The analgesic efficacy of acetaminophen, ketoprofen, or their combination for pediatric surgical patients having soft tissue or orthopedic procedures

The combined use of acetaminophen and a nonsteroidal antiinflammatory drug has been shown to provide better postoperative analgesia than either drug alone in several adult studies. However, there are no pediatric studies analyzing similar effects when the currently recommended doses of acetaminophen are used. In a double-blind, placebo-controlled design we randomized 120 children, aged 1-9 yr, undergoing orthopedic or soft tissue surgery, into 3 groups to receive either acetaminophen 60 mg/kg rectally and 40 mg/kg orally, ketoprofen 2 mg/kg IV twice, or the combination of the active drugs. The first drug doses were given at anesthetic induction and the second doses 8 h thereafter. During anesthesia all children received sevoflurane and a continuous infusion of remifentanil. Postoperative pain was evaluated by the behavioral objective pain scale (0-9) for 24 h. The rescue medication was morphine 0.05 mg/kg IV. The primary outcome variable was morphine consumption. For statistical analysis, analysis of variance, chi2 test and Kaplan-Meier survival analysis were used. Morphine requirement was less in the combination than in the acetaminophen group both in the postanesthesia care unit (2.5 +/- 1.7 versus 3.9 +/- 2.1 morphine doses) and during the 24-h postoperative follow-up (4.1 +/- 2.5 versus 5.9 +/- 2.9 morphine doses) (P < 0.05). No differences existed between the ketoprofen and the acetaminophen groups. The objective pain scale scores were lowest in the combination group both in the postanesthesia care unit and in the postoperative ward (P < 0.05). When children were divided based on their surgery, opioid requirement and pain scores were less in the combination than in the parent drug groups only after orthopedic surgery. The combination of acetaminophen 100 mg/kg and ketoprofen 4 mg/kg in a day provided better analgesia and lower pain scores after orthopedic, but not soft tissue, surgery in children.     

Effect of resection of the lateral retinaculum of the knee in surgical treatment of symptomatic patello-femoral incongruency

Biomechanical malfunction of the knee extensor mechanism in the patello femoral joint is regarded as patella malalignment but major patients complaints are anterior knee pain and patellar slipping. Lateral retinacular release is one of the basic surgical procedures in the treatment of patellar malalignment. The aim of the study was to estimate the achievements of the lateral retinacular release in solving particular biomechanical disorders of the patello femoral joint, as well as individual patients complaints. Evaluation of objective parameters x-ray and clinical findings before and after the operation, shows statistically highly significant difference, thus confirming implementation of the fore mentioned surgical procedure. Despite the fact that anterior knee pain subsided postoperatively in the number of patients, statistically significant values, comparing to the preoperative findings, could not be obtained. Incidence of the patellar slipping has shown statistically significant reduction two years following the surgery. Achieving proper biomechanical alignment of the patello femoral joint is obviously not sufficient to provide relief of subjective complaints, especially concerning anterior knee pain, although considerable improvements were registered in the number of patients.     

Phasic non-micturition contractions in the bladder of the anaesthetized and awake rat

OBJECTIVE: To characterize the contractile activity that occurs in the bladder during the filling phase of the micturition cycle (non-micturition contractions, NMCs), which generate transient rises in intravesical pressure not associated with urine flow. MATERIALS AND METHODS: The experiments were conducted using anaesthetized (chloral hydrate) and un-anaesthetized rats. In un-anaesthetized rats bladder contractile activity was measured using an intravesical cannula implanted under full surgical anaesthesia 3 days previously. In the anaesthetized rats the bladder was exteriorized and a cannula inserted through the dome. In these experiments electrical activity within the detrusor was also measured with a suction electrode on the bladder surface. For each rat, the experimental protocol involved filling the bladder at a constant rate (10 mL/h) to evoke micturition cycles, or infusion of a fixed volume and recording made under effective isovolumetric conditions. RESULTS: In both anaesthetized and un-anaesthetized rats there were transient rises in bladder pressure (0.5-3 cmH2O). In the anaesthetized rats the amplitude of the transients increased throughout the filling phase, with little change in frequency. The phasic NMCs generating these pressure transients were accompanied by electrical changes in the detrusor. In the middle phase of bladder filling the slow pressure changes were accompanied by slow waves of electrical activity which changed in the pressure cycles immediately before micturition to high-frequency low-amplitude signals. In the un-anaesthetized rats there was a period immediately after voiding where there was no activity. As filling proceeded, low-amplitude low-frequency NMCs appeared that gradually increased in frequency and amplitude during the filling phase. However, the frequency of the transients decreased immediately before micturition despite an increase in amplitude. Similar responses were seen during isovolumetric recording. CONCLUSION: The present results show the presence of NMCs in the rat bladder, identify volume-dependent changes in the pattern of this activity during the micturition cycle, and show that NMCs are accompanied by electrical changes in the detrusor. The physiological significance of NMCs is not known but it might be linked to the generation of afferent discharge from mechanoreceptors in the wall, so contributing to sensations related to bladder volume.     

