Validation of Self-Monitoring Devices Supporting Sodium Intake Reduction: An Experimental Feeding Study Using Standardized Low-Salt and High-Salt Meals among Healthy Japanese Volunteers.

INTRODUCTION: Although several approaches for approximating daily Na intake and the Na/K ratio using casual urine are available, the most useful method remains unclear during daily practice and at home. METHODS: Twenty-seven participants measured their casual urinary Na/K ratio repeatedly using a Na/K ratio monitor and also measured overnight urine once daily using a monitoring device which delivers on-site feedback to estimate their salt intake under unrestricted, low-salt (LS) (6 g/day), and high-salt (HS) (12 g/day) diets. RESULTS: The monitoring method utilizing overnight urine to estimate daily Na remained insensitive, resulting in significant overestimation during the LS diet and underestimation during the HS diet periods; estimated salt intake during the LS and HS diet periods plateaued at 7-8 g/day and 9-10 g/day within 3 day; mean estimated salt intake was 11.3 g/day, 7.9 g/day, and 9.8 g/day on the last day of the unrestricted, LS, and HS diets; the coefficient of variation (CV) of the estimated Na intake was 0.23 and 0.17 in the latter half of the low- and high-salt diet periods, respectively. The mean urinary Na/K molar ratio was 5.6, 2.5, and 5.3 on the last day of the unrestricted, LS, and HS diets; the CV of the daily mean Na/K ratio was 0.41 and 0.36 in the latter half of the LS and HS diet periods, respectively. The urinary Na/K ratio during the LS and HS diet periods plateaued within 2 days. The monitoring method based on the daily mean of the casual urinary Na/K ratio reflected the actual change in Na intake, and the estimated value tracked the actual changes in salt intake with smaller difference than the overnight urine estimates when using the estimation coefficient set at 2; estimated salt intake during the LS and HS diet periods plateaued at 5-6 g/day and 10-12 g/day within 2-3 day; mean estimated salt intake was 11.0 g/day, 5.7 g/day, and 10.7 g/day on the last day of the unrestricted, LS, and HS diets, respectively. DISCUSSION/CONCLUSION: Estimates of daily Na intake derived from overnight urine may remain insensitive during dietary interventions. The urinary Na/K ratio reflects the actual change in Na intake during dietary modification and may serve as a practical marker, particularly during short-term interventions. Conversion from the urinary Na/K ratio to estimated salt intake may be useful, if the coefficient was set appropriate by further investigations.

A Metal-Free, Disulfide Oxidized Form of Superoxide Dismutase 1 as a Primary Misfolded Species with Prion-Like Properties in the Extracellular Environments Surrounding Motor Neuron-Like Cells.

Superoxide dismutase 1 (SOD1) is a metalloenzyme with high structural stability, but a lack of Cu and Zn ions decreases its stability and enhances the likelihood of misfolding, which is a pathological hallmark of amyotrophic lateral sclerosis (ALS). A growing body of evidence has demonstrated that misfolded SOD1 has prion-like properties such as transmissibility between cells and intracellular propagation of misfolding of natively folded SOD1. Recently, we found that SOD1 is misfolded in the cerebrospinal fluid of sporadic ALS patients, providing a route by which misfolded SOD1 spreads via the extracellular environment of the central nervous system. Unlike intracellular misfolded SOD1, it is unknown which extracellular misfolded species is most relevant to prion-like properties. Here, we determined a conformational feature of extracellular misfolded SOD1 that is linked to prion-like properties. Using culture media from motor neuron-like cells, NSC-34, extracellular misfolded wild-type, and four ALS-causing SOD1 mutants were characterized as a metal-free, disulfide oxidized form of SOD1 (apo-SOD1S-S). Extracellular misfolded apo-SOD1S-S exhibited cell-to-cell transmission from the culture medium to recipient cells as well as intracellular propagation of SOD1 misfolding in recipient cells. Furthermore, culture medium containing misfolded apo-SOD1S-S exerted cytotoxicity to motor neuron-like cells, which was blocked by removal of misfolded apo-SOD1S-S from the medium. We conclude that misfolded apo-SOD1S-S is a primary extracellular species that is linked to prion-like properties.

