Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats

PURPOSE: To determine whether acute experimental glaucoma in rats obstructs retrograde transport of brain-derived neurotrophic factor (BDNF) to retinal ganglion cells (RGCs). METHODS: Forty rats had unilateral injection of either (125)I-BDNF (20 animals) or a mixture of (125)I-BDNF and 100-fold excess nonradiolabeled BDNF (20 animals). In each group of 20 animals, eyes contralateral to injection had either normal intraocular pressure (IOP; 10 animals) or IOP elevated to 25 mm Hg below the systolic blood pressure of the eye (10 animals). In each group of 20 rats, ipsilateral eyes had IOP set at systolic blood pressure (4 eyes), had optic nerve transection (10 eyes), or had normal IOP (6 eyes). Six hours after injection, animals were killed and tissues were fixed, embedded, and sectioned for autoradiography. Grain counts were performed over retina and optic nerve using automated image analysis. RESULTS: IOP elevation to 25 mm Hg below systolic blood pressure (perfusion pressure [PP] 25) decreased median retinal nerve fiber layer (NFL) grains by 38% compared with controls (P: < 0.001). Competition by cold BDNF reduced NFL grains by 28% (P: = 0.013). Considering only the radioactivity representing specific retrograde transport of BDNF, IOP elevation to PP25 reduced transport by 74%, whereas elevation to PP0 (equaling systolic blood pressure) reduced specific transport by 83%. CONCLUSIONS: BDNF is transported retrogradely from the superior colliculus in adult rats, and this transport is substantially inhibited by acute IOP elevation. Deprivation of BDNF among RGCs may contribute to neuron loss in glaucoma.     

Prevalence of glaucoma in a rural East African population

PURPOSE: To determine the prevalence of glaucoma in an adult population in rural central Tanzania. METHODS: Six villages were randomly selected from eligible villages in the Kongwa district, and all residents more than 40 years of age were enumerated and invited to a comprehensive eye examination including presenting visual acuity, refraction, automated 40-point Dicon (San Diego, CA) suprathreshold screening field test, Tono-Pen (Bio-Rad, Inc., Boston, MA) intraocular pressure (IOP) measurement, and standardized examination by an ophthalmologist of anterior segment, optic nerve head, and retina after pupil dilation. Gonioscopy and Glaucoma-Scope (Ophthalmic Imaging Systems, Sacramento, CA) optic disc imaging were performed on those with IOP higher than 23 mm Hg and cup-to-disc ratio (c/d) more than 0.6 and on a 20% random sample of participants. RESULTS: Of 3641 eligible persons, 3268 (90%) underwent ophthalmic examination. The prevalence of glaucoma of all types was 4.16% (95% confidence interval [CI] = 3.5, 4.9%). Primary open-angle glaucoma (OAG) was diagnosed in 3.1% (95% CI = 2.5, 3.8%), primary angle-closure glaucoma (ACG) in 0.59% (95% CI = 0.35, 0.91%), and other forms of glaucoma in 0.49%. The prevalence of glaucoma was found to be sensitive to changes in the diagnostic criteria. CONCLUSIONS: The high prevalence of OAG in this group was similar to that of African-derived persons in the United States but less than in African-Caribbean populations. ACG was more prevalent in east Africans than suggested by anecdotal reports.     

Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma

PURPOSE: In both animal model system and in human glaucoma, retinal ganglion cells (RGCs) die by apoptosis. To understand how RGC apoptosis is initiated in these systems, the authors studied RGC neurotrophin transport in experimental glaucoma using acute intraocular pressure (IOP) elevations in rats and chronic IOP elevation and unilateral optic nerve transections in monkeys. METHODS: Eyes were studied in masked fashion by light and electron microscopy and by immunohistochemistry with antibodies directed against the tyrosine kinase receptors (TrkA, B, and C) and against brain-derived neurotrophic factor (BDNF), as well as by autoradiography to identify retrograde axonal transport of 125I-BDNF injected into the superior colliculus. RESULTS: With acute glaucoma in the rat, RGC axons became abnormally dilated, accumulating vesicles presumed to be moving in axonal transport at the optic nerve head. Label for TrkB, but not TrkA, was relatively increased at and behind the optic nerve head with IOP elevation. Abnormal, focal labeling for TrkB and BDNF was identified in axons of monkey optic nerve heads with chronic glaucoma. With acute IOP elevation in rats, radiolabeled BDNF arrived at cells in the RGC layer at less than half the level of control eyes. CONCLUSIONS: Interruption of BDNF retrograde transport and accumulation of TrkB at the optic nerve head in acute and chronic glaucoma models suggest a role for neurotrophin deprivation in the pathogenesis of RGC death in glaucoma.     

