Charles Lu

Regulation of Parathyroid Hormone-Related Peptide Gene Expression by Estrogen in GH4C1 Rat Pituitary Cells Has the Pattern of a Primary Response Gene

The parathyroid hormone‐related peptide (PTHrP) gene has been reported to be subject to a wide variety of physiological and pharmacological controls. Two distinct patterns of PTHrP mRNA response have been recognized, one characterized by a prolonged or plateau response lasting many hours to days and the second characterized by rapid induction‐deinduction kinetics and lasting 1 to several hours. The kinetics of the second pattern are similar to those displayed by primary response genes like nuclear protooncogenes, cytokines, and growth factors. In GH4C1, rat pituitary cells, 17β‐estradiol induced a rapid and transient increase in PTHrP mRNA expression, with a peak response at 1–2 h. This response appeared to be due to a rapid and transient burst in gene transcription, which by runoff analysis was maximal at 20–40 min and declined thereafter. PTHrP mRNA half‐life was 30 min in these cells and was unaltered by estradiol. Cy‐cloheximide did not block the 17β‐estradiol‐induced response but rather prolonged it, and runoff analysis revealed that this effect was due to a prolongation or persistence of PTHrP gene transcription. These findings suggest that the transient nature of the native response reflects the effects of an estrogen‐inducible represser. All of these features are characteristic of a prototypical primary response gene.

Reengineering a Database for Clinical Trials Management: Lessons for System Architects

This paper describes the process of enhancing Trial/DB, a database system for clinical studies management. The systems enhancements have been driven by the need to maximize the effectiveness of developer personnel in supporting numerous and diverse users, of study designers in setting up new studies, and of administrators in managing ongoing studies. Trial/DB was originally designed to work over a local area network within a single institution, and basic architectural changes were necessary to make it work over the Internet efficiently as well as securely. Further, as its use spread to diverse communities of users, changes were made to let the processes of study design and project management adapt to the working styles of the principal investigators and administrators for each study. The lessons learned in the process should prove instructive for system architects as well as managers of electronic patient record systems.

Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE): A Cluster-Randomized Pragmatic Trial of a Multifactorial Fall Injury Prevention Strategy: Design and Methods

Background Fall injuries are a major cause of morbidity and mortality among older adults. We describe the design of a pragmatic trial to compare the effectiveness of an evidence-based, patient-centered multifactorial fall injury prevention strategy to an enhanced usual care. Methods Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) is a 40-month cluster-randomized, parallel-group, superiority, pragmatic trial being conducted at 86 primary care practices in 10 health care systems across United States. The 86 practices were randomized to intervention or control group using covariate-based constrained randomization, stratified by health care system. Participants are community-living persons, ≥70 years, at increased risk for serious fall injuries. The intervention is a comanagement model in which a nurse Falls Care Manager performs multifactorial risk assessments, develops individualized care plans, which include surveillance, follow-up evaluation, and intervention strategies. Control group receives enhanced usual care, with clinicians and patients receiving evidence-based information on falls prevention. Primary outcome is serious fall injuries, operationalized as those leading to medical attention (nonvertebral fractures, joint dislocation, head injury, lacerations, and other major sequelae). Secondary outcomes include all fall injuries, all falls, and well-being (concern for falling; anxiety and depressive symptoms; physical function and disability). Target sample size was 5,322 participants to provide 90% power to detect 20% reduction in primary outcome rate relative to control. Results Trial enrolled 5,451 subjects in 20 months. Intervention and follow-up are ongoing. Conclusions The findings of the STRIDE study will have important clinical and policy implications for the prevention of fall injuries in older adults.

Screening, Recruitment, and Baseline Characteristics for the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) Study

Background We describe the recruitment of participants for Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE), a large pragmatic cluster randomized trial that is testing the effectiveness of a multifactorial intervention to prevent serious fall injuries. Eligible persons were 70 years or older, community-living, and at increased risk for serious fall injuries. The modified goal was to recruit 5,322 participants over 20 months from 86 primary care practices within 10 diverse health care systems across the United States. Methods The at-risk population was identified using two distinct but complementary screening strategies that included three questions administered centrally via the mail (nine sites) or in the clinic (one site), while recruitment was completed centrally by staff at Yale. Results For central screening, 226,603 letters mailed to 135,118 patients yielded 28,719 positive screens (12.7% of those mailed and 46.5% of the 61,729 returned). In the clinic, 22,537 screens were completed, leading to 5,732 positive screens (25.4%). Of the 34,451 patients who screened positive for high risk of serious fall injuries, 31,872 were sent a recruitment packet and, of these, 5,451 (17.1%) were enrolled over 20 months (mean age: 80 years; 62% female). The participation rate was 34.0% among eligible patients. The enrollment yields were 3.6% (vs 5% projected) for each patient screened centrally, despite multiple screens, and 10.5% (vs 33.9% projected) for each positive clinic screen. Conclusions Despite lower-than-expected yields, the STRIDE Study exceeded its modified recruitment goal. If the STRIDE intervention is found to be effective, the two distinct strategies for identifying a high-risk population of older persons could be implemented by most health care systems.

Tactile neutral codes for the shapes and orientation of objects

A series of small, three dimensional objects of differing shape each mounted on a flat plate were constructed. The objects were a cylinder and sphere, each with a 5 mm radius, and two toroids each with a radius of 5 mm along one axis and differing radii of 1 or 3 mm along the orthogonal axis. Using a servocontrolled translation device with 3 degrees of freedom, each object was stroked back and forth across the skin under a maintained compressional force along a series of laterally shifted parallel linear trajectories oriented 90° with respect to the long axis of the finger. The toroid was oriented at 0,30,60 or 90°. Three dimensional “spatial event plots” (SEPs)-discharge rate vs location of object on the receptive field- were obtained for slowly- and rapidly-adapting mechanoreceptive type I fibers (SAs and RAs) with receptive fields centrally located on the fingerpad