase elevation (44%), hyperphosphatemia (24%), anemia (19%), and peripheral edema (19%). Among the 12 evaluable patients, stable disease (SD) was the best response observed in 7 patients by RECIST v1.1 and 9 patients by CHOI. Stable disease ≥ 32 weeks was observed in 3 patients (25%). Median progression free survival was 12.1 weeks (95% CI 4.7-19.5 weeks). Conclusions Toxicity was encountered with the combination therapy of BGJ398 and imatinib. Due to withdrawal of sponsor support the study closed before the RP2D or dosing schedule of the combination therapy was identified. In heavily pre-treated patients, stable disease ≥ 32 weeks was observed in 3 of 12 evaluable patients. Trial Registration: NCT02257541 .

Purpose: To evaluate the risk of cataract in the setting of AIDS., Design: Prospective cohort study., Participants: Subjects with AIDS free of ocular opportunistic infections throughout catamnesis., Methods: From 1998 through 2008, subjects 13 years of age or older were enrolled. Demographic characteristics and clinical characteristics were documented at enrollment and semiannually., Main Outcome Measures: Cataract was defined as high-grade lens opacity observed by biomicroscopy judged to be the cause of a best-corrected visual acuity worse than 20/40. Eyes that underwent cataract surgery during follow-up were considered to have developed cataract before the first visit when pseudophakia or aphakia was observed., Results: Among 1606 participants (3212 eyes) at enrollment, 1.9% (95% confidence interval [CI]: 1.3%-2.7%) were observed to have cataract or prior cataract surgery. Among the 2812 eyes initially free of cataract and followed longitudinally (median follow-up, 4.6 years), the incidence of cataract was 0.37%/eye-year (95% CI: 0.26%-0.53%). In addition to age, significant cataract risk factors included prior cataract in the contralateral eye (adjusted hazard ratio [aHR], 21.6; 95% CI: 10.4-44.8), anterior segment inflammation (aHR, 4.40; 95% CI: 1.64-11.9), prior retinal detachment (aHR, 4.94; 95% CI: 2.21-11.0), and vitreous inflammation (aHR, 7.12; 95% CI: 2.02-25.0), each studied as a time-updated characteristic. Detectable human immunodeficiency virus RNA in peripheral blood was associated with lower risk of cataract at enrollment (adjusted odds ratio, 0.32; 95% CI: 0.12-0.80) but not of incident cataract (aHR, 1.58; 95% CI: 0.90-2.76). After adjustment for other factors, neither the then-current absolute CD4+ T-cell count nor antiretroviral therapy status showed consistent association with cataract risk, nor did an additive diagnosis of other comorbidities. Compared with the available population-based studies that used similar definitions of cataract, the age-specific prevalence of cataract in our cohort was higher than in 1 of 2 such studies, and the age-specific incidence of cataract surgery was higher., Conclusions: Our results suggest cataract may occur earlier among patients with AIDS free of ocular opportunistic infections than in the general population. Cataract risk was associated most strongly with age and with other ocular morbidity in this population. With improved survival, the burden of cataract likely will increase for persons with the human immunodeficiency virus or AIDS., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To characterize the analgesic potency and toxicity of topical synthetic neurotensin analogues, and localize neurotensin receptors in the cornea and trigeminal ganglion., Methods: Cochet-Bonnet esthesiometry was performed on the rabbit cornea to test the analgesic dose response and duration of effect for two synthetic neurotensin analogues: NT71 and NT72. Receptors for neurotensin were localized in the murine cornea and trigeminal ganglion using quantitative PCR (qPCR), Western blotting, and immunohistochemistry. In vitro toxicity of NT71, NT72, and sodium channel blockers was evaluated using cytotoxicity, single-cell migration, and scratch closure assays performed on rabbit corneal epithelial cells. In vivo toxicity of these agents was assessed using a rabbit laser phototherapeutic keratectomy (PTK) model and histology., Results: NT71 and NT72 induced potent analgesic effects on