Barriers to recruitment of children with cerebral palsy in a trial of home-based training.

Many trials fail to include the targeted number of participants, causing scientific and ethical problems. The COAD trial of home-based training programs (HBTPs) for children with unilateral cerebral palsy (CP) encountered recruitment problems, even though the parent-delivered home-based approach complies with recent health-care developments in the Netherlands. The current project aimed to identify the barriers to recruitment in the COAD trial. This summative, multidimensional evaluation comprised informal conversational interviews in which stakeholders who had been involved reflected on the factors that impeded successful recruitment of participants into the COAD trial. Barriers to implementation and recruitment were clustered according to the constructs of the Consolidated Framework for Implementation Research (CFIR). Member checking validated the findings. A total of 41 stakeholders contributed to the evaluation. Barriers to the implementation of the HBTPs were identified within every domain of the CFIR (intervention characteristics, outer setting, inner setting, characteristics of individuals, and process). Parent-delivered home-based training was perceived as highly complex and in conflict with the pressures on and the needs of parents. Many parents preferred the alternative center-based group interventions. The involvement of a resonance group was highly valued, and opportunities for further enhancements emerged. Additionally, the importance of research consortia was emphasized. The appropriateness of the RCT as the study design was criticized. The findings of this study are summarized in a tool which provides a dozen directions for the successful recruitment of participants in pediatric rehabilitation research.

Clinical disease activity is associated with anxiety and depressive symptoms in adolescents and young adults with inflammatory bowel disease.

BACKGROUND: Youths with inflammatory bowel disease (IBD) are at risk for developing anxiety and depressive symptoms with a reported 20%-50% prevalence rate. AIMS: This prospective study aimed to: (1) describe the prevalence and severity of anxiety and depressive symptoms in a large Dutch cohort of young IBD patients, and (2) identify demographic and clinical risk factors for anxiety and depression. METHODS: IBD patients (n = 374; 10-25 years) were screened for anxiety, depression and quality of life using validated age-specific questionnaires. Patients with elevated scores for anxiety and/or depressive symptoms received a diagnostic interview assessing psychiatric disorders. Demographic and clinical characteristics were retrieved from medical charts. Multiple logistic regression analysis was performed to identify risk factors for anxiety and/or depression. RESULTS: Patients (mean age 18.9 years, 44.1% male, Crohn's disease 60.4%) had disease in remission (75.4%), or mild, moderate and severe clinical disease activity in, respectively, 19.8%, 2.7% and 2.1%. Mild anxiety/depressive symptoms were present in 35.2% and severe symptoms in 12.4% of patients. Elevated symptoms of either anxiety (28.3%), depression (2.9%) or both (15.8%) were found and did not differ between adolescents (10-17 years) and young adults (18-25 years). Active disease significantly predicted depressive symptoms (odds ratio (OR): 4.6 [95% confidence interval [CI]: 2.4-8.8], P < 0.001). Female gender (OR: 1.7 [95% CI: 1.1-2.7]), active disease (OR: 1.9 [95% CI: 1.1-3.2]) and a shorter disease duration (OR: 1.3 [95% CI: 0.6-1.0) (all P < 0.025) significantly predicted anxiety and/or depressive symptoms. CONCLUSIONS: Considering the high prevalence of anxiety and depressive symptoms, psychological screening is recommended in young IBD patients. Screening facilitates early recognition and psychological treatment. Female patients and patients with active disease are the most vulnerable.

Development of the Drooling Infants and Preschoolers Scale (DRIPS) and reference charts for monitoring saliva control in children aged 0-4 years.

