Validation of pediatric index of mortality 2 (PIM2) in a single pediatric intensive care unit in Japan

Objective  

The Pediatric Index of Mortality 2 (PIM2), one of the key mortality prediction models for children in intensive care units, has not been validated in Japan. The purpose of this study was to validate the performance of PIM2 in a population of patients admitted to one pediatric intensive care unit (PICU) in Japan.     

Early rehabilitation with weight-bearing standing-shaking-board exercise in combination with electrical muscle stimulation after anterior cruciate ligament reconstruction

The objective of early rehabilitation after anterior cruciate ligament (ACL) reconstruction is to increase the muscle strength of the lower extremities. Closed kinetic chain (CKC) exercise induces co-contraction of the agonist and antagonist muscles. The purpose of this study was to compare the postoperative muscle strength/mass of subjects who performed our new CKC exercise (new rehabilitation group:group N) from week 4, and subjects who received traditional rehabilitation alone (traditional rehabilitation group:group T). The subjects stood on the device and maintained balance. Then, low-frequency stimulation waves were applied to 2 points each in the anterior and posterior region of the injured thigh 3 times a week for 3 months. Measurement of muscle strength was performed 4 times (before the start, and then once a month). Muscle mass was evaluated in CT images of the extensor and flexor muscles of 10 knees (10 subjects) in each group. The injured legs of group N showed significant improvement after one month compared to group T. The cross-sectional area of the extensor muscles of the injured legs tended to a show a greater increase at 3 months in group N. This rehabilitation method makes it possible to contract fast-twitch muscles, which may be a useful for improving extensor muscle strength after ACL reconstruction.     

Different pathophysiology underlying animal models of fibromyalgia and neuropathic pain: comparison of reserpine-induced myalgia and chronic constriction injury rats

The reserpine-induced myalgia (RIM) rat manifests fibromyalgia-like chronic pain symptoms. The present study explored the pathophysiology underlying the pain symptoms in the RIM rat and the chronic constriction injury (CCI) rat, an animal model of neuropathic pain as a reference. Nerve tissue samples were collected from the nociception-tested animals for pathological examinations. Additionally, the therapeutic efficacy of a sodium channel blocker mexiletine was assessed in both rats. A slight vacuolization in the substantia nigra (SN) occurred in some of the RIM rats without any other histopathological changes in the brain or peripheral neurons. All the RIM rats, with or without vacuolization, showed hypersensitivity to tactile, muscle pressure, and cold stimuli. In the CCI rat, neurodegenerative changes were apparent in the sciatic nerve and the spinal cord only. CCI rats displayed muscle hyperalgesia in addition to tactile and cold allodynia. Pharmacotherapy with mexiletine did not attenuate the pain in the RIM rat, although it was effective in the CCI rat. Taken together, it is not likely that pain symptoms in RIM rats are caused by degenerative changes at the level of primary afferents and spinal cord, as is the case for CCI rats. The significance of the vacuolization in the SN is less clear at present because of the minor extent of the change and the lack of correlation with nociceptive sensitivity. The pain symptoms in RIM rats could be associated with dysfunction of biogenic amines-mediated CNS pain control even without apparent pathologies in the nervous system.     

Cerebellar long-term depression requires dephosphorylation of TARP in Purkinje cells

Cerebellar long-term depression (LTD) at parallel fiber (PF)-Purkinje cell synapses is thought to play an essential role in certain forms of motor learning. Like hippocampal LTD, cerebellar LTD is mediated by the endocytosis of AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) receptors at postsynaptic sites. However, similar sets of kinases and phosphatases have opposite regulatory effects on hippocampal and cerebellar LTD, although the mechanisms responsible for this difference remain largely unclear. Activity-dependent dephosphorylation of stargazin (an AMPA receptor auxiliary protein) by calcineurin regulates hippocampal LTD, but whether and how stargazin is involved in cerebellar LTD is unknown. In this study, we showed that stargazin is highly phosphorylated at basal states and is dephosphorylated by the application of high KCl plus glutamate (K-glu) or of a metabotropic glutamate receptor agonist, (S)-3,5-dihydroxyphenylglycine (DHPG), both of which chemically induced LTD in cerebellar slices. This chemically induced dephosphorylation of stargazin was specifically blocked by a calcineurin inhibitor. Indeed, inclusion of the calcineurin auto-inhibitory peptide in the patch pipette solution completely inhibited the LTD induced by the conjunctive stimulation of PFs and Purkinje cells. Furthermore, in Purkinje cells expressing stargazin-9D, in which all nine serine residues are mutated to aspartate, neither conjunctive stimulus nor DHPG treatment induced LTD. Finally, immunohistochemical analyses revealed that neither K-glu nor DHPG induced the endocytosis of AMPA receptors in Purkinje cells expressing stargazin-9D. Together, these results indicate that hippocampal and cerebellar LTD share a common pathway, namely dephosphorylation of stargazin by calcineurin.     

