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Vagus nerve stimulation (VNS) is an adjunctive therapy for drug-resistant epilepsy. Noninvasive evoked potential recordings in laryngeal muscles (LMEPs) innervated by vagal branches may provide a marker to assess effective vagal nerve fiber activation. We investigated VNS-induced LMEPs in patients with epilepsy in acute and chronic settings.

ObjectiveTo improve the Manchester Triage System (MTS) in paediatric emergency care.MethodsThe authors performed a prospective observational study at the emergency departments of a university and teaching hospital in The Netherlands and included children attending in 2007 and 2008. The authors developed and implemented specific age-dependent modifications for the MTS, based on patient groups where the system's performance was low. Nurses applied the modified system in 11 481 (84%) patients. The reference standard for urgency defined five levels based on a combination of vital signs at presentation, potentially life-threatening conditions, diagnostic resources, therapeutic interventions and follow-up. The reference standard for urgency was previously defined and available in 11 260/11 481 (96%) patients.ResultsCompared with the original MTS specificity improved from 79% (95% CI 79% to 80%) to 87% (95% CI 86% to 87%) while sensitivity remained similar ((63%, 95% CI 59% to 66%) vs (64%, 95% CI 60% to 68%)). The diagnostic OR increased (4.1 vs 11).ConclusionsModifications of the MTS for paediatric emergency care resulted in an improved specificity while sensitivity remained unchanged. Further research should focus on the improvement of sensitivity.

To evaluate compliance and costs of referral of nonurgent children, who present at the emergency department, to the general practitioner cooperative (GPC).

A substantial amount of experimental evidence implicates neuropeptide Y (NPY) in the pathophysiology of epilepsy. Over the past 20 years, remarkable progress has been made in unraveling the mechanisms and receptors involved in the anticonvulsant effect of this abundantly expressed neuropeptide. Activation of Y2 and/or Y5 receptors and blockade of Y1 receptors in the central nervous system suppresses seizures in a variety of animal seizure models. Orally available, brain penetrating Y2 and/or Y5 agonists, and possibly Y1 antagonists, may therefore constitute a novel class of antiepileptic drugs, which could greatly benefit patients with medically refractory epilepsy. Significant progress has been made in identifying non-peptidergic Y1 antagonists that fulfill these criteria, but suitable Y2 and/or Y5 agonists have proven to be more elusive. Innovative oral and parental drug delivery strategies which are currently under development may offer a means of using the more readily available peptidergic NPY receptor ligands in a clinical setting. Finally, gene therapy, antisense probes or RNA interference strategies which alter the expression of NPY or its receptors in specific brain regions may also be of use in the treatment of epilepsy, but will probably benefit a smaller subgroup of epilepsy patients, since they typically require an invasive procedure.

Various antiepileptic drugs were shown to be substrates for multidrug transporters at the level of the blood-brain barrier. These ATP-dependent efflux pumps actively limit brain accumulation of xenobiotics and drugs. Intrahippocampal oxcarbazepine perfusion in rat was previously shown to exert anticonvulsant effects associated with increases in extracellular dopamine and serotonin levels. In contrast, preliminary studies in our laboratory revealed that no anticonvulsant or monoaminergic effects could be obtained after systemic oxcarbazepine administration. The present in vivo microdialysis study was conducted to investigate the impact of the transport kinetics of oxcarbazepine across the blood-brain barrier on the observed treatment refractoriness. More precisely, the influence of intrahippocampal perfusion of verapamil, a P-glycoprotein inhibitor, and probenecid, a multidrug resistance protein inhibitor, on the blood-brain barrier passage and anticonvulsant properties of oxcarbazepine were investigated in the focal pilocarpine model for limbic seizures. Simultaneously, the effects on hippocampal monoamines were studied as pharmacodynamic markers for the anticonvulsant activity. Although systemic oxcarbazepine administration alone failed in preventing the animals from developing seizures, coadministration with verapamil or probenecid offered complete protection. Concomitantly, significant increases in extracellular hippocampal dopamine and serotonin levels were observed within our previously defined anticonvulsant monoamine range. The present data indicate that oxcarbazepine is a substrate for multidrug transporters at the blood-brain barrier. Coadministration with multidrug transporter inhibitors significantly potentiates the anticonvulsant activity of oxcarbazepine and offers opportunities for treatment of pharmacoresistant epilepsy.

