Modified constraint-induced therapy for children with hemiplegic cerebral palsy: a randomized trial

Aim Conventional constraint‐based therapies are intensive and demanding to implement, particularly for children. Modified forms of constraint‐based therapies that are family‐centred may be more acceptable and feasible for families of children with cerebral palsy (CP)‐but require rigorous evaluation using randomized trials. The aim of this study was to determine the effects of modified constraint‐induced therapy compared with intensive occupational therapy on activities of daily living and upper limb outcomes in children with hemiplegic CP. Method In this assessor‐blinded pragmatic randomized trial, 50 children (27 males, 23 females; age range 19mo–7y 10mo) with hemiplegic CP were randomized using a concealed allocation procedure to one of two 8‐week interventions: intensive occupational therapy (n=25), or modified constraint‐induced therapy (n=25). Manual Ability Classification System (MACS) levels of the participants were, level I n=2, II n=37, III n=8, and level IV n=1; Gross Motor Function Classification System (GMFCS) levels were, level I n=33, level II n=15, and level III n=1. Participants were recruited through three specialist CP centres in Australia and randomized between January 2008 and April 2010. Children randomized to modified constraint‐induced therapy wore a mitt on the unaffected hand for 2 hours each day, during which time the children participated in targeted therapy. The primary outcome was the Canadian Occupational Performance Measure (COPM – measured on a 10‐point scale) at completion of therapy. Other outcome measures were Goal Attainment Scaling, Assisting Hand Assessment, Pediatric Motor Activity Log, Modified Ashworth Scale, Modified Tardieu Scale, and a parent questionnaire. Assessments were carried out at 10 weeks and 6 months following randomization. Results All participants were included in the analysis. Between‐group differences for all outcomes were neither clinically important nor statistically significant. The mean difference in COPM was 0.3 (95% confidence interval [CI] −0.8 to 1.4; p=0.61) and mean difference in COPM satisfaction was 0.1 (95% CI −1.1 to 1.2; p=0.90). Minor adverse events were reported by five of the 25 participants in the modified constraint‐induced therapy group and by one of the 25 in the intensive occupational therapy group. All adverse events were related to participants’ lack of acceptance of therapy. Interpretation Modified constraint‐induced therapy is no more effective than intensive occupational therapy for improving completion of activities of daily living or upper limb function in children with hemiplegic CP.     

Carisbamate as adjunctive treatment of partial onset seizures in adults in two randomized,placebo‐controlled trials

Purpose: To assess the efficacy, safety, and tolerability of the investigational drug carisbamate as adjunctive treatment for partial‐onset seizures (POS). Methods: Two identical, randomized, placebo‐controlled, double‐blind studies were conducted in adults with POS uncontrolled for ≥1 year. Therapy‐refractory epilepsy patients (≥16 years) remained on stable doses of prescribed antiepileptic drugs (≤2) for an 8‐week prospective baseline phase and were then randomized (1:1:1) to carisbamate 200 mg/day, carisbamate 400 mg/day, or placebo, for a 12‐week double‐blind phase. Primary efficacy end points were percent reduction in seizure frequency and responder rate (patients with ≥50% reduction in POS frequency) during the double‐blind phase compared with the prospective baseline phase. Results: Of the 565 patients randomized in study 1, 93% completed the study; of the 562 randomized in study 2, 94% completed the study. Patient characteristics were similar across both studies and treatment arms: mean age, 35 years (study 1, range 16–75 years) and 36 years (study 2, range 16–74 years); approximately 50% were men. Treatment with carisbamate 400 mg/day resulted in significant improvement (p < 0.01) in both efficacy measures compared with placebo in study 1 but not in study 2. Carisbamate 200 mg/day did not differ statistically from placebo in either study. Among the most common treatment‐emergent adverse events (≥5% in any group), those with an incidence exceeding placebo (≥3%) were dizziness (400 mg/day group) and somnolence. Conclusions: Carisbamate 400 mg/day was effective in patients with refractory partial‐onset seizures in one of these global studies. More than 200 mg/day of carisbamate is required for efficacy. Carisbamate was well‐tolerated in both studies.     

