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Biomedical subjects

Paul Sharpe

Publications and source records attributed to Paul Sharpe.

8 recordsLinked to original sources
PubMed2006

Satb2 haploinsufficiency phenocopies 2q32-q33 deletions, whereas loss suggests a fundamental role in the coordination of jaw development.

The recent identification of SATB2 as a candidate gene responsible for the craniofacial dysmorphologies associated with deletions and translocations at 2q32-q33, one of only three regions of the genome for which haploinsufficiency has been significantly associated with isolated cleft palate, led us to investigate the in vivo functions of murine Satb2. We find that, similar to the way in which SATB2 is perceived to act in humans, craniofacial defects due to haploinsufficiency of Satb2, including cleft palate (in approximately 25% of cases), phenocopy those seen with 2q32-q33 deletions and translocations in humans. Full functional loss of Satb2 results in amplification of these defects and leads both to increased apoptosis in the craniofacial mesenchyme where Satb2 is usually expressed and to changes in the pattern of expression of three genes implicated in the regulation of craniofacial development in humans and mice: Pax9, Alx4, and Msx1. The Satb2-dosage sensitivity in craniofacial development is conspicuous--along with its control of cell survival, pattern of expression, and reversible functional modification by SUMOylation, it suggests that Satb2/SATB2 function in craniofacial development may prove to be more profound than has been anticipated previously. Because jaw development is Satb2-dosage sensitive, the regulators of Satb2 expression and posttranslational modification become of critical importance both ontogenetically and evolutionarily, especially since such regulators plausibly play undetected roles in jaw and palate development and in the etiology of craniofacial malformations.

Animals↗
PubMed2006

Biological tooth replacement.

Teeth develop from a series of reciprocal interactions that take place between epithelium and mesenchyme during development of the mouth that begin early in mammalian embryogenesis. The molecular control of key processes in tooth development such as initiation, morphogenesis and cytodifferentiation are being increasingly better understood, to the point where this information can be used as the basis for approaches to produce biological replacement teeth (BioTeeth). This review outlines the current approaches, ideas and progress towards the production of BioTeeth that could form an alternative method for replacing lost or damaged teeth.

Biocompatible Materials↗
PubMed2006

Perioperative nimodipine and postoperative analgesia.

There is experimental evidence that nimodipine, an L-type dihydropiridine calcium channel blocker with relatively high blood-brain barrier penetration, enhances the antinociceptive properties of morphine. We tested the hypothesis that oral nimodipine taken preoperatively and 6 hourly for 48 h postoperatively would reduce visual analog scale pain scores and morphine consumption in morphine-naive patients with acute postoperative pain. Forty patients undergoing total knee replacement surgery (age 70 +/- 7 yr, 28 male) were randomized by computer-generated numbers to receive capsules containing either nimodipine 30 mg or placebo in a double-blind study design. All patients received 3 capsules (nimodipine 90 mg or placebo) 1-2 h before induction of anesthesia followed by oral nimodipine 30 mg or placebo 6 hourly for 48 hours postoperatively. Spinal anesthesia was induced with hyperbaric bupivacaine 0.5% (2.4-3.0 mL) and fluids and ephedrine were given at the discretion of the anesthesiologist. Morphine patient-controlled analgesia (PCA, bolus 1 mg, lockout 5 min) was given for postoperative analgesia. Primary outcome measures were visual analog pain scores at rest and on moving (sitting forward) and PCA morphine consumption. Morphine consumption was significantly larger in nimodipine patients at 12 h (39 +/- 18 versus 29 +/- 15; P = 0.04), 24 h (62 +/- 23 versus 45 +/- 24; P = 0.02), and 48 h (88 +/- 34 versus 61 +/- 27; P = 0.01). There were no significant differences in pain scores at rest or moving or in time to first use of morphine analgesia. This study has demonstrated increased morphine consumption after 12 h in postoperative patients receiving nimodipine, suggesting that, in patients undergoing knee replacement surgery, it has no adjunctive analgesic effect and may actually inhibit the analgesic effect of morphine.

Administration, Oral↗
PubMed2005

Expression of Claudin-3 during chick development.

