Comparison of two population pharmacokinetic programs, NONMEM and P-PHARM, for tacrolimus

Objectives: To compare the population modelling programs NONMEM and P-PHARM during investigation of the pharmacokinetics of tacrolimus in paediatric liver-transplant recipients. Methods: Population pharmacokinetic analysis was performed using NONMEM and P-PHARM on retrospective data from 35 paediatric liver-transplant patients receiving tacrolimus therapy. The same data were presented to both programs. Maximum likelihood estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F). Covariates screened for influence on these parameters were weight, age, gender, post-operative day, days of tacrolimus therapy, transplant type, biliary reconstructive procedure, liver function tests, creatinine clearance, haematocrit, corticosteroid dose, and potential interacting drugs. Results: A satisfactory model was developed in both programs with a single categorical covariate - transplant type - providing stable parameter estimates and small, normally distributed (weighted) residuals. In NONMEM, the continuous covariates - age and liver function tests - improved modelling further. Mean parameter estimates were CL/F (whole liver) = 16.3 1/h, CL/F (cut-down liver) = 8.5 1/h and V/F = 565 1 in NONMEM, and CL/F = 8.3 1/h and V/F = 155 1 in P-PHARM. Individual Bayesian parameter estimates were CL/F (whole liver) = 17.9 +/- 8.8 1/h, CL/F (cutdown liver) = 11.6 +/- 18.8 1/h and V/F = 712 792 1 in NONMEM, and CL/F (whole liver) = 12.8 +/- 3.5 1/h, CL/F (cut-down liver) = 8.2 +/- 3.4 1/h and V/F = 221 1641 in P-PHARM. Marked interindividual kinetic variability (38-108%) and residual random error (approximately 3 ng/ml) were observed. P-PHARM was more user friendly and readily provided informative graphical presentation of results. NONMEM allowed a wider choice of errors for statistical modelling and coped better with complex covariate data sets. Conclusion: Results from parametric modelling programs can vary due to different algorithms employed to estimate parameters, alternative methods of covariate analysis and variations and limitations in the software itself.

Angiotensin AT-1 receptor antagonism: complementary or alternative to ACE inhibition in cardiovascular and renal disease

Both angiotensin-converting enzyme (ACE) inhibitors and AT-1 receptor antagonists reduce the effects of angiotensin II, however they may have different clinical effects. This is because the ACE inhibitors, but not the AT-1 receptor antagonists, increase the levels of substance P, bradykinin and tissue plasminogen activator. The AT-1 receptor antagonists, but not the ACE inhibitors, are capable of inhibiting the effects of angiotensin II produced by enzymes other than ACE. On the basis of the present clinical trial evidence, AT-1 receptor antagonists, rather than the ACE inhibitors, should be used to treat hypertension associated with left ventricular (LV) hypertrophy. Both groups of drugs are useful when hypertension is not complicated by LV hypertrophy, and in diabetes. In the treatment of diabetes with or without hypertension, there is good clinical support for the use of either an ACE inhibitor or an AT-1 receptor antagonist. ACE inhibitors are recommended in the treatment of renal disease that is not associated with diabetes, after myocardial infarction when left ventricular dysfunction is present, and in heart failure. As the incidence of cough is much lower with the AT-1 receptor antagonists, these can be substituted for ACE inhibitors in patients with hypertension or heart failure who have persistent cough. Preliminary studies suggest that combining an AT-1 receptor antagonist with an ACE inhibitor may be more effective than an ACE inhibitor alone in the treatment of hypertension, diabetes with hypertension, renal disease without diabetes and heart failure. However, further trials are required before combination therapy can be recommended in these conditions.

Complementary and layered expression of Ephs and Ephrins in developing mouse inner ear

The distributions of the Eph-class receptors EphA4 and EphB 1, and their ligands ephrin-A2, ephrin-B1, and ephrin-B2, were analysed by immunostaining in the mouse inner ear. Complementary patterns of EphA4 and its potential ligand ephrin-A2 were found, with ephrin-A2 in many of the structures lining the cochlear duct and within the cochlear nerve cells, and EphA4 in the deeper structures underlying the cochlear duct and in the cells lining the nerve pathway. EphB1 and its potential ligands ephrin-B1 and ephrin-B2 showed a segregated layered expression in the lateral wall of the cochlear duct (the external sulcus), which together with EphA4 expressed in the area, form a four-layered structure with an alternating pattern of receptors and ligands in the different layers. This arrangement gives the potential for different bidirectional Eph-mediated interactions between each of the layers. The results suggest that the Eph system in the cochlea may have a role in maintaining cell segregation during phases of cochlear development. (C) 2002 Wiley-Liss, Inc.

The regulation of complementary health: sacrificing integrity?

In response to the increasing use of complementary and alternative medicine (CAM), governments are exploring ways to ensure patients' safety and respond to complaints. One solution is to establish registration boards and procedures based on the model of existing health practitioner Acts. Registration will require defined minimum standards for competence, which will have to be based on scientific evidence. As scientific evidence accumulates, these modalities are likely to lose their identities as alternative and become assimilated into Western medicine.