the rabbit cornea at concentrations between 1.0 and 2.5 mg/mL, lasting up to 180 minutes. A site-specific distribution of neurotensin receptors was observed in the murine cornea and trigeminal ganglion. NT71 and NT72 did not cause any significant in vitro or in vivo toxicity, in contrast to sodium channel blockers., Conclusions: Synthetic neurotensin analogues are potent analgesics that avoid the toxicities associated with established topical analgesic agents. Receptors for neurotensin are present in both the cornea and trigeminal ganglion., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Objective: To evaluate cataract risk in eyes of patients with AIDS and cytomegalovirus (CMV) retinitis and to identify risk factors., Design: Prospective cohort study., Participants: Patients with AIDS and CMV retinitis., Methods: Patients 13 years of age and older were enrolled between 1998 and 2008. Demographic and clinical characteristics, slit-lamp biomicroscopy findings, and dilated ophthalmoscopy results were documented at quarterly visits. Cataract status was determined at the initial visit (prevalence) and at follow-up visits (incidence)., Main Outcome Measures: For cataract, a high grade of lens opacity by biomicroscopy to which best-corrected visual acuity worse than 20/40 was attributed. Eyes that had undergone cataract surgery before enrollment or between visits also were counted as having cataract., Results: Seven hundred twenty-nine eyes of 489 patients diagnosed with CMV retinitis were evaluated. Higher prevalence was observed for patients with bilateral versus unilateral CMV retinitis (adjusted odds ratio [aOR], 2.74; 95% confidence interval [CI], 1.76-4.26) and, among unilateral CMV retinitis cases, for eyes with retinitis versus without retinitis (15% vs. 1.4%; P<0.0001). The age-adjusted prevalence of cataract among CMV retinitis cases was higher than that in a population-based sample (P<0.0001). Cataract prevalence increased with age (aOR, 11.77; 95% CI, 2.28-60.65 for age ≥ 60 years vs. younger than 40 years) and longer duration of retinitis (aOR, 1.36; 95% CI, 1.20-1.54 per year). Among eyes with CMV retinitis initially free of cataract, the cataract incidence was 8.1%/eye-year (95% CI, 6.7%-10.0%). Prior retinal detachment was associated with higher cataract risk (if repaired with silicone oil: adjusted hazard ratio [aHR], 10.37; 95% CI, 6.51-16.52; otherwise: aHR, 2.90; 95% CI, 1.73-4.87). Large CMV retinitis lesions also were associated with higher risk of cataract (for involvement of 25-49% retinal area: aHR, 2.30; 95% CI, 1.51-3.50; for ≥ 50% involvement: aHR, 3.63; 95% CI, 2.18-6.04), each with respect to ≤ 24% involvement, as were anterior segment inflammation (aHR, 2.27; 95% CI, 1.59-3.25) and contralateral cataract (aHR, 2.52; 95% CI, 1.74-3.66)., Conclusions: Cytomegalovirus retinitis is associated with a high absolute and relative risk of cataract. Among several risk factors, large retinal lesion size and use of silicone oil in retinal detachment repair are potentially modifiable, albeit not in all cases. Cataract is likely to be an increasingly important cause of visual morbidity in this population., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: The use of gefitinib, the first drug approved to inhibit the epidermal growth factor receptor tyrosine kinase, is indicated in patients with non-small-cell lung cancer with tumors progressive after chemotherapy. The unique mechanism of action of this agent leads to distinctive patterns of response and toxicity in persons with lung cancer. Many of the principles of management relevant to gefitinib are distinct from those with conventional cytotoxic drugs. To meet this need, we present practical guidelines on the use of gefitinib in patients with non-small-cell lung cancer., Methods: This article reviews gefitinib's indications, dosing, response phenomena, and patterns of relapse in individuals with radiographic response., Results: We present our recommendations for the management of rash and diarrhea caused by this agent., Conclusion: This information can guide practitioners and help them inform their patients about what to expect when they receive gefitinib.