Overexpression of metallothionein-I, a copper-regulating protein, attenuates intracellular copper dyshomeostasis and extends lifespan in a mouse model of amyotrophic lateral sclerosis caused by mutant superoxide dismutase-1.

Over 170 mutations in superoxide dismutase-1 (SOD1) cause familial amyotrophic lateral sclerosis (ALS), a lethal motor neuron disease. Although the molecular properties of SOD1 mutants differ considerably, we have recently shown that intracellular copper dyshomeostasis is a common pathogenic feature of different SOD1 mutants. Thus, the potentiation of endogenous copper regulation could be a therapeutic strategy. In this study, we investigated the effects of the overexpression of metallothionein-I (MT-I), a major copper-regulating protein, on the disease course of a mouse model of ALS (SOD1(G93A)). Using double transgenic techniques, we found that the overexpression of MT-I in SOD1(G93A) mice significantly extended the lifespan and slowed disease progression, but the effects on disease onset were modest. Genetically induced MT-I normalized copper dyshomeostasis in the spinal cord without influencing SOD1 enzymatic activity. The overexpression of MT-I in SOD1(G93A) mice markedly attenuated the pathological features of the mice, including the death of motor neurons, the degeneration of ventral root axons, the atrophy of skeletal muscles, and the activation of glial cells. Double transgenic mice also showed a decreased level of SOD1 aggregates within the glial cells of the spinal cord. Furthermore, the overexpression of MT-I in SOD1(G93A) mice reduced the number of spheroid-shaped astrocytes cleaved by active caspase-3. We concluded that therapeutic strategies aimed at the potentiation of copper regulation by MT-I could be of benefit in cases of ALS caused by SOD1 mutations.

Identification, characterization and full-length sequence analysis of a novel dsRNA virus isolated from the arboreal ant Camponotus yamaokai.

A novel dsRNA virus was identified from the arboreal ant Camponotus yamaokai. The complete nucleotide sequence analysis of the virus revealed that the virus consisted of 5704 bp with two ORFs. ORF1 (3084 nt) encoded a putative capsid protein. ORF2 (1977 nt) encoded a viral RNA-dependent RNA polymerase (RdRp). ORF2 could be translated as a fusion with the ORF1 product by a - 1 frameshift in the overlapping ORF1. Phylogenetic analyses based on the RdRp revealed that the virus from C. yamaokai was most likely a novel totivirus, but it was not closely related to the previously known totiviruses in arthropods. Transmission electron microscopy revealed isometric virus particles of ~30 nm diameter in the cytoplasm, which was consistent with the characteristics of the family Totiviridae. The virus was detected by reverse transcription-PCR in all caste members and developmental stages of ants, including eggs, larvae, pupae, adult workers, alates (male and female) and queens. To our knowledge, this is the first report of a member of the family Totiviridae in a hymenopteran; the virus was designated Camponotus yamaokai virus.

Dysregulation of intracellular copper homeostasis is common to transgenic mice expressing human mutant superoxide dismutase-1s regardless of their copper-binding abilities.

Over 170 mutations in superoxide dismutase-1 (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). The properties of SOD1 mutants differ considerably including copper-binding abilities. Nevertheless, they cause the same disease phenotype, suggesting a common neurotoxic pathway. We have previously reported that copper homeostasis is disturbed in spinal cords of SOD1(G93A) mice. However, it is unknown whether copper dyshomeostasis is induced by other SOD1 mutants. Using the additional mouse strains SOD1(G127insTGGG), SOD1(G85R), and SOD1(D90A), which express SOD1 mutants with different copper-binding abilities, we show that copper dyshomeostasis is common to SOD1 mutants. The SOD1 mutants shifted the copper trafficking systems toward copper accumulation in spinal cords of the mice. Copper contents bound to the SOD1 active site varied considerably between SOD1 mutants. Still, copper bound to other ligands in the spinal cord were markedly increased in all. Zinc was also increased, whereas there were no changes in magnesium, calcium, aluminum, manganese and iron. Further support for a role of copper dyshomeostasis in ALS was gained from results of pharmacological intervention. Ammonium tetrathiomolybdate (TTM), a copper chelating agent, prolonged survival and slowed the disease progression of SOD1(G93A) mice, even when the treatment was started after the disease onset. TTM markedly attenuated pathology, including the loss of motor neurons and axons, and atrophy of skeletal muscles. Additionally, TTM decreased amounts of SOD1 aggregates. We propose that pharmacological agents that are capable of modulating copper dyshomeostasis, such as TTM, might be beneficial for the treatment of ALS caused by SOD1 mutations.

