Schwann cell-autonomous role of neuropilin-2

Neuropilins and group A plexins are components of receptor complexes for class 3 semaphorins, gradients of which help to guide migration of neural progenitor cells and axonal growth cones during development. We demonstrated previously that neuropilins and class 3 semaphorins are induced in sciatic nerve by crush or transection. We now report that in cultured rat Schwann cells, expression of mRNA encoding neuropilin-2 (NRP2) and plexin-A3 (PlexA3), proteins involved in semaphorin-3F (Sema3F) signal transduction, is diminished markedly by forskolin, an adenylate cyclase activator that, like axonal contact, induces Schwann cell synthesis of myelin lipids and proteins. Interestingly, Schwann cell expression of mRNA encoding NRP1, which participates in Sema3A signaling, is not downregulated by forskolin. Antibodies that recognize ectodomains of NRP2 but not control antibodies prevented cultured Schwann cells from aligning in parallel and forming columns. These results are consistent with the view that in nerves undergoing Wallerian degeneration, Schwann cell NRP2 facilitates assembly of Schwann cells into the tubular aggregates (bands of Büngner) that guide regenerating axons.     

A multimedia psychosocial support program for couples receiving infertility treatment: a feasibility study

OBJECTIVE: To develop and test the feasibility of a theory-driven, psychosocial support CD-ROM prototype for couples in infertility treatment. DESIGN: Focus group meetings with reproductive health experts, semistructured interviews with infertility patients, and content analysis of an infertility message board to determine content domains of the CD-ROM. Usability and acceptance testing of prototype CD-ROM based on predetermined feasibility criteria. SETTING: Private offices and fertility centers. PATIENT(S): Expert panel of 5 reproductive health specialists; interviews with 62 individuals with infertility (35 women, 27 men); feasibility study with 12 patients and 12 experts in reproductive medicine and infertility support. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Product usability/acceptance test. RESULT(S): Participant feedback and content analysis informed the development of a prototype patient education CD-ROM that uses audio, video, interactive tasks, and personalized feedback. Over 80% of participants successfully completed usability tasks, and over 90% rated prototype satisfaction as "good" to "excellent." Some areas were noted for improvement in navigation and refinement in delivery of instructions. Results strongly indicate an interest in an infertility multimedia support tool. CONCLUSION(S): Multimedia methods may serve as an effective, innovative psychosocial intervention for infertility patients and overcome barriers of limited local access to educational and support services.     

Preoperative rofecoxib oral suspension as an analgesic adjunct after lower abdominal surgery: the effects on effort-dependent pain and pulmonary function

Rofecoxib is a selective cyclooxygenase-2 inhibitor that reduces pain and inflammation without inhibiting platelet function. We examined its effects on effort-dependent pain, postoperative morphine requirements, and pulmonary function in 48 patients recovering from open abdominal surgery. Spirometric measurement of forced expiratory volume(1) and vital capacity (FVC) were assessed preoperatively. One hour before the induction of a standardized general anesthetic, patients were given either placebo oral suspension (Group A), or rofecoxib oral suspension (25 mg [Group B] or 50 mg [Group C]) in a double-blinded manner. Postoperative pain control was provided with IV morphine in the postanesthesia care unit and IV-patient-controlled analgesia morphine on the patient care unit. Morphine dose, pain intensity at rest, and pain after respiratory effort (postoperative spirometry) were assessed at 12 and 24 h after study drug administration. The patient-controlled analgesia morphine dose at 24 h was reduced 44% in Group B (30.3 +/- 17.5 mg) and 59% in Group C (22.1 +/- 16.5 mg) versus Group A (53.7 +/- 31.1 mg); P < 0.01 (A versus B). At 12 h, pain scores at rest and after spirometry were lower in Groups B and C than in A (P < 0.05). At 24 h, resting pain scores were lowest in Group C (P < 0.05). Twelve-hour FVC was best preserved in Group C (P < 0.03). There were no inter-group differences in adverse effects or perioperative blood loss. Rofecoxib oral suspension provided a morphine-sparing effect, as well as improvements in pain control and 12-h FVC in patients recovering from open abdominal surgery. IMPLICATIONS: Rofecoxib belongs to class of analgesics known as cyclooxygenase-2 inhibitors that reduce pain and inflammation with less risk of bleeding than standard nonsteroidal antiinflammatory drugs. We found that patients treated with rofecoxib 25 or 50 mg before open abdominal surgery required less IV morphine during the first day of recovery. Despite reductions in morphine requirements, rofecoxib-treated patients reported lower pain intensity scores at rest and after a vigorous cough. In the 50-mg group, improvements in pain control correlated with greater preservation of baseline cough effectiveness (vital capacity) at 12 h. These findings may offer clinical advantages in patients with preexisting pulmonary disease.     

Genetic determinants of arterial calcification associated with atherosclerosis

Increasing research interest has focused on arterial calcification in the setting of atherosclerosis. Many features of atherosclerosis-related calcification provide useful clinical information. For example, calcium mineral deposits frequently form in atherosclerotic plaque, and intimal arterial calcification can be used as a surrogate marker for atherosclerosis; also, calcium deposits are readily and noninvasively quantified, which is useful because greater amounts of coronary calcification predict a higher risk of myocardial infarction and death. Several mechanisms leading to calcification associated with atherosclerosis have been proposed; however, no direct testing of proposed mechanisms has yet been reported. Studies in genetically altered animals and in humans have shed light on potential genetic determinants, which in turn could form the basis for a more comprehensive understanding of the factors affecting calcification within plaque and the associated pathobiologic implications. We review proposed molecular and cellular mechanisms of atherosclerosis-associated arterial calcification, summarize genetic influences, and suggest areas in which further investigation is needed. Understanding the molecular and genetic determinants of specific structural plaque components such as calcification can provide a solid foundation for the development of novel therapeutic approaches to favorably alter plaque structure and minimize vulnerability to arterial rupture.     

Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms

Redundant mechanisms mediate colon cancer angiogenesis. Targeting multiple angiogenic factors simultaneously may improve survival of mice with colon cancer metastases. BALB/c mice underwent splenic injection with CT-26 colon cancer cells to generate liver metastases and received administration of either vehicle alone or a tyrosine kinase inhibitor for vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor receptors (SU6668). Mice were sacrificed when they became moribund as determined by a blinded observer. In a parallel experiment, groups of mice were sacrificed at earlier time points to better define the kinetics of the effect of SU6668 on angiogenic parameters over time. SU6668 increased median survival by 58% (P < 0.001) and led to a progressive increase in tumor cell and endothelial cell apoptosis that increased over time. In addition, pericyte vessel coverage and tumor vascularity were significantly decreased in mice treated with SU6668. Based on current knowledge of endothelial cell survival, these data suggest that SU6668 may prevent tumor endothelial cell survival directly (vascular endothelial growth factor) and indirectly (pericyte coverage) by affecting endothelial cell survival mechanisms.