Is it resectable? A survey regarding tumor classification and vascular involvement.

INTRODUCTION: The anatomic location of the pancreas can result in involvement of major vasculature, which may act as a contraindication to resection. Several classification systems have been developed. We sought to discover the variations in the HPB community determining PDAC resectability. METHODS: The multiple-choice survey was distributed to all full members of the IHPBA. Questions were asked regarding demographics and clinical scenarios regarding tumor resectability. RESULTS: 164 responses were submitted. Most of the respondents were male and had been in practice for over 10 years. The median age range was 40-50 years old. Most practiced in either Asia (n = 57,35.9%), North America (n = 52,32.7%), or Europe (n = 32,20.1%). Classification systems used to determine resectability were: NCCN (n = 42,26.3%), JPS (n = 35,21.9%), International consensus (n = 33,20.6%), AHPBA/SSO (n = 23,14.4%), Alliance (n = 3,1.9%), and other/no-classification (n = 23,14.5%). There was significant variation in the frequency of the most common answer within the scenarios (84.7%-33.5%). Participant concordance with their stated classification system found a median rate of 62.5%. Participant decision of tumor resectability was not dependent on their adopted classification system. CONCLUSION: When classifying PDAC resectability, there is significant variation between surgeons as to how they would classify a specific tumour, independent of the classification system they use. In addition, surgeons do not show high concordance with the definitions within that classification system.

The Impact of Spatial Distribution of Pain on Long-Term Trajectories for Chronic Pain Outcomes After Intensive Interdisciplinary Pain Treatment.

OBJECTIVES: Evidence for the effectiveness of intensive interdisciplinary pain treatment (IIPT) for pediatric chronic pain is growing; however, little research has considered factors that contribute to differences in patients' treatment response. The present study utilized multilevel modeling to examine trajectory of change over time in functional disability from clinic assessment to 6-month follow-up in pediatric patients participating in IIPT, considering spatial distribution of pain, coping efficacy, and pain intensity. MATERIALS AND METHODS: Participants included 110 pediatric patients (Mage=14.65, SD=2.37; localized pain, 27.3%; widespread pain, 72.7%) consecutively admitted into IIPT. Patients completed self-report measures of functional disability, pain intensity, and coping efficacy at pretreatment assessment, admission, weekly during IIPT, discharge, and several follow-ups. RESULTS: Analysis identified a model with 3 three-way interactions, including time, time squared, pain intensity, coping efficacy, and pain distribution, on functional disability. The spatial distribution of pain had the greatest impact on treatment trajectory in patients with widespread pain, high pain intensity, and poor coping efficacy; these patients demonstrated greater functional disability compared with patients with localized pain. In addition, patients with widespread pain and poor coping efficacy had the most functional disability across all levels of pain intensity. Patients with localized pain and poor coping efficacy demonstrated initial treatment gains, but evidenced an increase in functional disability at follow-up. DISCUSSION: Overall, spatial distribution of pain, coping efficacy, and pain intensity played an important role in patients' response to treatment. Better understanding of these variables could improve treatment response, particularly for the most severely disabled chronic pain patients.

Treatment expectations among adolescents with chronic musculoskeletal pain and their parents before an initial pain clinic evaluation.

OBJECTIVES: To understand expectations regarding treatment recommendations among treatment-seeking adolescents with chronic musculoskeletal pain and their parents. METHODS: A total of 102 adolescent-parent dyads were recruited at the time of initial contact with a multidisciplinary pain management clinic. Each participant completed reports of adolescent pain intensity and disability, biopsychosocial perspective of pain, and treatment expectations related to recommendations and feedback for a vignette description of an adolescent presenting at an initial multidisciplinary pain clinic evaluation. RESULTS: Descriptive findings for individual treatment expectations and adolescent-parent dyad agreement statistics were examined. Slight to fair levels of agreement occurred for 50% of the expectations assessed. The strongest shared expectations were for recommendations to return to school, pursue psychological counseling, and pursue PT/OT treatment. Stronger agreement occurred for items reflecting alternative, emotional, behavioral, and activity recommendations with weaker agreement for medical interventions (eg, medication and surgery). Correlations emerged between individual expectations and adolescent pain intensity, disability, with the greatest number of significant relationships found for adolescent and parent expectations and biopsychosocial perspectives of pain. DISCUSSION: Our results document that adolescents and parents show modest levels of agreement on expectations for treatment at the time of an initial pain clinic evaluation. This may relate to expectations being internal perspectives not clearly expressed within families; thus, the initial treatment consultation may provide an important opportunity to create and align appropriate expectations. Implications of our findings are considered with respect to education, treatment, and future research to understand factors that contribute to treatment adherence and outcomes.

