Multiple-system atrophy.

Etomidate is a carboxylated, imidazole-containing intravenous anesthetic agent introduced into clinical anesthesia practice in 1972. Its distinctive features that make it useful as an anesthetic induction include a lack of adverse effects on hemodynamic function as well as beneficial effects on cerebral blood flow and intracranial pressure. Because of these properties, its major role in anesthetic practice has been for the induction of anesthesia in patients with diminished cardiovascular function. As opposed to the considerable reported clinical experience with etomidate in the adult population, there remains limited reported information concerning its use in pediatric patients. This article reviews the specific end-organ effects of etomidate, the reports concerning its use in pediatric patients, and its adverse effect profile.

Dexmedetomidine: applications in pediatric critical care and pediatric anesthesiology.

The development of α-synuclein immunoreactive aggregates in selectively vulnerable neuronal types of the human central, peripheral, and enteric nervous systems is crucial for the pathogenesis of sporadic Parkinson's disease. The presence of these lesions persists into the end phase of the disease, a process that is not subject to remission. The initial induction of α-synuclein misfolding and subsequent aggregation probably occurs in the olfactory bulb and/or the enteric nervous system. Each of these sites is exposed to potentially hostile environmental factors. Once formed, the aggregates appear to be capable of propagating trans-synaptically from nerve cell to nerve cell in a virtually self-promoting pathological process. A regional distribution pattern of aggregated α-synuclein emerges that entails the involvement of only a few types of susceptible and axonally interconnected projection neurons within the human nervous system. One major route of disease progression may originate in the enteric nervous system and retrogradely reach the dorsal motor nucleus of the vagal nerve in the lower brainstem. From there, the disease process proceeds chiefly in a caudo-rostral direction through visceromotor and somatomotor brainstem centres to the midbrain, forebrain, and cerebral cortex. Spinal cord centres may become involved by means of descending projections from involved lower brainstem nuclei as well as by sympathetic projections connecting the enteric nervous system with postganglionic peripheral ganglia and preganglionic nuclei of the spinal cord. The development of experimental cellular and animal models is helping to explain the mechanisms of how abnormal α-synuclein can undergo aggregation and how transmission along axonal connectivities can occur, thereby encouraging the initiation of potential disease-modifying therapeutic strategies for sporadic Parkinson's disease.

Review: Sporadic Parkinson's disease: development and distribution of α-synuclein pathology.

BACKGROUND\nMultiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components.\n\n\nMETHODS\nIn combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography.\n\n\nRESULTS\nWe identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population.\n\n\nCONCLUSIONS\nFunctionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.).

Mutations in COQ2 in familial and sporadic multiple-system atrophy the multiple-system atrophy research collaboration

Update on bispectral index monitoring.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, which leads to the loss of upper and lower motor neurons, with a currently unknown etiology. Specific biomarkers could help in early detection and diagnosis, and could also act as indicators of disease progression and therapy effectiveness. MicroRNAs (miRNAs) are small (18–25 nucleotides), single-stranded non-coding RNA molecules that play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression, and are essential for nervous system development. Many of the genes associated with genetic ALS have pathological biological pathways related to RNA metabolism, and their pathogenesis may be affecting the maturing processes of miRNA. We compared miRNA from the plasma of sALS patients and healthy controls using two cohorts; a discovery cohort analyzed with microarray (16 sALS patients and ten healthy controls) and a validation cohort confirmed with qPCR (48 sALS patients, 47 healthy controls and 30 disease controls). We measured the total amount of extracted RNA along with a spike-in control that ensured the quality of our quantification. A percentage of the 10–40 nt RNAs extracted from the total RNA showed a significant increase in ALS patients. There was a negative correlation between total RNA concentration and disease duration from onset to end point. Three of the miRNAs were up-regulated and six were down-regulated significantly in the discovery cohort. Since an internal control is required as a sample stability indicator of both the patients and controls in microarray analysis, we selected the miRNA showing the smallest dispersion and equivalency between the two groups’ mean value, and decided to use hsa-miR-4516. We found hsa-miR-4649-5p to be up-regulated, and hsa-miR-4299 to be down-regulated, where each was not influenced by clinical characteristics. EPHA4, a target gene linked to the nervous system which has also been reported to be a disease modifier of ALS, is the common and most notable target gene of hsa-miR-4649-5p and hsa-miR-4299. We have shown the relationship circulating plasma miRNA has with both healthy controls and diseased patients. Hsa-miR-4649-5p and hsa-miR-4299 have the potential to be ALS diagnosis biomarkers.