Primary ocular lymphoma (POL), a lymphoma of the globe, is a restricted form of primary central nervous system lymphoma (PCNSL) that often progresses to the brain and meninges; frequently it is misdiagnosed until central nervous system (CNS) lymphoma develops. The optimal treatment has not yet been identified. We retrospectively reviewed the course and the treatment of POL in 31 patients. Seventeen patients were treated for isolated POL (group A) and 14 were treated only after CNS disease was diagnosed (group B). The treatment in both groups consisted of systemic chemotherapy, chemotherapy plus radiotherapy (RT) or RT alone. In group A, nine patients (53%) developed CNS progression and five (29%) had ocular recurrence. In group B, seven (50%) had CNS progression and three (21%) ocular relapse. To control for diagnostic lead time, median survival was calculated from initial ocular symptoms and was 60 months in group A and 35 months in group B (P < 0.05). Ocular lymphoma responds to a variety of therapies but treatment with chemotherapy and/or ocular radiotherapy (ORT) failed to prevent CNS progression. Patients whose ocular disease was identified and treated before CNS progression had a significantly improved survival.

Objective: To evaluate the efficacy of the ganciclovir implant in the setting of silicone oil vitreous substitute., Materials and Methods: The authors retrospectively reviewed the charts of 19 patients with cytomegalovirus retinitis who had both a ganciclovir implant and silicone oil vitreous substitute. None of the patients was receiving highly active antiretroviral therapy during the study period. Kaplan-Meier analysis was used to evaluate time to progression in eyes with the ganciclovir implant and silicone oil., Results: In all eyes, the ganciclovir device implantation preceded or coincided with silicone injection. Kaplan-Meier analysis revealed that time to 25% failure from the date of the presence of both the implant and oil was 129 days. Time to 25% failure from the date of ganciclovir device implantation was 179 days., Conclusions: These results compare favorably with conventional treatment. The ganciclovir implant can be a useful treatment modality in eyes with silicone oil.

Purpose: To report uveitis associated with human immunodeficiency virus (HIV) infection and to suggest guidelines for treatment., Methods: Six HIV-seropositive patients (10 eyes) with anterior or posterior uveitis or both were evaluated. After ineffective prolonged treatment with systemic and topical corticosteroids, specific systemic antiretroviral therapy with zidovudine was initiated in all patients. Aqueous humor was cultured in three eyes of three patients, and vitreous humor was cultured in one eye of one patient., Results: In all 10 eyes of six patients, there was resolution of inflammation in 10 to 42 days after commencement of treatment with zidovudine (600 to 800 mg/day), despite no or minimal response to corticosteroids. Cultures of aqueous humor from three eyes of three patients and culture of vitreous humor from one eye of one patient were positive for HIV; no other organism was isolated. Systemic evaluation disclosed no other identifiable cause for the uveitis in any patient., Conclusions: Infection with HIV appears to be a cause of uveitis. A trial of zidovudine may be warranted in HIV-seropositive patients with uveitis that is poorly responsive to corticosteroid treatment when no other cause is identified. The efficacy of other retroviral agents was not determined.

Rhegmatogenous retinal detachments are associated with cytomegalovirus (CMV) retinitis and the use of the ganciclovir intraocular device. Pars plana vitrectomy with silicone oil tamponade is the preferred technique to repair such detachments. The authors describe the use of pneumatic retinopexy as part of a treatment strategy in the management of multiple retinal detachments in a patient with CMV retinitis treated with ganciclovir implants. Pneumatic retinopexy may benefit patients when the causative retinal break is superior and is located in an area of retina uninvolved with CMV infection, because it can be used to delay surgical intervention.

Purpose: To report a case in which we treated cytomegalovirus retinitis using an intravitreal ganciclovir sustained-release device in a patient negative for the human immunodeficiency virus, with a history of myeloproliferative syndrome with myelofibrosis and profound immunosuppression after allogeneic bone marrow transplantation., Methods: Case report. Review of medical records and fundus photographs., Results: After the ganciclovir device was implanted, the cytomegalovirus retinitis did not progress, and visual acuity improved. We removed the device 9 months after implantation., Conclusions: The ganciclovir sustained-release device may be useful for treating cytomegalovirus retinitis in patients without the acquired immunodeficiency syndrome who are profoundly immunosuppressed and fail conventional intravenous therapy. If immune suppression is of limited duration, the device can be removed.

