Evidence-based perspective on CP rehabilitation : Reviews on physiotherapy, physiotherapy-related motor-based interventions and orthotic devices

This thesis utilises an evidence-based approach to critically evaluate and summarize effectiveness research on physiotherapy, physiotherapy-related motor-based interventions and orthotic devices in children and adolescents with cerebral palsy (CP). It aims to assess the methodological challenges of the systematic reviews and trials, to evaluate the effectiveness of interventions in current use, and to make suggestions for future trials Methods: Systematic reviews were searched from computerized bibliographic databases up to August 2007 for physiotherapy and physiotherapy-related interventions, and up to May 2003 for orthotic devices. Two reviewers independently identified, selected, and assessed the quality of the reviews using the Overview Quality Assessment Questionnaire complemented with decision rules. From a sample of 14 randomized controlled trials (RCT) published between January 1990 and June 2003 we analysed the methods of sampling, recruitment, and comparability of groups; defined the components of a complex intervention; identified outcome measures based on the International Classification of Functioning, Disability and Health (ICF); analysed the clinical interpretation of score changes; and analysed trial reporting using a modified 33-item CONSORT (Consolidated Standards of Reporting Trials) checklist. The effectiveness of physiotherapy and physiotherapy-related interventions in children with diagnosed CP was evaluated in a systematic review of randomised controlled trials that were searched from computerized databases from January 1990 up to February 2007. Two reviewers independently assessed the methodological quality, extracted the data, classified the outcomes using the ICF, and considered the level of evidence according to van Tulder et al. (2003). Results: We identified 21 reviews on physiotherapy and physiotherapy-related interventions and five on orthotic devices. These reviews summarized 23 or 5 randomised controlled trials and 104 or 27 observational studies, respectively. Only six reviews were of high quality. These found some evidence supporting strength training, constraint-induced movement therapy or hippotherapy, and insufficient evidence on comprehensive interventions. Based on the original studies included in the reviews on orthotic devices we found some short-term effects of lower limb casting on passive range of movement, and of ankle-foot orthoses on equinus walk. Long term effects of lower limb orthoses have not been studied. Evidence of upper limb casting or orthoses is conflicting. In the sample of 14 RCTs, most trials used simple randomisation, complemented with matching or stratification, but only three specified the concealed allocation. Numerous studies provided sufficient details on the components of a complex intervention, but the overlap of outcome measures across studies was poor and the clinical interpretation of observed score changes was mostly missing. Almost half (48%) of the applicable CONSORT-based items (range 28 32) were reported adequately. Most reporting inadequacies were in outcome measures, sample size determination, details of the sequence generation, allocation concealment and implementation of the randomization, success of assessor blinding, recruitment and follow-up dates, intention-to-treat analysis, precision of the effect size, co-interventions, and adverse events. The systematic review identified 22 trials on eight intervention categories. Four trials were of high quality. Moderate evidence of effectiveness was established for upper extremity treatments on attained goals, active supination and developmental status, and of constraint-induced therapy on the amount and quality of hand use and new emerging behaviours. Moderate evidence of ineffectiveness was found for strength training's effect on walking speed and stride length. Conflicting evidence was found for strength training's effect on gross motor function. For the other intervention categories the evidence was limited due to the low methodological quality and the statistically insignificant results of the studies. Conclusions: The high-quality reviews provide both supportive and insufficient evidence on some physiotherapy interventions. The poor quality of most reviews calls for caution, although most reviews drew no conclusions on effectiveness due to the poor quality of the primary studies. A considerable number of RCTs of good to fair methodological and reporting quality indicate that informative and well-reported RCTs on complex interventions in children and adolescents with CP are feasible. Nevertheless, methodological improvement is needed in certain areas of the trial design and performance, and the trial authors are encouraged to follow the CONSORT criteria. Based on RCTs we established moderate evidence for some effectiveness of upper extremity training. Due to limitations in methodological quality and variations in population, interventions and outcomes, mostly limited evidence on the effectiveness of most physiotherapy interventions is available to guide clinical practice. Well-designed trials are needed, especially for focused physiotherapy interventions.

Do Measurement Errors in GDP Announcements Cause Output Fluctuations?