OBJECTIVES: To develop and validate a parent questionnaire to quantify drooling severity and frequency in young children (the Drooling Infants and Preschoolers Scale - the DRIPS). To investigate development of saliva control in typically developing young children in the age of 0-4 years. To construct sex-specific reference charts presenting percentile curves for drooling plotted for age to monitor the development of saliva control in infancy and preschool age. STUDY DESIGN: The DRIPS was developed consisting of 20 items to identify severity and frequency of drooling during meaningful daily activities. Factor analysis was performed to test construct validity. A piecewise logistic regression was followed by a piecewise linear regression to construct sex-specific reference charts. RESULTS: We obtained 652 completed questionnaires from parents of typically developing children. The factor analysis revealed four discriminating components: drooling during Activities, Feeding, Non nutritive sucking, and Sleep. To illustrate the development of saliva control, eight sex-specific reference curves were constructed to plot the scores of the DRIPS by age group, at the 15th, 50th, 85th and 97th percentile. About 3-15% of the preschoolers in our cohort did not acquire full saliva control at the age of 4 years. CONCLUSIONS: With the DRIPS it is possible to validly compare and visualize the development of saliva control in an individual infant or preschooler and allow clinicians to timely initiate individually targeted interventions if children outperform.

The pan phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) blocks survival, adhesion and proliferation of primary chronic lymphocytic leukemia cells.

The phosphoinositide 3-kinases (PI3Ks) are critical components of the B-cell receptor (BCR) pathway and have an important role in the pathobiology of chronic lymphocytic leukemia (CLL). Inhibitors of PI3Kδ block BCR-mediated cross-talk between CLL cells and the lymph node microenvironment and provide significant clinical benefit to CLL patients. However, the PI3Kδ inhibitors applied thus far have limited direct impact on leukemia cell survival and thus are unlikely to eradicate the disease. The use of inhibitors of multiple isoforms of PI3K might lead to deeper remissions. Here we demonstrate that the pan-PI3K/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) was more pro-apoptotic to CLL cells--irrespective of their ATM/p53 status--than PI3Kα or PI3Kδ isoform selective inhibitors. Furthermore, SAR245409 blocked CLL survival, adhesion and proliferation. Moreover, SAR245409 was a more potent inhibitor of T-cell-mediated production of cytokines, which support CLL survival. Taken together, our in vitro data provide a rationale for the evaluation of a pan-PI3K inhibitor in CLL patients.

Inertial control as novel technique for in vitro gait simulations.

In vitro gait simulations are a preferential platform to study new intervention techniques or surgical procedures as they allow studying the isolated effect of surgical interventions. Commonly, simulations are performed by applying pre-defined setpoints for the kinetics and kinematics on all degrees of freedom (DOFs) of the cadaveric specimen. This however limits the applicability of the experiment to simulations for which pre-defined kinematics and kinetics can be measured in vivo. In this study we introduce inertial control as a new methodology for gait simulations that omits the need for pre-defined setpoints for the externally applied vertical ground reaction force (vGRF) and therefore allows the effect of interventions to be reflected upon it. Gait simulations of stance (1 s) were performed in 10 cadaveric specimens under three clinically relevant conditions: native ankle, total ankle prosthesis (TAP) and total ankle prosthesis plus triple arthrodesis (TAP+TA). In the native ankle, simulated vGRF was compared against the vGRF measured in vivo in 15 healthy volunteers and high correlations were found (R(2)=0.956, slope of regression line S=1.004). In TAP and TAP+TA, vGRF changed, therefore confirming the sensitivity of the method to kinematic constrains imposed with surgery. Inertial control can replicate in vivo kinetic conditions and allows investigating the isolated effect of surgical interventions on kinematic as well as kinetics.

Low-dose valganciclovir for cytomegalovirus prophylaxis in heart transplant recipients.

We retrospectively assessed our center's experience with a protocol of low-dose (450 mg once daily) valganciclovir administered for 3-6 months (median 5 months) in a cohort of of 55 cytomegalovirus (CMV) donor-positive (D+) and/or recipient-positive (R+) heart transplant recipients. Although no CMV disease occurred in patients while receiving low-dose valganciclovir, during the 12-month post-transplantation observation period of this study, 4 (22.2%) of the 18 D+/R- patients and 1 (2.7%) of the 37 R+ patients developed symptomatic CMV viremia. Leukopenia was frequent, including neutropenia [absolute neutrophil count (ANC), <1,000 cells/µL] that occurred in 21.8% and severe neutropenia (ANC <500 cells/µL) in 7.3%. Among CMV R+ heart transplant recipients, low-dose valganciclovir appeared to be an effective, less expensive strategy for CMV prophylaxis; however, caution may be necessary among D+/R- recipients.