Dysregulation of intracellular copper trafficking pathway in a mouse model of mutant copper/zinc superoxide dismutase-linked familial amyotrophic lateral sclerosis.

Mutations in copper/zinc superoxide dismutase (SOD1) are responsible for 20% of familial amyotrophic lateral sclerosis through a gain-of-toxic function. We have recently shown that ammonium tetrathiomolybdate, an intracellular copper-chelating reagent, has an excellent therapeutic benefit in a mouse model for amyotrophic lateral sclerosis. This finding suggests that mutant SOD1 might disrupt intracellular copper homeostasis. In this study, we investigated the effects of mutant SOD1 on the components of the copper trafficking pathway, which regulate intracellular copper homeostasis. We found that mutant, but not wild-type, SOD1 shifts intracellular copper homeostasis toward copper accumulation in the spinal cord during disease progression: copper influx increases, copper chaperones are up-regulated, and copper efflux decreases. This dysregulation was observed within spinal motor neurons and was proportionally associated with an age-dependent increase in spinal copper ion levels. We also found that a subset of the copper trafficking pathway constituents co-aggregated with mutant SOD1. These results indicate that the nature of mutant SOD1 toxicity might involve the dysregulation of the copper trafficking pathway, resulting in the disruption of intracellular copper homeostasis.

Effect of cell differentiation for neuroblastoma by vitamin k analogs.

BACKGROUND: Lack of receptor tyrosine kinase (TrkA), a high-affinity nerve growth factor (NGF) receptor, is closely associated with the malignant progression of neuroblastoma (NB) and its prognosis. Vitamin K3 (VK3) analogs inhibit the activity of protein tyrosine phosphatases (PTPases), which causes hydrolysis of the phosphate groups bound to the tyrosine residues on tyrosine kinase, resulting in sustained tyrosine phosphorylation. METHODS: In order to reverse this abnormal NGF/TrkA signal transduction in NB cells, we synthesized new VK3 analogs and examined their activity against NB cells. RESULTS: VK3 analogs increased or maintained the expression level of c-fos mRNA in the NB cells, which express the downstream genes of NGF/TrkA signal transduction. Moreover, the expression level of GAP-43 mRNA, which is a marker of neurite outgrowth and neuronal differentiation, was increased and morphological differentiation was also observed. VK3 analogs (especially COOH analog) continued to express c-fos and GAP-43 mRNAs and induced differentiation of NB cells after stimulation of NGF by strong inhibition of PTPase without affecting TrkA autophosphorylation. CONCLUSIONS: Vitamin K3 analogs may have potential as clinical therapeutic agents for NB.

Effects of pergolide mesilate on metallothionein mRNAs expression in a mouse model for Parkinson disease.

Dopamine agonists have neuroprotective properties in addition to their original pharmacologic function. We examined the effects of pergolide mesilate (PM) on the levels of metallothionein mRNA expression and lipid peroxidation in the corpus striata of 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonian mice. Mice were administered normal saline (vehicle as a control), PM, or MPTP. A consecutive 7-d administration of MPTP via a gastric tube at a dose of 30 mg/kg significantly decreased metallothionein (MT)-I mRNA expression but did not influence MT-III mRNA expression. Lipid peroxidation, measured as the production of malondialdehyde reactive substances, did not increase after MPTP treatment. Although PM administration alone did not effect MT-I expression, an additional consecutive 7-d administration of PM (30 mug/kg) following MPTP treatment recovered the decreased MT-I level and increased MT-III expression. Lipid peroxidation was significantly suppressed. These results suggest that PM exerts an antioxidative property through the induction of MT-I and MT-III mRNAs simultaneously in response to cellular and/or tissue injury.