Pain beliefs and readiness to change among adolescents with chronic musculoskeletal pain and their parents before an initial pain clinic evaluation.

OBJECTIVES: To understand relationships between pain-related beliefs and readiness to change among treatment-seeking adolescents with chronic musculoskeletal pain and their parents. METHODS: A total of 102 adolescent-parent dyads were recruited at the time of initial evaluation at a multidisciplinary pain management clinic. Dyads completed self-report measures to assess pain, catastrophizing, endorsement of a biopsychosocial perspective of pain, and readiness to change/motivation to adopt a self-management approach to pain coping. RESULTS: Agreement between adolescent-parent dyad reports of pain catastrophizing and readiness to change was found; however, adolescents were less likely to view pain as "affected by feelings and emotions" than parents. The hypothesis that greater pain catastrophizing would be correlated with less readiness to change was partially supported. Adolescent and parents who reported lower levels of endorsement of a biopsychosocial perspective were less willing to adopt a self-management approach to pain coping. Endorsement of a biopsychosocial perspective of pain aligned with readiness to change stages more consistently for parents. DISCUSSION: This study documents initial relationships among pain catastrophizing, biopsychosocial perspectives of pain, and readiness to engage in a self-management approach to pain coping for adolescents with chronic pain and their parents. Although agreement exists between dyads regarding catastrophizing and readiness to change, differences were noted in biopsychosocial perspective and dominant readiness to change stage before an initial pain clinic encounter. Findings are considered in terms of future research to advance knowledge regarding the role these factors may play in treatment adherence and outcomes.

Relationships among pain, protective parental responses, and disability for adolescents with chronic musculoskeletal pain: the mediating role of pain catastrophizing.

OBJECTIVES: Children learn to cope with pain within the context of the family and parental responses to pediatric pain can impact health outcomes. The aim of this study was to examine relationships among pain, protective parental responses to pain, functional disability, and pain catastrophizing for adolescents with chronic musculoskeletal pain syndromes. METHODS: Initial evaluation records for 138 adolescents with chronic musculoskeletal pain who consulted a pediatric multidisciplinary pain management clinic were examined. Measures were collected at the time of the initial evaluation and included adolescent self-reports of their own usual pain intensity, perceived parental responses to their pain, adolescent functional disability, and pain catastrophizing. RESULTS: Pain catastrophizing was significantly correlated with pain intensity, protective parental responses to pain, and functional disability. Multiple regression analyses further suggest that pain catastrophizing serves as a mediator of relationships between: (1) pain and disability and (2) protective parenting responses and disability. Evidence supporting a significant indirect effect for pain catastrophizing on disability was found within both models through bootstrap and Sobel analyses. DISCUSSION: Pain catastrophizing seems to play an important role in understanding relationships between pain, protective parental responses, and disability for adolescents with musculoskeletal pain. Our findings suggest that strategies that help modify adolescent catastrophic pain beliefs and parental responses to pain, may help improve adolescent functioning.

Pharmacologic management of acute pediatric pain.

The accurate assessment and effective treatment of acute pain in children in the hospital setting is a high priority. During the past 2 to 3 decades, pediatric pain management has gained tremendous knowledge with respect to the understanding of developmental neurobiology, developmental pharmacology the use of analgesics in children, the use of regional techniques in children, and of the psychological needs of children in pain. A wide range of medications is available to treat a variety of pain types. This article provides an overview of the most common analgesic medications and techniques used to treat acute pain in children.

Parental beliefs and worries regarding adolescent chronic pain.

