Influence of personalized extended interval dosing on the natalizumab wearing-off effect - a sub-study of the NEXT-MS trial.

BACKGROUND AND OBJECTIVES: Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID. METHODS: Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4-7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated. RESULTS: 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms. DISCUSSION: Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations.

The effect of nanoparticle permeation on the bulk rheological properties of mucus from the small intestine.

The effectiveness of delivering oral therapeutic peptides, proteins and nucleotides is often hindered by the protective mucus barrier that covers mucosal surfaces of the gastrointestinal (GI) tract. Encapsulation of active pharmaceutical ingredients (API) in nanocarriers is a potential strategy to protect the cargo but they still have to pass the mucus barrier. Decorating nanoparticles with proteolytic enzymes has been shown to increase the permeation through mucus. Here we investigate the effect of poly(acrylic acid) (PAA) nanoparticles decorated with bromelain (BRO), a proteolytic enzyme from pineapple stem, on the bulk rheology of mucus as well as non-decorated poly(lactic-co-glycolic acid) (PLGA) nanoparticles. Porcine intestinal mucus from the small intestine was incubated for 30min in the presence of PLGA nanoparticles or polyacrylic nanoparticles decorated with bromelain (PAA-BRO). The effect of nanoparticles on the rheological properties, weight of gel, released glycoprotein content from mucus as well as the viscosity of liquid removed was assessed. Treatment with nanoparticles decreased mucus gel strength with PAA-BRO reducing it the most. PAA-BRO nanoparticles resulted in the release of increased glycoprotein from the gel network whereas mucus remained a gel and exhibited a similar breakdown stress to control mucus. Therefore it would be possible to use bromelain to increase the permeability of nanoparticles through mucus without destroying the gel and leaving the underlying mucosa unprotected.

Validation of a database on acrylamide for use in epidemiological studies.

BACKGROUND/OBJECTIVES: Acrylamide, a probable human carcinogen, was detected in various heat-treated foods such as French fries and potato crisps. Recently, positive associations have been found between dietary acrylamide intakes, as estimated with a food frequency questionnaire using an acrylamide database, and cancer risk in some epidemiological studies. As acrylamide levels vary considerably within the same type of foods, a validation study was performed to investigate whether use of an acrylamide food database containing calculated mean acrylamide content, based on extensive sampling and chemical analysis of Dutch foods (several samples per food), can classify subjects with respect to true acrylamide intake. SUBJECTS/METHODS: We used the data from a 24-h duplicate diet study. The acrylamide content of 39 Dutch 24-h duplicate diets collected in 2004 was estimated using the mean acrylamide levels of foods available from the database and the menu list, on which the participants of the duplicate diet study had listed the amounts of individual foods and drinks in household units. Next, the acrylamide content of the total duplicate diets was analytically measured and correlated to the estimated acrylamide contents. RESULTS: The Spearman's correlation coefficient between chemically determined acrylamide content and the calculated acrylamide content of the duplicate diets was 0.82 (P<0.001). CONCLUSIONS: This study indicates that it is possible to classify subjects with respect to acrylamide intake if mean instead of actual content of each food is applied. The database can therefore be applied in epidemiological studies on acrylamide intake and cancer risk, such as the Netherlands Cohort Study on Diet and Cancer.

An algorithm for the automatic detection of seizures in neonatal amplitude-integrated EEG.

AIM: To develop and evaluate an algorithm for the automatic screening of electrographic neonatal seizures (ENS) in amplitude-integrated electroencephalography (aEEG) signals. METHODS: CFM recordings were recorded in asphyxiated (near)term newborns. ENS of at least 60 sec were detected based on their characteristic pattern in the aEEG signal, an increase of its lower boundary. The algorithm was trained using five CFM recordings (training set) annotated by a neurophysiologist, observer1. The evaluation of the algorithm was based on eight different CFM recordings annotated by observer1 (test set observer 1) and an independent neurophysiologist, observer2 (test set observer 2). RESULTS: The interobserver agreement between observer1 and 2 in interpreting ENS from the CFM recordings was high (G coefficient: 0.82). After dividing the eight CFM recordings into 1-min segments and classification in ENS or non-ENS, the intraclass correlation coefficient showed high correlations of the algorithm with both test sets (respectively, 0.95 and 0.85 with observer1 and 2). The algorithm showed in five recordings a sensitivity > or = 90% and approximately 1 false positive ENS per hour. However, the algorithm showed in three recordings much lower sensitivities: one recording showed ENSs of extremely high amplitude that were incorrectly classified by the algorithm as artefacts and two recordings suffered from low interobserver agreement. CONCLUSION: This study shows the feasibility of automatic ENS screening based on aEEG signals and may facilitate in the bed-side interpretation of aEEG signals in clinical practice.

Recovery of amplitude integrated electroencephalographic background patterns within 24 hours of perinatal asphyxia.