Comparative study of hydrogen peroxide- and 4-hydroxy-2-nonenal-induced cell death in HT22 cells.

Several studies have indicated that lipid peroxidation often occurs in response to oxidative stress, and that many aldehydic products including 4-hydroxy-2-nonenal (HNE) are formed when lipid hydroperoxides break down. In order to clarify the mechanism of oxidative stress-induced neuronal death in the nervous system, we investigated H(2)O(2)- and HNE-induced cell death pathways in HT22 cells, a mouse hippocampal cell line, under the same experimental conditions. Treatment with H(2)O(2) and HNE decreased the viability of these cells in a time- and concentration-dependent manner. In the cells treated with H(2)O(2), significant increases in the immunoreactivities of DJ-1 and nuclear factor-kappaB (NF-kappaB) subunits (p65 and p50) were observed in the nuclear fraction. H(2)O(2) also induced an increase in the intracellular concentration of Ca(2+), and cobalt chloride (CoCl(2)), a Ca(2+) channel inhibitor, suppressed the H(2)O(2)-induced cell death. In HNE-treated cells, none of these phenomena were observed; however, HNE adduct proteins were formed after exposure to HNE, but not to H(2)O(2). N-Acetyl-L-cysteine (NAC) suppressed both HNE-induced cell death and HNE-induced expression of HNE adduct proteins, whereas H(2)O(2)-induced cell death was not affected. These findings suggest that the mechanisms of cell death induced by H(2)O(2) different from those induced by HNE in HT22 cells, and that HNE adduct proteins play an important role in HNE-induced cell death. It is also suggested that the pathway for H(2)O(2)-induced cell death in HT22 cells does not involve HNE production.

Dysequilibrium between caspases and their inhibitors in a mouse model for amyotrophic lateral sclerosis.

Mutations in copper/zinc superoxide dismutase (SOD1) have been implicated in the pathogenesis of familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 protein likely gains a novel cytotoxic property, leading to the death of motor neurons. We therefore investigated whether caspase-mediated apoptosis is associated with novel cytotoxic properties in a rodent model for familial ALS (G93A SOD1 transgenic mice). Caspase-9 (an effecter in the mitochondrial apoptotic pathway), caspase-8 (an effecter in the Fas apoptotic pathway), and caspase-3 (an executioner of both pathways) proteins were all present in nonactive forms in the spinal cords of wild-type mice during the early stage of the disease (8 weeks), at which time the mice had not yet exhibited motor paralysis. In transgenic mice, however, these proteins were present in their active forms, and their mRNA levels were significantly upregulated in the represent to this conversion from nonactive to active forms. During the advanced stage of the disease (16 weeks), when paralysis was evident, the active caspase levels were further elevated. On the other hand, the mRNA and protein levels of survivin, a counteraction protein against caspases, were significantly suppressed during the early stage, and sharply increased during the advanced stage. Although the mRNA and protein levels of X-linked inhibitor of apoptosis protein (XIAP) remained at the same levels as those seen in the control (wild-type mice) during the early stage, they were significantly depressed at an age of 16 weeks. These findings were observed exclusively in the spinal cord, the region responsible for the disease, and not in the cerebellum, a non-responsible region. We conclude that conditions facilitating the apoptotic process during the early stage of the disease play causative roles in the pathogenesis of ALS and that the suppression of XIAP levels during the advanced stage could contribute to disease expression and/or progression.

Metallothionein proteins expression, copper and zinc concentrations, and lipid peroxidation level in a rodent model for amyotrophic lateral sclerosis.

