Alemtuzumab for multiple sclerosis: Long term follow-up in a multi-centre cohort.

BACKGROUND: Alemtuzumab has recently been approved for treatment of relapsing MS, but concerns remain about its use since long-term studies of adverse events remain limited. Furthermore, a clear understanding of its application and durability of effect in clinical practice has yet to evolve. OBJECTIVES: To investigate long-term efficacy and safety outcomes in a multicentre cohort of patients treated with alemtuzumab. METHODS: Patients treated from 2000 and followed-up at three regional centres were identified. Baseline and prospective data were obtained and validated by clinical record review. RESULTS: One hundred patients were identified with a mean follow-up of 6.1 years (range 1-13). Forty patients were retreated with at least one further treatment cycle. Annualized relapse rates fell from 2.1 to 0.2 (p<0.0001) post-treatment and were sustained for up to eight years of follow-up. Mean change in EDSS score was +0.14. Forty-seven patients developed secondary autoimmunity. CONCLUSION: Observed reduction in relapse rates reflected those reported in clinical trials, but we were unable to corroborate previous observations of disability reversal. 40% of patients required additional treatment cycles. Autoimmune adverse events were common, occurring at a higher rate than previously reported, but were largely predictable, and could be managed effectively within a rigorous monitoring regime.

Cultural niche construction and human evolution.

Organisms frequently choose, regulate, construct and destroy important components of their environments, in the process changing the selection pressures to which they and other organisms are exposed. We refer to these processes as niche construction. In humans, culture has greatly amplified our capacity for niche construction and our ability to modify selection pressures. We use gene-culture coevolutionary models to explore the evolutionary consequences of culturally generated niche construction through human evolution. Our analysis suggests that where cultural traits are transmitted in an unbiased fashion from parent to offspring, cultural niche construction will have a similar effect to gene-based niche construction. However, cultural transmission biases favouring particular cultural traits may either increase or reduce the range of parameter space over which niche construction has an impact, which means that niche construction with biased transmission will either have a much smaller or a much bigger effect than gene-based niche construction. The analysis also reveals circumstances under which cultural transmission can overwhelm natural selection, accelerate the rate at which a favoured gene spreads, initiate novel evolutionary events and trigger hominid speciation. Because cultural processes typically operate faster than natural selection, cultural niche construction probably has more profound consequences than gene-based niche construction, and is likely to have played an important role in human evolution.

Niche construction, biological evolution, and cultural change.

We propose a conceptual model that maps the causal pathways relating biological evolution to cultural change. It builds on conventional evolutionary theory by placing emphasis on the capacity of organisms to modify sources of natural selection in their environment (niche construction) and by broadening the evolutionary dynamic to incorporate ontogenetic and cultural processes. In this model, phenotypes have a much more active role in evolution than generally conceived. This sheds light on hominid evolution, on the evolution of culture, and on altruism and cooperation. Culture amplifies the capacity of human beings to modify sources of natural selection in their environments to the point where that capacity raises some new questions about the processes of human adaptation.

Subtle bite-angle influences on N(2)S(2)Ni complexes.

A new N(2)S(2)Ni complex based on the 1,4-diazacycloheptane (dach) framework allows the study of the effects of ring size, in fused diamines, on the structural and chemical properties of nickel(II) dithiolate and dithioether complexes. Compared to its 1,5-diazacyclooctane (daco) derivatives, the dithiolate complex (bmedach)Ni and the S-templated, macrocyclic dithioether complex (propyl-bmedach)NiBr(2) show decreased cavity sizes with narrower angleN-Ni-N angles (by ca. 6 degrees ) and wider angleS-Ni-S angles (also by ca. 6 degrees ). The electrochemical properties of the dithiolate complexes based on dach and daco are nearly identical, while the (propyl-bmedach)NiBr(2) complex shows a 140 mV destabilization of the Ni(I) oxidation state relative to its daco analogue. Molecular structures for the (bmedach)Ni and (propyl-bmedach)NiBr(2) complexes and their respective electrochemical and spectroscopic properties are reported.