Metabolism and disposition of a potent group II metabotropic glutamate receptor agonist, in rats, dogs, and monkeys.

Metabolism and disposition of MGS0028 [(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate], a potent group II metabotropic glutamate receptor agonist, were examined in three preclinical species (Sprague-Dawley rats, beagle dogs, and rhesus monkeys). In rats, MGS0028 was widely distributed and primarily excreted in urine as parent and as a single reductive metabolite, identified as the 4R-isomer MGS0034 [(1R,2S,4R,5S,6S)-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]-hexane-2,6-dicarboxylic acid]. MGS0028 had a low brain to plasma ratio at efficacious doses in rats and was eliminated more slowly in rat brain than in plasma. Exposure increased proportionally (1--10 mg/kg p.o.) in rats, with bioavailability>60% at all doses. However, bioavailability was only approximately 20% in monkeys, and MGS0034 was found in relatively high abundance in plasma. In dogs, oral bioavailability was >60%, and the metabolite was not detected. In vitro metabolism was examined in liver subcellular fractions (microsomes and cytosol) from rat, dog, monkey, and human. Reductive metabolism was observed in rat, monkey, and human liver cytosol incubations, but not in dog liver cytosol incubations. No metabolism of MGS0028 was detected in incubations with liver microsomes from any species. Similar to in vivo results, MGS0028 was reduced in cytosol stereospecifically to MGS0034. The rank order of in vitro metabolite formation (monkey > rat approximately human > dog) was in agreement with in vivo observations in rats, dogs, and monkeys. Based on the observation of species difference in reductive metabolism, rat and monkey were recommended to be the preclinical species for further characterization prior to testing in humans. Finally, allometric scaling predicts that human pharmacokinetic parameters would be acceptable for further development.     

Genetic screening,health care and the insurance industry

The potential use of genetic tests in insurance has raised concerns about discrimination and individuals losing access to health care either because of refusals to test for treatable diseases, or because test-positives cannot afford premiums. Governments have so far largely sought to restrict the use of genetic information by insurance companies. To date the number of tests available with significant actuarial value is limited. However, this is likely to change, raising more clearly the question as to whether the social costs of adverse selection outweigh the social costs of individuals not accessing health care for fear of the consequences of test information being used in insurance markets. In this contribution we set out the policy context and model the potential trade-offs between the losses faced by insurers from adverse selection by insurees (which will increase premiums reducing consumer welfare) and the detrimental health effects that may result from persons refusing to undergo tests that could identify treatable health conditions. It argues that the optimal public policy on genetic testing should reflect overall societal benefit, taking account of these trade-offs. Based on our model, the factors that influence the outcome include: the size of and value attached to the health gains from treatment; deterrent effects of a disclosure requirement on testing for health reasons; incidence of the disease; propensity of test-positives to adverse select; policy value adverse selectors buy in a non-disclosure environment; and price elasticity of demand for insurance. Our illustrative model can be used as a benchmark for developing other scenarios or incorporating real data in order to address the impact of different policies on disclosure and requirement to test.     

National Performance Measures for Diabetes Mellitus Care

When considering the trends in disease management, the focus of healthcare in the US has shifted from communicable diseases, which can most often be managed successfully, to chronic diseases, which are currently not managed very well. Chronic diseases, such as diabetes mellitus, become a lifelong health problem for the individual, the family, and in the workplace. Currently, there is no vaccine to prevent diabetes and no cure for diabetes once acquired. In order to improve the quality of care for diabetes, national performance measures have been developed to provide a unified set of diabetes-specific performance and outcome measures.The Diabetes Quality Improvement Project (DQIP) founded in 1997 through a partnership between the Center for Medicare and Medicaid Services, the National Committee for Quality Assurance, and the American Diabetes Association, established a single, standardized set of performance measures for diabetes care quality improvement and accountability in the US, which were published in 1998. The DQIP measures are noteworthy as a model for many other chronic diseases. Indeed, the DQIP represents the first widely adopted comprehensive performance measurement standards, not just for diabetes but for any single chronic disease. This is of further significance since it was developed by a coalition of public and private entities in the US.In order to prevent long-term complications from diabetes, there needs to be a physician-coordinated treatment plan involving a team approach to the problem. When such a physician-coordinated treatment plan is developed in conformance with the comprehensive performance measures, the prospects for a greater impact on diabetes might be enhanced.Overall, national performance measures for diabetes care have been widely adopted into health plan quality initiatives and have resulted in increased efforts to promote preventative screening and testing. Better compliance has lead to more stringent glucose control and helped to educate the public on the utility of the glycosylated hemoglobin level test for finding those at risk for microvascular and neuropathic complications. While more Americans with diabetes are receiving the recommended standards of care as a result of the implementation of national performance measures, diabetes management remains suboptimal but achievable.The authors concluded from this review that national performance measures have provided health plans and providers with objective tools to measure quality; however, these measures now need to move to prevention standards and initiatives. Policy development for diabetes care must continue to move from managing chronic illness to preventative screening of pre-diabetes through to identification and modification of lifestyle risk factors.     

