Proliferative and nonproliferative lesions of the rat and mouse hepatobiliary system.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and differential diagnosis for classifying microscopic lesions observed in the hepatobiliary system of laboratory rats and mice, with color microphotographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available for society members electronically on the internet (http://goreni.org). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions of the hepatobiliary system in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

Vitrectomy in cases of nonaccidental injury.

Nonaccidental head injuries may present in several ways, requiring prompt recognition and management because of the risk of death or permanent neurologic and visual impairment. Dense amblyopia and high anisometropic myopia induced by prolonged occlusion of the macula by hemorrhage is a concern in these infants, although the prognosis also depends on the extent of associated brain injury. There are few reports of the visual and general outcome of children with a diagnosis of nonaccidental injury who have undergone vitrectomy. This report describes the outcome in six eyes of four patients diagnosed as having nonaccidental injury who underwent vitrectomy. The results are more favorable than in previous reports.

The importance of acuity, stereopsis, and contrast sensitivity for health-related quality of life in elderly women with cataracts.

PURPOSE: To investigate the relative contribution of visual and other factors to quality of life among elderly women with bilateral cataract. METHODS: Data were analyzed from a trial of first-eye cataract surgery. Visual parameters, general health, and social variables, and disease-specific (VF-14 Index of Visual Function), generic (Euroqol: EQ-5D, London Handicap Scale, Barthel), and intermediate (anxiety, depression, and activity) outcomes were measured at baseline and 6 months later, when approximately half the group had had surgery. RESULTS: Three hundred six participants provided data at baseline, and 289 at 6 months. At baseline, acuity, stereopsis, and contrast sensitivity were all associated with quality of life. Acuity and stereopsis were most strongly and consistently associated. Change in VF-14 was associated with changes in stereopsis and contrast sensitivity, while change in handicap was associated with change in stereopsis. CONCLUSIONS: Acuity, stereopsis, and contrast sensitivity each contributed to quality of life, across a range of measures, in elderly women with cataract. Acuity was marginally the most consistently and generally the most strongly associated, but in some analyses stereopsis was more important. Change in quality of life was associated with change in stereopsis and contrast sensitivity.

Oxymorphone hydrochloride, a potent opioid analgesic, is not carcinogenic in rats or mice.

Despite their long history of chronic use, little information is available regarding the carcinogenicity of opioid analgesics. Oxymorphone is a potent morphinan-type mu-opioid analgesic used for treatment of moderate-to-severe pain. Oxymorphone was tested for carcinogenicity in Crl:CD IGS BR rats and CD-1 mice. Oxymorphone hydrochloride was administered orally once daily for 2 years to rats at doses of 2.5, 5 and 10 mg/kg/day (males) and 5, 10 and 25 mg/kg/day (females), and mice at 10, 25, 75 and 150 mg/kg/day (65 animals per sex per group; 100 animals per sex in controls). In rats, survival was generally higher than controls in oxymorphone-treated groups, attributable to lower body weight gain. In mice, survival was generally higher than controls in females at all doses and males given < or = 25 mg/kg/day but lower in males given > or = 75 mg/kg/day due to a high incidence of obstructive uropathy. Opioid-related clinical signs and reduced body weight gain occurred in both species throughout the study. Nonneoplastic findings associated with oxymorphone pharmacology included ocular and pulmonary changes in rats considered secondary to inhibition of blinking and mydriasis, and antitussive activity, respectively, and urinary tract and renal findings in mice considered secondary to urinary retention. There was no target organ toxicity, and no increase in any neoplastic lesions attributed to oxymorphone. Plasma oxymorphone levels achieved in these studies exceeded those in patients taking high therapeutic doses of oxymorphone (Area under the curve [AUC(0-24 h)] values up to 5.6-fold and 64-fold in rats and mice, respectively). Oxymorphone is not considered to be carcinogenic in rats or mice under the conditions of these studies.

Extended oligoarthritis and other risk factors for developing JIA-associated uveitis under ILAR classification and its implication for current screening guideline.

PURPOSE: To investigate the risk factors for developing uveitis in a regional cohort of patients with juvenile idiopathic arthritis (JIA) as classified under ILAR criteria. PATIENTS AND METHODS: The clinical factors for developing uveitis and its visual outcome were studied retrospectively for all children diagnosed with JIA at Nottingham University Hospital, England from 1974 to 2001. RESULTS: A total of 202 patients with juvenile idiopathic arthritis were identified. Twenty-three patients (11.4%) were found to have uveitis. The mean age of arthritis onset in those with uveitis was 4.9 (95% CI 3.4-6.4) and in those without uveitis was 7.6 (95% CI 7.0-8.3), p = 0.002. Both the persistent and extended oligoarthritis groups are at significant risk of developing uveitis on Kaplan-Meier analysis with p = 0.001 and 0.013, respectively, compared to other ILAR subtypes. Extended oligoarthritis (1 to 4 joints affected in first 6 months of disease but 5 or more cumulative joints after first 6 months) had the highest prevalence of uveitis (25%) among the ILAR subtypes. Patients with extended oligoarthritis also developed uveitis earlier than persistent group, p = 0.017. Gender, race, and antinuclear antibody (ANA) status were not significant risk factors. The visual outcome was favorable, with 90% achieving acuity of 6/12 or better. CONCLUSION: Patients with extended oligoarthritis are at higher risk and have a shorter interval from diagnosis of arthritis to development of uveitis and need to be monitored more closely. Screening guideline for JIA-associated uveitis based on ILAR classification is called for.