Oral treatment with a vitamin D3 analogue (BXL628) has anti-inflammatory effects in rodent model of interstitial cystitis

OBJECTIVE: To investigate the effects of a vitamin D3 analogue (BXL628) in a model of chronic cystitis, as calcitriol analogues might be an interesting new therapeutic option for interstitial cystitis, for although the cause of the disease remains unclear, the increase in mast cells in the mucosa and detrusor muscle are significant. MATERIALS AND METHODS: We devised a mouse model of allergen-induced allergic cystitis that is associated with the up-regulation of genes for interleukin-13, FcepsilonRIalpha and mast cells-derived proteases, a massive inflammatory reaction in the bladder tissue, and augmented levels of mast cell-derived protease 1 (MMCP1) detected in mouse sera. RESULTS: Oral administration of BXL628 significantly reduced the expression of interleukin-13, FcepsilonRIalpha and MMCP1 in the bladder. Furthermore, histological analysis showed a decrease in oedema and leukocyte infiltration in the bladder wall. BXL628 treatment reduced serum MMCP1 levels, indicating an effect on mast cell degranulation in vivo. CONCLUSIONS: Vitamin D3 analogues may successfully be used as anti-inflammatory agents in allergen-mediated inflammatory reactions. Moreover, the modulatory effect shown on mast cell activation by the BXL628 analogue strongly supports its potential therapeutic use in a possibly mast cell-dependent disease such as human interstitial cystitis.     

Virtual screening of novel CB2 ligands using a comparative model of the human cannabinoid CB2 receptor

To identify novel selective CB2 lead compounds, a comparative model of the CB2 receptor was constructed using the high-resolution bovine rhodopsin X-ray structure as a template. The CB2 model was utilized both in building the database queries and in filtering the hit compounds by a docking and scoring method. In G-protein activation assays, 1-isoquinolyl[3-(trifluoromethyl)phenyl]methanone (40, NRB 04079) was found to act as a selective agonist at the human CB2 receptor.     

Thiol/disulfide exchange is a prerequisite for CXCR4-tropic HIV-1 envelope-mediated T-cell fusion during viral entry

Attachment of gp120 to CD4 during HIV-1 entry triggers structural rearrangement in gp120 that enables binding to an appropriate coreceptor. Following coreceptor engagement, additional conformational changes occur in the envelope (Env), resulting in fusion of virion and cell membranes. Catalysts with redox-isomerase activity, such as protein disulfide isomerase (PDI), facilitate Env conversion from its inactive to its fusion-competent conformation. We report here that anti-PDI agents effectively block CXCR4 Env-mediated fusion and spread of virus infection. Exogenously added PDI, in turn, can rescue fusion from this blockade. We further find that PDI facilitates thiol/disulfide rearrangement in gp120 during conformational change, whereas inhibition of this redox shuffling prevents gp41 from assuming the fusogenic 6-helix bundle conformation. At the virus-cell contact site, gp120 induces assembly of PDI, CD4, and CXCR4 into a tetramolecular protein complex serving as a portal for viral entry. Our findings support the hypothesis that Env conformational change depends on a well-coordinated action of a tripartite system in which PDI works in concert with the receptor and the coreceptor to effectively lower the activation energy barrier required for Env conformational rearrangement.     

Craniofacial morphology but not excess body fat is associated with risk of having sleep-disordered breathing—The PANIC Study (a questionnaire-based inquiry in 6–8-year-olds)

We investigated the associations of dental occlusion, other craniofacial features and body fat with paediatric sleep-disordered breathing (SDB) in a representative population sample of 491 Finnish children 6?C8?years of age. Overweight and obesity were defined using age- and sex-specific body mass index cutoffs by International Obesity Task Force (IOTF) criteria. Body fat percentage was assessed by dual-energy X-ray absorptiometry. Facial proportions, dental occlusion and soft tissue structures were evaluated by an orthodontist. Sleep was assessed by a sleep questionnaire administered by the parents. SDB was defined as apnoeas, frequent or loud snoring or nocturnal mouth breathing observed by the parents. The prevalence of SDB was 9.9?% with no difference between boys and girls. The median (interquartile range) of body fat percentage was 20.6 (17.4?C27.1) in girls and 15.0 (11.4?C21.6) in boys. Altogether 11.4?% of boys and 15.6?% of girls were classified as having overweight or obesity according to the IOTF criteria. There was no difference in the prevalence of overweight, obesity or body fat percentage between children with SDB and those without it. Children with tonsillar hypertrophy had a 3.7 times higher risk of suffering SDB than those with normal size tonsils after adjustment for age, sex and body fat percentage. Furthermore, children with cross bite had a 3.3 times higher risk of having SDB than those without cross bite, and children with a convex facial profile had a 2.6 times higher risk of having SDB than those with a normal facial profile. Conclusion: Abnormal craniofacial morphology, but not excess body fat, is associated with an increased risk of having SDB in 6?C8-year-old children. A simple model of necessary clinical examinations (i.e. facial profile, dental occlusion and tonsils) is recommended to recognize children with an increased risk of SDB.     