Development of a Regionalized,Comprehensive Care Network for Pediatric Sickle Cell Disease to Improve Access to Care in a Rural State

Sickle cell disease (SCD), an inherited group of blood disorders, is a major public health problem worldwide. Patients experience severe anemia, increased risk of life-threatening infections, painful crisis, and chronic organ damage. Access to comprehensive care for SCD is known to improve outcomes; however, it is only reported from large urban centers serving one metropolitan area. Alabama, US, is a largely rural state with a significant number of children born each year with SCD. Prior to the development of our regional clinic network, the Children and Youth Sickle Network (CYSN^SM), 50% of patients identified by newborn screening were not enrolled in comprehensive sickle cell care. The majority of non-enrolled patients lived in southern Alabama. Rural areas in this region are particularly plagued by poverty and poor access to healthcare. Life expectancy is equivalent to residents of Sri Lanka. This area has 15.7 doctors/10 000 residents compared with the statewide ratio of 41.9 doctors/10 000 residents.To improve access to care, a regional clinic network, the CYSN^SM, was established in 1995. This paper reviews the impact of the CYSN^SM on pediatrie SCD in Alabama over the first 5 years of implementation.Since its inception in 1995, the CYSN^SM has provided care for 923 patients compared with 450 prior to the development of the clinic network. Currently, 90% of all cases identified by newborn screening are enrolled compared with 50% pre-CYSN^SM. Prior to the network, the average age of patients at their first clinic visit was 21 months. In the post-CYSN^SM period, the average age at first clinic visit decreased substantially to 5.3 months. Prior to the CYSN^SM, patients traveled on average 90 miles to a comprehensive clinic. Post-CYSN^SM, this distance has been cut in half to an average of 45 miles. A total of 70% of patients now live within 30 miles of a clinic. Most importantly, the infection death rate has decreased from 5.71 deaths/100 patient years to 1.94 deaths/100 patient years.The development, implementation, and evaluation of the CYSN^SM show that comprehensive care delivery in a rural setting is feasible and improves outcomes in pediatric SCD.     

A Comparison of Visual Field and Optic Disc Appearance Depending on the Peak Intraocular Pressure in Patients with Normal-tension Glaucoma

Purpose To review the outcome of surgery for strabismus due to ethmoid sinus surgery.Cases and Methods The series comprised 13 cases, 1 of inferior rectus paresis, 1 of superior oblique paresis, 6 of medial rectus paresis, and 5 of medial rectus muscle palsy due to third nerve palsy. In the cases of paresis of the rectus muscle, resection of the rectus muscles was mainly performed. In the cases of palsy of the rectus muscle, transposition of the extraocular muscle with simultaneous recession of the lateral rectus muscle was performed. The major aim of surgery was to bring both eyes into alignment and to eliminate diplopia in the primary position.Results The mean preoperative horizontal deviation of 18.1 degrees of exotropia in the paresis cases was reduced to 1.4 degrees of exotropia after surgery. The mean preoperative vertical deviation of 3.8 degrees of hypertropia was reduced to 1.4 degrees of hypertropia postoperatively. The mean preoperative horizontal deviation of 35.6 degrees of exotropia in the palsy cases was reduced to 9.4 degrees of exotropia after surgery. The mean preoperative vertical deviation of 2.0 degrees of hypertropia was increased to 2.6 degrees of hypertropia postoperatively. Postoperatively, diplopia was absent in 11 cases with a slightly compensatory head posture.Conclusions Surgery for strabismus due to sinus surgery induces improvements in eye position and diplopia. Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc 107:425–432, 2003)     

Estimating numbers of injecting drug users in metropolitan areas for structural analyses of community vulnerability and for assessing relative degrees of service provision for injecting drug users

This article estimates the population prevalence of current injection drug users (IDUs) in 96 large US metropolitan areas to facilitate structural analyses of its predictors and sequelae and assesses the extent to which drug abuse treatment and human immunodeficiency virus (HIV) counseling and testing are made available to drug injectors in each metropolitan area. We estimated the total number of current IDUs in the United States and then allocated the large metropolitan area total among large metropolitan areas using four different multiplier methods. Mean values were used as best estimates, and their validity and limitations were assessed. Prevalence of drug injectors per 10,000 population varied from 19 to 173 (median 60; interquartile range 42–87). Proportions of drug injectors in treatment varied from 1.0% to 39.3% (median 8.6%); and the ratio of HIV counseling and testing events to the estimated number of IDUs varied from 0.013 to 0.285 (median 0.082). Despite limitations in the accuracy of these estimates, they can be used for structural analyses of the correlates and predictors of the population density of drug injectors in metropolitan areas and for assessing the extent of service delivery to drug injectors. Although service provision levels varied considerably, few if any metropolitan areas seemed to be providing adequate levels of services.     

Capacity and Competence in Child and Adolescent Psychiatry

Capacity and competence in the field of child and adolescent psychiatry are complex issues, because of the many different influences that are involved in how children and adolescents make treatment decisions within the setting of mental health. This article will examine some of the influences which must be considered, namely: developmental aspects, the paradoxical relationship between the need for autonomy and participation and the capacity of children, family psychiatry, and the duty of care towards children and adolescents. The legal frameworks relevant to consideration of consent and competence will be briefly considered, as well as some studies of children's consent, participation and competence. A case vignette will be used as a focus to consider the complexity of the issue of competence in child and adolescent psychiatry, in the particular mental disorder of anorexia nervosa.     

Patient Capacity in Mental Health Care: Legal Overview

The discriminatory effects of categorizing psychiatric patients into competent and incompetent, have urged lawyers, philosophers and health care professionals to seek a functional approach to capacity assessment. Dutch and English law have produced some guidelines concerning this issue. So far, most legal systems under investigation have concentrated on alternatives for informed consent by the patient in case of mental incapacity, notably substitute decision-making, intervention of a judge and advance directives. It is hard to judge the way in which the law may further adapt to a more functional assessment of capacity, because the nature of law shows that legal reforms usually take place only when new methods have been accepted by the field. This is not yet the case today.