Self-management treatment of drooling: a case series.

Behavioral treatment of drooling is advocated widely, but evidence of its effectiveness is lacking. In a center-based case-series study, 10 participants with severe drooling were taught self-management skills to reduce drooling. Following treatment, all participants remained dry for intervals of 30-60 min, while being engaged in daily activities. Generalization to the classroom occurred in each participant. For three participants, maintenance of treatment effect was established at 6 and 24 weeks. Seven participants failed to maintain self-management skills at follow-up. Although the self-management procedure showed promising results, further adaptations are required to improve efficacy, generalization, and maintenance.

Weight loss in Huntington disease increases with higher CAG repeat number.

OBJECTIVE: Huntington disease (HD) is a hereditary neurodegenerative disorder caused by an expanded number of CAG repeats in the huntingtin gene. A hallmark of HD is unintended weight loss, the cause of which is unknown. In order to elucidate the underlying mechanisms of weight loss in HD, we studied its relation to other disease characteristics including motor, cognitive, and behavioral disturbances and CAG repeat number. METHODS: In 517 patients with early stage HD, we applied mixed-effects model analyses to correlate weight changes over 3 years to CAG repeat number and various components of the Unified Huntington's Disease Rating Scale (UHDRS). We also assessed the relation between CAG repeat number and body weight and caloric intake in the R6/2 mouse model of HD. RESULTS: In patients with HD, mean body mass index decreased with -0.15 units per year (p < 0.001). However, no single UHDRS component, including motor, cognitive, and behavioral scores, was independently associated with the rate of weight loss. Patients with HD with a higher CAG repeat number had a faster rate of weight loss. Similarly, R6/2 mice with a larger CAG repeat length had a lower body weight, whereas caloric intake increased with larger CAG repeat length. CONCLUSIONS: Weight loss in Huntington disease (HD) is directly linked to CAG repeat length and is likely to result from a hypermetabolic state. Other signs and symptoms of HD are unlikely to contribute to weight loss in early disease stages. Elucidation of the responsible mechanisms could lead to effective energy-based therapeutics.

The influence of artificially increased trunk stiffness on the balance recovery after a trip.

Falls occur frequently in the growing population of elderly. Since trunk control is critical for maintaining balance, the higher trunk stiffness in elderly people compared to the general population has been associated with their increased fall-risk. Theoretically, trunk stiffness may be beneficial for balance recovery in walking, i.e. after a trip. A stiff joint may provide a torque that restricts the perturbation effects and thereby reduces the probability of a fall. The aim of this study was to test whether trunk stiffness impaired or assisted balance recovery after a trip during walking. An orthopedic corset was used to simulate trunk stiffness in 11 young male adults. Subjects walked over a platform, with or without the corset on, and were occasionally tripped over a hidden obstacle. Kinematics of the tripping reaction were measured. Initial trunk accelerations were significantly attenuated by the corset, which indicates a positive effect of the stiffening corset. However, no subsequent effects on peak trunk inclination and on the peak moment arm of gravity on the trunk were found. The pattern of trunk motion allowed ample time for triggered or voluntary muscle responses to be generated, before a substantial inclination occurred. It appears that such active responses were sufficient in the young subjects tested to obtain a similar net effect with or without the increased trunk stiffness induced by the corset.

Postural control of the trunk during unstable sitting in Parkinson's disease.