In patients with a short small bowel, D‐lactic acidemia and D‐lactic aciduria are caused by intestinal lactobacilli. The purpose of this study was to obtain a detailed picture of the metabolic acidosis in young children with short small bowel. Feces, blood, and urine of children with short small bowel and acidosis were studied microbiologically and/or biochemically. Previous findings were confirmed that more than 60% of the fecal flora of patients with small short bowel, who are not receiving antibiotics, consists of lactic acid‐producing lactobacilli. In blood, D‐lactic acid was the most prominent metabolite: the highest serum D‐lactate (15.5 mmol/l) was observed in a sample taken immediately after the onset of hyperventilation. The highest D‐lactate excretion was in urine collected some hours after the onset of hyperventilation, and amounted to 59 mol/mol creatinine. Acidosis in the patients with short small bowel was related to strongly increased serum D‐lactate and anion gap and to strongly decreased serum bicarbonate and pH. In children with small short bowel and acidosis, the common intestinal flora of mainly lactobacilli abundantly produces D‐lactic acid from easily fermentable carbohydrates. Thus, these bacteria directly cause shifts of bicarbonate, pH, and base excess and indirectly cause shifts of the anion gap, as well as hyperventilation. These kinetic parameters are strongly associated.

Fijnvandraat: Bayer: Research Funding; CSL Behring: Research Funding.

Transfusion of red blood cells (RBC) is a common intervention to treat and prevent complications in sickle cell disease (SCD). However, frequent transfusions may lead to erythrocyte alloimmunization, thereby complicating donor matching procedures and posing patients at risk for hemolytic transfusion reactions. Little information is available about the risk of alloimmunization of sickle cell patients living in European countries. In the Netherlands extensive matching procedures to prevent alloimmunization were introduced a decade ago, but the effect on alloimmunization has not been evaluated yet.The primary aim of this study is to evaluate the cumulative incidence of first alloantibody formation in a Dutch cohort of transfused SCD patients, and to compare this with a general Dutch RBC-transfused population. In addition, the effect of extended RBC matching protocols on the incidence of alloantibody formation in SCD and potential clinical determinants of alloimmunization will be assessed.We conducted a retrospective cohort study and collected data on SCD patients (genotypes HbSS, HbSC, HbSβ0 and HbSβ+ thalassemia), diagnosed in three Dutch Sickle Cell Treatment Centers that received non-extended matched (ABO, RhD) RBC transfusions between 1984-2004 and extended matched (at least ABO, Rhesus phenotype, Kell) RBC transfusions between 2004-2011.In addition, we compared this population with a general population of 3 042 patients that received non-extended matched (ABO, RhD) RBC transfusions between 2005-2009 in the Leiden University Medical Center (Zalpuri et al. 2012). Cohorts were not matched for ethnicity. Alloimmunization risk was calculated as Kaplan-Meier incidence with cumulative number of transfusions as time variable. The association with the clinical determinants gender, SCD-phenotype and ethnicity was analyzed with Cox-regression analysis.A total of 291 SCD patients received 7 957 RBC units. Alloantibody formation occurred in 52 (17.9%) patients. The cumulative incidence of alloimmunization was 9% after 5 RBC units, 15% after 10, 24% after 20 and 34% after 40 RBC units. Multivariate analysis, correcting for the cumulative number of transfusions, demonstrated a significantly increased risk of alloantibody formation in our SCD cohort when compared to a general population of transfused patients (HR 7.5 (95% CI: 5.06-11.14), where the cumulative incidence of alloimmunization was 1.1% after 5, 2.4% after 10, 3.4% after 20 and 6.5% after 40 RBC units. No association could be demonstrated between alloantibody formation and clinical determinants such as gender, SCD-phenotype or ethnicity. However, a significant reduction in alloimmunization was observed in SCD patients that received their first transfusion from the year 2004 onwards, after preventive matching for Rhesus phenotype and Kell was introduced for SCD patients (HR 0.48 (95% CI: 0.24-0.97)).The overall rate of first RBC alloantibody formation in our cohort was 17.9% and the risk of alloimmunization increased substantially with an increasing number of RBC transfusions. A unique comparison with a general cohort of Dutch transfused patients demonstrates a significantly higher risk of alloantibody formation in SCD, acknowledging earlier findings. This may partially be explained by differences in RBC antigens between patients of African descent and the predominantly Caucasian donors. Besides the number of RBC units, no other clinical risk factors for allo-immunization in SCD could be identified. The effectiveness of extended RBC matching protocols in the prevention of alloimmunization for chronically transfused patients in the participating centers was confirmed.No relevant conflicts of interest to declare.