OBJECTIVE: To assess the time course of recovery of severely abnormal initial amplitude integrated electroencephalographic (aEEG) patterns (flat trace (FT), continuous low voltage (CLV), or burst suppression (BS)) in full term asphyxiated neonates, in relation to other neurophysiological and neuroimaging findings and neurodevelopmental outcome. METHODS: A total of 190 aEEGs of full term infants were reviewed. The neonates were admitted within 6 hours of birth to the neonatal intensive care unit because of perinatal asphyxia, and aEEG recording was started immediately. In all, 160 infants were included; 65 of these had an initial FT or CLV pattern and 25 an initial BS pattern. Neurodevelopmental outcome was assessed using a full neurological examination and the Griffiths' mental developmental scale. RESULTS: In the FT/CLV group, the background pattern recovered to continuous normal voltage within 24 hours in six of the 65 infants (9%). All six infants survived the neonatal period; one had a severe disability, and five were normal at follow up. In the BS group, the background pattern improved to normal voltage in 12 of the 25 infants (48%) within 24 hours. Of these infants, one died, five survived with moderate to severe disability, two with mild disability, and four were normal. The patients who did not recover within 24 hours either died in the neonatal period or survived with a severe disability. CONCLUSION: In this study there was a small group of infants who presented with a severely abnormal aEEG background pattern within six hours of birth, but who achieved recovery to a continuous normal background pattern within the first 24 hours. Sixty one percent of these infants survived without, or with a mild, disability.

Prediction of cervical spine injury risk for the 6-year-old child in frontal crashes.

This article presents a series of 49 km/h sled tests using the Hybrid III 6-year-old dummy in a high-back booster, a low-back booster, and a three-point belt. Although a 10-year review at a level I trauma center showed that noncontact cervical spine injuries are rare in correctly restrained booster-age children, dummy neck loads exceeded published injury thresholds in all tests. The dummy underwent extreme neck flexion during the test, causing full-face contact with the dummy's chest. These dummy kinematics were compared to the kinematics of a 12-year-old cadaver tested in a similar impact environment. The cadaver test showed neck flexion, but also significant thoracic spinal flexion which was nonexistent in the dummy. This comparison was expanded using MADYMO simulations in which the thoracic spinal stiffness of the dummy model was decreased to give a more biofidelic kinematic response. We conclude that the stiff thoracic spine of the dummy results in high neck forces and moments that are not representative of the true injury potential.

The development, validation and application of a finite element upper extremity model subjected to air bag loading.

Both frontal and side air bags can inflict injuries to the upper extremities in cases where the limb is close to the air bag module at the time of impact. Current dummy limbs show qualitatively correct kinematics under air bag loading, but they lack biofidelity in long bone bending and fracture. Thus, an effective research tool is needed to investigate the injury mechanisms involved in air bag loading and to judge the improvements of new air bag designs. The objective of this study is to create an efficient numerical model that exhibits both correct global kinematics as well as localized tissue deformation and initiation of fracture under various impact conditions. The development of the model includes the creation of a sufficiently accurate finite element mesh, the adaptation of material properties from literature into constitutive models and the definition of kinematic constraints at articular joint locations. In order to make the model applicable for full-scale simulations, it was coupled with a computationally efficient human model. The model was validated against available cadaver experiments, including static and dynamic three-point-bending tests to the arm and forearm, as well as frontal air bag to forearm impact tests. The sensitivity of the model to changes in air bag properties and upper limb orientation are demonstrated by performing parametric studies. It is shown that the risk of forearm fracture increases substantially with proximity to the deploying frontal air bag and air bag aggressiveness, which corresponds to experimental findings. However, it is shown that increasing the forearm supination angle is protective for the occurrence of forearm fracture. In conclusion, the developed model proves to be a useful research tool to investigate trends in injury severity as a result of a changing frontal air bag to upper extremity loading environment.

Prediction of cervical spine injury risk for the 6-year-old child in frontal crashes.

This paper presents a series of 49 km/h sled tests using the Hybrid III 6-year-old dummy in a high-back booster, a low-back booster, and a three-point belt. Although it is shown that non-contact cervical spine injuries are rare in correctly restrained children in this age group, neck loads exceeded published injury thresholds in all tests. The dummy kinematics were compared to the kinematics of a 12-year-old cadaver tested in a similar impact environment. This comparison was expanded using MADYMO simulations. It is concluded that the stiff thoracic spine of the dummy results in high neck forces and moments that are not representative of the true injury potential.

Differentiation between portal-systemic encephalopathy and neurodegenerative disorders in patients with Wilson disease: H-1 MR spectroscopy.

PURPOSE: To investigate the extent to which neurodegeneration and metabolic changes caused by portosystemic shunting occur in Wilson disease. MATERIALS AND METHODS: Twenty-two adult patients with biochemically proved Wilson disease underwent magnetic resonance (MR) imaging, hydrogen-1 MR spectroscopy, neurologic and psychometric testing, and ultrasound evaluation of the liver. In addition, 13 age-matched adult control subjects underwent MR imaging and H-1 MR spectroscopy. For MR spectroscopy, the authors used a single-voxel technique with a repetition time of 2,000 msec and an echo time of 31 msec. The volume of interest included the right and left globi pallidus, which are the most common sites of lesions in Wilson disease. RESULTS: N-acetylaspartate-creatine and choline-creatine ratios were decreased in patients with Wilson disease versus control subjects (P < .001 for N-acetylaspartate-creatine ratio, P < .05 for choline-creatine ratio). Also, patients with Wilson disease and portosystemic shunting had lower myo-inositol-creatine ratios than did patients with Wilson disease and no portosystemic shunting (P < .05). CONCLUSION: Reductions in N-acetylaspartate indicate neuronal loss consistent with the neurodegenerative pattern associated with Wilson disease. In addition, H-1 MR spectroscopy shows metabolic abnormality in the brain, as decreased myoinositol, caused by portosystemic shunting.