Postural instability and falls, both common in Parkinson's disease (PD), have been related to altered trunk control. In this study, we investigated dynamic trunk control with subjects balancing on a seat mounted on a hemisphere, for up to 15s in five trials. We compared eight PD patients with a fall-history, eight without a fall-history, and eight matched healthy subjects. The number of trials completed without balance loss and the time to balance loss were significantly lower in PD patients as compared to healthy controls, whereas the PD patients with a fall-history did not perform significantly less than the patients without a fall-history. Multivariate analysis of variance showed significant effects of group on movements of the center of pressure (CoP) under the seat with the largest amplitudes among the PD fallers and the smallest amplitudes among the healthy controls. Univariate analyses revealed that this effect was mainly based on a significantly larger root mean square CoP displacement in the medio-lateral direction, with significant post hoc differences between all three groups. Trunk angular deviations were significantly smaller among PD patients than controls. Finally, both CoP movements and trunk movements had a significantly lower frequency content and were thus slower in PD patients than in controls, except for anterior-posterior CoP movements. The results show that trunk control is affected in PD and suggest that these changes may be related to postural instability and fall risk.

Relative abundance and survival of the tick Amblyomma americanum collected from sunlit and shaded habitats.

The population density of host-searching nymphal and adult lone star ticks, Amblyomma americanum (L.) (Acari: Ixodidae), was determined at the Robinson tract of the Kansas Ecological Reserves and a private farm 5 km north-west of the Robinson tract using standard drag cloth methods. Nymphs, males and females were counted and collected weekly from shaded habitats and adjacent sunlit habitats from mid-May through late July, 2003. Of the 1598 nymphs and 549 males collected by drag sampling, 74.0% and 72.1%, respectively, were collected from shaded sections of the habitats, whereas 77.3% of 472 females were found in sunlit sections. A. americanum collected during each sampling period were maintained unfed at >95% relative humidity and a 14 : 10 h photoperiod, and survival was recorded weekly until all ticks had died. Survival of nymphs, males and females did not differ between ticks collected in the shade vs. those collected in the sun. Nymphs survived significantly longer than adults, whereas male and female survival did not differ from each other. These results suggest that host-searching A. americanum populations may partition their environment to increase the chances of coming into contact with a potential vertebrate host.

Factors underlying the perturbation resistance of the trunk in the first part of a lifting movement.

In the first part of lifting movements, the trunk movement is surprisingly resistant to perturbations. This study examined which factors contribute to this perturbation resistance of the trunk during lifting. Three possible mechanisms were studied: force-length-velocity characteristics of muscles, the momentum of the trunk as well as the effect of passive extending of the elbows. A forward dynamics modelling and simulation approach was adopted with two different input signals: (1) stimulation of Hill-type muscles versus (2) net joint moments. Experimental data collected during an unperturbed lifting movement were used as a reference, which a simulated lifting movement had to resemble. Subsequently, the simulated lifting movement was perturbed by applying 10 kg extra mass at the wrist (both before and after lift-off and with/without a fixed elbow), without modifying the input signals. The momentum of the trunk appeared to be insufficient to explain the perturbation resistance of trunk movements as found experimentally. In addition to the momentum of the trunk, the force-length-velocity characteristics of the muscles are necessary to account for the observed perturbation resistance. Initial extension of the elbow due to the mass perturbation delayed the propagation of the load to the shoulder. However, this delay is reduced due to the impedance at the elbow provided by the characteristics of muscles spanning the elbow. So, the force-length-velocity characteristics of the muscles spanning the elbow joint increase the perturbation at the trunk.

Out-of-plane trunk movements and trunk muscle activity after a trip during walking.