This thesis studies empirically whether measurement errors in aggregate production statistics affect sentiment and future output. Initial announcements of aggregate production are subject to measurement error, because many of the data required to compile the statistics are produced with a lag. This measurement error can be gauged as the difference between the latest revised statistic and its initial announcement. Assuming aggregate production statistics help forecast future aggregate production, these measurement errors are expected to affect macroeconomic forecasts. Assuming agents’ macroeconomic forecasts affect their production choices, these measurement errors should affect future output through sentiment. This thesis is primarily empirical, so the theoretical basis, strategic complementarity, is discussed quite briefly. However, it is a model in which higher aggregate production increases each agent’s incentive to produce. In this circumstance a statistical announcement which suggests aggregate production is high would increase each agent’s incentive to produce, thus resulting in higher aggregate production. In this way the existence of strategic complementarity provides the theoretical basis for output fluctuations caused by measurement mistakes in aggregate production statistics. Previous empirical studies suggest that measurement errors in gross national product affect future aggregate production in the United States. Additionally it has been demonstrated that measurement errors in the Index of Leading Indicators affect forecasts by professional economists as well as future industrial production in the United States. This thesis aims to verify the applicability of these findings to other countries, as well as study the link between measurement errors in gross domestic product and sentiment. This thesis explores the relationship between measurement errors in gross domestic production and sentiment and future output. Professional forecasts and consumer sentiment in the United States and Finland, as well as producer sentiment in Finland, are used as the measures of sentiment. Using statistical techniques it is found that measurement errors in gross domestic product affect forecasts and producer sentiment. The effect on consumer sentiment is ambiguous. The relationship between measurement errors and future output is explored using data from Finland, United States, United Kingdom, New Zealand and Sweden. It is found that measurement errors have affected aggregate production or investment in Finland, United States, United Kingdom and Sweden. Specifically, it was found that overly optimistic statistics announcements are associated with higher output and vice versa.

Essays on Labor Market Frictions, Technological Change and Macroeconomic Fluctuations

The dissertation consists of an introductory chapter and three essays that apply search-matching theory to study the interaction of labor market frictions, technological change and macroeconomic fluctuations. The first essay studies the impact of capital-embodied growth on equilibrium unemployment by extending a vintage capital/search model to incorporate vintage human capital. In addition to the capital obsolescence (or creative destruction) effect that tends to raise unemployment, vintage human capital introduces a skill obsolescence effect of faster growth that has the opposite sign. Faster skill obsolescence reduces the value of unemployment, hence wages and leads to more job creation and less job destruction, unambiguously reducing unemployment. The second essay studies the effect of skill biased technological change on skill mismatch and the allocation of workers and firms in the labor market. By allowing workers to invest in education, we extend a matching model with two-sided heterogeneity to incorporate an endogenous distribution of high and low skill workers. We consider various possibilities for the cost of acquiring skills and show that while unemployment increases in most scenarios, the effect on the distribution of vacancy and worker types varies according to the structure of skill costs. When the model is extended to incorporate endogenous labor market participation, we show that the unemployment rate becomes less informative of the state of the labor market as the participation margin absorbs employment effects. The third essay studies the effects of labor taxes on equilibrium labor market outcomes and macroeconomic dynamics in a New Keynesian model with matching frictions. Three policy instruments are considered: a marginal tax and a tax subsidy to produce tax progression schemes, and a replacement ratio to account for variability in outside options. In equilibrium, the marginal tax rate and replacement ratio dampen economic activity whereas tax subsidies boost the economy. The marginal tax rate and replacement ratio amplify shock responses whereas employment subsidies weaken them. The tax instruments affect the degree to which the wage absorbs shocks. We show that increasing tax progression when taxation is initially progressive is harmful for steady state employment and output, and amplifies the sensitivity of macroeconomic variables to shocks. When taxation is initially proportional, increasing progression is beneficial for output and employment and dampens shock responses.

