Retinal pigment epithelial tears after intravitreal bevacizumab injection for exudative age-related macular degeneration.

PURPOSE: To determine the incidence of and the risk factors for the development of retinal pigment epithelial (RPE) tears after intravitreal bevacizumab (Avastin) injection for the treatment of exudative age-related macular degeneration (AMD). METHODS: A retrospective, multicentre, consecutive interventional case series of all patients with subfoveal exudative AMD treated with intravitreal bevacizumab between August 2005 and April 2007. The main outcome measures were pre- and post-RPE tear visual acuity and choroidal neovascular membrane lesion types, incidence of tears and time from first injection until development of the tear. RESULTS: A total of 920 eyes with exudative AMD were treated with intravitreal bevacizumab. Fifteen eyes from 15 patients developed a RPE tear for an incidence of 1.6%. The average patient age was 79 years. Fourteen of the fifteen eyes (93%) had an occult subfoveal choroidal neovascular membrane. Forty-seven per cent (7/15) of the RPE tears occurred within the first 6 weeks of treatment, and all tears occurred within the first 18 weeks of treatment initiation. The mean pre-injection visual acuity was 20/100 with a mean post-tear visual acuity of 20/200. In all 10 eyes in which the tear involved the fovea, the final visual acuity was poor. Six of the 15 eyes continued with bevacizumab/ranibizumab (Lucentis) injections after tear development, and four of these six eyes continued to have visual improvement. CONCLUSION: RPE tears occur after intravitreal bevacizumab injections for exudative AMD in approximately 1.6% of eyes and can cause severe vision loss. Maintenance of therapy may help preserve vision after RPE tear development

Sensitivity of preference to reinforcement amount depends upon the method used to manipulate amount

Four pigeons were trained on concurrent variable-interval 30-s schedules. Relative reinforcer amounts arranged across the two alternatives was varied. During Experiment 1, sessions consisted of a mixed concurrent schedule with different ratios of reinforcer amounts arranged for the two alternatives across components. Sessions consisted of 5 components that differed only with respect to the relative reinforcer amounts arranged for each alternative. Reinforcer amount was manipulated by presenting an arranged number of brief (1.2-s) hopper presentations. The amounts presented ranged from one to five presentations and the ratios used were 1/5, 2/4, 3/3, 4/2, and 5/1 (L/R). The order of ratios within each session was randomly determined, and there were no exteroceptive stimuli signaling the particular ratio in effect. After 60 sessions of training, responding for all subjects remained insensitive to reinforcer amount ratios. During Experiment 2, relative reinforcer was held constant within and across sessions until responding became stable, at which point, the absolute amounts arranged for each alternative were switched. The ratios used were 1/7 and 7/1 hopper presentations. After six sessions in each condition, all subjects showed an appreciable shift in preference toward the alternative providing the larger amount, and asymptotic sensitivity was comparable to previous reports using a similar procedure. During Experiment 3, sessions were identical to those used during Experiment 2, except that the amount ratio (either 1/7 or 7/1) presented during each session changed from session to session according to a pseudorandom binary sequence (cf., Hunter & Davison, 1985). After 30 sessions, response ratios within each session for all subjects began to shift in the direction of the amount ratio in effect for that session (i.e., subjects’ responding showed a moderate increase in sensitivity to reinforcer amount). Characteristics of responding under this procedure were quite similar to responding procedures under which reinforcer rate and delay were manipulated in much the same fashion. The procedure used in Experiment 3 may serve as a method for studying the effects of certain environmental manipulations (e.g., drug administration) on sensitivity to reinforcer amount

Long-lasting effects of methocinnamox on opioid self-administration in rhesus monkeys

Opioid abuse remains a serious public health challenge, despite the availability of medications that are effective in some patients (naltrexone, buprenorphine, and methadone). This study explored the potential of a pseudoirreversible mu-opioid receptor antagonist [methocinnamox (MCAM)] as a treatment for opioid abuse by examining its capacity to attenuate the reinforcing effects of mu-opioid receptor agonists in rhesus monkeys. In one experiment, monkeys responded for heroin (n 5 5) or cocaine (n 5 4) under a fixed-ratio schedule. Another group (n 5 3) worked under a choice procedure with one alternative delivering food and the other alternative delivering the mu-opioid receptor agonist remifentanil. A third group (n 5 4) responded for food and physiologic parameters were measured via telemetry. The effects of MCAM were determined in all experiments and, in some cases, were compared with those of naltrexone. When given immediately before sessions, naltrexone dose-dependently decreased responding for heroin and decreased choice of remifentanil while increasing choice of food, with responding returning to baseline levels 1 day after naltrexone injection. MCAM also decreased responding for heroin and decreased choice of remifentanil while increasing choice of food; however, opioid-maintained responding remained decreased for several days after treatment. Doses of MCAM that significantly decreased opioid-maintained responding did not decrease responding for cocaine or food. MCAM did not impact heart rate, blood pressure, body temperature, or activity at doses that decreased opioid self-administration. Because MCAM selectively attenuates opioid self-administration for prolonged periods, this novel drug could be a safe and effective alternative to currently available treatments for opioid abuse.</p