It has been hypothesized that copper-mediated oxidative stress contributes to the pathogenesis of familial amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease in humans. To verify this hypothesis, we examined the copper and zinc concentrations and the amounts of lipid peroxides, together with that of the expression of metallothionein (MT) isoforms in a mouse model [superoxide dismutase1 transgenic (SOD1 Tg) mouse] of ALS. The expression of MT-I and MT-II (MT-I/II) isoforms were measured together with Western blotting, copper level, and lipid peroxides amounts increased in an age-dependent manner in the spinal cord, the region responsible for motor paralysis. A significant increase was already seen as early as 8-week-old SOD1 Tg mice, at which time the mice had not yet exhibited motor paralysis, and showed a further increase at 16 weeks of age, when paralysis was evident. Inversely, the spinal zinc level had significantly decreased at both 8 and 16 weeks of age. The third isoform, the MT-III level, remained at the same level as an 8-week-old wild-type mouse, finally increasing to a significant level at 16 weeks of age. It has been believed that a mutant SOD1 protein, encoded by a mutant SOD1, gains a novel cytotoxic function while maintaining its original enzymatic activity, and causes motor neuron death (gain-of-toxic function). Copper-mediated oxidative stress seems to be a probable underlying pathogenesis of gain-of-toxic function. Taking the above current concepts and the classic functions of MT into account, MTs could have a disease modifying property: the MT-I/II isoform for attenuating the gain-of-toxic function at the early stage of the disease, and the MT-III isoform at an advanced stage.

Different patterns in the induction of metallothionein mRNA synthesis among isoforms after acute ethanol administration.

The induction of metallothionein (MT) isoform synthesis was investigated in mouse cerebral cortex 18 h after oral ethanol administration. The expression of MT-I isoform mRNA increased in a dose-dependent manner after ethanol loading at doses between 2 g/kg (ethanol/body weight) and 8 g/kg. Lipid peroxide formation, measured as the amount of malondialdehyde- reactive substances, remained at the control level after all of the administered ethanol doses. The expression of MT-III isoform mRNA remained at the control level up until an ethanol loading dose of 4 g/kg and then finally increased to a significant level at a dose of 8 g/kg, which is almost the LD50 for oral ethanol in mice. The different patterns of MT synthesis induction among MT isoforms suggests that the MT-I isoform, which is ubiquitous in mammalian tissues, plays a significant role as an antioxidant. On the other hand, the MT-III isoform, which has a limited tissue distribution, especially in the central nervous system, seems to be implicated in tissue repair and/or protection against critical tissue injury.

Metallothionein is a Potential Therapeutic Strategy for Amyotrophic Lateral Sclerosis.

Lou Gehrig's disease, a synonym of amyotrophic lateral sclerosis, is an adult-onset lethal neurodegenerative disorder. Irrespective of extensive efforts to elucidate the pathogenesis of the disease and searches for therapies, no favorable pharmacotherapeutic strategies have yet to be proposed. In a popular rodent model of ALS, G93A SOD1 strain of mouse, intracellular copper conditions were geared toward copper accumulation inside cells, resulting in an acceleration of oxidative stress and apoptotic process. Disruption of intracellular copper homeostasis was common to transgenic mice expressing human mutant SOD1s. In this review, the novel hypothesis that disruption of intracellular copper homeostasis could be involved in the development of the disease was introduced. Based upon the hypothesis, therapeutic outcomes of agents that are capable of correcting and/or modifying intracellular copper homeostasis are described. Administration of ammonium tetrathiomolybdate, a selective intracellular copper chelator, delayed onset, slowed progression, and prolonged survival of a rodent model of the disease (G93A SOD1 mice). Metallothionein is a low molecular weight, cysteine-rich, metal-binding cytoplasmic protein that has beneficial properties in detoxification of toxic heavy metals, homeostatic regulation of intracellular essential trace elements, including copper, antioxidant, and antiapoptotic roles. In animal experiments of the G93A SOD1 mice, an increase of metallothionein proteins by means of induction by exercise or dexamethasone, genetic overexpression, or intraperitoneal administration, all resulted in a preferable outcome. The therapeutic effects were not inferior to those of approved drugs for ALS in humans. These observations suggest that metallothionein could be worth investigating the therapeutic potential in clinical use.