Mechanism of RNA Translocation by a Viral Packaging Motor

Molecular motors are proteins that convert chemical energy into mechanical work. The viral packaging ATPase P4 is a hexameric molecular motor that translocates RNA into preformed viral capsids. P4 belongs to the ubiquitous class of hexameric helicases. Although its structure is known, the mechanism of RNA translocation remains elusive. Here we present a detailed kinetic study of nucleotide binding, hydrolysis, and product release by P4. We propose a stochastic-sequential cooperative model to describe the coordination of ATP hydrolysis within the hexamer. In this model the apparent cooperativity is a result of hydrolysis stimulation by ATP and RNA binding to neighboring subunits rather than cooperative nucleotide binding. Simultaneous interaction of neighboring subunits with RNA makes the otherwise random hydrolysis sequential and processive. Further, we use hydrogen/deuterium exchange detected by high resolution mass spectrometry to visualize P4 conformational dynamics during the catalytic cycle. Concerted changes of exchange kinetics reveal a cooperative unit that dynamically links ATP binding sites and the central RNA binding channel. The cooperative unit is compatible with the structure-based model in which translocation is effected by conformational changes of a limited protein region. Deuterium labeling also discloses the transition state associated with RNA loading which proceeds via opening of the hexameric ring. Hydrogen/deuterium exchange is further used to delineate the interactions of the P4 hexamer with the viral procapsid. P4 associates with the procapsid via its C-terminal face. The interactions stabilize subunit interfaces within the hexamer. The conformation of the virus-bound hexamer is more stable than the hexamer in solution, which is prone to spontaneous ring openings. We propose that the stabilization within the viral capsid increases the packaging processivity and confers selectivity during RNA loading. Finally, we use single molecule techniques to characterize P4 translocation along RNA. While the P4 hexamer encloses RNA topologically within the central channel, it diffuses randomly along the RNA. In the presence of ATP, unidirectional net movement is discernible in addition to the stochastic motion. The diffusion is hindered by activation energy barriers that depend on the nucleotide binding state. The results suggest that P4 employs an electrostatic clutch instead of cycling through stable, discrete, RNA binding states during translocation. Conformational changes coupled to ATP hydrolysis modify the electrostatic potential inside the central channel, which in turn biases RNA motion in one direction. Implications of the P4 model for other hexameric molecular motors are discussed.

The effects of entacapone on cardiorespiratory, autonomic, and clinical responses in L-dopa-treated patients with Parkinson's disease

Rest tremor, rigidity, and slowness of movements-considered to be mainly due to markedly reduced levels of dopamine (DA) in the basal ganglia-are characteristic motor symptoms of Parkinson's disease (PD). Although there is yet no cure for this illness, several drugs can alleviate the motor symptoms. Among these symptomatic therapies, L-dopa is the most effective. As a precursor to DA, it is able to replace the loss of DA in the basal ganglia. In the long run L-dopa has, however, disadvantages. Motor response complications, such as shortening of the duration of drug effect ("wearing-off"), develop in many patients. In addition, extensive peripheral metabolism of L-dopa by aromatic amino acid decarboxylase and catechol-O-methyltransferase (COMT) results in its short half-life, low bioavailability, and reduced efficacy. Entacapone, a nitrocatechol-structured compound, is a highly selective, reversible, and orally active inhibitor of COMT. It increases the bioavailability of L-dopa by reducing its peripheral elimination rate. Entacapone extends the duration of clinical response to each L-dopa dose in PD patients with wearing-off fluctuations. COMT is important in the metabolism of catecholamines. Its inhibition could, therefore, theoretically lead to adverse cardiovascular reactions, especially in circumstances of enhanced sympathetic activity (physical exercise). PD patients may be particularly vulnerable to such effects due to high prevalence of cardiovascular autonomic dysfunction, and the common use of monoamine oxidase B inhibitor selegiline, another drug with effects on catecholamine metabolism. Both entacapone and selegiline enhance L-dopa's clinical effect. Their co-administration may therefore lead to pharmacodynamic interactions, either beneficial (improved L-dopa efficacy) or harmful (increased dyskinesia). We investigated the effects of repeated dosing (3-5 daily doses for 1-2 weeks) of entacapone 200 mg administered either with or without selegiline (10 mg once daily), on several safety and efficacy parameters in 39 L-dopa-treated patients with mild to moderate PD in three double-blind placebo-controlled, crossover studies. In the first two, the cardiovascular, clinical, and biochemical responses were assessed repeatedly for 6 hours after drug intake, first with L-dopa only (control), and then after a 2 weeks on study drugs (entacapone vs. entacapone plus selegiline in one; entacapone vs. selegiline vs. entacapone plus selegiline in the other). The third study included cardiovascular reflex and spiroergometric exercise testing, first after overnight L-dopa withdrawal (control), and then after 1 week on entacapone plus selegiline as adjuncts to L-dopa. Ambulatory ECG was recorded in two of the studies. Blood pressure, heart rate, ECG, cardiovascular autonomic function, cardiorespiratory exercise responses, and the resting/exercise levels of circulating catecholamines remained unaffected by entacapone, irrespective of selegiline. Entacapone significantly enhanced both L-dopa bioavailability and its clinical response, the latter being more pronounced with the co-administration of selegiline. Dyskinesias were also increased during simultaneous use of both entacapone and selegiline as L-dopa adjuncts. Entacapone had no effect on either work capacity or work efficiency. The drug was well tolerated, both with and without selegiline. Conclusions: the use of entacapone-either alone or combined with selegiline-seems to be hemodynamically safe in L-dopa-treated PD patients, also during maximal physical effort. This is in line with the safety experience from larger phase III studies. Entacapone had no effect on cardiovascular autonomic function. Concomitant administration of entacapone and selegiline may enhance L-dopa's clinical efficacy but may also lead to increased dyskinesia.