Long-lasting effects of methocinnamox on opioid self-administration in rhesus monkeys

Opioid abuse remains a serious public health challenge, despite the availability of medications that are effective in some patients (naltrexone, buprenorphine, and methadone). This study explored the potential of a pseudoirreversible mu-opioid receptor antagonist [methocinnamox (MCAM)] as a treatment for opioid abuse by examining its capacity to attenuate the reinforcing effects of mu-opioid receptor agonists in rhesus monkeys. In one experiment, monkeys responded for heroin (n 5 5) or cocaine (n 5 4) under a fixed-ratio schedule. Another group (n 5 3) worked under a choice procedure with one alternative delivering food and the other alternative delivering the mu-opioid receptor agonist remifentanil. A third group (n 5 4) responded for food and physiologic parameters were measured via telemetry. The effects of MCAM were determined in all experiments and, in some cases, were compared with those of naltrexone. When given immediately before sessions, naltrexone dose-dependently decreased responding for heroin and decreased choice of remifentanil while increasing choice of food, with responding returning to baseline levels 1 day after naltrexone injection. MCAM also decreased responding for heroin and decreased choice of remifentanil while increasing choice of food; however, opioid-maintained responding remained decreased for several days after treatment. Doses of MCAM that significantly decreased opioid-maintained responding did not decrease responding for cocaine or food. MCAM did not impact heart rate, blood pressure, body temperature, or activity at doses that decreased opioid self-administration. Because MCAM selectively attenuates opioid self-administration for prolonged periods, this novel drug could be a safe and effective alternative to currently available treatments for opioid abuse.</p

Hospital admission patterns in children with CAH: admission rates and adrenal crises decline with age

Objective: To examine patterns of hospitalisation for acute medical conditions in children with congenital adrenal hyperplasia (CAH). Design: A retrospective study of hospitalisation using administrative data. Setting. All hospitals in NSW, Australia. Patients: All patients admitted with CAH and a random sample of admissions in patients aged 0 to 18 years without adrenal insufficiency (AI). Main Outcome Measures: Admissions and comorbidities by age and sex. Results: Of 573 admissions for medical problems in CAH children, 286 (49.9%) were in males, and 236 (41.2%) had a principal diagnosis of CAH or had an adrenal crisis (AC). 37 (6.5%) ACs were recorded. An infection was found in 43.5% ( = 249) of the CAH patient admissions and 51.7% ( = 1613) of the non-AI group, \u3c 0.001. Children aged up to one year had the highest number of admissions ( = 149) and six ACs (four in males).There were 21 ACs recorded for children aged 1–5 years. Older CAH children had fewer admissions and fewer ACs. No in-hospital deaths were recorded. Conclusions. Admission for medical problems in CAH children declines with age. An AC was recorded in 6.5% of the admissions, with the majority of ACs occurring in the 1 to 5 years age group and there were no deaths

Effects of acute and repeated treatment with methocinnamox, a mu opioid receptor antagonist, on fentanyl self-administration in rhesus monkeys

Methocinnamox (MCAM), a mu opioid receptor antagonist with a long duration of action, attenuates heroin self-administration in rhesus monkeys, suggesting it could be an effective treatment for opioid use disorder (OUD). This study examined effects of acute and repeated MCAM administration on self-administration of the high-efficacy mu opioid receptor agonist fentanyl and characterized MCAM pharmacokinetics. Four rhesus monkeys self-administered i.v. infusions of fentanyl (0.00032 mg/kg/infusion) or cocaine (0.032 mg/kg/infusion). MCAM (0.1–0.32 mg/kg) or the opioid receptor antagonist naltrexone (0.001–0.032 mg/kg) was injected prior to test sessions to evaluate acute effects. On a separate occasion, 0.32 mg/kg MCAM was injected every 12 days for 5 total injections to evaluate the effectiveness of repeated treatment. Following acute injection, MCAM and naltrexone decreased fentanyl self-administration on the day of treatment, with attenuation lasting for up to 2 weeks after the larger MCAM dose and <1 day after naltrexone. Repeated MCAM administration decreased fentanyl self-administration for more than 2 months without altering cocaine self-administration. MCAM plasma concentrations peaked 15–45 min after injection, with a half-life ranging from 13.7 to 199.8 min, and decreased markedly 1 day after injection. MCAM selectively reduced opioid self-administration and remained effective with repeated administration. Moreover, MCAM was effective at times when plasma levels were very low, suggesting that pharmacodynamic (i.e., pseudoirreversible binding to mu opioid receptors) and not pharmacokinetic factors play a significant role in its long-lasting effects. Taken together with previous studies, these data indicate that MCAM could be a safe, effective, and long-acting treatment for OUD

