Botulinum toxin injections minimally affect modelled muscle forces during gait in children with cerebral palsy.

BACKGROUND: Children with cerebral palsy (CP) present altered gait patterns and electromyography (EMG) activity compared to typically developing children. To temporarily reduce muscular activity and to correct the abnormal muscle force balance, Botulinum Toxin type A (BTX-A) injections are used. RESEARCH QUESTION: What is the effect of BTX-A injections on dynamic muscle forces during gait, when calculated using an EMG-constrained approach?. METHODS: Retrospective data of ten typically developing (TD) and fourteen children with spastic diplegic CP were used for musculoskeletal modeling and dynamic simulations of gait, before and after BTX-A treatment. Individual muscle forces were calculated using an EMG-constrained optimization, in which EMG of eight muscles was used as muscle excitation signal to constrain the muscle activation patterns. Paired t-tests were used to compare average modelled muscle forces in different phases of the gait cycle pre- and post-BTX-A, summarized in the muscle profile score. Two-sample t-tests were used to determine significant differences between TD and pre- and post-BTX-A modelled muscle forces. RESULTS: For most muscles, the force was decreased in CP compared to TD children in all phases of the gait cycle, both before and after BTX-A treatment. Differences in muscle forces before and after BTX-A treatment were limited, with only few significant differences between pre- and post-BTX-A. Compared to a standard static optimization approach, imposing the EMG activity increased modelled muscle forces for most muscles. SIGNIFICANCE: Our findings indicate that BTX-A treatment has a limited effect on the muscle balance in CP children. Besides that, the use of EMG-constrained optimization is recommended when studying muscle balance in children with CP.

Single-event multilevel surgery, but not botulinum toxin injections normalize joint loading in cerebral palsy patients.

BACKGROUND: Many patients with cerebral palsy present a pathologic gait pattern, which presumably induces aberrant musculoskeletal loading that interferes with natural bone growth, causing bone deformations on the long term. Botulinum toxin interventions and single-event multilevel surgeries are used to restore the gait pattern, assuming that a normal gait pattern restores musculoskeletal loading and thus prevents further bone deformation. However, it is unknown if these interventions are able to restore musculoskeletal loading. Hence, we investigated the impact of botulinum toxin injections and single-event multilevel surgery on musculoskeletal loading. METHODS: Gait data collected in 93 children with bilateral cerebral palsy, which included pre- and post multi-level botulinum toxin (49 children) and single-event multilevel surgery (44 children) assessments, and 15 typically developing children were retrospectively processed using a musculoskeletal modelling workflow to calculate joint angles, moments, muscle and joint contact force magnitudes and orientations. Differences from the typically developing waveform were expressed by a root-mean square difference were compared using paired t-tests for each intervention separately (alpha <0.05). FINDINGS: Botulinum toxin induced significant changes in the joint angles, but did not improve the muscle and joint contact forces. Single-event multilevel surgery induced significant kinematic and kinetic changes, which were associated with improved muscle and joint contact forces. INTERPRETATION: The present results indicate that botulinum toxin injections were not able to restore normal gait kinematics nor musculoskeletal loading, whereas single-event multilevel surgery did successfully restore both. Therefore, single-event multilevel surgery might be protective against the re-occurrence of bone deformation on the longer term.

Reliability of joint kinematic calculations based on direct kinematic and inverse kinematic models in obese children.

