John B. Rose

Neuroprotective Effects of Regulators of the Glycogen Synthase Kinase-3β Signaling Pathway in a Transgenic Model of Alzheimer's Disease Are Associated with Reduced Amyloid Precursor Protein Phosphorylation

The glycogen synthase kinase-3β (GSK3β) pathway plays an important role in mediating neuronal fate and synaptic plasticity. In Alzheimers disease (AD), abnormal activation of this pathway might play an important role in neurodegeneration, and compounds such as lithium that modulate GSK3β activity have been shown to reduce amyloid production and tau phosphorylation in amyloid precursor protein (APP) transgenic (tg) mice. However, it is unclear whether regulation of GSK3β is neuroprotective in APP tg mice. In this context, the main objective of the present study was to determine whether pharmacological or genetic manipulations that block the GSK3β pathway might ameliorate the neurodegenerative alterations in APP tg mice and to better understand the mechanisms involved. For this purpose, two sets of experiments were performed. First, tg mice expressing mutant human APP under the Thy1 promoter (hAPP tg) were treated with either lithium chloride or saline alone. Second, hAPP tg mice were crossed with GSK3β tg mice, in which overexpression of this signaling molecule results in a dominant-negative (DN) effect with inhibition of activity. hAPP tg mice that were treated with lithium or that were crossed with DN–GSK3β tg mice displayed improved performance in the water maze, preservation of the dendritic structure in the frontal cortex and hippocampus, and decreased tau phosphorylation. Moreover, reduced activation of GSK3β was associated with decreased levels of APP phosphorylation that resulted in decreased amyloid-β production. In conclusion, the present study showed that modulation of the GSK3β signaling pathway might also have neuroprotective effects in tg mice by regulating APP maturation and processing and further supports the notion that GSK3β might be a suitable target for the treatment of AD.

A comparison of three doses of a commercially prepared oral midazolam syrup in children.

Midazolam is widely used as a preanesthetic medication for children. Prior studies have used extemporaneous formulations to disguise the bitter taste of IV midazolam and to improve patient acceptance, but with unknown bioavailability. In this prospective, randomized, double-blinded study we examined the efficacy, safety, and taste acceptability of three doses (0.25, 0.5, and 1.0 mg/kg, up to a maximum of 20 mg) of commercially prepared Versed® syrup (midazolam HCl) in children stratified by age (6 mo to <2 yr, 2 to <6 yr, and 6 to <16 yr). All children were ASA class I–III scheduled for elective surgery. Subjects were continuously observed and monitored with pulse oximetry. Ninety-five percent of patients accepted the syrup, and 97% demonstrated satisfactory sedation before induction. There was an apparent relationship between dose and onset of sedation and anxiolysis (P < 0.01). Eight-eight percent had satisfactory anxiety ratings at the time of attempted separation from parents, and 86% had satisfactory anxiety ratings at face mask application. The youngest age group recovered earlier than the two older age groups (P < 0.001). There was no relationship between midazolam dose and duration of postanesthesia care unit stay. Before induction, there were no episodes of desaturation, but there were two episodes of nausea and three episodes of emesis. At the time of induction, during anesthesia, and in the postanesthesia care unit, there were several adverse respiratory events. Oral midazolam syrup is effective for producing sedation and anxiolysis at a dose of 0.25 mg/kg, with minimal effects on respiration and oxygen saturation even when administered at doses as large as 1.0 mg/kg (maximum, 20 mg) as the sole sedating medication to healthy children in a supervised clinical setting.