Bone health and vitamin D status in children with motor disability and adults with intellectual disability

Osteoporosis is not only a disease of the elderly, but is increasingly diagnosed in chronically ill children. Children with severe motor disabilities, such as cerebral palsy (CP), have many risk factors for osteoporosis. Adults with intellectual disability (ID) are also prone to low bone mineral density (BMD) and increased fractures. This study was carried out to identify risk factors for low BMD and osteoporosis in children with severe motor disability and in adults with ID. In this study 59 children with severe motor disability, ranging in age from 5 to 16 years were evaluated. Lumbar spine BMD was measured with dual-energy x-ray absorptiometry. BMD values were corrected for bone size by calculating bone mineral apparent density (BMAD), and for bone age. The values were transformed into Z-scores by comparison with normative data. Spinal radiographs were assessed for vertebral morphology. Blood samples were obtained for biochemical parameters. Parents were requested to keep a food diary for three days. The median daily energy and nutrient intakes were calculated. Fractures were common; 17% of the children had sustained peripheral fractures and 25% had compression fractures. BMD was low in children; the median spinal BMAD Z-score was -1.0 (range -5.0 – +2.0) and the BMAD Z-score <-2.0 in 20% of the children. Low BMAD Z-score and hypercalciuria were significant risk factors for fractures. In children with motor disability, calcium intakes were sufficient, while total energy and vitamin D intakes were not. In the vitamin D intervention studies, 44 children and adolescents with severe motor disability and 138 adults with ID were studied. After baseline blood samples, the children were divided into two groups; those in the treatment group received 1000 IU peroral vitamin D3 five days a week for 10 weeks, and subjects in the control group continued with their normal diet. Adults with ID were allocated to receive either 800 IU peroral vitamin D3 daily for six months or a single intramuscular injection of 150 000 IU D3. Blood samples were obtained at baseline and after treatment. Serum concentrations of 25-OH-vitamin D (S-25-OHD) were low in all subgroups before vitamin D intervention: in almost 60% of children and in 77% of adults the S-25-OHD concentration was below 50 nmol/L, indicating vitamin D insufficiency. After vitamin D intervention, 19% of children and 42% adults who received vitamin D perorally and 12% of adults who received vitamin D intramuscularly had optimal S-25-OHD (>80 nmol/L). This study demonstrated that low BMD and peripheral and spinal fractures are common in children with severe motor disabilities. Vitamin D status was suboptimal in the majority of children with motor disability and adults with ID. Vitamin D insufficiency can be corrected with vitamin D supplements; the peroral dose should be at least 800 IU per day.

Seasonal fluctuations in blue-green algae, especially in heterocystous species in polluted coastal waters off Helsinki city, in the northern part of the Gulf of Finland

Tiivistelmä