Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent NaV1.7 inhibitors.

NaV1.7 is a particularly compelling target for the treatment of pain. Herein, we report the discovery and evaluation of a series of piperazine amides that exhibit state-dependent inhibition of NaV1.7. After demonstrating significant pharmacodynamic activity with early lead compound 14 in a NaV1.7-dependent behavioural mouse model, we systematically established SAR trends throughout each sector of the scaffold. The information gleaned from this modular analysis was then applied additively to quickly access analogues that encompass an optimal balance of properties, including NaV1.7 potency, selectivity over NaV1.5, aqueous solubility, and microsomal stability.

Stability and convergent validity of the Physical Activity Scale for the Elderly (PASE).

AIM: The purpose of this study was to assess the stability and convergent validity of the Physical Activity Scale for the Elderly (PASE) among rural, community dwelling elderly persons using Computer Science and Applications, Inc. Actigraph Monitors (Actigraph) as the direct criterion measure. EXPERIMENTAL DESIGN: a correlational design was employed. SETTING: rural community in the United States. PARTICIPANTS: 56 subjects (age=75.7+/-7.9 years) who were living independently and volunteered to participate in the study. MEASURES: subjects wore an Actigraph monitor during all waking hours for 7 consecutive days. At the conclusion of the 7 days, each subject met with a trained interviewer to complete the PASE questionnaire. Three days later the subjects met with the same interviewer to complete the PASE a 2nd time recalling their physical activity for the same 7-day period. RESULTS: Actigraph data indicated that subjects averaged 168.1+/-76.3 counts x minute(-1) during the 7-day period. A high intraclass correlation coefficient (r=0.91) was calculated between the 1st interview total PASE score (115.97+/-59.91) and the 2nd interview total PASE score (115.71+/-50.97). In addition, there was a statistically significant Spearman correlation coefficient of 0.43 (p<0.01) between Actigraph mean counts x minute(-1) and 1st interview total PASE scores. CONCLUSION: In this rural elderly sample, the PASE was a stable instrument with validity indices similar to those previously reported in younger, more active, populations.

Impact of skin-sparing mastectomy with immediate reconstruction and breast-sparing reconstruction with miniflaps on the outcomes of oncoplastic breast surgery.

BACKGROUND: The aim of this study was to compare the outcomes of skin-sparing mastectomy (SSM) with immediate myocutaneous flap reconstruction and partial mastectomy with latissimus dorsi miniflap reconstruction (LDMF) for breast cancer. METHODS: Some 106 disease-free patients (57 SSM, 49 LDMF) who had breast reconstruction between 1991 and 1999 participated in this retrospective review. The mean duration of follow-up was 42 (range 6-102) months. Measured outcomes included surgical complications, functional disability, cosmetic result and psychological morbidity. RESULTS: SSM outcomes were less favourable than LDMF outcomes with regard to postoperative complications (14 versus 8 per cent), further surgical interventions (79 versus 12 per cent), nipple sensory loss (98 versus 2 per cent), restricted activities (73 versus 54 per cent) and cosmetic outcome by panel assessment. Anxiety about residual cancer and ease of breast self-examination were similar in both groups. CONCLUSION: LDMF was associated with fewer adverse surgical and physical sequelae than SSM, without compromising local control or cosmetic outcome. Both operations were associated with low psychological morbidity.