Efficacy of baby-CIMT: study protocol for a randomised controlled trial on infants below age 12 months, with clinical signs of unilateral CP

BACKGROUND: Infants with unilateral brain lesions are at high risk of developing unilateral cerebral palsy (CP). Given the great plasticity of the young brain, possible interventions for infants at risk of unilateral CP deserve exploration. Constraint-induced movement therapy (CIMT) is known to be effective for older children with unilateral CP but is not systematically used for infants. The development of CIMT for infants (baby-CIMT) is described here, as is the methodology of an RCT comparing the effects on manual ability development of baby-CIMT versus baby-massage. The main hypothesis is that infants receiving baby-CIMT will develop manual ability in the involved hand faster than will infants receiving baby-massage in the first year of life. METHOD AND DESIGN: The study will be a randomised, controlled, prospective parallel-group trial. Invited infants will be to be randomised to either the baby-CIMT or the baby-massage group if they: 1) are at risk of developing unilateral CP due to a known neonatal event affecting the brain or 2) have been referred to Astrid Lindgren Children’s Hospital due to asymmetric hand function. The inclusion criteria are age 3–8 months and established asymmetric hand use. Infants in both groups will receive two 6-weeks training periods separated by a 6-week pause, for 12 weeks in total of treatment. The primary outcome measure will be the new Hand Assessment for Infants (HAI) for evaluating manual ability. In addition, the Parenting Sense of Competence scale and Alberta Infant Motor Scale will be used. Clinical neuroimaging will be utilized to characterise the brain lesion type. To compare outcomes between treatment groups generalised linear models will be used. DISCUSSION: The model of early intensive intervention for hand function, baby-CIMT evaluated by the Hand Assessment for Infants (HAI) will have the potential to significantly increase our understanding of how early intervention of upper limb function in infants at risk of developing unilateral CP can be performed and measured. TRIAL REGISTRATION: SFO-V4072/2012, 05/22/201

On the Determinants of Underwriting in Swedish Equity Offerings

This thesis studies the choice of floatation method using a dataset based on 703 public offerings in Sweden between 2006 and 2017. A logistic model is utilised to study the determinants of underwriting, an ordinary least square model to estimate the direct cost of floatation, and the cost of underwriting is estimated using the Heckman sample selection model. The results are generally aligned with existing research and suggest that underwriters are providers of signalling in equity offerings, but are for our sample to be considered imperfect in providing certification. In contrast to existing beliefs of shareholder takeup, the likelihood of underwriting is increasing in expected shareholder takeup from subscription precommitments. Our explanation for this is bilateral. On the one side, we argue that risk averse firms can ensure successful offerings by using a combination of subscription precommitments and underwriting. On the other side, we reason that high subscription precommitments indicate concentrations of large shareholders. Accordingly, we propose that underwriting in these equity offerings may be a result of agency problems between shareholders. Furthermore, a rights issue paradox is insinuated in the Swedish equity market. However, we limit our inference to mere indications as opposed to definite conclusions, and emphasise that an estimation of the indirect costs is needed to assert the presence of such paradox. Finally, we find that there are economies of scale of underwriting and that the cost of underwriting is decreasing in the insured share in the equity offering.This thesis studies the choice of floatation method using a dataset based on 703 public offerings in Sweden between 2006 and 2017. A logistic model is utilised to study the determinants of underwriting, an ordinary least square model to estimate the direct cost of floatation, and the cost of underwriting is estimated using the Heckman sample selection model. The results are generally aligned with existing research and suggest that underwriters are providers of signalling in equity offerings, but are for our sample to be considered imperfect in providing certification. In contrast to existing beliefs of shareholder takeup, the likelihood of underwriting is increasing in expected shareholder takeup from subscription precommitments. Our explanation for this is bilateral. On the one side, we argue that risk averse firms can ensure successful offerings by using a combination of subscription precommitments and underwriting. On the other side, we reason that high subscription precommitments indicate concentrations of large shareholders. Accordingly, we propose that underwriting in these equity offerings may be a result of agency problems between shareholders. Furthermore, a rights issue paradox is insinuated in the Swedish equity market. However, we limit our inference to mere indications as opposed to definite conclusions, and emphasise that an estimation of the indirect costs is needed to assert the presence of such paradox. Finally, we find that there are economies of scale of underwriting and that the cost of underwriting is decreasing in the insured share in the equity offering

