The role of the cerebellum in procedural learning—Are there implications for physiotherapists’ clinical practice?

Motor learning is the means by which we acquire skilled movements and consign them to permanent memory. Multiple brain areas are involved, and patients with neurological damage often experience difficulty when attempting to relearn previously learned skills. For these patients, the location of the lesion may be critical in influencing their motor skill relearning. The cerebellum has been described as an “on-line” comparator and corrector of movement, but recent research suggests that the cerebellum may also have a role in the later stages of motor learning, including the automation of movement patterns, although conflicting research in this area means that there is as yet no consensus. This knowledge may have implications for the way physiotherapists treat patients with cerebellar lesions. Some treatments in regular use by physiotherapists are discussed, and possible implications for practice are considered.     

Malaria control in Malawi: Current status and directions for the future

The last decade has seen an increase in investment and concerted efforts by the Malawi Ministry of Health and partners to control malaria disease. This report summarizes what is known about the burden of malaria and the strategies being implemented to control it in Malawi. Over the past 5 years, roll out of treatment and prevention efforts have been successful in the country, as demonstrated by increased use of insecticide treated nets, improved access to prompt and effective treatment and the initiation of pilot studies of indoor residual spraying. However, unlike other countries in the region, the recent data have not suggested a decrease in the burden of disease. We describe the environment in which the activities of Malawi's International Center for Excellence in Malaria Research (ICEMR) will be carried out and provide the rationale for the clinical, entomological and molecular studies. Our approach is to establish consistent, stainable data collection systems that are embedded within the public health sector. Through standardized and long-term studies of hosts, parasites and vectors, we hope to contribute to assessment of malaria disease burden, the appropriate application of interventions and policies and provide both the data collection and the health care infrastructure to ultimately eliminate the disease.     

Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms

Variable clinical responses, tumor heterogeneity, and drug resistance reduce long-term survival outcomes for metastatic melanoma patients. To guide and accelerate drug development, we characterized tumor responses for five melanoma patient derived xenograft models treated with Vemurafenib. Three BRAF^V600E models showed acquired drug resistance, one BRAF^V600E model had a complete and durable response, and a BRAF^V600V model was expectedly unresponsive. In progressing tumors, a variety of resistance mechanisms to BRAF inhibition were uncovered, including mutant BRAF alternative splicing, NRAS mutation, COT (MAP3K8) overexpression, and increased mutant BRAF gene amplification and copy number. The resistance mechanisms among the patient derived xenograft models were similar to the resistance pathways identified in clinical specimens from patients progressing on BRAF inhibitor therapy. In addition, there was both inter- and intra-patient heterogeneity in resistance mechanisms, accompanied by heterogeneous pERK expression immunostaining profiles. MEK monotherapy of Vemurafenib-resistant tumors caused toxicity and acquired drug resistance. However, tumors were eradicated when Vemurafenib was combined the MEK inhibitor. The diversity of drug responses among the xenograft models; the distinct mechanisms of resistance; and the ability to overcome resistance by the addition of a MEK inhibitor provide a scheduling rationale for clinical trials of next-generation drug combinations.     

Biochemical Binding and Distribution of Protactinium-233 in the Rat

Summary

Following intravenous injection into male Sprague–Dawley rats ²³³Pa, like other elements, deposits predominantly in the skeleton (ca. 70–80 per cent), but unlike Pu and Am the liver deposition of ²³³Pa is low, about 2–3 per cent between 1 and 7 days. About 99 per cent of the injected ²³³Pa is lost from the plasma compartment in 3 days, a clearance comparable to that of Pu but much slower than that of Np, Am or Cm. On entering the liver cell cytosol ²³³Pa is bound rapidly to an unidentified protein of molecular mass 200 kDa and to a protein of 80 kDa, which is probably transferrin. Within a few hours the metal migrates to bind to a protein of > 400 kDa which has been tentatively identified as ferritin. Some ²³³Pa remains bound to small ligands until virtually all the intracellular ²³³Pa has been deposited in the lysosomes, or to a lesser extent in some other, as yet, unidentified organelles.     

Pharmacoeconomics and the Medicinal Chemist

Pharmacoeconomics is a rational, scientific approach to compare the value (in terms of both cost and patient outcome) of one medication or drug therapy regimen to another. The impact of this new approach on both the practicing medicinal chemist and broader drug discovery efforts is considered.