A disciplina de história da educação em perspectiva histórica : da Faculdade de Filosofia, Ciências e Letras à Universidade Federal do Espírito Santo (1951-2000)

A pesquisa analisa da constituição histórica da disciplina História da Educação ministrada na Faculdade de Filosofia Ciências e Letras do Estado do Espírito Santo, posteriormente incorporada a Universidade Federal do Espírito Santo entre os anos de 1951 e 2000. Investiga a constituição histórica da disciplina, as transformações programáticas, legais e institucionais referentes à disciplina de História da Educação, como também as abordagens historiográficas, periodizações e os conceitos de tempo, história e educação. A fundamentação teórica e metodológica articula-se dialogicamente a partir das construções conceituais e metodológicas de Carlo Ginzburg e Mikhail Bakhtin. A partir dos conceitos de polifonia e dialogismo, comum a ambos, investigou-se as vozes e diálogos impressos nas narrativas da disciplina de História da Educação e seu ensino, sejam em camadas mais superficiais ou profundas, encontradas no corpus documental consultado e analisado, que correspondem a: programas de ensino, transparências, leis, estruturas curriculares, documentos de departamento; resenhas e fichamentos de textos, bibliografia obrigatória e complementar, avaliações e entrevistas. Procurou-se no corpus documental dados aparentemente negligenciáveis – pistas, indícios e sinais – remontar uma realidade histórica complexa e não experimentável diretamente. Ao investigar historicamente a trajetória da disciplina História da Educação e seu ensino a partir dos parâmetros legais, programáticos e institucionais, foi possível perceber que as mudanças mais profundas operadas na disciplina não se originam das legislações e reestruturações curriculares, mas dos locais de produção e socialização do conhecimento histórico. Durante o período analisado, as duas esferas de produção historiográficas que mais influenciaram nas abordagens, periodizações e conceitos de tempo, história e educação da disciplina História da Educação do curso de pedagogia pesquisado foram: a editora responsável pela publicação e divulgação dos Manuais de História da Educação da coleção Atualidades Pedagógicas (1951-1979) e os Programas de Pós-graduação em Educação e História (1980 - 2000). Entre 1951 e finais de 1970 observa-se a influência dos Manuais de História da Educação, na organização e programação do ensino de História da Educação e uma abordagem filosófica voltada para a história das ideias pedagógicas e análises do pensamento de filósofos e educadores sobre a educação e respectivas inserções em doutrinas filosóficas europeias. A partir de 1980 as abordagens de cunho econômico, político e ideológico dos contextos históricos educativos passaram a predominar nos programas de ensino das disciplinas de História da Educação I e II, e vigoraram até meados nos anos de 1990. Na disciplina de História da Educação I a abordagem é marcada por análises do contexto de produção e organização das classes sociais; com relação à disciplina História da Educação II, até meados de 1995, trata da educação brasileira. A partir da abordagem fundamentada na Teoria da Dependência após 1995, os documentos consultados começam a mostrar outras marcas que sugerem uma abordagem voltada para a dimensão política e social, abordando a História da Educação Brasileira, a partir dos movimentos sociais e seus respectivos projetos educacionais.

Bone mineral density of rat femurs after hindlimb unloading and different physical rehabilitation programs

Bone weakening can occur due to the absence of load on the skeleton or even short periods of decreased physical activity. Therefore, musculoskeletal diseases that involve temporary immobilization by casts, inactivity or tension increases the risk of fractures. Physical activity is the most studied procedure both to prevent damage and to restore bone structure. The present study aimed at evaluating, by bone densitometry on rat femurs, the influence of hindlimb unloading and later running activity on treadmill or free movement. Sixty-four Wistar rats were used, aged 65 days with a mean corporal mass of 316.11g, randomly divided into eight experimental groups: group 1, the suspended control with seven animals under hindlimb unloading regimen for 28 days, then euthanized; groups 2 and 3, the trained suspended comprising of 7 and five animals, respectively, subjected to hindlimb unloading for 28 days, followed by treadmill exercise for 28 days (group 2) or 56 days (group 3), then euthanized; groups 4 and 5, designated free suspended, comprised of 7 animals each under hindlimb unloading regimen for 28 days followed by free activity in cages for 28 days (group 4) or 56 days (group 5), then euthanized; groups 6, 7 and 8, negative controls, each with 8 animals allowed to free activity in cages and euthanized at the ages of 93, 121 and 149 days, respectively. Bone mineral density (BMD) of the left femur was analyzed by bone densitometry. Unloading by tail-suspension decreased BMD while treadmill training and free activity in cages promoted its recovery in a similar way and over time.

Higher-order lazy functional slicing

Program slicing is a well known family of techniques intended to identify and isolate code fragments which depend on, or are depended upon, specific program entities. This is particularly useful in the areas of reverse engineering, program understanding, testing and software maintenance. Most slicing methods, and corresponding tools, target either the imperative or the object oriented paradigms, where program slices are computed with respect to a variable or a program statement. Taking a complementary point of view, this paper focuses on the slicing of higher-order functional programs under a lazy evaluation strategy. A prototype of a Haskell slicer, built as proof-of-concept for these ideas, is also introduced

Identifying clones in functional programs for refactoring

Clone detection is well established for imperative programs. It works mostly on the statement level and therefore is ill-suited for func- tional programs, whose main constituents are expressions and types. In this paper we introduce clone detection for functional programs using a new intermediate program representation, dubbed Functional Control Tree. We extend clone detection to the identi cation of non-trivial func- tional program clones based on the recursion patterns from the so-called Bird-Meertens formalism