Spatial distribution,blood feeding pattern,and role of <Emphasis Type="Italic">Anopheles funestus</Emphasis> complex in malaria transmission in central Kenya

Studies were conducted to determine the role of sibling species of Anopheles funestus complex in malaria transmission in three agro-ecosystems in central Kenya. Mosquitoes were sampled indoors and outdoors, and rDNA PCR was successfully used to identify 340 specimens. Anopheles parensis (91.8%), A. funestus (6.8%), and Anopheles leesoni (1.5%) were the three sibling species identified. A. parensis was the dominant species at all study sites, while 22 of 23 A. funestus were collected in the non-irrigated study site. None of the 362 specimens tested was positive for Plasmodium falciparum circumsporozoite proteins by enzyme-linked immunosorbent assay. The most common blood-meal sources (mixed blood meals included) for A. parensis were goat (54.0%), human (47.6%), and bovine (39.7%), while the few A. funestus s.s. samples had fed mostly on humans. The human blood index (HBI) for A. parensis (mixed blood meals included) in the non-irrigated agro-ecosystem was 0.93 and significantly higher than 0.33 in planned rice agro-ecosystem. The few samples of A. funestus s.s. and A. funestus s.l. also showed a trend of higher HBI in the non-irrigated agro-ecosystem. We conclude that agricultural practices have significant influence on distribution and blood feeding behavior of A. funestus complex. Although none of the species was implicated with malaria transmission, these results may partly explain why non-irrigated agro-ecosystems are associated with higher risk of malaria transmission by this species compared to irrigated agro-ecosystems.     

Spatiotemporal dynamics of immature culicines (subfamily Culicinae) and their larval habitats in Mwea Rice Scheme,Kenya

An ecological study was conducted at three study sites in Mwea Rice Scheme, Kenya to identify the diverse aquatic habitats in which culicine mosquitoes thrived and to explore the best strategies for mosquito control in the area. During the 11-month study period, ten habitat categories and 11 culicine species mainly dominated by Culex quinquefasciatus (72.0%) and Culex annulioris (17.9%) were identified from pupae and late instars larval samples. Two of the 11 culicine species, Ficalbia (Mimomyia) plumosa and Uranotaenia spp., have not been reported previously in the study area. Rurumi had more habitat types than either of the other study sites but the least number of mosquito species. In contrast, Karima had the least number of habitat types but significantly higher density of early instars than the other study sites. The relative abundance of late instars and pupae did not vary significantly among study sites. The contribution of different habitat types to larval production varied markedly between seasons and among study sites. Paddies and canals were perennial contributors of culicine mosquito larvae while the other habitat types were important mainly during the wet season. Some habitat types such as ditches, seeps, marshes, and fishpond were absent in some study sites but of great significance in other study sites. C. quinquefasciatus was positively associated with turbidity at all study sites and also negatively associated with emergent vegetation and distance to the nearest homestead in Karima, emergent vegetation in Kiuria, and other aquatic invertebrates in Rurumi. C. annulioris was positively associated with emergent vegetation at all study sites and also with depth in Kiuria. These findings indicate that besides rice fields and associated habitats, a diversity of other aquatic habitats contribute to culicine adult mosquito production in the study area and that environmental factors that determine the occurrence of a particular mosquito species may vary significantly even among areas of similar land use. This information is critical when designing and implementing mosquito larval control programs.     

Enhanced long-term potentiation and impaired learning in phosphodiesterase 4D-knockout (PDE4D) mice

Elevation of intracellular cyclic adenosine monophosphate (cAMP) concentrations and subsequent regulation of downstream target gene expression through phosphorylation of cAMP-responsive element binding protein (CREB) is hypothesized to underlie the mechanism(s) of long-term memory (LTM) formation. The phosphodiesterase 4 (PDE4) enzyme family is believed to play a key role in LTM by regulating cAMP levels. Thus far, four PDE4 isoforms have been identified ( PDE4A , B , C and D ); however, the requisite involvement of each of these isoforms in mediating LTM has yet to be elucidated. In the present study, genetic knockout mice were used to investigate the involvement of the PDE4D isoform in both in vitro and in vivo models of learning and memory. Hippocampal synaptic transmission measured electrophysiologically in CA1 slice preparations was similar between wild-type and PDE4D ^−/− mice yet, relative to wild-type controls, knockout mice displayed enhanced early long-term potentiation (LTP) following multiple induction protocols. Interestingly, the PDE4D ^−/− animals exhibited significant behavioral deficits in associative learning using a conditioned fear paradigm as compared with control littermates. The impairment in fear conditioning observed in the PDE4D ^−/− mice could not be attributed to differences in acquisition of the task, alterations in locomotor activity or effects on shock sensitivity. Overall, the in vitro and in vivo alterations in synaptic plasticity observed in the PDE4D ^−/− mice may be explained by adaptive responses occurring throughout development, and suggest that the PDE4D isoform may be an important mediator of LTM formation.