Transient hypoglycorrhachia with paroxysmal abnormal eye movement in early infancy.

Paroxysmal abnormal eye movement in early infancy is one of the initial symptoms of glucose transporter 1 deficiency syndrome (GLUT1DS). We describe four early infants with transient hypoglycorrhachia presenting with abnormal eye movements. Their symptoms disappeared after the introduction of a ketogenic diet (KD), and their development was normal. Since no variants in SLC2A1 were detected, the CSF-to-blood glucose ratios (C/B) were re-examined, and within normal range. None of the four patients displayed recurrent symptoms after withdrawal from the KD. Because long-term KD has potential adverse effects and could affect the quality of life of patients and their families, re-examination of CSF glucose during late infancy should be considered in the case of absence of the SLC2A1 pathogenic variant.

A case of subacute combined degeneration of the spinal cord due to folic acid and copper deficiency.

Subacute combined degeneration of the spinal cord (SACD) is a rare neurologic disorder manifesting progressive symptoms of paresthesia and spastic paralysis. Herein we present an autopsy case of SACD caused by folic acid and copper deficiency. A 16-year-old male presented with gradually worsening unsteady gait, and bladder and rectal dysfunction. He had a medical history of T-cell acute lymphoblastic leukemia (T-ALL), diagnosed 1.5 years previously. The patient had undergone chemotherapy, including methotrexate, as well as allogeneic bone mallow transplantation. Laboratory tests revealed normal vitamin B12 and methylmalonic acid concentration, but reduced serum copper, ceruloplasmin and folic acid concentrations. Magnetic resonance imaging revealed symmetrical T2 signal hyperintensities in the posterior and lateral spinal cord. The patient was treated with oral copper, oral folate, and intravenous vitamin B12. A month after this treatment, the patient's symptoms were unchanged, and 2 months later he died of acute adrenal insufficiency. The pathological findings of the spinal cord were compatible with SACD. Because SACD is usually reversible with early treatment, it should be suspected in high-risk patients undergoing chemotherapy or those who are malnourished with characteristic symptoms of SACD, even in young patients.

A dramatic synergistic effect of a flexible achiral linker on a rigid chiral cis-1,2-diamine bifunctional organocatalyst.

The combination of a "rigid" chiral bicyclic cis-1,2-diamine skeleton with steric bulkiness and a "flexible" achiral linker was newly designed as a bifunctional organocatalyst framework and it showed excellent catalytic activity of up to 0.05 mol%, accompanied by the reversal of enantioselection depending on the position of the linker, in an amine-thiourea organocatalyzed asymmetric Michael reaction.

Visualization Method for Proprioceptive Drift on a 2D Plane Using Support Vector Machine.

Proprioceptive drift, which is a perceptual shift in body-part position from the unseen real body to a visible body-like image, has been measured as the behavioral correlate for the sense of ownership. Previously, the estimation of proprioceptive drift was limited to one spatial dimension, such as height, width, or depth. As the hand can move freely in 3D, measuring proprioceptive drift in only one dimension is not sufficient for the estimation of the drift in real life situations. In this article, we provide a novel method to estimate proprioceptive drift on a 2D plane using the mirror illusion by combining an objective behavioral measurement (hand position tracking) and subjective, phenomenological assessment (subjective assessment of hand position and questionnaire) with a sophisticated machine learning approach. This technique permits not only an investigation of the underlying mechanisms of the sense of ownership and agency but also assists in the rehabilitation of a missing or paralyzed limb and in the design rules of real-time control systems with a self-body-like usability, in which the operator controls the system as if it were part of his/her own body.

De novo GABRA1 mutations in Ohtahara and West syndromes.

OBJECTIVE: GABRA1 mutations have been identified in patients with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, and idiopathic familial generalized epilepsy. In addition, de novo GABRA1 mutations were recently reported in a patient with infantile spasms and four patients with Dravet syndrome. Those reports suggest that GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies. In this study, we searched for GABRA1 mutations in patients with infantile epilepsy to investigate the phenotypic spectrum of GABRA1 mutations. METHODS: In total, 526 and 145 patients with infantile epilepsy were analyzed by whole-exome sequencing and GABRA1-targeted resequencing, respectively. RESULTS: We identified five de novo missense GABRA1 mutations in six unrelated patients. A p.R112Q mutation in the long extracellular N-terminus was identified in a patient with infantile epilepsy; p.P260L, p.M263T, and p.M263I in transmembrane spanning domain 1 (TM1) were identified in three unrelated patients with West syndrome and a patient with Ohtahara syndrome, respectively; and p.V287L in TM2 was identified in a patient with unclassified early onset epileptic encephalopathy. Four of these mutations have not been observed previously. SIGNIFICANCE: Our study suggests that de novo GABRA1 mutations can cause early onset epileptic encephalopathies, including Ohtahara syndrome and West syndrome.

