6-(4-chlorophenyl)-3-substituted-thieno[3,2-d]pyrimidin-4(3H)-one-based melanin-concentrating hormone receptor 1 antagonist

Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.     

Immunological profile changes following perioperative autologous vs. homologous blood transfusion in oncologic patients

To determine the effect of perioperative blood transfusion on immunological parameters, T cells, T-cell subsets, and concanavalin A-induced suppression were measured in 25 patients with colorectal and breast cancer. During the operation, 15 patients received autologous blood and 10 patients had homologous transfusion. The immunological status was again determined after curative surgery. Before surgery, normal percentage of T lymphocytes, decreased ratios of helper/suppressor cells, and impaired con A-induced suppression were found. Following the operation, the helper and suppressor cell percentages reversed to normal, whereas the con A-induced suppression remained impaired. This change was significantly more pronounced in patients who received autologous blood transfusion than in the other group. Autotransfusion has an impact on immune parameters that might prove less detrimental to the clinical outcome in oncologic surgery than homologous transfusion. © 1994 Wiley-Liss, Inc.     

Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study

OBJECTIVES: The objectives of this study were to estimate the clinical response rate and toxicity of daily tamoxifen combined with intermittent weekly medroxyprogesterone acetate (MPA). METHODS: This study reports the results of 61 patients with measurable advanced or recurrent endometrial carcinoma enrolled on this study to be treated with tamoxifen 40 mg p.o. daily plus alternating weekly cycles of MPA 200 mg p.o. daily. RESULTS: One patient was excluded and two patients did not receive study treatment. The percent of patients responding (6 complete and 13 partial) was 33% (95% confidence interval [CI]: 21-46%) among 58 eligible patients who received therapy. Median progression-free survival (PFS) was 3 months and median overall survival (OS) was 13 months. CONCLUSION: The combination of daily tamoxifen and intermittent weekly medroxyprogesterone acetate is an active treatment for advanced or recurrent endometrial carcinoma. Further investigation of this combination is appropriate.     

Accept No Substitutes: The Ethics of Alternatives

It is common to argue that animal experimentation is justified by its essential contribution to the advancement of medical science. But note that this argument actually contains two premises: an empirical claim that animal experimentation is essential to the advancement of medical science and an ethical claim that if research is essential to the advancement of medical science, then it is justified. Neither premise looks weak; the first premise is an article of faith for most biomedical researchers, and the second is usually considered so obviously true that it goes unstated. In fact, however, both are open to challenge. In the logic of the case, only one of the premises needs to be shown false or moot in order to refute the argument. A number of other commentators have questioned the first, but it is the ethical premise that I find particularly wanting.     

The Feasibility and Validity of Body-Worn Sensors to Supplement Timed Walking Tests for Children with Neurological Conditions

Aims: The 10-meter walk test (10 mWT) and Timed Up and Go (TUG) are assessments of speed/time with a ceiling effect in pediatric populations. This study aimed to (1) determine whether collecting spatiotemporal data with inertial sensors (Mobility Lab, APDM Inc.) during these tests improves their discriminative validity, and (2) evaluate the clinical feasibility of Mobility Lab. Methods: Fifteen children with spina bifida (SB) or cerebral palsy (CP) (7.9 ± 3.1 years old) and fifteen age- and sex-matched typically-developing (TD) children completed the 10 mWT and TUG wearing Mobility Lab. Spatiotemporal data were compared between groups. Mobility Lab's potential to distinguish children with SB/CP from TD children was examined using conditional logistic regression. Feasibility was evaluated through participant adherence and a clinical utility scale. Results: For the 10 mWT, group differences (p < 0.01) were found in horizontal and frontal trunk range of motion, horizontal trunk velocity, and swing asymmetry. Children with SB/CP took significantly longer to turn during the TUG. These five variables together distinguished the two groups (p = 0.006). 78% of participants with SB/CP completed the testing protocol. Mobility Lab scored 4/10 on the clinical utility scale. Conclusions: Instrumenting the 10 mWT and TUG improves the tests’ ability to discriminate between children with SB/CP and TD children.