Immune-mediated cerebellar ataxias: from bench to bedside

Abstract The cerebellum is a vulnerable target of autoimmunity in the CNS. The category of immune-mediated cerebellar ataxias (IMCAs) was recently established, and includes in particular paraneoplastic cerebellar degenerations (PCDs), gluten ataxia (GA) and anti-GAD65 antibody (Ab) associated-CA, all characterized by the presence of autoantibodies. The significance of onconeuronal autoantibodies remains uncertain in some cases. The pathogenic role of anti-GAD65Ab has been established both in vitro and in vivo, but a consensus has not been reached yet. Recent studies of anti-GAD65 Ab-associated CA have clarified that (1) autoantibodies are generally polyclonal and elicit pathogenic effects related to epitope specificity, and (2) the clinical course can be divided into two phases: a phase of functional disorder followed by cell death. These features provide the rationale for prompt diagnosis and therapeutic strategies. The concept “Time is brain” has been completely underestimated in the field of immune ataxias. We now put forward the concept “Time is cerebellum” to underline the importance of very early therapeutic strategies in order to prevent or stop the loss of neurons and synapses. The diagnosis of IMCAs should depend not only on Ab testing, but rather on a rapid and comprehensive assessment of the clinical/immune profile. Treatment should be applied during the period of preserved cerebellar reserve, and should encompass early removal of the conditions (such as remote primary tumors) or diseases that trigger the autoimmunity, followed by the combinations of various immunotherapies

Allometric scaling of xenobiotic clearance: Uncertainty versus universality

Statistical analysis and Monte Carlo simulation were used to characterize uncertainty in the allometric exponent (b) of xenobiotic clearance (CL). CL values for 115 xenobiotics were from published studies in which at least 3 species were used for the purpose of interspecies comparison of pharmacokinetics. The b value for each xenobiotic was calculated along with its confidence interval (CI). For 24 xenobiotics (21%), there was no correlation between log CL and log body weight. For the other 91 cases, the mean±standard deviation of the b values was 0.74±0.16; range: 0.29 to 1.2. Most (81%) of these individual b values did not differ from either 0.67 or 0.75 at P=0.05. When CL values for the subset of 91 substances were normalized to a common body weight coefficient (a), the b value for the 460 adjusted CL values was 0.74; the 99% CI was 0.71 to 0.76, which excluded 0.67. Monte Carlo simulation indicated that the wide range of observed b values could have resulted from random variability in CL values determined in a limited number of species, even though the underlying b value was 0.75. From the normalized CL values, 4 xenobiotic subgroups were examined: those that were (i) protein, and those that were (ii) eliminated mainly by renal excretion, (iii) by metabolism, or (iv) by renal excretion and metabolism combined. All subgroups except (ii) showed a b value not different from 0.75. The b value for the renal excretion subgroup (21 xenobiotics, 105 CL values) was 0.65, which differed from 0.75 but not from 0.67