Dwarfism and impaired gut development in insulin-like growth factor II mRNA-binding protein 1-deficient mice.

Insulin-like growth factor II mRNA-binding protein 1 (IMP1) belongs to a family of RNA-binding proteins implicated in mRNA localization, turnover, and translational control. Mouse IMP1 is expressed during early development, and an increase in expression occurs around embryonic day 12.5 (E12.5). To characterize the physiological role of IMP1, we generated IMP1-deficient mice carrying a gene trap insertion in the Imp1 gene. Imp1(-/-) mice were on average 40% smaller than wild-type and heterozygous sex-matched littermates. Growth retardation was apparent from E17.5 and remained permanent into adult life. Moreover, Imp1(-/-) mice exhibited high perinatal mortality, and only 50% were alive 3 days after birth. In contrast to most other organs, intestinal epithelial cells continue to express IMP1 postnatally, and Imp1(-/-) mice exhibited impaired development of the intestine, with small and misshapen villi and twisted colon crypts. Analysis of target mRNAs and global expression profiling at E12.5 indicated that Igf2 translation was downregulated, whereas the postnatal intestine showed reduced expression of transcripts encoding extracellular matrix components, such as galectin- 1, lumican, tenascin-C, procollagen transcripts, and the Hsp47 procollagen chaperone. Taken together, the results demonstrate that IMP1 is essential for normal growth and development. Moreover, IMP1 may facilitate intestinal morphogenesis via regulation of extracellular matrix formation.

Expression of IGF-II mRNA-binding proteins (IMPs) in gonads and testicular cancer.

Insulin-like growth factor-II mRNA-binding proteins 1, 2 and 3 (IMP1, IMP2 and IMP3) belong to a family of RNA-binding proteins implicated in mRNA localization, turnover and translational control. We examined their expression pattern during development of murine and human testis and ovaries. In the mouse, IMPs were expressed in male and female gonadal cells at embryonic day 12.5 (E12.5). From E16.5, IMP1 and IMP3 became restricted to the developing germ cells, whereas IMP2 expression persisted in the interstitial cells. In mature mouse and human ovaries, IMP1, IMP2 and IMP3 were detected in resting and growing oocytes and in the granulosa cells. In testis, IMP1 and IMP3 were found mainly in the spermatogonia, whereas IMP2 was expressed in the immature Leydig cells. Moreover, all three IMPs were detected in human semen. The developmental expression pattern of IMP1 and IMP3 in the human testis prompted us to examine their possible involvement in testicular neoplasia. IMPs were detected primarily in germ-cell neoplasms, including preinvasive testicular carcinoma in situ, classical and spermatocytic seminoma, and nonseminomas, with particularly high expression in undifferentiated embryonal carcinoma. The relative expression of IMP1, IMP2 and IMP3 varied among tumor types and only IMP1 was detected in all carcinoma in situ cells. Thus IMPs, and in particular IMP1, may be useful auxiliary markers of testicular neoplasia.

Bupivacaine in microcapsules prolongs analgesia after subcutaneous infiltration in humans: a dose-finding study.

In this study, we examined the onset and duration of local analgesic effects of bupivacaine incorporated into biodegradable microcapsules (extended-duration local anesthetic; EDLA) administered as subcutaneous infiltrations in different doses in humans. In 18 volunteers, the skin on the medial calf was infiltrated with 10 mL of EDLA, and the opposite calf was infiltrated with 10 mL of aqueous bupivacaine (5.0 mg/mL) in a double-blinded, randomized manner. Three different concentrations of EDLA were tested (6.25, 12.5, and 25 mg/mL), with 6 subjects in each group. Pain responses to mechanical and heat stimuli and sensory thresholds (touch, warm, and cold detection thresholds) were examined by von Frey hairs and contact thermodes. Assessments were made before and 2, 4, 6, 8, 24, 48, 72, 96, and 168 h after the injections. Safety evaluations were performed daily for the first week and at 2 wk, 6 wk, and 6 mo after the injections. The time to maximum effects was significantly shorter for aqueous bupivacaine (2-6 h) than for EDLA (4-24 h), but there were no significant differences between the maximum effects of EDLA and aqueous bupivacaine. From 24 to 96 h after the injections, EDLA was significantly more efficient than aqueous bupivacaine for all variables, and significant effects of EDLA were demonstrated for at least 96 h for all variables. In general, a dose-response gradient was seen in the EDLA group for 5 of 7 variables when the curves expressing effect over time for the different concentrations were evaluated. No serious side effects were observed for up to 6 mo after administration. In conclusion, bupivacaine incorporated in microcapsules provided analgesia for 96 h after subcutaneous infiltration.

Thiopental and propofol affect different regions of the brain at similar pharmacologic effects.

Propofol has a greater amnesic effect than thiopental. In this study we tested whether different brain regions were affected by propofol and thiopental at similar drug effects. Changes in regional cerebral blood flow (rCBF) were identified by using SPM99 analysis of images obtained with positron emission tomography with (15)O water. Ten right-handed male volunteers (age, 35 +/- 10 yr; weight, 74.1 +/- 7.5 kg; mean +/- sd) were randomized to receive thiopental (n = 4) or propofol (n = 6) to target sedative and hypnotic concentrations with bispectral index (BIS) monitoring. Four positron emission tomography images were obtained during various tasks at baseline and with sedative and hypnotic effects. Two participants receiving propofol were unresponsive at sedative concentrations and were not included in the final analyses. Median serum concentrations were 1.2 and 2.7 microg/mL for sedative and hypnotic propofol effects, respectively. Similarly, thiopental concentrations were 4.8 and 10.6 microg/mL. BIS decreased similarly in both groups. The pattern of rCBF change was markedly different for propofol and thiopental. Propofol decreased rCBF in the anterior (right-sided during sedation) brain regions, whereas thiopental decreased rCBF primarily in the cerebellar and posterior brain regions. At similar levels of drug effect, propofol and thiopental affect different regions of the brain. These differences may help to identify the loci of action for the nonsedative effects of propofol, such as amnesia.