Muscle strength does not explain standing ability in children with bilateral spastic cerebral palsy: a cross sectional descriptive study

BACKGROUND: In bilateral cerebral palsy (CP) muscle strength is considered important for development of gross motor functions, but its influence on standing ability has not been explored. Our aims were to examine muscle strength with respect to the ability to stand with (SwS) or without (SwoS) hand support, asymmetrical weight bearing (WB), and whether the ability to produce strength was influenced by different seated conditions. METHODS: In this cross sectional descriptive study standing posture was recorded with 3D motion analysis, and muscle strength was measured with a hand-held dynamometer, in 25 children with bilateral CP, GMFCS levels II-III, SwS (n = 14, median age 11.4 years), or SwoS, (n = 11, median age 11.4 years). Strength measurements were taken in the hip flexors, knee extensors, dorsiflexors and plantarflexors, in two seated conditions; a chair with arm- and backrests, and a stool. RESULTS: Compared to SwoS, children SwS stood with a more flexed posture, but presented with equal strength in the hip flexors, dorsiflexors and plantarflexors, and with somewhat more strength in the knee extensors. Despite asymmetric WB during standing, both limbs were equally strong in the two groups. No differences in strength were measured between the two seated conditions. CONCLUSIONS: Despite challenges measuring muscle strength in CP, the lower limb muscle strength cannot be considered an explanatory factor for variations in standing in this group of children with bilateral CP. The findings rather strengthen our hypothesis that deficits in the sensory systems could be as determinant for standing as muscle weakness in children with bilateral spastic CP

Preclinical Pharmacology of [2-(3-Fluoro-5-Methanesulfonyl-phenoxy)Ethyl](Propyl)amine (IRL790), a Novel Dopamine Transmission Modulator for the Treatment of Motor and Psychiatric Complications in Parkinson Disease.

IRL790 ([2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine, mesdopetam) is a novel compound in development for the clinical management of motor and psychiatric disabilities in Parkinson disease. The discovery of IRL790 was made applying a systems pharmacology approach based on in vivo response profiling. The chemical design idea was to develop a new type of DA D3/D2 receptor type antagonist built on agonist rather than antagonist structural motifs. We hypothesized that such a dopamine antagonist with physicochemical properties similar to agonists would exert antidyskinetic and antipsychotic effects in states of dysregulated dopaminergic signaling while having little negative impact on physiologic dopamine transmission and, hence, minimal liability for side effects related to dopamine-dependent functions. At the level of in vivo pharmacology, IRL790 displays balancing effects on aberrant motor phenotypes, reducing l-DOPA-induced dyskinesias in the rodent 6-hydroxydopamine lesion model and reducing psychostimulant-induced locomotor hyperactivity elicited by pretreatment with either d-amphetamine or dizocilpine, without negatively impacting normal motor performance. Thus, IRL790 has the ability to normalize the behavioral phenotype in hyperdopaminergic as well as hypoglutamatergic states. Neurochemical and immediate early gene (IEG) response profiles suggest modulation of DA neurotransmission, with some features, such as increased DA metabolites and extracellular DA, shared by atypical antipsychotics and others, such as increased frontal cortex IEGs, unique to IRL790. IRL790 also increases extracellular levels of acetylcholine in the prefrontal cortex and ventral hippocampus. At the receptor level, IRL790 appears to act as a preferential DA D3 receptor antagonist. Computational docking studies support preferential affinity at D3 receptors with an agonist-like binding mode. SIGNIFICANCE STATEMENT: This paper reports preclinical pharmacology along with molecular modeling results on IRL790, a novel compound in clinical development for the treatment of motor and psychiatric complications in advanced Parkinson disease. IRL790 is active in models of perturbed dopaminergic and glutamatergic signaling, including rodent 6-hydroxydopamine l-DOPA-induced dyskinesias and psychostimulant-induced hyperactivity, in a dose range that does not impair normal behavior. This effect profile is attributed to interactions at dopamine D2/D3 receptors, with a 6- to 8-fold preference for the D3 subtype

(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) - a novel cortical-preferring catecholamine transmission- and cognition-promoting agent