Tripping during gait occurs frequently. A successful balance recovery implies that the forward body rotation is sufficiently reduced. In view of this, adequate control of the trunk momentum is important, as the trunk has a high inertia. The aim of this study was to establish out-of-plane trunk movements after a trip and to determine trunk muscle responses. Ten male volunteers repeatedly walked over a platform in which 21 obstacles were hidden. Each subject was tripped over one of these obstacles at mid-swing of the left foot in at least five trials. Kinematics, dynamics, and muscle activity of the main trunk muscles were measured. After a trip, an increase in trunk flexion was observed (peak flexion 37 degrees). In addition, considerable movements outside the sagittal plane (up to 20 degrees) occurred. Already before landing of the blocked foot, the trunk forward bending movement was reduced, while trunk torsion and lateral rotation were still increasing. Fast responses were seen in both abdominal and back muscles, indicating stiffening of the trunk. These muscle responses preceded the mechanical trunk disturbances, which implies that these responses were triggered by other mechanisms (such as afferent signals from the extremities) rather than a simple stretch reflex. A second burst of predominantly trunk muscle extensor activity was seen at landing, suggesting specific anticipation of the trunk muscles to minimize trunk movements due to landing. In conclusion, despite large movements outside the sagittal plane, it appears that trunk muscle responses to trips are aspecific and especially aimed at minimizing trunk forward bending.

Intrathecal injection of GDNF and BDNF induces immediate early gene expression in rat spinal dorsal horn.

Glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) are potent trophic factors for dorsal root ganglion cells. In addition, these factors are produced in subsets of dorsal root ganglion cells and transported anterogradely to their terminals in the superficial dorsal horn of the spinal cord, where they constitute the only source of GDNF and BDNF. We investigated the effect of 10 mug GDNF and BDNF injected by lumbar puncture on the expression of the immediate early gene (IEG) products c-Fos, c-Jun, and Krox-24 in the adult rat dorsal horn. In the dorsal horn of S1 spinal segments, GDNF and BDNF induced a strong increase in IEG expression, which was most pronounced in laminae I and II (2.9- to 4.5-fold). More distal from the injection site, in the dorsal horn of L1/L2 spinal segments, the increase in IEG expression was less pronounced, suggesting a concentration-dependent effect. In order to explain the effects of intrathecally injected GDNF, we investigated whether lumbo-sacral dorsal horn neurons expressed RET protein, the signal-transducing element of the receptor complex for GDNF. It was found that several of these neurons contained RET immunoreactivity and that some of the RET-labeled neurons had the appearance of nociceptive-specific cells, confirming their presumed role in pain transmission. Additionally, using double-labeling immunofluorescence combined with confocal microscopy, it was found that after intrathecal GDNF injection 35% of c-Fos-labeled cells were also labeled for RET. These results demonstrate that intrathecally administered GDNF and BDNF induce IEG expression in dorsal horn neurons in the adult rat, supposedly by way of their cognate receptors, which are present on these neurons. We further suggest that the endogenous release of GDNF and BDNF, triggered by nociceptive stimuli, is involved in the induction of changes in spinal nociceptive transmission as in various pain states.

Cervical adult rhabdomyoma presenting as a rapidly growing mass in a patient with diffuse large B-cell non-Hodgkin's lymphoma.

BACKGROUND: Adult rhabdomyoma is a rare mesenchymal tumor, which generally grows slowly and is mainly localized in the head and neck area. PATIENT AND METHODS: We report the extraordinary case of a rapidly growing adult rhabdomyoma in a 73-year-old man. The patient was treated for diffuse large B-cell non-Hodgkin's lymphoma with CHOP therapy (doxorubicin, cyclophosphamide, vincristine, and prednisone). Comparison of the respective computed tomography scans showed prominent enlargement of 35% in the tumor mass volume on the right side of the neck within 3 months. The tumor was highly suspicious for lymphoma. Surgical resection was performed. RESULTS: Histological examination revealed a tumor which was composed of tightly packed polygonal cells with a PAS-positive granular or vacuolated cytoplasm, occasionally with cross-striations. Immunohistochemically, the cells were positive for desmin, myogenin, Myo-D1, but negative for S-100. Due to these characteristic morphologies, adult rhabdomyoma was diagnosed. CONCLUSION: This is the first report on an adult rhabdomyoma with a proven rapid enlargement. The possible pathomechanisms are discussed.

Modulation of cutaneous reflexes in hindlimb muscles during locomotion in the freely walking rat: A model for studying cerebellar involvement in the adaptive control of reflexes during rhythmic movements.