The mirror illusion: does proprioceptive drift go hand in hand with sense of agency?

Vection can be regarded as the illusion of "whole-body" position perception. In contrast, the mirror illusion is that of "body-part" position perception. When participants viewed their left hands in a mirror positioned along the midsaggital axis while moving both hands synchronously, they hardly noticed the spatial offset between the hand in the mirror and the obscured real right hand. This illusion encompasses two phenomena: proprioceptive drift and sense of agency. Proprioceptive drift represented a perceptual change in the position of the obscured hand relative to that of the hand in the mirror. Sense of agency referred to the participants' subjective sense of controlling body image as they would their own bodies. We examined the spatial offset between these two phenomena. Participants responded to a two-alternative forced choice (2AFC) question regarding the subjective position of their right hands and questionnaires regarding sense of agency at various positions of the right hand. We analyzed the 2AFC data using a support vector machine and compared its classification result and the questionnaire results. Our data analysis suggested that the two phenomena were observed in concentric space, but the estimated range of the proprioceptive drift was slightly narrower than the range of agency. Although this outcome can be attributed to differences in measurement or analysis, to our knowledge, this is the first report to suggest that proprioceptive drift and sense of agency are concentric and almost overlap.

Characterization of childhood-onset complex partial seizures associated with autism spectrum disorder.

Autism spectrum disorder (ASD) has a close relationship with epilepsy. A previous study showed complex partial seizures (CPS) to be the most frequent type of epileptic seizures in cases of ASD. Patients with childhood-onset CPS were retrospectively studied to investigate the prevalence of ASD and to characterize the association between CPS and ASD. The study cohort comprised 86 patients with CPS manifesting at 1 to 9 years of age. Symptomatic CPS and Panayiotopoulos syndrome were excluded. Patients with ASD (ASD group) were compared with those without ASD (non-ASD group). Of the 86 patients with childhood-onset CPS, 36 (42%) also had ASD. This ASD group was predominantly male (68.6%), with higher rates of intellectual disability (69%), and reported frequent seizures (60% had monthly or more frequent seizures). CPS without secondary generalization were more common in the ASD group (69%) than in the non-ASD group (36%), as were frontal paroxysms on EEG (54.5% vs 30%, respectively). In the non-ASD group, 82% of cases had been seizure free for 2 or more years, in comparison to 50% in the ASD group. ASD is frequently associated with childhood-onset CPS. Male gender, cognitive deficits, frequent seizures, and frontal paroxysms are risk factors for the association of ASD with CPS.

Acute central infusion of leptin modulates fatty acid mobilization by affecting lipolysis and mRNA expression for uncoupling proteins.

Chronic administration of leptin has been shown to reduce adiposity through energy intake and expenditure. The present study aims to examine how acute central infusion of leptin regulates peripheral lipid metabolism, as assessed by markers indicative of their mobilization and utilization. A bolus infusion of 1 microg/rat leptin into the third cerebroventricle increased the expression of mRNA for hormone-sensitive lipase (HSL), an indicator of lipolysis, in white adipose tissue (WAT). This was accompanied by elevation of plasma levels of glycerol, but not of free fatty acids, as compared to the saline control (P < 0.03). The same treatment with leptin decreased plasma insulin levels but did not affect the plasma glucose level (P < 0.05 for insulin). Among the major regulators of the transportation or utilization of energy substrates, leptin treatment increased expression of mRNA for uncoupling protein 1 (UCP1) in brown adipose tissue (BAT), UCP2 in WAT, and UCP3 in quadriceps skeletal muscle, but not those for fatty acid-binding protein in WAT, carnitine phosphate transferase-1, a marker for beta oxidation of fatty acids in muscle, nor glucose transporter 4 in WAT and muscle (P < 0.01 for HSL, P < 0.05 for UCP1, and P < 0.005 for UCP2 and UCP3). These results indicate that, even in a single bolus, leptin may regulate the mobilization and/or utilization of energy substrates such as fatty acids by affecting lipolytic activity in WAT and by increasing the expression of UCPs in BAT, WAT, and muscle.