Value of β2-microglobulin in the serum of healthy subjects older than 40 years

The aim of this research was to determine if the age of healthy subjects older than 40 years of age has an influence on the concentration of β(2) -microglobulin in the serum of subjects of different populations. We examined the values of β(2) -microglobulin in the serum of 51 healthy subjects aged 40-86 years using the microparticle enzyme immunoassay AxSYM β(2) -microglobulin test. The reference values of β(2) -microglobulin according to the nonparametric statistical method is 0.95-2.73 mg/L. A correlation was found between β(2) -microglobulin and age: 40-50 years (0.94-1.54 mg/L), 51-65 years (0.96-2.62 mg/L), and >65 years (1.13-2.84 mg/L). There was no significant statistical difference of β(2) -microglobulin between genders (P > 0.05); however, there was a statistically significant difference between the concentration of β(2) -microglobulin and the subjects' age. (Spearman's rank correlation coefficient ρ = 0.66; P < 0.01). A direct correlation between age and the concentration of β(2) -microglobulin was observed. This research is a contribution to determining reference values of β(2) -microglobulin in subjects of different populations.     

Morphologic and functional correlates of synaptic pathology in the cathepsin D knockout mouse model of congenital neuronal ceroid lipofuscinosis

Mutations in the cathepsin D (CTSD) gene cause an aggressive neurodegenerative disease (congenital neuronal ceroid lipofuscinosis) that leads to early death. Recent evidence suggests that presynaptic abnormalities play a major role in the pathogenesis of CTSD deficiencies. To identify the early events that lead to synaptic alterations, we investigated synaptic ultrastructure and function in presymptomatic CTSD knockout (Ctsd) mice. Electron microscopy revealed that there were significantly greater numbers of readily releasable synaptic vesicles present in Ctsd mice than in wild-type control mice as early as postnatal day 16. The size of this synaptic vesicle pool continued to increase with disease progression in the hippocampus and thalamus of the Ctsd mice. Electrophysiology revealed a markedly decreased frequency of miniature excitatory postsynaptic currents (mEPSCs) with no effect on paired-pulse modulation of the evoked excitatory post synaptic potentials in the hippocampus of Ctsd mice. The reduced mEPSCs frequency was observed before the appearance of epilepsy or any morphologic sign of synaptic degeneration. Taken together, these data indicate that CTSD is required for normal synaptic function and that a failure in synaptic trafficking or recycling may bean early and important pathologic mechanism in Ctsd mice; these presynaptic abnormalities may initiate synaptic degeneration in advance of subsequent neuronal loss.     

Vasoactive intestinal peptide--release from the heart and response in heart failure due to left ventricular pressure overload

BACKGROUND: Vasoactive intestinal peptide (VIP) is a peptidergic neurotransmitter and a vasodilator with positive inotropic and chronotropic properties. Whether and how VIP contributes to the neuroendocrine response in heart failure (HF) is disputed, and there are no data on VIP in pressure overload-induced HF. METHODS: We studied 129 adults with isolated aortic valve stenosis (AS). Blood was sampled from the aortic root and, in a subset of 48 patients, also from the coronary sinus for determination of VIP by radioimmunoassay. HF was diagnosed according to the European Society of Cardiology criteria. RESULTS: Plasma VIP (mean+/-S.E.M.) was slightly higher in patients with HF (22.6+/-0.9 pmol/l, n=41) than in patients free of HF (21.1+/-0.5 pmol/l, n=88) or in 11 control patients without structural heart disease (20.0+/-1.3 pmol/l, n=11) (p=0.030 across the groups). VIP did not correlate with any measurement of cardiac structure or function in AS. The change in plasma VIP from aortic root to coronary sinus averaged +1.2+/-0.4 pmol/l in the 11 control patients (p=0.021), +1.2+/-0.2 pmol/l in 33 AS patients free of HF (p<0.001) and +0.8+/-0.3 pmol/l in 15 AS patients with HF (p=0.037). CONCLUSIONS: Both structurally normal and diseased hearts release VIP into the coronary sinus. Although marginally elevated in the systemic circulation, VIP is unlikely to contribute significantly to the neuroendocrine activation in HF due to pressure overload.