Purpose: To describe and classify ophthalmic, ultrasonographic findings in patients with primary central nervous system lymphoma with ocular involvement., Methods: B- and A-scan ultrasonography was performed on the eyes of 13 patients with primary central nervous system lymphoma with ocular involvement., Results: In seven patients, the eyes were the site of initial involvement. In the other six patients, both ocular and central nervous system disease were present at the initial evaluation. All patients had abnormal ultrasonographic findings. The most common were vitreous debris (n = 10), choroidal-scleral thickening (n = 6), and widening of the optic nerve (n = 4). Elevated chorioretinal lesions (n = 3) and retinal detachment (n = 2) were also found., Conclusion: Ophthalmic ultrasonography is a useful adjunctive diagnostic technique for characterizing ocular involvement in lymphoma. Ocular lymphoma may present as chorioretinitis, vitreitis and nonspecific uveitis; it produces characteristic, but nonspecific findings on ultrasonography. The diagnosis of ocular involvement is an important factor in determining treatment.

Purpose: To report treatment of bilateral cytomegalovirus (CMV) retinitis in an 11-year-old girl with acquired immunodeficiency syndrome (AIDS)., Method: Case report describing the use of intravitreal ganciclovir sustained-release devices to treat CMV retinitis, involving zones 1 through 3, which progressed despite single and combination intravenous therapy with ganciclovir and foscarnet., Results: Stabilization with no active CMV retinitis was achieved after bilateral implantation of intravitreal sustained-release ganciclovir devices. There was no reactivation of the retinitis during the 5 months of follow-up., Conclusion: Sustained-release ganciclovir implants can be used to achieve local control of CMV retinitis in the pediatric patient.

We established the frequency of Horner's syndrome (HS) in 248 elective patients after coronary artery bypass surgery. Patients were evaluated neurologically pre- and post-operatively and 6 months after surgery. Nineteen patients (7.7%) developed unilateral HS postoperatively, 12 involving the left eye. The finding persisted in 10 patients (4%) at 6 months. When assessed 2 to 6 days, or 6 months, postoperatively, HS tended to be isolated and not associated with C8/T1 plexopathy. Among nondiabetic subjects, hypertensive patients had a higher frequency of HS than normotensive patients (10.6% versus 2.9%, p = 0.05). Among normotensive subjects, diabetic patients had a higher frequency than nondiabetic patients (15% versus 2.9%, p = 0.08). There was no association between HS, age, sex, internal mammary artery grafting, or length of cardiopulmonary bypass time. In summary, HS is a common and sometimes persistent complication of coronary artery bypass surgery. Hypertensive, and possibly diabetic, patients appear to be at greatest risk for developing HS.

Sera obtained from AIDS patients with cytomegalovirus (CMV) retinitis before and after treatment with foscarnet, AIDS patients with human immunodeficiency virus (HIV) retinopathy, AIDS patients without retinal disease, and normal healthy controls with and without positive CMV serologies were assayed for the presence of antibodies against the 200-kDa outer, 160-kDa middle, and 68-kDa core subunits of the neurofilament triplet. Additional studies were performed to determine the presence of antibodies reactive with proteins extracted from crude human retinal antigen preparations. Antibodies against the 200-, 260-, and 68-kDa proteins of the neurofilament triplet were detected in 15 of 15 AIDS patients with CMV retinitis. The expression of these antibodies was unaffected, qualitatively, by successful treatment with foscarnet. In contrast, only 30% of patients with HIV retinopathy unrelated to CMV, fewer than 35% of AIDS patients with positive CMV titers but without evident retinitis, and fewer than 25% of healthy controls with positive or negative CMV titers possessed antibodies against any of the triplet proteins (P < 0.001). Antibodies against several clusters of retinal antigens were also identified in the sera of patients with CMV retinitis. In summary, the data indicate that retinal elements damaged by CMV infection induce an antibody response against the 200-, 160-, and 68kDa components of the neurofilament triplet as well as other, as yet undefined retinal antigens.