BACKGROUND: In recent years, the reliability of inverse (IK) and direct kinematic (DK) models in gait analysis have been assessed intensively, but mainly for lean populations. However, obesity is a growing issue. So far, the sparse results available for the reliability of clinical gait analysis in obese populations are limited to direct kinematic models. Reliability error-margins for inverse kinematic models in obese populations have not been reported yet. RESEARCH QUESTIONS: Is there a difference in the reliability of IK models compared with a DK model in obese children? Are there any differences in the joint kinematic output between IK and DK models? METHODS: A test-retest study was conducted using three-dimensional gait analysis data from two obese female and eight obese male participants from an earlier study. Data were analyzed using a DK model and two OpenSim-based IK models. Test-retest reliability was compared by calculating the Standard Error of Measurement (SEM) along with similar absolute reliability measures. A Friedman Test was used to assess whether there were any significant differences in the reliability between the models. Kinematic output of the models was compared by using Statistical Parametric Mapping (SPM). RESULTS: No significant differences were found in the reliability between the DK and IK models. The SPM analysis indicated several significant differences between both IK models and the DK approach. Most of these differences were continuous offsets. SIGNIFICANCE: Reliability values showed clinically acceptable error-margins and were comparable between all models. Therefore, our results support the careful use of IK models in overweight or obese populations, e.g. for musculoskeletal modelling studies. The inconsistent kinematic output can mainly be explained by different model conventions and anatomical segment coordinate frame definitions.

Joint kinematic calculation based on clinical direct kinematic versus inverse kinematic gait models.

Most clinical gait laboratories use the conventional gait analysis model. This model uses a computational method called Direct Kinematics (DK) to calculate joint kinematics. In contrast, musculoskeletal modelling approaches use Inverse Kinematics (IK) to obtain joint angles. IK allows additional analysis (e.g. muscle-tendon length estimates), which may provide valuable information for clinical decision-making in people with movement disorders. The twofold aims of the current study were: (1) to compare joint kinematics obtained by a clinical DK model (Vicon Plug-in-Gait) with those produced by a widely used IK model (available with the OpenSim distribution), and (2) to evaluate the difference in joint kinematics that can be solely attributed to the different computational methods (DK versus IK), anatomical models and marker sets by using MRI based models. Eight children with cerebral palsy were recruited and presented for gait and MRI data collection sessions. Differences in joint kinematics up to 13° were found between the Plug-in-Gait and the gait 2392 OpenSim model. The majority of these differences (94.4%) were attributed to differences in the anatomical models, which included different anatomical segment frames and joint constraints. Different computational methods (DK versus IK) were responsible for only 2.7% of the differences. We recommend using the same anatomical model for kinematic and musculoskeletal analysis to ensure consistency between the obtained joint angles and musculoskeletal estimates.

Influence of secondary settling tank performance on suspended solids mass balance in activated sludge systems.

Secondary settling is the final step of the activated sludge-based biological waste water treatment. Secondary settling tanks (SSTs) are therefore an essential unit of producing a clear effluent. A further important function of SSTs is the sufficient thickening to achieve highly concentrated return sludge and biomass within the biological reactor. In addition, the storage of activated sludge is also needed in case of peak flow events (Ekama et al., 1997). Due to the importance of a high SST performance the problem has long been investigated (Larsen, 1977; Krebs, 1991; Takács et al., 1991; Ekama et al., 1997; Freimann, 1999; Patziger et al., 2005; Bürger et al., 2011), however, a lot of questions are still to solve regarding e.g. the geometrical features (inflow, outflow) and operations (return sludge control, scraper mechanism, allowable maximum values of surface overflow rates). In our study we focused on SSTs under dynamic load considering both the overall unsteady behaviour and the features around the peaks, investigating the effect of various sludge return strategies as well as the inlet geometry on SST performance. The main research tool was a FLUENT-based novel mass transport model consisting of two modules, a 2D axisymmetric SST model and a mixed reactor model of the biological reactor (BR). The model was calibrated and verified against detailed measurements of flow and concentration patterns, sludge settling, accompanied with continuous on-line measurement of in- and outflow as well as returned flow rates of total suspended solids (TSS) and water. As to the inlet arrangement a reasonable modification of the geometry could result in the suppression of the large scale flow structures of the sludge-water interface thus providing a significant improvement in the SST performance. Furthermore, a critical value of the overflow rate (q(crit)) was found at which a pronounced large scale circulation pattern develops in the vertical plane, the density current in such a way hitting the outer wall of the SST, turning then to the vertical direction accompanied with significant flow velocities. This phenomenon strengthens with the hydraulic load and can entrain part of the sludge thus resulting in unfavourable turbid effluent. As a representative case study an operating circular SST most commonly used in practice was investigated. Focusing on the sludge return strategies, it was found that up to a threshold peak flow rate the most efficient way is to keep the return sludge flow rate constant, at 0.4Q(MAX). However, once the inflow rate exceeds the threshold value the return sludge flow rate should be slowly increased up to 0.6Q(MAX), performed in a delayed manner, about 20-30 min after the threshold value is exceeded. For preserving the methodology outlined in the present paper, other types of SSTs, however, need further individual investigations.