A multivalent DNA aptamer specific for the B-cell receptor on human lymphoma and leukemia

Long-term survival still eludes most patients with leukemia and non-Hodgkin’s lymphoma. No approved therapies target the hallmark of the B cell, its mIgM, also known as the B-cell receptor (BCR). Aptamers are small oligonucleotides that can specifically bind to a wide range of target molecules and offer some advantages over antibodies as therapeutic agents. Here, we report the rational engineering of aptamer TD05 into multimeric forms reactive with the BCR that may be useful in biomedical applications. Systematic truncation of TD05 coupled with modification with locked nucleic acids (LNA) increased conformational stability and nuclease resistance. Trimeric and tetrameric versions with optimized polyethyleneglycol (PEG) linker lengths exhibited high avidity at physiological temperatures both in vitro and in vivo. Competition and protease studies showed that the multimeric, optimized aptamer bound to membrane-associated human mIgM, but not with soluble IgM in plasma, allowing the possibility of targeting leukemias and lymphomas in vivo. The B-cell specificity of the multivalent aptamer was confirmed on lymphoma cell lines and fresh clinical leukemia samples. The chemically engineered aptamers, with significantly improved kinetic and biochemical features, unique specificity and desirable pharmacological properties, may be useful in biomedical applications

Back Pay in Employment Discrimination Cases

This Special Project examines the back pay decisions and analyzes the problems that have confronted the courts dealing with this remedy for employment discrimination in the context of Title VII and section 1981. Because of the enormity of the issues that have arisen in Stage I of the proceedings, however, and the extensive coverage given those problems by the courts and commentators, the Special Project will deal only with the recovery stage, or Stage II, of the litigation. Consequently, the reader should assume that liability for employment discrimination has already been established in each of the cases discussed below. Before reaching the various procedural and substantive issues surrounding back pay awards, however, the Project, in part II, presents an over-view of the statutory authority for back pay including the legislative history of Title VII and section 1981. Part II also discusses the development of the appropriate standard for the exercise of judicial discretion in awarding back pay. Part III examines the parties liable for the payment of back pay. In part IV the Project explores presumptive eligibility for back pay and in part V considers possible grounds on which a defendant may seek to rebut the presumption. Parts VI and VII discuss the proof-of-claim procedure that must be followed by discriminatees claiming back pay and the procedure for determining individual awards. Part VIII then identifies and analyzes the various problems facing courts in allocating the burdens of proof that plaintiffs and defendants must meet before the court can determine individual awards. Following the discussion of the order and allocation of the burdens of proof, part IX outlines the various methods used by the courts to compute individual back pay awards and also discusses other issues such as the elements includable and deductible, the mitigation requirement,and the limitation periods for back pay. In part X the Special Project examines the problems that may arise when the parties agree to a settlement of back pay claims

OREX-1038:A potential new treatment for pain with low abuse liability and limited adverse effects

Drugs targeting mu opioid receptors are the mainstay of clinical practice for treating moderate-to-severe pain. While they can offer excellent analgesia, their use can be limited by adverse effects, including constipation, respiratory depression, tolerance, and abuse liability. Multifunctional ligands acting at mu opioid and nociceptin/orphanin FQ peptide receptors might provide antinociception with substantially improved adverse-effect profiles. This study explored one of these ligands, OREX-1038 (BU10038), in several assays in rodents and nonhuman primates. Binding and functional studies confirmed OREX-1038 to be a low-efficacy agonist at mu opioid and nociceptin/orphanin FQ peptide receptors and an antagonist at delta and kappa opioid receptors with selectivity for opioid receptors over other proteins. OREX-1038 had long-acting antinociceptive effects in postsurgical and complete Freund's adjuvant (CFA)-induced thermal hyperalgesia assays in rats and a warm water tail-withdrawal assay in monkeys. OREX-1038 was active for at least 24 h in each antinociception assay, and its effects in monkeys did not diminish over 22 days of daily administration. This activity was coupled with limited effects on physiological signs (arterial pressure, heart rate, and body temperature) and no evidence of withdrawal after administration of naltrexone or discontinuation of treatment in monkeys receiving OREX-1038 daily. Over a range of doses, OREX-1038 was only transiently self-administered, which diminished rapidly to nonsignificant levels; overall, both OREX-1038 and buprenorphine maintained less responding than remifentanil. These results support the concept of dual mu and nociceptin/orphanin FQ peptide receptor partial agonists having improved pharmacological profiles compared with opioids currently used to treat pain.</p