Nav1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons

Inherited erythromelalgia/erythermalgia (IEM) is a neuropathy characterized by pain and redness of the extremities that is triggered by warmth. IEM has been associated with missense mutations of the voltage-gated sodium channel Nav1.7, which is preferentially expressed in most nociceptive dorsal root ganglia (DRGs) and sympathetic ganglion neurons. Several mutations occur in cytoplasmic linkers of Nav1.7, with only two mutations in segment 4 (S4) and S6 of domain I. We report here a simplex case with an alanine 863 substitution by proline (A863P) in S5 of domain II of Nav1.7. The functional effect of A863P was investigated by voltage-clamp analysis in human embryonic kidney 293 cells and by current-clamp analysis to determine the effects of A863P on firing properties of small DRG neurons. Activation of mutant channels was shifted by −8 mV, whereas steady-state fast inactivation was shifted by +10 mV, compared with wild-type (WT) channels. There was a marked decrease in the rate of deactivation of mutant channels, and currents elicited by slow ramp depolarizations were 12 times larger than for WT. These results suggested that A863P could render DRG neurons hyperexcitable. We tested this hypothesis by studying properties of rat DRG neurons transfected with either A863P or WT channels. A863P depolarized resting potential of DRG neurons by +6 mV compared with WT channels, reduced the threshold for triggering single action potentials to 63% of that for WT channels, and increased firing frequency of neurons when stimulated with suprathreshold stimuli. Thus, A863P mutant channels produce hyperexcitability in DRG neurons, which contributes to the pathophysiology of IEM.

A comparison of oral clonidine and oral midazolam as preanesthetic medications in the pediatric tonsillectomy patient.

We compared the effects of oral clonidine (4 &mgr;g/kg) and midazolam (0.5 mg/kg) on the preanesthetic sedation and postoperative recovery profile in children during tonsillectomy with or without adenoidectomy. In a double-blinded, double-dummy study design, 134 ASA physical status I-II children aged 4–12 yr were randomized to receive a combination of either clonidine and placebo (Group A), or placebo and midazolam (Group B) at 60–90 min and 30 min, respectively, before the induction of anesthesia. Children in the clonidine group exhibited more intense anxiety on separation and during induction of anesthesia via a mask as measured by the modified Yale Preoperative Anxiety Scores. They also had significantly lower mean intraoperative arterial blood pressures, shorter surgery, anesthesia, and emergence times, and a decreased need for supplemental oxygen during recovery compared with the midazolam group. However, the clonidine group had larger postoperative opioid requirements, maximum excitement and pain scores based on the Children’s Hospital of Eastern Ontario scale in the Phase 1 postanesthetic care unit. There were no differences between the two groups in the times to discharge readiness, postoperative emesis, unanticipated hospital admission rates, postdischarge maximum pain scores, and 24 h analgesic requirements. The percentage of parents who were completely satisfied with the child’s preoperative experience was significantly higher in the midazolam group. There were no differences in parental satisfaction with the recovery period. We conclude that under the conditions of this study, oral midazolam is superior to oral clonidine as a preanesthetic medication in this patient population. Implications We compared preanesthetic sedation and postoperative recovery after oral clonidine (4 &mgr;g/kg) and midazolam (0.5 mg/kg) in children during tonsillectomy. The clonidine group had greater preoperative anxiety and shorter surgery and anesthesia times, but required more postoperative analgesia. Delayed recovery and discharge times did not differ. Midazolam was superior to clonidine as oral preanesthetic medication for these patients.

Ondansetron reduces the incidence and severity of poststrabismus repair vomiting in children

This prospective, randomized, placebo-controlled, double-blinded study evaluated the antiemetic efficacy of ondansetron and metoclopramide in 90 ASA physical status I or II children, 2-17 yr of age, undergoing strabismus repair. After anesthetic induction and prior to eye muscle manipulation, subjects received normal saline 0.3 mL/kg (Group 1), metoclopramide 0.25 mg/kg (Group 2), or ondansetron 0.15 mg/kg (Group 3), intravenously. There were no differences between groups with respect to age, weight, gender, fluids received, number of eye muscles repaired, anesthetic technique, or time in the operating room. The incidence of vomiting in Groups 1, 2, and 3 was 50%, 27%, and 10% prior to discharge, and 67%, 53%, and 30% during the 24 h after surgery, respectively. The number of children vomiting prior to discharge and within 24 h of surgery was significantly reduced in Group 3 compared with Group 1 (P < 0.003 and P < 0.015, respectively). The number of vomiting episodes per patient in Groups 1, 2, and 3 was 1.1, 0.5, and 0.1 prior to discharge, and 4.5, 2.6, and 1.2 during the 24 h after surgery (P < 0.0005 and P < 0.004, respectively). Ondansetron 0.15 mg/kg intravenously after the induction of anesthesia reduces the incidence and severity of vomiting after strabismus repair both prior to discharge from the hospital and during the 24 h after surgery.