Analysing sludge balance in activated sludge systems with a novel mass transport model.

In activated sludge systems the mechanically treated wastewater is biologically cleaned by biomass (activated sludge). The basic requirement of an efficient biological wastewater treatment is to have as a high biomass concentration in the biological reactor (BR) as possible. The activated sludge balance in activated sludge systems is controlled by the settling, thickening, scraper mechanism in the secondary settling tank (SST) and sludge returning. These processes aim at keeping maximum sludge mass in the BR and minimum sludge mass in the SST even in peak flow events (storm water flow). It can be, however, only reached by a high SST performance. The main physical processes and boundary conditions such as inhomogeneous turbulent flow, geometrical features of the SST, wastewater treatment plant (WWTP) load, return sludge flow, sludge volume index etc. all influence settling thickening and sludge returning. In the paper a novel mass transport model of an activated sludge system is presented which involves a 2-dimensional SST model coupled with a mixed reactor model of the biological reactor. It makes possible to investigate different sludge returning strategies and their influence on the sludge balance of the investigated activated sludge system, furthermore, the processes determining the flow and concentration patterns in the SST. The paper gives an overview on the first promising model results of a prevailing peak flow event investigation at the WWTP of Graz.

Assessment of CSO loads--based on UVIVIS-spectroscopy by means of different regression methods.

The use of UV/VIS-spectroscopy for water quality measurements is based on the solution of the correlation between the surrogate parameter absorbance and the resulting equivalence parameters. The coherence of absorbance and equivalence parameters (CODtot, CODsol, TSS) is solved in this paper with different regression methods. The correlation of absorbance and concentrations are analysed based on linear regression methods, model tree regressions, multivariate regression methods and support vector machines using sequential minimal optimisation algorithm. For this purpose the regression methods are calibrated on three 24hours measurement campaigns of a combined sewer measurement station situated in the combined sewer overflow chamber in Graz (Austria). The online measurement station has been conveying data for more than 2 1/2 years up to now. Finally, the load calculation based on the different regression methods and its comparison demonstrate that an apparently complex model does not inevitably lead to accurate concentration values due to possible model overfitting. Hence, the paper points out the possibilities and the drawbacks of spectroscopy measuring in sewers and the arising concentration values.

Clinical evaluation of new assays for determination of serum calcitonin concentrations.

In order to test the clinical usefulness of new commercially available kits for determination of calcitonin serum concentrations, we investigated the family (N = 10) of a patient with medullary thyroid carcinoma and bilateral pheochromocytoma including his affected son, 10 athyreotic patients, totally thyroidectomized for non-medullary thyroid cancer, and 4 normal volunteers. Pentagastrin tests were performed in all subjects. Serum calcitonin levels before and after pentagastrin were determined by 4 kits. Kits A and B are immunoradiometric assays of the sandwich-type, kits C and D are radioimmunoassays, D being the one hitherto routinely used. Our results show that the new assays (kits A, B and C) have a better diagnostic accuracy in screening for medullary thyroid cancer than the RIA (kit D), hitherto used, where basal values overlapped with normals. Although basal values of normals were mostly near the detection limit of all 4 kits, kits A and B were sensitive enough to detect stimulation of calcitonin secretion by pentagastrin in all subjects with intact thyroid glands and kit C in most of them. The lack of increase in calcitonin after pentagastrin observed by kits A, B and C in athyreotic patients suggests deficiency of secretion of this hormone. Only kit D was unable to show this deficiency.