Diurnal rhythm of apolipoprotein A-IV in rat hypothalamus and its relation to food intake and corticosterone.

Apolipoprotein A-IV (apo A-IV) is a satiety protein synthesized in the small intestine and hypothalamus. To further understand the roles of central apo A-IV in the management of daily food intake, we have examined the diurnal patterns of hypothalamic apo A-IV gene and protein expression in freely feeding and food-restricted (food provided 4 h daily between 1000 h and 1400 h) rats. In freely feeding rats, the hypothalamic apo A-IV mRNA and protein levels fluctuated, with high levels during the light phase, peaking at 0900 h (3 h after lights on), and low levels during the dark phase, with a nadir at 2100 h (3 h after lights off). The daily patterns of the fluctuation, however, were altered in food-restricted rats, which had a marked decrease in hypothalamic apo A-IV mRNA and protein levels during the 4 h-feeding period of the light phase. Although corticosterone (CORT) secretion temporally coincided with the decreasing phase of apo A-IV in the hypothalamus, depletion of CORT by adrenalectomy significantly decreased, rather than increased, hypothalamic apo A-IV mRNA and protein levels. These results indicate that the diurnal expression of hypothalamic apo A-IV is regulated by factors other than the circulating CORT, for example, the reduced food intake and body weight in adrenalectomized animals. The fact that hypothalamic apo A-IV level and food intake were inversely related during the normal diurnal cycle as well as in the period of restricted feeding suggests that hypothalamic apo A-IV is involved in the regulation of daily food intake.

Expression of biologically active rat apolipoprotein AIV in Escherichia coli.

Rat apolipoprotein AIV (apo AIV) is a 43-kDa intestinal apolipoprotein that is important in lipid metabolism and the suppression of food intake. In this study, a full-length rat apo AIV was expressed in Escherichia coli and purified in a bioactive form. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometric analysis revealed that the isolated recombinant protein has a molecular mass of approximately 43 kDa, similar to that of natural rat apo AIV. Immunoblot analysis and N-terminal amino acid sequencing confirmed the identity of the recombinant apo AIV protein as natural rat apo AIV. The recombinant protein was functional in lipoprotein binding assays. Biological activity was assessed behaviorally in that the recombinant protein suppressed food intake of fasted rats comparably to natural rat apo AIV. Neither native nor recombinant apo AIV elicited a conditioned taste aversion (CTA) at doses that suppress feeding. These results indicate that the recombinant apo AIV is structurally and functionally indistinguishable from rat natural apo AIV, making this overexpression and purification scheme a powerful tool for future structure and function studies.

Histidine suppresses food intake through its conversion into neuronal histamine.

Hypothalamic neuronal histamine has been shown to regulate feeding behavior and energy metabolism as a target of leptin action in the brain. The present study aimed to examine the involvement of L-histidine, a precursor of neuronal histamine, in the regulation of feeding behavior in rats. Intraperitoneal (ip) injection of L-histidine at doses of 0.35 and 0.70 mmol/kg body weight significantly decreased the 24-hr cumulative food and water intakes compared to phosphate buffered saline injected controls (P < 0.05 for each). This suppression of feeding was mimicked dose-dependently by intracerebroventricular infusion of histidine at doses of 0.5, 1.0, and 2.0 micromol/rat (P < 0.05 for each). Pretreatment of the rats with an ip bolus injection of alpha-fluoromethylhistidine, a suicide inhibitor of a histidine decarboxylase (HDC), at a dosage of 224 micromol/kg blocked the conversion of histidine into histamine and attenuated the suppressive effect of histidine on food intake from 64.2% to 88.1% of the controls (P < 0.05). Administration of 0.35 mmol/kg histidine ip increased the concentration of hypothalamic neuronal histamine compared with the controls (P < 0.05). HDC activity was increased simultaneously by histidine administration compared with the controls (P < 0.05). The present findings indicate that L-histidine suppresses food intake through its conversion into histamine in the hypothalamus.