OBJECTIVES: To explore relationships between beliefs and worries held by parents of adolescents with chronic, nondisease specific, musculoskeletal pain and (1) parental pain promoting behaviors, (2) the adolescent's pain-related disability, (3) family functioning, and (4) parenting stress. METHODS: A retrospective chart review was conducted for 138 adolescents with chronic musculoskeletal pain syndromes presenting at an outpatient pediatric multidisciplinary pain management clinic. Adolescents reported on pain, disability, and parental pain promoting behaviors. Parents reported on their beliefs about the cause of and their responsibility for the adolescent's pain, worry about the adolescent's physical and emotional/behavioral health, parental pain promoting behaviors, family functioning, and parenting stress. RESULTS: Parental beliefs that the cause of the adolescent's pain was "medical only" significantly moderated the relationship between adolescent pain and disability. Adolescent disability was positively correlated with parental worry about the adolescent's physical, but not emotional/behavioral, health. Parental worries about both physical and emotional/behavioral health were positively correlated with parents' use of pain promoting behaviors. A positive relationship between poorer family functioning and parenting stress was found to be partially mediated by parent beliefs that the adolescent's pain was "medical only." DISCUSSION: These findings provide insight into the complex interrelationships that exist among parents' beliefs and worries about adolescent pain, parental pain promoting behavior, adolescent disability, family functioning, and parenting stress that may have implications for treatment decisions made on the adolescent's behalf.

Neuropeptide Y fragments derived from neprilysin processing are neuroprotective in a transgenic model of Alzheimer's disease.

The endopeptidase neprilysin (NEP) is a major amyloid-beta (Abeta) degrading enzyme and has been implicated in the pathogenesis of Alzheimer's disease. Because NEP cleaves substrates other than Abeta, we investigated the potential role of NEP-mediated processing of neuropeptides in the mechanisms of neuroprotection in vivo. Overexpression of NEP at low levels in transgenic (tg) mice affected primarily the levels of neuropeptide Y (NPY) compared with other neuropeptides. Ex vivo and in vivo studies in tg mice and in mice that received lentiviral vector injections showed that NEP cleaved NPY into C-terminal fragments (CTFs), whereas silencing NEP reduced NPY processing. Immunoblot and mass spectrometry analysis showed that NPY 21-36 and 31-36 were the most abundant fragments generated by NEP activity in vivo. Infusion of these NPY CTFs into the brains of APP (amyloid precursor protein) tg mice ameliorated the neurodegenerative pathology in this model. Moreover, the amidated NPY CTFs protected human neuronal cultures from the neurotoxic effects of Abeta. This study supports the possibility that the NPY CTFs generated during NEP-mediated proteolysis might exert neuroprotective effects in vivo. This function of NEP represents a unique example of a proteolytic enzyme with dual action, namely, degradation of Abeta as well as processing of NPY.

Needle-free powder lidocaine delivery system provides rapid effective analgesia for venipuncture or cannulation pain in children: randomized, double-blind Comparison of Venipuncture and Venous Cannulation Pain After Fast-Onset Needle-Free Powder Lidocaine or Placebo Treatment trial.

OBJECTIVE: The Comparison of Venipuncture and Venous Cannulation Pain After Fast-Onset Needle-Free Powder Lidocaine or Placebo Treatment trial was a randomized, single-dose, double-blind, phase 3 study investigating whether a needle-free powder lidocaine delivery system (a sterile, prefilled, disposable system that delivers lidocaine powder into the epidermis) produces effective local analgesia within 1 to 3 minutes for venipuncture and peripheral venous cannulation procedures in children. METHODS: Pediatric patients (3-18 years of age) were randomly assigned to treatment with the needle-free powder lidocaine delivery system (0.5 mg of lidocaine and 21 +/- 1 bar of pressure; n = 292) or a sham placebo system (n = 287) at the antecubital fossa or the back of the hand 1 to 3 minutes before venipuncture or cannulation. All patients rated the administration comfort of the needle-free systems and the pain of the subsequent venous access procedures with the Wong-Baker Faces Pain Rating Scale (from 0 to 5). Patients 8 to 18 years of age also provided self-reports with a visual analog scale, and parents provided observational visual analog scale scores for their child's venous access pain. Safety also was assessed. RESULTS: Immediately after administration, mean Wong-Baker Faces scale scores were 0.54 and 0.24 in the active system and sham placebo system groups, respectively. After venipuncture or cannulation, mean Wong-Baker Faces scale scores were 1.77 +/- 0.09 and 2.10 +/- 0.09 and mean visual analog scale scores were 22.62 +/- 1.80 mm and 31.97 +/- 1.82 mm in the active system and sham placebo system groups, respectively. Parents' assessments of their child's procedural pain were also lower in the active system group (21.35 +/- 1.43 vs 28.67 +/- 1.66). Treatment-related adverse events were generally mild and resolved without sequelae. Erythema and petechiae were more frequent in the active system group. CONCLUSIONS: The needle-free powder lidocaine delivery system was well tolerated and produced significant analgesia within 1 to 3 minutes.

