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Progressive accumulation of specific misfolded protein is a defining feature of amyotrophic lateral sclerosis (ALS), similarly seen in Alzheimer disease, Parkinson disease, Huntington disease and Creutzfeldt–Jakob disease. The intercellular transfer of inclusions made of tau, α-synuclein and huntingtin has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system. Evidence for such a prion-like propagation mechanism has now spread to the major misfolded proteins, superoxide dismutase 1 (SOD1) and the 43 kDa transactive response DNA binding protein (TDP-43), implicated in ALS. The focus in this review is on what is known about ALS progression in terms of clinical as well as molecular aspects. Furthermore, the concept of ‘propagation’ is dissected into contiguous and non-contiguous types, and this concept is expanded to the severity of the focal symptom as well as its regional spread which can be explained by cell to cell propagation in the local neuron pool.

RNA interference is a powerful tool for target-specific knockdown of gene expression. However, efficient and safe in vivo delivery of short interfering RNA (siRNA) to the target organ, which is essential for therapeutic applications, has not been established. In this study we used alpha-tocopherol (vitamin E), which has its own physiological transport pathway to most of the organs, as a carrier molecule of siRNA in vivo. The alpha-tocopherol was covalently bound to the antisense strand of 27/29-mer siRNA at the 5'-end (Toc-siRNA). The 27/29-mer Toc-siRNA was designed to be cleaved by Dicer, producing a mature form of 21/21-mer siRNA after releasing alpha-tocopherol. The C6 hydroxyl group of alpha-tocopherol, associated with antioxidant activity, was abolished. Using this new vector, intravenous injection of 2 mg/kg of Toc-siRNA, targeting apolipoprotein B (apoB), achieved efficient reduction of endogenous apoB messenger RNA (mRNA) in the liver. The downregulation of apoB mRNA was confirmed by the accumulation of lipid droplets in the liver as a phenotype. Neither induction of interferons (IFNs) nor other overt side effects were revealed by biochemical and pathological analyses. These findings indicate that Toc-siRNA is effective and safe for RNA interference-mediated gene silencing in vivo.

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BackgroundIt remains unclear whether glycemic variability is related to diabetes microvascular disease, especially diabetes peripheral neuropathy (DPN). We investigated the association between glycemic variability and DPN with type 1 or 2 diabetes.MethodsForty patients (23 males and 17 females; aged 34–79 years) underwent continuous glucose monitoring (CGM) and a nerve conduction study (NCS). Glycemic variability was estimated by mean amplitude of glycemic excursions (MAGE) in CGM. DPN was quantitatively evaluated by NCS in the median, tibial, sural and medial plantar nerves.ResultsMAGE had a significantly positive correlation with disease duration and low-density lipoprotein cholesterol level (r = 0.462, p = 0.003; and r = 0.40, p = 0.011, respectively), and a significantly negative correlation with BMI and medial plantar compound nerve action potential amplitude (r = − 0.39, p = 0.012; and r = − 0.32, p = 0.042, respectively). Multivariate linear regression analysis with adjustment for clinical background showed that MAGE (β = − 0.49, p= 0.007) was independently associated with a higher risk of medial plantar neuropathy.ConclusionsGlycemic variability may be an independent risk factor for DPN.

The mechanism of mirror movements in two patients was investigated; one with congenital mirror movement, the other with schizencephaly. Transcranial magnetic stimulation on one side elicited motor evoked potentials (MEPs) in their thenar muscles on both sides with almost the same latencies, minimal thresholds, and cortical topographies. During voluntary contraction of the thenar muscle on one side, contralateral transcranial magnetic stimulation induced a silent period not only on the voluntary contraction side but on the mirror movement side and of the same duration. By contrast, ipsilateral transcranial magnetic stimulation elicited MEPs without silent periods in both muscles. With intended unilateral finger movements, an H,'50-PET activation study showed that the regional cerebral blood flow increased predominantly in the contralateral sensorimotor cortex, as seen in normal subjects, although mirror movements occurred.It is considered that the ipsilateral motor cortex plays a major part in the generation of mirror movements, which may be induced through the ipsilateral uncrossed corticospinal tract. (JNeurolNeurosurg Psychiatry 1997;62:629-632)