Lidocaine Iontophoresis Versus Eutectic Mixture of Local Anesthetics (emla®) for Iv Placement in Children

Pain during venipuncture is a major source of concern to children and their caretakers. Iontophoresis is a novel technique that uses an electrical current to facilitate movement of solute ions (lidocaine) across the stratum corneum barrier to provide dermal analgesia. In this study, we compared dermal analgesia provided by lidocaine iontophoresis and eutectic mixture of local anesthetics (EMLA®). After informed consent, 26 children, aged 7–16 yr, who required venous cannulation on multiple occasions, were enrolled in this prospective, randomized, crossover study to receive EMLA and iontophoresis on separate occasions. During a third session, each subject received his or her preferred treatment. Pain during venipuncture was assessed by the subject, parent, observer, and technician performing the procedure, by use of a 100-mm visual analog scale. The observer also used the Children’s Hospital of Eastern Ontario Pain Scale to rate the subject’s pain. Ratings of subject satisfaction were also assessed. There were no significant differences between the two groups in the subject-rated visual analog scale or the Children’s Hospital of Eastern Ontario Pain Scale scores. Eleven (50%; 95% confidence interval [CI], 31%–69%) of the 22 subjects who completed both sessions preferred iontophoresis. Five subjects (23%; 95% CI, 10%–44%), including two who did not tolerate treatment with iontophoresis, preferred EMLA, and six (27%; 95% CI, 13%–48%) had no preference for the intervention to provide dermal analgesia. We conclude that lidocaine iontophoresis provides similar pain relief for insertion of IV catheters as EMLA and is a useful noninvasive alternative to establish dermal analgesia for venous cannulation.

An evaluation of the efficacy and tolerability of oral tramadol hydrochloride tablets for the treatment of postsurgical pain in children.

In this double-blinded, randomized, multicenter study, we examined analgesic efficacy and tolerability of tramadol in postoperative pediatric patients. Eighty-one postsurgical ASA physical status I and II patients ages 7–16 yr received oral tramadol (approximately 1 or 2 mg/kg) for postoperative analgesia when they were ready to transition from morphine patient-controlled analgesia to oral analgesics. Rescue analgesia consisted of morphine patient-controlled analgesia or an oral equivalent dose of oxycodone. Patients rated their pain just before the administration of tramadol and at regular intervals for 8 h afterwards using the Wong-Baker Faces Pain Rating Scale. The 2-mg/kg group required approximately half as much rescue analgesia as the 1-mg/kg group (P = 0.006). Parents rated the larger dose more favorably. Adverse events were generally mild to moderate in severity (vomiting [10%], nausea [9%], pruritus [7%], rash [4%]) and similar between the two treatment groups. There were no significant changes in hemodynamic variables, respiratory rate, or Spo2 percentages between the two treatment groups or in all patients compared with pretreatment values.

Primary Erythromelalgia in a Child Responding to Intravenous Lidocaine and Oral Mexiletine Treatment