Continuous peripheral nerve blockade for inpatient and outpatient postoperative analgesia in children.

BACKGROUND: This is an audit of the continuous peripheral nerve blockade (CPNB) program that was implemented at our institution to provide postoperative analgesia after orthopedic procedures in children. METHODS: We reviewed the departmental regional anesthesia registry and the medical records of consecutive children who received CPNB for postoperative analgesia at The Children's Hospital of Philadelphia between February 2003 and July 2006. Patients were prospectively followed until cessation of the effects of CPNB and/or resolution of any related complications. Data collected contemporaneously included presence of sensory and motor blockade, pain scores in inpatients, opioid administration, and complications related to CPNB. RESULTS: A total of 226 peripheral nerve catheters were placed in 217 patients. One hundred eight patients (112 catheters) were discharged home with CPNB. The ages ranged from 4 to 18 yr (13.7 +/- 3.4). Local anesthetic solution (0.125% bupivacaine [n = 164], 0.1% ropivacaine [n = 12], or 0.15% ropivacaine [n = 27]) was infused at an initial rate of 2-12 mL/h based on patients' weights and locations of catheters. The mean duration of local anesthetic infusion was 48.4 +/- 29.3 h (range 0-160 h). The percentage of patients who did not require any opioids in the first 8, 24, and 48 h after surgery was 56%, 26%, and 21%, respectively. The incidence of nausea and vomiting was 14% (13% in outpatients, 15% in inpatients). Complications were noted in 2.8% of patients. Three patients had prolonged numbness (>24 h) that resolved spontaneously; one developed superficial cellulitis that resolved with a course of antibiotics; one had difficulty removing the catheter at home and one developed tinnitus 24 h after starting CPNB that resolved quickly after clamping of the catheter followed by removal. CONCLUSION: It is feasible to implement a CPNB program to provide an alternative method of inpatient and outpatient postoperative analgesia after orthopedic surgery in children when appropriate expertise is available. Patient and family education along with frequent follow-up are crucial to detect and address adverse events promptly.

Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer's disease are associated with reduced amyloid precursor protein phosphorylation.

The glycogen synthase kinase-3beta (GSK3beta) pathway plays an important role in mediating neuronal fate and synaptic plasticity. In Alzheimer's disease (AD), abnormal activation of this pathway might play an important role in neurodegeneration, and compounds such as lithium that modulate GSK3beta 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 GSK3beta 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 GSK3beta 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 GSK3beta 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-GSK3beta 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 GSK3beta was associated with decreased levels of APP phosphorylation that resulted in decreased amyloid-beta production. In conclusion, the present study showed that modulation of the GSK3beta signaling pathway might also have neuroprotective effects in tg mice by regulating APP maturation and processing and further supports the notion that GSK3beta might be a suitable target for the treatment of AD.

Adolescent self-perception: associations with chronic musculoskeletal pain and functional disability.

