Time course of satisfaction of search

"Satisfaction of search" (SOS) refers to the effect in which a second lesion remains undetected after detection of another lesion on the same radiograph. The objective of this study was to clarify our understanding of SOS by relating it to total time of inspection and time intervals before, between, and after discovery of lesions. Detection accuracy of native lesions in chest radiographs, before and after the addition of a simulated nodular lesion, was measured for ten observers. Analysis of data from this and a previous experiment showed that average perceptual accuracy of individual receiver operating characteristic curves was significantly reduced with the addition of the nodules. Plots and analyses of search time revealed that, on average, during a typical 46-second inspection of a case, simulated nodules were found at 18 seconds, native abnormalities at 25 seconds, and false positives occurred at 33 seconds. Time needed to find nodules did not depend on whether native lesions were present; time to find native lesions did not change with addition of nodules; and total search time was the same for images with one, two, or no lesions. The detection results show that the SOS effect was obtained, but that interrupting search in order to measure it also diminishes accuracy. Analysis of the time course data relates SOS to perceptual capture and strategic halting of search.     

Dopamine distribution and behavioral alterations resulting from dopamine infusion into the brain of the lesioned rat

In an effort to verify the "dopamine secretion hypothesis" as the mechanism responsible for the antiparkinsonian efficacy of adrenal medullary transplants into the brain, the effects of dopamine infusion into the brains of rats with unilateral substantia nigra lesions were examined. The apomorphine-induced rotation, characteristic of this animal model, was diminished after 7 days of continuous dopamine infusion (10 micrograms/hr) into the ipsilateral striatum, whereas intraventricular infusion was without effect. Chromatographic analysis of the dopamine distribution after 10 days of infusion into either region revealed that ipsilateral delivery of dopamine did not result in contralateral increases in dopamine content. Examination of the adjacent striatum following ipsilateral intraventricular delivery indicated that dopamine had only penetrated 1 mm. Even with intrastriatal delivery, there were still parts of the infused striatum which had below-normal levels of dopamine. The fact that striatal tissue presents a significant barrier to the penetration of dopamine is discussed in relation to adrenal medullary and fetal nigral transplants.     

The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective.

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.     

Phase II trial of gefitinib in recurrent glioblastoma.

PURPOSE: To evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. PATIENTS AND METHODS: This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. RESULTS: Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-week cycles, and the 6-month event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 weeks, and the median overall survival (OS) time from treatment initiation was 39.4 weeks. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea positively predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. CONCLUSION: Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.     

Technetium-99m tetrofosmin SPECT predicts chemotherapy response in small cell lung cancer.

The multidrug resistance gene 1 encoding human P-glycoprotein (Pgp) is thought to play an important role in the multidrug resistance of lung cancer. The purpose of this study was to predict chemotherapy response by technetium-99m tetrofosmin (Tc-99m TF) lung single photon emission computed tomography (SPECT) and compare Pgp expression in patients with untreated small cell lung cancer (SCLC). Forty patients with untreated SCLC received Tc-99m TF lung SPECT prior to chemotherapy. The chemotherapy response was evaluated in the 3rd month after completion of treatment. Immunohistochemical staining of Pgp expression was performed on multiple nonconsecutive sections of biopsy specimens. By quantitative analyses, tumor to background ratios were 1.86 +/- 0.27 and 1.17 +/- 0.26 for patients with a good and poor response, respectively (p < 0.05). All of the 20 patients with a good chemotherapy response also had a positive Tc-99m TF lung SPECT and negative Pgp expression. In contrast, only 4 of the 20 patients with a poor chemotherapy response had a positive Tc-99m TF lung SPECT. Moreover, 10 of the 20 patients with a poor chemotherapy response also had negative Pgp expression (p < 0.05). Therefore, we concluded that Tc-99m TF lung SPECT can accurately predict the chemotherapy response, and Tc-99m TF lung SPECT findings can be partially compatible with Pgp expression in patients with untreated SCLC.     

Incident type 2 diabetes mellitus in African American and white adults: the Atherosclerosis Risk in Communities Study

Context  Although the excess prevalence of type 2 diabetes mellitus in African Americans is well established, few studies have compared incident diabetes in African American and white persons. Objectives  To compare risk of incident diabetes in African American vs white adults and to identify explanatory factors for racial disparities. Design  Prospective cohort study using baseline data collected from 1986 to 1989 from the ongoing Atherosclerosis Risk in Communities (ARIC) Study, with 9 years of follow-up. Setting and Participants  A total of 2646 African American and 9461 white adults aged 45 to 64 years without diabetes at baseline, sampled from 4 US communities. Main Outcome Measures  Incident type 2 diabetes, ascertained by self-report of physician diagnosis, use of diabetes medications, or fasting glucose level of at least 7.0 mmol/L (126 mg/dL), compared among white and African American subjects and by presence of potentially modifiable risk factors. Results  Diabetes incidence per 1000 person-years was about 2.4-fold greater in African American women (25.1 [95% confidence interval {CI}, 22.4-28.1] vs 10.4 [95% CI, 9.4-11.4]) and about 1.5-fold greater in men (23.4 [95% CI, 19.9-27.2] vs 15.9 [95% CI, 14.6-17.2]) than in their white counterparts (P<.001). Results from proportional hazards regression models indicated that racial differences in potentially modifiable risk factors, particularly adiposity, accounted for 47.8% of the excess risk in African American women but accounted for little excess risk in African American men. Compared with their white counterparts, African American men and women had higher blood pressures before diabetes onset (diastolic blood pressure difference=5.6 mm Hg in women and 8.4 mm Hg in men; P=.005). Conclusions  Our data indicate that compared with their white counterparts, middle-aged African Americans are at greater risk of developing type 2 diabetes and have higher blood pressure prior to development of diabetes. In women, almost 50% of this excess risk might be related to potentially modifiable factors.      

艾灸足三里治疗顺铂所致迟发性呕吐的临床观察

目的:观察艾灸足三里治疗顺铂所致迟发性呕吐的临床效果.方法:100例患者随机分A、B两组各50例,A组(治疗组):枢星3mg 0.9%NS20ml化疗前30min iv d1-3 艾灸足三里d1-7;B组(对照组):枢星3mg 0.9%NS20ml化疗前30min iv d1～3,观察化疗后7d内呕吐情况.结果:A组控制迟发性呕吐的有效率明显高于B组(P＜0.05).结论:艾灸足三里治疗顺铂所致迟发性呕吐疗效好、经济、方便、安全.