/pdf/identification-of-plasma-micrornas-as-a-biomarker-of-2d5rfy9m1h.pdf

Identification of plasma microRNAs as a biomarker of sporadic Amyotrophic Lateral Sclerosis

UNLABELLED Xenon (Xe) suppresses wide dynamic range neurons in cat spinal cord to a similar extent as nitrous oxide (N2O). The antinociceptive action of N2O involves the descending inhibitory system. To clarify whether the descending inhibitory system is also involved in the antinociceptive action of Xe, we compared the effects of Xe on the spinal cord dorsal horn neurons with those of N2O in spinal cord-transected cats anesthetized with alpha-chloralose and urethane. We investigated the change of wide dynamic range neuron responses to touch and pinch by both anesthetics. Seventy percent Xe significantly suppressed both touch- and pinch-evoked responses in all 12 neurons. In contrast, 70% N2O did not show significant suppression in touch- and pinch-evoked responses. These results suggest that the antinociceptive action of Xe might not be mediated by the descending inhibitory system, but instead may be produced by the direct effect on spinal dorsal horn neurons. IMPLICATIONS Xenon (Xe) is an inert gas with anesthetic properties. We examined the antinociceptive effects of Xe and nitrous oxide (N2O) in spinal cord-transected cats. Our studies indicate that Xe has a direct antinociceptive action on the spinal cord that is greater than that of N2O.

/pdf/xenon-has-greater-inhibitory-effects-on-spinal-dorsal-horn-1seecnhij3.pdf

Xenon has greater inhibitory effects on spinal dorsal horn neurons than nitrous oxide in spinal cord transected cats.

Dexmedetomidine is an alpha 2 agonist and has been reported to have proconvulsant actions. To investigate the interaction of dexmedetomidine with convulsant anaesthetics, we studied effects on seizure threshold in cats during enflurane anaesthesia. Cats were prepared with chronic implantation of electrodes for recording of the cortical electroencephalogram (EEG) and midbrain reticular formation multi-unit activity (R-MUA). Seizure threshold, the reciprocal of the number of electrical stimuli required to induce generalized EEG seizure activity × 1000 (seizure induction index (SII)), was assessed. The effects of dexmedetomidine 1, 10 and 100 micrograms kg-1 i.v. and yohimbine 500 micrograms kg-1, an alpha 2 antagonist, on SII during 3.5% enflurane anaesthesia were investigated. Dexmedetomidine significantly increased SII at 10 and 100 micrograms kg-1, and this effect was reversed by yohimbine. We found that high-dose dexmedetomidine reduced seizure threshold during enflurane anaesthesia.

Dexmedetomidine reduces seizure threshold during enflurane anaesthesia in cats.

MicroRNA expression profiles of neuron-derived extracellular vesicles in plasma from patients with amyotrophic lateral sclerosis.

MicroRNAs (miRNAs) are endogenous small (18–25 nt), single-stranded, non-coding RNAs that play key roles in post-transcriptional gene expression regulation. The expression profiles of miRNAs in biofluids and tissues change in various diseases. Multiple system atrophy (MSA) and Parkinson’s disease (PD) are both categorized as α-synucleinopathies and often present with similar clinical manifestations. This study aimed to identify miRNAs that are differently expressed in plasma samples of PD patients, MSA patients, and healthy controls. We used microarray analysis to screen for miRNAs that are up- and down-regulated in these patients and analyzed the relative-quantitative expression levels of the identified miRNAs by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Hsa-miR-671-5p, hsa-miR-19b-3p, and hsa-miR-24-3p showed significantly different expression levels among patients with MSA-C, MSA-P, or PD, and healthy controls. Hsa-miR-671-5p levels were lower in the MSA-P and PD than the MSA-C and control groups, hsa-miR-19b-3p levels were higher in the PD than the other groups, and hsa-miR-24-3p levels were higher in the PD than the MSA-C group. Hsa-miR-671-5p was the first miRNA shown to be expressed differently between MSA-C and MSA-P in plasma. Interestingly, the expression levels of hsa-miR-19b-3p and hsa-miR-24-3p were positively correlated, indicating that these miRNAs may be involved in the same processes in PD pathogenesis. Our findings suggest that hsa-miR-671-5p, hsa-miR-19b-3p, and hsa-miR-24-3p may reflect the pathophysiology or symptoms of PD and MSA.

/pdf/identification-of-plasma-microrna-expression-changes-in-2j9qz4vtpn.pdf

Jun Utsumi

Papers

Identification of plasma microRNAs as a biomarker of sporadic Amyotrophic Lateral Sclerosis

Xenon has greater inhibitory effects on spinal dorsal horn neurons than nitrous oxide in spinal cord transected cats.

Dexmedetomidine reduces seizure threshold during enflurane anaesthesia in cats.

MicroRNA expression profiles of neuron-derived extracellular vesicles in plasma from patients with amyotrophic lateral sclerosis.

Identification of plasma microRNA expression changes in multiple system atrophy and Parkinson's disease.