Erythromelalgia is a rare, chronic, debilitating condition characterized by redness, warmth, and severe burning pain of the distal extremities. The feet are more commonly affected than the hands. Pain is precipitated by increases in temperature and by exercise. Patients often obtain relief by immersing the affected extremity in cold water. The pain is often refractory to treatment. For many patients, multiple pain medications have been useless in achieving complete relief of pain symptoms. Previous reports of erythromelalgia among adolescents indicated prolonged relief of pain with sodium nitroprusside infusions, epidural infusions of local anesthetics, or gabapentin treatment. We present a case of an 11-year-old, white, male child with primary erythromelalgia, whose initial symptoms started in his preschool years and whose childhood was marked by escalating episodes of pain with warmth and redness of his feet, precipitated especially by increases in temperature and by activity. All conventional pain management techniques had failed to relieve our patient of his symptoms, and he obtained some relief only by soaking his affected extremities in ice water. He had experienced minimal benefit from seeing a pain psychologist, who helped him develop techniques to cope with the pain. At the time of presentation, the patients episodes of pain had increased to 15 to 20 per day, and there was evidence of chronic immersion injury to the skin of his feet. Before his most recent hospitalization, the pain had spread to involve his hands as well. The patient was overwhelmed with anxiety and could not participate in school or social activities at the time of admission. During his current hospitalization, he did show some therapeutic response to sodium nitroprusside infusion, which unfortunately had to be discontinued because of side effects and because his family desired to leave the ICU environment, which was stressful to the patient. He also had some response to lumbar epidural infusion of local anesthetics, which could not be continued because he found the motor blockade that accompanied his analgesia intolerable. However, intravenous lidocaine infusion, with subsequent transition to oral mexiletine therapy, proved very effective in reducing the frequency and severity of the pain episodes. The patient was discharged from the hospital with oral mexiletine therapy and has been monitored at the pain management clinic. He returned to and completed school, attended summer camp, and enjoys an active happy life. He walks without precipitating pain in his feet and sleeps 9 to 10 hours every night. He has needed to soak his feet on only 4 occasions in the 6 months since his discharge from the hospital. His quality of life has improved significantly. He has shown no evidence of liver toxicity, and his mexiletine levels have been stable.

Preoperative oral dextromethorphan does not reduce pain or analgesic consumption in children after adenotonsillectomy.

UNLABELLED In this randomized, double-blinded, placebo-controlled, prospective study, we evaluated the analgesic efficacy of dextromethorphan 0.5 mg/kg or 1.0 mg/kg p.o. 1 h before adenotonsillectomy in 57 children 6-12 yr of age. Anesthetic management was standardized. Morphine 0.075 mg/kg i.v. and acetaminophen 25-35 mg/kg p.r. were administered after anesthetic induction but before the start of surgery. A 4-point behavioral score (1 = asleep, 2 = awake and calm, 3 = awake and crying, 4 = thrashing) was recorded on admission to and discharge from the postanesthesia care unit (PACU). In the PACU, pain was assessed with Childrens Hospital of Eastern Ontario Pain Scale (CHEOPS) and recorded every 15 min until the patient was transferred to the day surgery unit (DSU). In the DSU, patients rated their pain using a 10-cm baseline 0-10 visual analog pain scale (VAS) every 30 min until they were discharged home. A 24-h VAS was obtained by phone interview, and parental satisfaction was scored (yes/no) regarding their childs postoperative analgesia. Morphine 0.025 mg/kg i.v. was administered to children with CHEOPS score >6, who verbalized pain, or who were crying in any consecutive 5-min observation periods in the PACU. Total morphine consumption was recorded. The study groups were comparable with respect to demographic variables. We were unable to detect any differences between study groups with respect to postoperative morphine consumption, CHEOPS, behavior scores, VAS, or parental satisfaction. IMPLICATIONS Premedication with dextromethorphan 0.5 or 1.0 mg/kg p.o. does not improve postoperative analgesia in school-aged children who receive preemptive morphine 0.075 mg/kg i.v. and acetaminophen 25-35 mg/kg p.r. during nitrous oxide and desflurane anesthesia for adenotonsillectomy.

Oral tramadol for the treatment of pain of 7-30 days' duration in children.

IMPLICATIONS This open-label, multicenter trial was designed to determine the safety profile and analgesic efficacy of tramadol for the treatment of painful conditions lasting 7-30 days in 7-16-yr-old children. We found that tramadol 1-2 mg/kg per os every 4-6 h (maximal dose = 8 mg x kg(-1). d(-1), not to exceed 400 mg/d) is a safe and effective analgesic in this patient population.