UNLABELLED: Associations among pain, functional disability, and self-perceived competence were examined in a retrospective record review of the initial clinical evaluations of 115 adolescents (ages 13 to 18 years) with chronic musculoskeletal pain not associated with a specific organic cause. Adolescents self-reported on pain intensity, functional disability, and 9 developmentally relevant domains of self-perceived competence, using the Self-Perception Profile for Adolescents (Harter, 1988). Results confirmed a relation between usual pain intensity and functional disability (r = 0.47, P < .001). A series of multiple regression analyses revealed that adolescents' perceptions of global self-worth significantly moderated the relation between pain and disability. These findings extend our understanding of the relations among self-perception, chronic pain, and disability to include adolescents with chronic musculoskeletal pain syndromes and have future research and therapeutic implications. PERSPECTIVE: Adolescents with chronic pain syndromes can face significant challenges in accomplishing developmental goals with respect to the pain and disability they experience. Perceptions of self-worth appear to play an important role in understanding the relation between pain and functional disability among adolescents with chronic pain.

The positional influence of the helical geometry of the heteroduplex substrate on human RNase H1 catalysis.

In a companion study published in this issue (p. 83), we showed that chimeric substrates containing 2'-methoxyethyl (MOE) nucleotides inhibited human RNase H1 activity. In this study, we prepared chimeric substrates containing a central DNA region with flanking northern-biased MOE nucleotides hybridized to complementary RNA. Conformationally biased and flexible modified nucleotides were positioned at the junctions between the DNA and MOE residues of the chimeric substrates to modulate the effects of the MOE residues on human RNase H1 activity. The strong northern-biased locked-nucleic acid modification exacerbated the negative effects of the MOE modifications resulting in slower human RNase H1 cleavage rates. Enhanced cleavage rates were observed for the eastern-biased 2'-ara-fluorothymidine and bulge inducing N-methylthymidine modifications positioned at the 5'-DNA/3'-MOE junction as well as the southern-biased 2'-methylthiothymidine and conformationally flexible tetrafluoroindole (TFI) modifications positioned at the 5'-MOE/3'-DNA junction. The heterocycle of the ribonucleotide opposing the TFI deoxyribonucleotide had no effect on the human RNase H1 activity, whereas nucleotide substitutions adjacent the TFI significantly affected the cleavage rate. Mismatch base pair(s) exhibited similar effects on human RNase H1 activity as the TFI modifications. The effects of the TFI modification and mismatch base pair(s) on human RNase H1 activity were influenced by the position of the modification relative to the nucleotides interacting with the catalytic site of the enzyme rather than the juxtaposition of the modification to the MOE residues. Finally, these results provide a method for enhancing the human RNase H1 activity of chimeric antisense oligonucleotides (ASO) as well as the design of more potent ASO drugs.

Human RNase H1 discriminates between subtle variations in the structure of the heteroduplex substrate.

In a previous study, we demonstrated that the sugar conformation and helical geometry of the heteroduplex substrate at the catalytic site of human RNase H1 directs the selective recognition of the substrate by the enzyme (J Biol Chem 279: 36317-36326, 2004). In this study, we systematically introduced 2'-methoxyethoxy (MOE) nucleotides into the antisense oligodeoxyribonucleotide (ASO) of the heteroduplex to alter the helical geometry of the substrate. The MOE substitutions at the 3' and 5' poles of the ASO resulted in fewer cleavage sites and slower cleavage rates compared with the unmodified substrates. Furthermore, a greater reduction in cleavage activity was observed for MOE substitutions at the 5' pole of the ASO. The 3'- and 5'-most cleavage sites were positioned two and four to five base pairs, respectively, from the nearest MOE residues, suggesting a conformational transmission of the MOE/RNA helical geometry into the DNA/RNA portion of the heteroduplex. Similar conformational transmission was observed for Okazaki-like substrates containing deoxyribonucleotide substitutions at the 3' pole of the oligoribonucleotide. Finally, the heteroduplex substrates exhibited preferred cleavage sites that were cleaved 2- to 3-fold faster than other sites in the substrate, and these sites exhibited the greatest influence on the initial cleavage rates. The data presented here offer further insights into the role substrate structure plays in directing human RNase H1 activity as well as the design of effective ASOs.

Na(V)1.7 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 Na(V)1.7, which is preferentially expressed in most nociceptive dorsal root ganglia (DRGs) and sympathetic ganglion neurons. Several mutations occur in cytoplasmic linkers of Na(V)1.7, 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 Na(V)1.7. 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 epidural bupivacaine-fentanyl and bupivacaine-clonidine in children undergoing the Nuss procedure.