The pharmacodynamic relationship between a range of foscarnet exposure measurements obtained from studying nine patients receiving ongoing maintenance therapy for cytomegalovirus retinitis and a range of efficacy values (days to retinitis progression) obtained by independent examination of serial retinal photographs from the same nine patients was analyzed. In the resulting proportional hazards models, the foscarnet area under the concentration-time curve approached statistical significance (P = 0.11) as a predictor of decreased risk of retinitis progression.

The efficacy and safety of a combination of ganciclovir plus GM-CSF was evaluated in AIDS patients with cytomegalovirus retinitis. In phase A, patients were randomized to receive ganciclovir, 5 mg/kg every 12 h for 14 days followed by 5 mg/kg daily, with (n = 24) or without (n = 29) GM-CSF (1-8 micrograms/kg daily subcutaneously) to maintain absolute neutrophil counts between 2500 and 5000 cells/microliters. In phase B, after 16 weeks zidovudine was added to the regimen of 16 patients receiving ganciclovir plus GM-CSF and 20 receiving ganciclovir alone. At this stage, GM-CSF was added to the treatment protocol of any patient receiving ganciclovir plus zidovudine who became neutropenic. In phase A, patients in the ganciclovir plus GM-CSF group had significantly higher neutrophil counts than ganciclovir-alone patients (p = 0.0001). Overall, 12.5% of patients treated with GM-CSF developed neutropenia (absolute neutrophil counts < 500/microliters phase A and < 750/microliters phase B) compared with 45% of patients treated without GM-CSF. GM-CSF patients missed 10 of a possible 4705 scheduled doses of ganciclovir compared with 34 missed doses of a possible 6584 in the ganciclovir-alone group (p = 0.011). There was a trend, although not statistically significant, for patients in the GM-CSF group to experience delayed progression of their retinitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Thirty-two patients with AIDS and previously untreated cytomegalovirus retinitis completed an induction course of foscarnet, 60 mg/kg every 8 h for 14 days, had retinitis stabilize, and were then randomly assigned to receive foscarnet maintenance as either a 90- or 120-mg/kg/day infusion administered over 2 h. Median survival was 157 and 336 days for the 90- and 120-mg/kg/day groups, respectively (P < .001). In an independent, masked analysis of retinal photographs, median time to progression of retinitis was 31 versus 95 days (P = .13). Daily intravenous foscarnet at a dose of 120 mg/kg (adjusted for renal function) resulted in significantly longer survival and tended to increase time to retinitis progression compared to the standard 90-mg/kg/day maintenance dose. Although a substantial increase in the risk of serious toxicity at the 120-mg/kg/day dose was not observed, the small sample size in this trial limited the power to detect differences that might be clinically important.

Background: Ocular lymphoma is an uncommon cause of chronic vitreitis or uveitis, often refractory to steroid treatment, and frequently representing another site of multifocal primary central nervous system lymphoma (PCNSL)., Methods: The authors reviewed the medical and ophthalmologic records of 24 patients with ocular lymphoma; 23 had associated PCNSL:, Results: In half, the eyes were the initial site of disease; in the others central nervous system (CNS) lymphoma developed before, or concurrent with, ocular lymphoma. Most patients had bilateral ocular symptoms; slit-lamp examination revealed asymptomatic disease in four. Vitrectomy was not always diagnostic, particularly in patients who had received steroids. Ocular ultrasound, performed on seven patients, provided an objective measure of disease and treatment response. Patients received a variety of therapeutic combinations of steroids, radiation, and chemotherapy, including high-dose cytosine arabinoside. Despite therapy, eventual ocular or CNS relapse or both was common. Thirteen patients have died, 12 with known recurrent CNS disease., Conclusions: Ocular lymphoma frequently is associated with PCNSL: The diagnosis should be considered in patients with steroid-resistant chronic vitreitis or uveitis. Patients with PCNSL should be carefully evaluated for ocular involvement, regardless of symptoms. Treatment can contribute to prolonged remission, but eventual ocular or CNS relapse is the rule.

Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS). The disease is inexorably progressive when untreated, making early detection and prompt treatment essential for preservation of functional vision. The retinitis tends to be unilateral at presentation but often becomes bilateral as it progresses. Lesions may be unifocal or multifocal and may appear in the posterior retina or peripheral retina. Primary ophthalmoscopic features of CMV retinitis include white granular zones of retinal necrosis, variable degrees of associated hemorrhage, and low-grade iritis and vitritis. Differential diagnosis is aided by characteristic features of CMV retinitis and other AIDS-related retinopathies. Initial treatment with ganciclovir or foscarnet has been found to stabilize retinitis, and maintenance therapy with either has been shown to prolong the time to retinitis progression. Further studies should help to determine the optimal approach to treatment of the disease.

The majority of AIDS patients will develop ocular complications at some point during the course of their illness. The most common complications involve the retina. Accurate diagnosis of noninfectious and infectious (especially CMV) retinopathy is extremely important as most forms of infectious retinitis can be treated, albeit not without significant complications in many cases. Close cooperation between the ophthalmologist and internist is essentially to ensure that timely therapeutic intervention, which can dramatically reduce the risk of visual impairment and blindness, can be initiated. AIDS-related diseases of the central nervous system, especially nonviral infections, are often associated with abnormalities of ocular function. Assessment of visual acuity, visual fields, extraocular movements, pupillary reflexes, color perception, and the condition of optic nerve and retina is important for accurate diagnosis.

Foscarnet and ganciclovir appear to be of similar effectiveness in halting active infection when given as induction therapy and in forestalling progression of disease when given as maintenance therapy in persons with AIDS who have cytomegalovirus (CMV) retinitis. The primary dose-limiting toxicity of foscarnet is nephrotoxicity, whereas that of ganciclovir is neutropenia. The availability of two effective agents with different toxicities permits selection of initial treatment for CMV retinitis based on individual patient characteristics and provides an alternative for therapy if drug intolerance or viral resistance develops. An approach to treatment of first-episode and recurrent CMV retinitis based on patient and drug characteristics is presented. Case reports detailing the use of foscarnet and ganciclovir and problems encountered in patient management are discussed.

A Phase I-II trial of gallium nitrate was conducted in 40 patients with bidimensionally measurable urothelial tract tumors who had failed to respond to combination chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin. Partial responses were observed in 4 of 23 patients (17.4%) who received 350 mg/m2/d or more for 5 days by continuous intravenous infusion. In two additional patients who received 350 mg/m2/d or more, a minor response and a mixed response were observed. The median duration of response was 4 months (range, 2 to 8 months). A dose-response relationship was suggested because no responses were observed in 17 patients who received less than 350 mg/m2/d. Myelosuppression was minimal. The dose-limiting toxic reaction was a reversible optic neuropathy that occurred in 3 of 11 patients who received 400 mg/m2/d. Further evaluation of infusional gallium nitrate is warranted in patients with urothelial tract malignant tumors.

Familial polyposis coli (FPC) is hereditary condition that conveys a virtual 100% risk for the development of colon cancer in the untreated patient. A total of 56 patients with FPC underwent complete ophthalmic examination. Highly pleomorphic pigmented retinal lesions were identified bilaterally in 52% (n = 29) and unilaterally in 14% (n = 8) of our subjects. In all, 33 patients had one or more extracolonic expressions associated with FPC, including desmoids, osteomas, epidermoid cysts, lipomas, fibromas, and upper gastrointestinal tract polyps. In 15 patients, pigmented fundus lesions were the only extracolonic manifestations. No significant association between eye findings and other extracolonic manifestations could be established. The presence or absence of pigmented fundus lesions was found to cluster within families. Pigmented fundus lesions are probably a variably penetrant expression of the polyposis gene and do not appear to be specifically associated with subgroups of inherited polyposis syndromes such as Gardner's syndrome.