Claudins are membrane proteins located within tight junctions. Using degenerate and gene specific primers the chick homologue of Claudin-3 was isolated. Here we show the expression of Claudin-3 transcripts in the developing chick embryo from Hamburger and Hamilton Stages (HH) 6-22. The early expression domains of Claudin 3 in the developing chick embryo include the mesoderm surrounding Hensen's node and the head fold. Between HH 9 and HH 11 expression domains include the anterior intestinal portal and otic vesicle. By HH 14, gene expression is observed in the pharyngeal endoderm and pouches, in addition to the continued expression in the otic vesicle. Expression in the more posterior pouches was also observed as development proceeded. At HH 20 expression is present in the mesonephric system and also the developing liver, lung bud and intestine.

Animals↗
PubMed2003

Development of teeth in chick embryos after mouse neural crest transplantations.

Teeth were lost in birds 70-80 million years ago. Current thinking holds that it is the avian cranial neural crest-derived mesenchyme that has lost odontogenic capacity, whereas the oral epithelium retains the signaling properties required to induce odontogenesis. To investigate the odontogenic capacity of ectomesenchyme, we have used neural tube transplantations from mice to chick embryos to replace the chick neural crest cell populations with mouse neural crest cells. The mouse/chick chimeras obtained show evidence of tooth formation showing that avian oral epithelium is able to induce a nonavian developmental program in mouse neural crest-derived mesenchymal cells.

Animals↗
PubMed2003

Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain.

We have evaluated the efficacy of delta-9-tetrahydrocannabinol (delta-9-THC), the main psychoactive constituent of cannabis, in postoperative pain. In a randomized double-blind, placebo-controlled, single-dose trial, we investigated 40 women undergoing elective abdominal hysterectomy. Randomization took place when postoperative patient-controlled analgesia was discontinued on the second postoperative day. When patients requested further analgesia, they received a single, identical capsule of either oral delta-9-THC 5 mg (n=20) or placebo (n=20) in a double-blind fashion. The primary outcome measure was summed pain intensity difference (SPID) at 6 h after administration of study medication derived from visual analogue pain scores on movement and at rest. Secondary outcome measures were time to rescue medication and adverse effects of study medication. Mean (SD) VAS pain scores before medication in the placebo and delta-9-THC groups were 6.3(2.6) and 6.4(1.3)cm on movement, and 3.2(1.9) and 3.3(0.9) on rest, respectively. There were no significant differences in mean (95% confidence interval of the difference) SPID at 6 h between the groups [placebo 7.9, delta-9-THC 4.3(-1.8 to 9.0)cm h on movement; placebo 8.8, delta-9-THC 4.9(-0.2 to 8.1)cm h at rest] and time to rescue analgesia [placebo 217, delta-9-THC 163(-22 to 130)min]. Increased awareness of surroundings was reported more frequently in patients receiving delta-9-THC (40 vs 5%, P=0.04). There were no other significant differences with respect to adverse events. This study demonstrates no evidence of an analgesic effect of orally administered delta-9-THC 5 mg in postoperative pain in humans.

Adult↗
PubMed2002

NBR1 interacts with fasciculation and elongation protein zeta-1 (FEZ1) and calcium and integrin binding protein (CIB) and shows developmentally restricted expression in the neural tube.

NBR1 (named as next to BRCA1) was originally cloned as a candidate gene for the ovarian cancer antigen CA125, using expression cloning with the anti-CA125 Ig, OC125. NBR1 has been of interest due to its position close to BRCA1, although no involvement in breast or ovarian cancer has been demonstrated. Recently, the antigen CA125 has been cloned, and identified as a new mucin, MUC16, entirely different from NBR1. The function of NBR1 remains unknown. To investigate its function, a yeast two-hybrid study was performed to identify interacting protein partners that may reflect a biological role for this protein. Here, we show that NBR1 interacts with two proteins; fasciculation and elongation protein zeta-1 (FEZ1), a PKCzeta interacting protein, and calcium and integrin binding protein (CIB), which is associated with polo-like kinases Fnk/Snk and the Alzheimer's disease presenilin 2 protein. Co-transfection of FEZ1 and NBR1 showed overlapping localization in the cytoplasm, whereas coexpression of NBR1 and CIB resulted in a shift of CIB protein expression from the nucleus to the perinuclear compartment. FEZ1 is highly expressed in the brain and in situ hybridization analysis of Nbr1 showed that its expression is also regulated in the murine brain during development. These data suggest that NBR1 may function, through interaction with CIB and FEZ1 in cell signalling pathways, with a developmentally restricted expression suggesting a possible role in neural development.

Adaptor Proteins, Signal Transducing↗