[Can the thyrotropin (TSH) suppressive dose of L-thyroxine (T4) be individually predicted in athyroid patients?]. / Kann die thyrotropin(TSH-)suppressive Dosis von L-Thyroxin (T4) bei athyreoten Patienten individuell vorausgesagt werden?

TSH-suppressive doses of L-thyroxine (T4) are needed in the treatment of athyreotic cancer patients in order to prevent metastases. We were interested to know whether the TSH-suppressive dose can be predicted on a body weight-or body surface basis in athyreotic individuals, which might save them the control TRH-test. 92 athyreotic patients (22 men, 70 females; age 25-81, mean 50.4 yrs; body weight ranging from 48-114 kg, mean 73), who have been operated for differentiated thyroid cancer and who have had at least one treatment ablative doses of 131-I, were investigated. After 4 weeks without thyroid hormone supplementation (checked by TSH serum concentration above 20 microU/ml) patients were set on 150 mcg of L-T4/day. TSH serum concentration before and 20' after 200 mcg of TRH were measured by the ultrasensitive TSH kit of Behringwerke. Total and free T4 as well as total T3 were also measured by radioimmunoassay kits. TRH tests were performed 6 weeks after start of treatment in 51 patients and 8 or more weeks respectively in 41 patients. Only the inclusion of the influence of age (multiple correlation) yielded a significant positive correlation between basal TSH and L-T4 dose/body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA-DR and differentiated thyroid cancer. Lack of association with the nonmedullary types and possible association with the medullary type.

One hundred twenty-seven white European patients with differentiated thyroid cancer were typed for human lymphocyte antigen (HLA) DR specificities. There was no significant deviation from the HLA-DR distribution observed in 160 normal patient controls, neither in the entire group nor in the patient groups with nonmedullary types of thyroid cancer (61 with papillary and 44 with follicular, all nonradiation associated). Also, subdivision of patients with nonmedullary thyroid cancer according to age at diagnosis, presence of metastases, and presence of thyroglobulin antibodies in serum showed no significant deviation from the HLA-DR distribution. For the patients with medullary thyroid cancer (only sporadic [n = 20] or inherited isolated [n = 2] forms, no multiple endocrine neoplasias), there was a significant increase of HLA-DR2 (11 of 22 cases [50%]) in comparison with control patients (22%; P corrected to 0.02; relative risk, 3.6). These data suggest, in contrast to previous reports, that there is no genetic influence on the development of nonmedullary types of differentiated thyroid cancer. Medullary thyroid cancer without multiple endocrine neoplasia, however, may be associated with HLA-DR2.

Changes in biochemical parameters during complete thyroid hormone deficiency of short duration in athyreotic patients.

The effect of withdrawal of suppressive therapy with thyroid hormones (200 micrograms L-thyroxine/day) on serum biochemical profiles and blood cell counts were studied in ten athyreotic thyroid carcinoma patients. After 14 days off therapy, all patients but one were still clinically and biochemically euthyroid. Twenty-eight days without thyroid hormones resulted in severe clinical and biochemical (TT4, TSH) hypothyroidism. At that time, the following parameters changed significantly: CPK activities increased (in five of ten patients above normal) as well as activities of SGOT, SGPT, and LDH (means and s.d.s within the respective normal ranges). Total cholesterol and triglycerides increased within the normal range. There were minimal but significant increases of serum creatinine and of mean corpuscular volume of erythrocytes as well as decreases of serum sodium and calcium. Our study underlines the importance of further investigation if pathologic biochemical or hematologic parameters are obtained in athyreotic patients after 4 wk withdrawal of thyroid hormone therapy.