ObjectiveTo derive, cross validate, and externally validate a clinical prediction model that assesses the risks of different serious bacterial infections in children with fever at the emergency department.DesignProspective observational diagnostic study.SettingThree paediatric emergency care units: two in the Netherlands and one in the United Kingdom.ParticipantsChildren with fever, aged 1 month to 15 years, at three paediatric emergency care units: Rotterdam (n=1750) and the Hague (n=967), the Netherlands, and Coventry (n=487), United Kingdom. A prediction model was constructed using multivariable polytomous logistic regression analysis and included the predefined predictor variables age, duration of fever, tachycardia, temperature, tachypnoea, ill appearance, chest wall retractions, prolonged capillary refill time (>3 seconds), oxygen saturation <94%, and C reactive protein.Main outcome measuresPneumonia, other serious bacterial infections (SBIs, including septicaemia/meningitis, urinary tract infections, and others), and no SBIs.ResultsOxygen saturation <94% and presence of tachypnoea were important predictors of pneumonia. A raised C reactive protein level predicted the presence of both pneumonia and other SBIs, whereas chest wall retractions and oxygen saturation <94% were useful to rule out the presence of other SBIs. Discriminative ability (C statistic) to predict pneumonia was 0.81 (95% confidence interval 0.73 to 0.88); for other SBIs this was even better: 0.86 (0.79 to 0.92). Risk thresholds of 10% or more were useful to identify children with serious bacterial infections; risk thresholds less than 2.5% were useful to rule out the presence of serious bacterial infections. External validation showed good discrimination for the prediction of pneumonia (0.81, 0.69 to 0.93); discriminative ability for the prediction of other SBIs was lower (0.69, 0.53 to 0.86).ConclusionA validated prediction model, including clinical signs, symptoms, and C reactive protein level, was useful for estimating the likelihood of pneumonia and other SBIs in children with fever, such as septicaemia/meningitis and urinary tract infections.

OBJECTIVE: To validate use of the Manchester triage system in paediatric emergency care. Design Prospective observational study. Setting Emergency departments of a university hospital and a teaching hospital in the Netherlands, 2006-7. Participants 17 600 children (aged <16) visiting an emergency department over 13 months (university hospital) and seven months (teaching hospital). Intervention Nurses triaged 16 735/17 600 patients (95%) using a computerised Manchester triage system, which calculated urgency levels from the selection of discriminators embedded in flowcharts for presenting problems. Nurses over-ruled the urgency level in 1714 (10%) children, who were excluded from analysis. Complete data for the reference standard were unavailable in 1467 (9%) children leaving 13 554 patients for analysis. MAIN OUTCOME MEASURES: Urgency according to the Manchester triage system compared with a predefined and independently assessed reference standard for five urgency levels. This reference standard was based on a combination of vital signs at presentation, potentially life threatening conditions, diagnostic resources, therapeutic interventions, and follow-up. Sensitivity, specificity, and likelihood ratios for high urgency (immediate and very urgent) and 95% confidence intervals for subgroups based on age, use of flowcharts, and discriminators. RESULTS: The Manchester urgency level agreed with the reference standard in 4582 of 13 554 (34%) children; 7311 (54%) were over-triaged and 1661 (12%) under-triaged. The likelihood ratio was 3.0 (95% confidence interval 2.8 to 3.2) for high urgency and 0.5 (0.4 to 0.5) for low urgency; though the likelihood ratios were lower for those presenting with a medical problem (2.3 (2.2 to 2.5) v 12.0 (7.8 to 18.0) for trauma) and in younger children (2.4 (1.9 to 2.9) at 0-3 months v 5.4 (4.5 to 6.5) at 8-16 years). CONCLUSIONS: The Manchester triage system has moderate validity in paediatric emergency care. It errs on the safe side, with much more over-triage than under-triage compared with an independent reference standard for urgency. Triage of patients with a medical problem or in younger children is particularly difficult.