Primary central nervous system lymphoma (PCNSL), an uncommon tumor, is occurring with increasing frequency. Conventional therapy with corticosteroids and cranial radiotherapy (RT) usually gives a dramatic initial response, but median survival is only 10 to 18 months. Chemotherapy is more successful in comparable systemic lymphoma and has been employed for PCNSL at relapse, causing remission but not cure. Between June 1985 and June 1988, we prospectively staged 32 patients with PCNSL at Memorial Sloan-Kettering Cancer Center and treated 28 on a new protocol that combined chemotherapy and radiotherapy at diagnosis. None had occult systemic lymphoma, but 19% had ocular and 69% had definite or probable leptomeningeal lymphoma. There were no complications in 19 stereotactic biopsies, but 4/10 patients who had a complete resection suffered a severe postoperative deficit. Four patients received RT alone, and 28 received chemotherapy and cranial RT, 17 of whom (group A) received a combination regimen using pre-RT systemic (1 g/m2) and intra-Ommaya methotrexate (MTX), 4,000 cGy whole-brain RT with a 1,440 cGy boost, and 2 courses of post-RT high-dose cytosine arabinoside; 5 other patients received an identical regimen but with a decreased dose of MTX (200 mg/m2). Sixty-three percent of assessable patients had a response to MTX independent of corticosteroid and prior to RT. Eighteen of 26 (69%) assessable patients who received combined therapy are alive with a median follow-up of 25.4 months. Twelve of 16 (75%) assessable group A patients are alive in the same period. Chemotherapy-related toxicity was minimal, and no late toxicities have occurred to date.(ABSTRACT TRUNCATED AT 250 WORDS)

The Hermansky-Pudlak Syndrome, a "tyrosinase positive' form of oculocutaneous albinism, is a triad comprising albinism, a hemorrhagic diathesis and ceroid-lipofuscin storage. A pedigree is presented showing consanguinity with a pattern of pseudodominance. Electroretinography in two isolated Hermansky-Pudlak subjects was distinctly abnormal, showing decreased rod and cone responses (as well as abnormal flicker fusion responses) in one patient, and reduced photopic and scotopic responses in another. The decreased ERG responses are discussed with reference to the known retinal abnormalities in both generalized oculocutaneous albinism and Batten's disease, another ceroid-lipofuscin storage disorder.

Using radioimmunoassay technique, levels of leukotriene B4 and C4 (LTB4 and LTC4) in the aqueous humor of rabbit eyes were measured following experimental nonpenetrating ocular trauma. Slit lamp examination showed a time-dependent increase of flare, cells, and fibrin in the anterior chamber of the traumatized eyes. Polymorphonuclear (PMN) leukocyte influx into the aqueous humor was not seen at 6 hours but increased significantly in traumatized eyes after 12 hours. No inflammatory cells were observed in control eyes. Histopathologic studies demonstrated injuries of the ciliary body, ruptures of the retina and choroid, with intraocular hemorrhage. LTB4 values peaked at 6 hours, prior to PMN cell infiltration and remained significantly higher than controls, which remained undetectable at all intervals after injury. LTC4 values also peaked by 6 hours in the traumatized eyes. These data demonstrate that elevations in LTB4 and LTC4 are associated with blunt trauma, and this precedes PMN cell infiltration. Leukotrienes may play a role in the early inflammatory response following concussive ocular injuries.

A 32-year-old patient with acquired immune deficiency syndrome (AIDS) was evaluated for bilateral visual loss accompanied by uveitis, vitritis and retinochoroiditis. Diagnostic vitrectomy was performed on the right eye, and the diagnosis of ocular toxoplasmosis made. Central nervous system involvement was suggested by ring enhancing lesions on CT scan. The patient improved on a pyrimethamine, sulfadiazine and clindamycin, but succumbed to disseminated toxoplasmosis when treatment was discontinued.