The administration of epidural opioids, though effective for producing analgesia, has severe side effects in most patients. It is unknown whether clonidine can effectively replace opioids and cause fewer side effects. We compared, in this randomized trial, the incidence of vomiting and pruritus as well as the analgesic profile of three different combinations of bupivacaine, fentanyl, and clonidine administered epidurally in patients undergoing the Nuss procedure: bupivacaine + fentanyl, bupivacaine + clonidine, bupivacaine + fentanyl + clonidine. The incidence of side effects was significantly less in the bupivacaine + clonidine group (33%) compared with the bupivacaine + fentanyl (92%) and bupivacaine + fentanyl + clonidine (73%) groups (P = 0.004). Quality of postoperative analgesia was similar in the three groups. No significant complications were observed. In conclusion, clonidine is an effective and safe alternative to epidural opioids.

Adolescent-parent relationships in the context of adolescent chronic pain conditions.

OBJECTIVE: This study explored adolescent-parent relationships in families of adolescents with chronic pain. METHODS: A retrospective review was conducted on 112 adolescents with chronic pain who presented for clinical evaluation at an outpatient pediatric multidisciplinary pain management clinic. Adolescents reported on pain severity and duration, functional disability, and psychological distress. Parents responded to a measure of adolescent-parent relationship distress. RESULTS: The findings show that as a group, parents of adolescents with chronic pain syndromes reported less adolescent-parent relationship distress compared to normative data. Adolescent-parent relationship distress was inversely correlated with pain severity. A multiple regression model containing indicators of global psychological distress, pain severity, and adolescent-parent relationship distress predicted levels of adolescents' functional disability. Pain severity and functional disability were more closely linked at the low end of Adolescent-Parent Relationship Domain scores. DISCUSSION: The findings suggest important directions for future research to advance our understanding of the role of adolescent-parent relationships in the pain-disability cycle.

Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease.

Cerebrolysin is a peptide mixture with neurotrophic effects that might reduce the neurodegenerative pathology in Alzheimer's disease (AD). We have previously shown in an amyloid protein precursor (APP) transgenic (tg) mouse model of AD-like neuropathology that Cerebrolysin ameliorates behavioral deficits, is neuroprotective, and decreases amyloid burden; however, the mechanisms involved are not completely clear. Cerebrolysin might reduce amyloid deposition by regulating amyloid-beta (Abeta) degradation or by modulating APP expression, maturation, or processing. To investigate these possibilities, APP tg mice were treated for 6 months with Cerebrolysin and analyzed in the water maze, followed by RNA, immunoblot, and confocal microscopy analysis of full-length (FL) APP and its fragments, beta-secretase (BACE1), and Abeta-degrading enzymes [neprilysin (Nep) and insulin-degrading enzyme (IDE)]. Consistent with previous studies, Cerebrolysin ameliorated the performance deficits in the spatial learning portion of the water maze and reduced the synaptic pathology and amyloid burden in the brains of APP tg mice. These effects were associated with reduced levels of FL APP and APP C-terminal fragments, but levels of BACE1, Notch1, Nep, and IDE were unchanged. In contrast, levels of active cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3beta [GSK-3beta; but not stress-activated protein kinase-1 (SAPK1)], kinases that phosphorylate APP, were reduced. Furthermore, Cerebrolysin reduced the levels of phosphorylated APP and the accumulation of APP in the neuritic processes. Taken together, these results suggest that Cerebrolysin might reduce AD-like pathology in the APP tg mice by regulating APP maturation and transport to sites where Abeta protein is generated. This study clarifies the mechanisms through which Cerebrolysin might reduce Abeta production and deposition in AD and further supports the importance of this compound in the potential treatment of early AD.

Pediatric acute pain management.

Children are benefiting from the advances made in developmental neurobiology and analgesic pharmacology over the past few decades. Heightened public awareness and increased political pressure from external regulatory agencies are helping to maintain the momentum in improving pediatric pain management. As a result, methods of assessing and managing children's pain are being refined, and new modalities of pain relief are being explored. This review summarizes selected current topics in pediatric acute pain management, with the major emphasis on acute postoperative pain management.