Stricture of oxygen outlet of the central piping identified by a decrease in the oxygen supply pressure into the anesthesia machine

We experienced an incident of the stricture caused by the degradation of an O-ring in the oxygen outlet of the central piping. The event was identified by the intermittent decrease of the central piping oxygen supply pressure into the anesthesia machine. In this case, pressure was judged normal by periodical checking. But the malfunction became clear when the parts of outlet were replaced, because similar incidents frequently had occurred. The cyclical rhythm of the declining oxygen supply pressure means that oxygen supplies decreases with the increase of oxygen consumption, and it may be a sign of serious malfunction. Therefore, it is necessary to check the pressure deviations under use of high-flow oxygen.     

In vivo imaging of axonal transport of mitochondria in the diseased and aged mammalian CNS

The lack of intravital imaging of axonal transport of mitochondria in the mammalian CNS precludes characterization of the dynamics of axonal transport of mitochondria in the diseased and aged mammalian CNS. Glaucoma, the most common neurodegenerative eye disease, is characterized by axon degeneration and the death of retinal ganglion cells (RGCs) and by an age-related increase in incidence. RGC death is hypothesized to result from disturbances in axonal transport and in mitochondrial function. Here we report minimally invasive intravital multiphoton imaging of anesthetized mouse RGCs through the sclera that provides sequential time-lapse images of mitochondria transported in a single axon with submicrometer resolution. Unlike findings from explants, we show that the axonal transport of mitochondria is highly dynamic in the mammalian CNS in vivo under physiological conditions. Furthermore, in the early stage of glaucoma modeled in adult (4-mo-old) mice, the number of transported mitochondria decreases before RGC death, although transport does not shorten. However, with increasing age up to 23–25 mo, mitochondrial transport (duration, distance, and duty cycle) shortens. In axons, mitochondria-free regions increase and lengths of transported mitochondria decrease with aging, although totally organized transport patterns are preserved in old (23- to 25-mo-old) mice. Moreover, axonal transport of mitochondria is more vulnerable to glaucomatous insults in old mice than in adult mice. These mitochondrial changes with aging may underlie the age-related increase in glaucoma incidence. Our method is useful for characterizing the dynamics of axonal transport of mitochondria and may be applied to other submicrometer structures in the diseased and aged mammalian CNS in vivo.Globally, longevity is increasing, and the cohort aged 60 y or over is the fastest growing portion of the population. These trends place neurodegenerative diseases among the greatest clinical threats. Glaucoma, the most common progressive neurodegenerative eye disease (1), globally affects an estimated 60.5 million people, of whom 8.4 million are bilaterally blind (2). Similar to other neurodegenerative diseases of the CNS, including Alzheimer’s disease (3) and Parkinson’s disease (4), the incidence of glaucoma (5) increases with aging. Glaucoma is characterized by axon degeneration and the death of retinal ganglion cells (RGCs) (6). Histological studies in glaucoma models have suggested disturbances in the axonal transport of mitochondria in RGCs (7, 8).Axonal transport is essential for delivering the organelles and proteins that are required for axonal function and maintenance. Mitochondria are organelles that must be transported in axons and distributed appropriately to function (9, 10), because mitochondria play a pivotal role in the function and survival of neurons by generating ATP, maintaining Ca²⁺ and reduction-oxidation (redox) homeostasis, and signaling in apoptosis. Disturbances in mitochondrial dynamics are suggested to be involved in neurodegenerative diseases and CNS aging (11–14). In vivo imaging of axonal transport of mitochondria has been reported using explant imaging of the Drosophila nervous system (15) and rat cerebellar slice cultures (16) and intravital imaging (direct in vivo imaging of living animals at subcellular resolution) of the mouse peripheral nervous system (17) and zebrafish nervous system (18). However, intravital imaging of axonal transport of mitochondria has not been achieved in the mammalian CNS. Importantly, the lack of intravital imaging of axonal transport of mitochondria in the mammalian CNS under physiological oxygen levels and metabolism and with intact blood flow has precluded the characterization of the dynamics of axonal transport of mitochondria in the CNS of diseased and aged mammals in vivo.To perform intravital imaging of axonal transport of mitochondria in the mammalian CNS, we developed the technique we call “MIMIR” (for “minimally invasive intravital imaging of mitochondrial axonal transport in RGCs”). MIMIR does not involve thinning or opening of the sclera or produce changes in the intraocular humor. MIMIR directly showed, at submicrometer resolution, that axonal transport of mitochondria is highly dynamic in the mammalian CNS in vivo under physiological conditions. It enabled us to characterize disturbances of mitochondrial transport in a mouse model of glaucoma and age-related changes of mitochondrial transport in old (23- to 25-mo-old) mice.