Randomised controlled trial of video clips and interactive games to improve vision in children with amblyopia using the I-BiT system.

BACKGROUND: Traditional treatment of amblyopia involves either wearing a patch or atropine penalisation of the better eye. A new treatment is being developed on the basis of virtual reality technology allowing either DVD footage or computer games which present a common background to both eyes and the foreground, containing the imagery of interest, only to the amblyopic eye. METHODS: A randomised control trial was performed on patients with amblyopia aged 4-8 years with three arms. All three arms had dichoptic stimulation using shutter glass technology. One arm had DVD footage shown to the amblyopic eye and common background to both, the second used a modified shooter game, Nux, with sprite and targets presented to the amblyopic eye (and background to both) while the third arm had both background and foreground presented to both eyes (non-interactive binocular treatment (non-I-BiT) games). RESULTS: Seventy-five patients were randomised; 67 were residual amblyopes and 70 had an associated strabismus. The visual acuity improved in all three arms by approximately 0.07 logMAR in the amblyopic eye at 6 weeks. There was no difference between I-BiT DVD and non-I-BiT games compared with I-BiT games (stated primary outcome) in terms of gain in vision. CONCLUSIONS: There was a modest vision improvement in all three arms. Treatment was well tolerated and safe. There was no difference between the three treatments in terms of primary stated outcomes but treatment duration was short and the high proportion of previously treated amblyopia and strabismic amblyopia disadvantaged dichoptic stimulation treatment. TRIAL REGISTRATION NUMBER: NCT01702727, results.

Evaluation and development of a novel binocular treatment (I-BiT™) system using video clips and interactive games to improve vision in children with amblyopia ('lazy eye'): study protocol for a randomised controlled trial.

BACKGROUND: Amblyopia (lazy eye) affects the vision of approximately 2% of all children. Traditional treatment consists of wearing a patch over their 'good' eye for a number of hours daily, over several months. This treatment is unpopular and compliance is often low. Therefore results can be poor. A novel binocular treatment which uses 3D technology to present specially developed computer games and video footage (I-BiT™) has been studied in a small group of patients and has shown positive results over a short period of time. The system is therefore now being examined in a randomised clinical trial. METHODS/DESIGN: Seventy-five patients aged between 4 and 8 years with a diagnosis of amblyopia will be randomised to one of three treatments with a ratio of 1:1:1 - I-BiT™ game, non-I-BiT™ game, and I-BiT™ DVD. They will be treated for 30 minutes once weekly for 6 weeks. Their visual acuity will be assessed independently at baseline, mid-treatment (week 3), at the end of treatment (week 6) and 4 weeks after completing treatment (week 10). The primary endpoint will be the change in visual acuity from baseline to the end of treatment. Secondary endpoints will be additional visual acuity measures, patient acceptability, compliance and the incidence of adverse events. DISCUSSION: This is the first randomised controlled trial using the I-BiT™ system. The results will determine if the I-BiT™ system is effective in the treatment of amblyopia and will also determine the optimal treatment for future development. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01702727.

Ophthalmological aspects of Pierson syndrome.

PURPOSE: To study the ocular phenotype of Pierson syndrome and to increase awareness among ophthalmologists of the diagnostic features of this condition. DESIGN: Retrospective, observational case series. METHODS: A multicenter study of 17 patients with molecularly confirmed Pierson syndrome. The eye findings were reviewed and compared to pertinent findings from the literature. RESULTS: The most characteristic ocular anomaly was microcoria. A wide range of additional abnormalities were found, including posterior embryotoxon, megalocornea, iris hypoplasia, cataract, abnormal lens shape, posterior lenticonus, persistent fetal vasculature, retinal detachment, variable axial lengths, and glaucoma. There was high interocular and intrafamilial variability. CONCLUSIONS: Loss-of-function mutations in laminin beta2 (LAMB2) cause a broad range of ocular pathology, emphasizing the importance of laminin beta2 in eye development. Patients with Pierson syndrome can initially present with ocular signs alone. In newborns with marked bilateral microcoria, Pierson syndrome should be considered and renal function investigated.