YesHere we describe for the first time the distinctive pharmacological profile for IRL752, a new phenyl-pyrrolidine derivative with regio-selective CNS transmission-enhancing properties. IRL752 (3.7-150 μmol/kg, s.c.) was characterised through extensive in vivo studies, using behavioural, tissue neurochemical and gene expression, as well as microdialysis methods. Behaviourally, the compound normalised tetrabenazine-induced hypoactivity, while unable to stimulate basal locomotion in normal animals or to either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across NA- and DA-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related IEGs (immediate early genes) however increased by 1.5- to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600-750% above baseline, while striatal DA remained unaltered and NA rose to ~250%; cortical and hippocampal dialysate ACh increased to ~250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also pro-cognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data, coupled to drug exposure support the hypothesis that 5‑HT7 receptor and α2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions where these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson's Disease

Teager–Kaiser energy operator signal conditioning improves EMG onset detection

Accurate identification of the onset of muscle activity is an important element in the biomechanical analysis of human movement. The purpose of this study was to determine if inclusion of the Teager–Kaiser energy operator (TKEO) in signal conditioning would increase the accuracy of popular electromyography (EMG) onset detection methods. Three methods, visual determination, threshold-based method, and approximated generalized likelihood ratio were used to estimate the onset of EMG burst with and without TKEO conditioning. Reference signals, with known onset times, were constructed from EMG signals collected during isometric contraction of the vastus lateralis (n = 17). Additionally, vastus lateralis EMG signals (n = 255) recorded during gait were used to evaluate a clinical application of the TKEO conditioning. Inclusion of TKEO in signal conditioning significantly reduced mean detection error of all three methods compared with signal conditioning without TKEO, using artificially generated reference data (13 vs. 98 ms, p < 0.001) and also compared with experimental data collected during gait (55 vs. 124 ms, p < 0.001). In conclusion, addition of TKEO as a step in conditioning surface EMG signals increases the detection accuracy of EMG burst boundaries

The neurochemistry of therapeutics: Levodopa pharmacodynamics in Parkinson's disease

No abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34884/1/62_ftp.pd

The role of visual stimuli on standing posture in children with bilateral cerebral palsy

BACKGROUND: In children with bilateral cerebral palsy (CP) maintaining a standing position can be difficult. The fundamental motor task of standing independently is achieved by an interaction between the visual, somatosensory, and vestibular systems. In CP, the motor disorders are commonly accompanied by sensory and perceptual disturbances. Our aims were to examine the influence of visual stimuli on standing posture in relation to standing ability. METHODS: Three dimensional motion analysis with surface electromyography was recorded to describe body position, body movement, and muscle activity during three standing tasks: in a self-selected position, while blindfolded, and during an attention-demanding task. Participants were twenty-seven typically-developing (TD) children and 36 children with bilateral CP, of which 17 required support for standing (CP-SwS) and 19 stood without support (CP-SwoS). RESULTS: All children with CP stood with a more flexed body position than the TD children, even more pronounced in the children in CP-SwS. While blindfolded, the CP-SwS group further flexed their hips and knees, and increased muscle activity in knee extensors. In contrast, the children in CP-SwoS maintained the same body position but increased calf muscle activity. During the attention-demanding task, the children in CP-SwoS stood with more still head and knee positions and with less muscle activity. CONCLUSIONS: Visual input was important for children with CP to maintain a standing position. Without visual input the children who required support dropped into a further crouched position. The somatosensory and vestibular systems alone could not provide enough information about the body position in space without visual cues as a reference frame. In the children who stood without support, an intensified visual stimulus enhanced the ability to maintain a quiet standing position. It may be that impairments in the sensory systems are major contributors to the difficulties to stand erect in children with CP

Imaging the Dopamine Uptake Site with Ex Vivo [ 18 F]GBR 13119 Binding Autoradiography in Rat Brain

We studied the binding of [ 18 F]GBR 13119 {1-[[(4-[ 18 F]fluorophenyl) (phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine} to rat brain with autoradiography after intravenous injection. The rank order of binding was dorsal striatum > nucleus accumbens = olfactory tubercle > sub-stantia nigra = ventral tegmental area > other areas. Binding was blocked by prior injection of dopamine uptake blockers but not by injection of dopamine receptor antagonists or drugs that bind to the dialkylpiperazine site. Unilateral 6-hydroxy dopamine lesions of dopamine neurons caused a marked decrease in striatal and nigral binding on the side of the lesion. We conclude that intravenous injection of [ 18 F]GBR 13119 provides a useful marker of presynaptic dopamine uptake sites.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66209/1/j.1471-4159.1990.tb04178.x.pd