Survey of raw egg use by home caterers

Outbreaks of egg related salmonella infection continue to occur despite over ten years of national guidance on this subject. Fifty-four out of 70 registered home caterers in Cheshire responded to a telephone questionnaire, which revealed that a sixth prepared raw egg dishes containing shell eggs, none used pasteurised egg, and advice about storage of eggs and handwashing was not always followed. A postal questionnaire sent to 13 wholesalers and major supermarket chains showed that pasteurised egg was available in large packs from wholesalers but not from supermarkets. It is time to consider new approaches to reinforce advice about pasteurised egg use for raw egg dishes, storage, and measures to prevent cross contamination. These findings have implications for the training of home caterers and the general public.     

Estradiol, estrone, and gonadotropin levels after use of vaginal estradiol

The vaginal absorption of 0.5-mg tablets of micronized estradiol was evaluated in postmenopausal women. In a single-dose study, one hour after insertion, a 5.3-fold rise in mean serum estradiol levels and 1.5-fold rise in mean serum estrone levels were observed. Mean levels of luteinizing hormone and follicle-stimulating hormone were significantly depressed. In a three-week alternate-day regimen, mean serum levels of estradiol were consistently two to three times greater than those of estrone 12 hours after insertion. Vaginal absorption of micronized estradiol tablets into the systemic circulation was found to be rapid and efficient. The vaginal route was acceptable and well tolerated by patients. In addition, the major conversion of estradiol to estrone that follows oral or sublingual administration was reduced. The vagina may be a preferred alternate route for estrogen replacement therapy in selected patients.     

Screening performance of functional and structural measurements of neural damage in open-angle glaucoma: a case-control study from the Baltimore Eye Survey

PURPOSE: To compare the sensitivity and specificity of four approaches to glaucoma screening. METHODS: Case patients were persons with possible, probable, or definite glaucomatous optic nerve damage, as judged by a glaucoma specialist using Humphrey 24-2 threshold findings and clinical assessment of disc and nerve fiber layer, identified in the population-based Baltimore Eye Survey Follow-up Study. Control patients were participants in the same study, frequency-matched for age, without evidence of glaucomatous optic nerve damage. Participants underwent optic disc photography (Topcon ImageNet), disc imaging (GlaucomaScope), scanning laser polarimetry (Nerve Fiber Analyzer), and suprathreshold field testing (Dicon). RESULTS: A total of 100 case patients with open-angle glaucoma and 149 control patients were included. Objective imaging had the best screening performance. For the GlaucomaScope, a criterion of cup-to-disc ratio of -0.68 had a sensitivity of 72% and specificity of 82% for detecting eyes with definite or probable glaucomatous optic nerve damage. For the nerve fiber layer, a criterion of The Number as > or = 20 had a sensitivity of 69% and specificity of 77% for detecting eyes with definite or probable glaucomatous optic nerve damage. Usable data could be obtained in 93% of participants with the Dicon and the Nerve Fiber Analyzer and in 82% and 87% of participants with the GlaucomaScope and Topcon instruments, respectively. CONCLUSIONS: Vertical cup-to-disc ratio, as measured by the GlaucomaScope or Topcon instruments, and the Nerve Fiber Layer neural network Number had the best combination of sensitivity and specificity among the instruments tested. The Nerve Fiber Analyzer had the highest percentage of participants with usable data.     