Falls and health status in elderly women following first eye cataract surgery: an economic evaluation conducted alongside a randomised controlled trial.

AIM: To evaluate the cost-effectiveness of first eye cataract surgery compared with no surgery from a health service and personal social services perspective. METHODS: An economic evaluation undertaken alongside a randomised controlled trial of first eye cataract surgery in secondary care ophthalmology clinics. A sample of 306 women over 70 years old with bilateral cataracts was randomised to cataract surgery (expedited, approximately four weeks) or control (routine, 12 months wait); 75% of participants had baseline acuity of 6/12 or better. Outcomes included falls and the EuroQol EQ-5D. RESULTS: The operated group cost a mean pounds sterling 2004 (bootstrapped) more than the control group over one year (95% confidence interval (CI), pounds sterling 1363 to pounds sterling 2833) (p<0.001), but experienced on average 0.456 fewer falls, an incremental cost per fall prevented of pounds sterling 4390. The bootstrapped mean gain in quality adjusted life years (QALYs) per patient was 0.056 (95% CI, 0.006 to 0.108) (p<0.001). The incremental cost-utility ratio was pounds sterling 35 704, above the currently accepted UK threshold level of willingness to pay per QALY of pounds sterling 30 000. However, in an analysis modelling costs and benefits over patients' expected lifetime, the incremental cost per QALY was pounds sterling 13 172, under conservative assumptions. CONCLUSIONS: First eye cataract surgery, while cost-ineffective over the trial period, was probably cost-effective over the participants' remaining lifetime.

Falls and health status in elderly women following second eye cataract surgery: a randomised controlled trial.

OBJECTIVE: first eye cataract surgery reduces the risk of falling. Most cataracts in elderly people are bilateral. Some binocular functions (e.g. stereopsis) are associated with falls. We aimed to determine if second eye cataract surgery reduces the risk of falling and to measure associated health gain. STUDY DESIGN AND SETTING: we randomised 239 women over 70, who had been referred to a hospital ophthalmology department, with one unoperated cataract, to expedited (approximately 4 weeks) or routine (12 months wait) surgery. Falls were ascertained by diary, with follow-up every 3 months for 12 months. We measured health status after 6 months. RESULTS: visual function (especially stereopsis) improved in the operated group. Over 12 months follow-up, 48 (40%) operated participants fell at least once, 22 (18%) fell more than once. Forty-one (34%) unoperated participants fell at least once, 22 (18%) fell more than once. Rate of falling was reduced by 32% in the operated group, but this was not statistically significant (rate ratio 0.68, 95% CI 0.39, 1.19, P = 0.18). Confidence, visual disability and handicap all improved in the operated compared with the control group. CONCLUSION: second eye cataract surgery improves visual disability and general health status. The effect on rate of falling remains uncertain.

A toxicity profile of osteoprotegerin in the cynomolgus monkey.

Osteoprotegerin (OPG) is a novel secreted glycoprotein of the tumor necrosis factor (TNF) receptor superfamily that acts as an antiresorptive agent inhibiting osteoclast maturation. OPG acts by competitively inhibiting the association of the OPG ligand with the RANK receptor on osteoclasts and osteoclast precursors. This inhibition of osteoclasts can lead to excess accumulation of newly synthesized bone and cartilage in vivo. The purpose of this study was to investigate the potential toxicity of a human recombinant form of OPG in the young cynomolgus monkey. OPG was administered by intravenous (i.v.) or subcutaneous (s.c.) injection three times per week for either 4 or 13 weeks. There were no deaths during the study, no clinical signs related to treatment, no effect on body weight, appetence, or ophthalmology. No toxicologically relevant changes in routine laboratory investigations, organ weights, or gross or histopathological findings were observed. Serum ionized calcium and phosphorus were decreased at all dose levels. Evaluations were performed to monitor biochemical markers of bone resorption (N-telopeptide [NTx], deoxypyridinoline [DPD]), bone formation (skeletal alkaline phosphatase [sALP], osteocalcin [OC]), parathyroid hormone [PTH], and bone density of the proximal tibia and distal radius in vivo. Dose-related decreases in NTx and/or DPD were observed at each dose level, with up to a 90% decrease in NTx noted for animals treated i.v. or s.c. at 15 mg/kg. Similar decreases were observed for sALP and OC. PTH was increased for animals treated at 5 and 15 mg/kg (i.v. or s.c.). Trabecular bone density was increased for the majority of males and females treated i.v. or s.c. at 15 mg/kg and males treated i.v. at 5 mg/kg. Microscopic examination of the sternebrae revealed corresponding increases in bone. Decreases in markers of bone turnover, and corresponding increases in bone density, were consistent with the pharmacological action of OPG as an osteoclast inhibitor. The no-observable-adverse-effect level (NOAEL) of OPG was 15 mg/kg.