The safety and efficacy of intravitreously administered ganciclovir sodium as sole treatment for cytomegalovirus retinitis complicating the acquired immunodeficiency syndrome was studied prospectively in seven patients. All but one of the patients had bilateral cytomegalovirus retinitis and none were able to tolerate therapy with systemically administered ganciclovir because of myelosuppression in six patients and hepatotoxicity in one patient. Intravitreal ganciclovir therapy was discontinued in two patients within the initial 2-week induction phase because of severe intractable thrombocytopenia in one patient and retinal detachment in the other. The retinal detachment could not be conclusively attributed to the injections and was probably a secondary complication of cytomegalovirus retinitis. The remaining five patients were treated weekly, with the course of therapy ranging from a minimum of 14 weeks (18 injections) to a maximum of 56 weeks (58 injections). The patients were followed up for an average of 23.5 weeks. All eyes responded to intravitreal therapy initially, while the six untreated control eyes with cytomegalovirus retinitis all demonstrated progression of disease. Two eyes relapsed while receiving intravitreal doses of 200 micrograms of ganciclovir sodium and were subsequently treated with 300 micrograms of ganciclovir sodium per injection. One eye responded to this regimen, while in the other one the disease progressed. In the long-term treatment group, one eye developed Staphylococcus epidermidis endophthalmitis, which was treated with vitrectomy and intravitreal and systemic antibiotics.

Because there have been reports of ocular and/or cerebral ischemic events associated with mitral valve prolapse, we reviewed a series of patients with mitral valve prolapse to determine the frequency of amaurosis fugax. Among 59 patients, 13 (22%) had symptoms while among 75 controls, only one had amaurosis fugax. We conclude that patients with mitral valve prolapse have an increased risk of ocular and/or cerebral ischemia.

A patient with human immunodeficiency virus (HIV) type 1 infection developed chronic iridocyclitis and anterior vitritis that were poorly responsive to topical and systemic corticosteroid therapy. Anterior chamber paracentesis was performed and HIV was isolated from culture of aqueous humor. Subsequent treatment with oral zidovudine resulted in resolution of the iridocyclitis and vitritis and full functional recovery of the eye. This case suggests that HIV may be a cause of uveitis responsive to systemic zidovudine therapy.

Ophthalmic examinations were performed on 56 patients with validated familial adenomatous polyposis (FAP) for hyperpigmented defects of the retinal pigment epithelium. Such lesions were seen bilaterally in 29 patients (52%) and unilaterally in 8 patients (14%). Of the 56 patients, 33 had one or more of the extracolonic expressions associated with Gardner syndrome. We found retinal lesions in 8 patients without any of the expressions of Gardner syndrome. No association was found between Gardner syndrome and the retinal lesions when these patients were compared to patients without any stigmata of Gardner syndrome, nor was any significant association found when each of the expressions was compared individually with the presence of the pigmented retinal lesions. The presence or absence of eye findings were seen to cluster within families. There was no association with sex. Fundus lesions are apparently a variable expression of the FAP gene and are not specifically associated with Gardner syndrome.

Low viscosity perfluorocarbon liquids were used as an intraoperative tool during vitrectomy for retinal detachment (RD) after penetrating ocular trauma. These liquids are immiscible with water and have specific gravities from 1.8 to 1.9. Intraoperatively, the perfluorocarbon liquids flattened the retina in 14 eyes by displacing the subretinal fluid through peripheral breaks. Posterior retinotomy was not required for internal drainage of subretinal fluid. Pooled subretinal fluid was displaced from the macular area in five patients. The perfluorocarbon bubble mechanically stabilized the retina during epiretinal membrane dissection. The perfluorocarbon liquid was removed and replaced perfluorocarbon gas or silicone oil. In 11 patients followed for more than 6 months after the final surgery, eight (73%) eyes were anatomically successful, with six (54.5%) gaining visual acuity of 20/400 or better.

Pericentric inversion of chromosome 6 (6p+q-) was found in a girl with Rieger's syndrome and in her father. The only ocular signs in the father were prominent iris mounds and Schwalbe's line. The association of chromosomal anomalies with Rieger's syndrome indicates the need for a chromosome banding test in familial or sporadic patients with the syndrome and in patients with mild anomalies of the anterior chamber angle.