Effective removal of methotrexate by high-flux hemodialysis

The purpose of the present study was to examine the clearance of methotrexate (MTX) by high-flux hemodialysis (HD) in pediatric oncology patients. We present three patients who experienced nephrotoxicity and prolonged exposure to toxic MTX concentrations following high-dose infusions during treatment for osteogenic sarcomas. Each patient was successfully treated with high-flux HD, followed by carboxypeptidase G2 (CPDG2) in two cases. Minimal systemic toxicity occurred. We review the literature and discuss guidelines for early and aggressive treatment for this complication of high-dose MTX therapy. Clinically important removal of MTX depends upon prompt initiation of HD after detection of nephrotoxicity and delayed clearance of MTX. Therapy is indicated in cases where compassionate use of CPDG(2) may not be available, or while awaiting its delivery.     

Caspase activation and amyloid precursor protein cleavage in rat ocular hypertension

PURPOSE: Retinal ganglion cell (RGC) death in glaucoma involves apoptosis. Activation of caspases and abnormal processing of amyloid precursor protein (APP) are important events in other chronic neurodegenerations, such as Alzheimer's disease (AD). The retinal expression and activation of caspases and the patterns of caspase-3-mediated APP processing in ocular hypertensive models of rat glaucoma were investigated. METHODS: RGC death was produced in one eye by chronic exposure to increased intraocular pressure (IOP) or by optic nerve transection. Elevated IOP was produced by obstruction of aqueous humor outflow with laser coagulation or limbal hypertonic saline injection. Caspase activity and APP processing in the retina were examined by RNase protection assay (RPA), immunocytochemistry, immunoblot assay, and colorimetric assay. RESULTS: RPA revealed elevations of caspase-3 mRNA, as well as other apoptosis-related mRNAs. Immunocytochemistry showed caspase-3 activation in RGCs damaged by ocular hypertension. The generation of the caspase-3-mediated APP cleavage product (DeltaC-APP) was also increased in ocular hypertensive RGCs. Western immunoblot assay and colorimetry revealed significantly more activated caspase-3 in ocular hypertensive retinas than in control retinas. The activated form of caspase-8, an initiator caspase, and amyloid-beta, a product of APP proteolysis and a component of senile plaques in AD, were detected in RGCs by immunohistochemistry significantly more often in ocular hypertensive than in control retinas. The amounts of full-length APP were reduced and amyloid-beta-containing fragments were increased in ocular hypertensive retinas by Western immunoblot assay. CONCLUSIONS: Rat RGCs subjected to chronic ocular hypertension demonstrate caspase activation and abnormal processing of APP, which may contribute to the pathophysiology of glaucoma.     

Effect of technique on intraocular pressure after combined cataract and glaucoma surgery: An evidence-based review

TOPIC: To analyze the literature pertaining to the techniques used in combined cataract and glaucoma surgery, including the technique of cataract extraction, the timing of the surgery (staged procedure versus combined procedure), the anatomic location of the operation, and the use of antifibrosis agents. CLINICAL RELEVANCE: Cataract and glaucoma are both common conditions and are often present in the same patient. There is no agreement concerning the optimal surgical management of these disorders when they coexist. METHODS/LITERATURE REVIEWED: Electronic searches of English language articles published since 1964 were conducted in Pub MED and CENTRAL, the Cochrane Collaboration's database. These were augmented by a hand search of six ophthalmology journals and the reference lists of a sample of studies included in the literature review. Evidence grades (A, strong; B, moderate; C, weak; I, insufficient) were assigned to the evidence that involved a direct comparison of alternative techniques. RESULTS: The preponderance of evidence from the literature suggests a small (2-4 mmHg) benefit from the use of mitomycin-C (MMC), but not 5-fluorouracil (5-FU), in combined cataract and glaucoma surgery (evidence grade B). Two-site surgery provides slightly lower (1-3 mmHg) intraocular pressure (IOP) than one-site surgery (evidence grade C), and IOP is lowered more (1-3 mmHg) by phacoemulsification than by nuclear expression in combined procedures (evidence grade C). There is insufficient evidence to conclude either that staged or combined procedures give better results or that alternative glaucoma procedures are superior to trabeculectomy in combined procedures. CONCLUSIONS: In the literature on surgical techniques and adjuvants used in the management of coexisting cataract and glaucoma, the strongest evidence of efficacy exists for using MMC, separating the incisions for cataract and glaucoma surgery, and removing the nucleus by phacoemulsification.