This study aims to demonstrate stepphase-dependent modulation in the gain of cutaneously triggered reflexes in the freely locomoting rat. Electromyographic recordings of biceps femoris (mainly involved in knee flexion) and gastrocnemius (mainly involved in ankle extension) muscles were continuously monitored during locomotion and cutaneous reflexes were induced by subcutaneously placed stimulation electrodes in the lateral malleolal region. The results show that the reflex responses in both muscles during locomotion were generally reduced compared to reflexes induces in rest. For the biceps femoris reduction of reflex gain was highest during the stance phase whereas for the gastrocnemius the period of highest depression was found during the swing phase. We conclude that stepphase-dependent modulation of peripheral reflexes can be measured in freely locomoting rats and generally concur with previous studies in cat and man that this type of modulation may be functionally important for maintaining and adjusting gait. Moreover, although the mechanism of inducing and maintaining this modulation is not fully known, it is now open to experimental investigation in rodents.

Minimal change esophagitis: prospective comparison of endoscopic and histological markers between patients with non-erosive reflux disease and normal controls using magnifying endoscopy.

INTRODUCTION: More than half the patients with gastroesophageal reflux disease (GERD) show no endoscopic abnormality or minimal change esophagitis (non-erosive reflux disease, NERD). We investigated the value of endoscopic and histological markers for the prediction of NERD before and after treatment with 20 mg esomeprazole. METHODS: Between July and October 2002, consecutive patients presenting for upper endoscopy were stratified into GERD and non-reflux patients (control group) with the help of a questionnaire. The endoscopist was blind to the presence of reflux symptoms. Using magnifying endoscopes minimal change esophagitis was defined by the presence of vascular injection or vascular spots above the Z-line, villous mucosal surface and islands of squamous cell epithelium below the Z-line. Targeted and random biopsies were taken below and above the Z-line. Patients with endoscopically visible classical signs of esophagitis (Los Angeles A-D) or histologically proven Barrett's esophagus were not further investigated in the study (drop out). The esophageal specimens were histologically evaluated for erosions, infiltration with leukocytes, hyperplasia of basal cells and length of papillae. Patients with NERD were treated with 20 mg esomeprazole/day for 4 weeks and reevaluated by endoscopy as described before. RESULTS: 39 patients with heartburn and 39 patients without reflux symptoms (controls) were finally included in the analysis (per protocol). Patients with NERD significantly (p = 0.005) more often showed endoscopic signs of minimal change esophagitis (27/39) than the control group (8/39). An increased length of papillae (14/39 versus 2/39; p = 0.005) and basal cell hyperplasia (17/39 versus 4/39; p = 0.009) were significantly more common in the heartburn group. After treatment with esomeprazole, no significant endoscopic or histological differences between the NERD and control group could be observed. CONCLUSIONS: Minimal change esophagitis can be seen with high resolution magnifying endoscopy. By combining endoscopic and histological markers NERD can be predicted with a sensitivity of 62% and a specificity of 74%. Treatment with esomeprazole for 4 weeks reverses the slight alterations to normal.

Is the trunk movement more perturbed after an asymmetric than after a symmetric perturbation during lifting?

Low back injury is associated with sudden movements and loading. Trunk motion after sudden loading depends on the stability of the spine prior to loading and on the trunk muscle activity in response to the loading. Both factors are not axis-symmetric. Therefore, it was hypothesized that the effects on trunk dynamics would be larger after an asymmetric than after a symmetric perturbation. Ten subjects lifted a crate in which, prior to lifting, a mass was displaced to the front or to the side without the subjects being aware of this. Crate and subject movements, crate reaction forces and muscle activity were recorded. From this, the stability prior to the perturbation was estimated, and the trunk angular kinematics and moments at the lumbo-sacral joint were calculated. Both perturbations only minimally affected the trunk kinematics, although the stability of the spine prior to the lifting movement was higher in the sagittal plane than in the frontal plane. In both conditions the stability appeared to be sufficient to absorb the applied perturbation.