[Verification of Learning Effects by Team-based Learning].

It has been recommended that active learning methods, such as team-based learning (TBL) and problem-based learning (PBL), be introduced into university classes by the Central Council for Education. As such, for the past 3 years, we have implemented TBL in a medical therapeutics course for 4-year students. Based upon our experience, TBL is characterized as follows: TBL needs fewer teachers than PBL to conduct a TBL module. TBL enables both students and teachers to recognize and confirm the learning results from preparation and reviewing. TBL grows students' responsibility for themselves and their teams, and likely facilitates learning activities through peer assessment.

Upregulation of metallothionein-I mRNA expression in a rodent model for amyotrophic lateral sclerosis.

Metallothionein (MT) mRNA expression was investigated in a rodent model (G93A SOD1 transgenic mouse) for a lethal motor neuron disease, amyotrophic lateral sclerosis (ALS). In 8-wk-old mice that did not yet exhibit motor paralysis, MT-I mRNA expression was already significantly upregulated in the region of the spinal cord responsible for motor paralysis. The expression of another isoform, MT-III, was not changed. In the cerebellum, which is not responsible for motor paralysis in ALS, neither the expression profiles of MT-I nor MT-III were altered. In 16-wk-old mice exhibiting motor paralysis, the expression of MT-I mRNA remained upregulated and the MT-III level tended to be elevated. Although no significant differences were found in the levels of both isoforms in the liver or kidney of 8-wk-old mice, the MT-I mRNA expression level was significantly upregulated in the kidney and liver of 16-wk-old mice. These results indicated that the MT-I isoform, but not the MT-III isoform, is associated with motor neuron death in ALS and suggested that the disease might be a systemic disorder to which the spinal cord is particularly susceptible.

Detection of Japanese eel endothelial cells-infecting virus in Anguilla japonica elvers.

Japanese eel endothelial cells-infecting virus (JEECV) has spread in eel farms and caused serious economic loss. In this study, we examined the prevalence of JEECV infection in 100 wild Japanese eel (Anguilla japonica) elvers caught from Yamaguchi prefecture, Japan, using quantitative PCR and conventional PCR. Total genomic DNA was obtained from the cranial quarter of the body in 70 of 100 eels and from the gill in the remaining. Of 30 gill samples, 20 were analyzed after pooling with other samples, and the remaining 10 were analyzed separately. A single positive result for JEECV was detected following analysis of the 10 separately analyzed samples. This result constitutes the first report of JEECV infection in wild A. japonica elvers.

Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis.

Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease. The pathogenesis of the disease is poorly understood, but intracellular copper dyshomeostasis has been implicated as a key process in the disease. We recently observed that metallothioneins (MTs) are an excellent target for the modification of copper dyshomeostasis in a mouse model of ALS (SOD1(G93A)). Here, we offer a therapeutic strategy designed to increase the level of endogenous MTs. The upregulation of endogenous MTs by dexamethasone, a synthetic glucocorticoid, significantly improved the disease course and rescued motor neurons in SOD1(G93A) mice, even if the induction was initiated when peak body weight had decreased by 10%. Neuroprotection was associated with the normalization of copper dyshomeostasis, as well as with decreased levels of SOD1(G93A) aggregates. Importantly, these benefits were clearly mediated in a MT-dependent manner, as dexamethasone did not provide any protection when endogenous MTs were abolished from SOD1(G93A) mice. In conclusion, the upregulation of endogenous MTs represents a promising strategy for the treatment of ALS linked to mutant SOD1.

Complete Genome Sequences of Two Japanese Eel Endothelial Cell-Infecting Virus Strains Isolated in Japan.

Japanese eel endothelial cell-infecting virus (JEECV) causes viral endothelial cell necrosis of eel (VECNE), resulting in severe economic losses in eel aquaculture in Japan. Here, we report the complete genome sequences of two new JEECV strains isolated from farmed Japanese eels.

[A case of anaphylactoid shock occurring immediately after the initiation of second intravenous administration of high-dose immunoglobulin (IVIg) in a patient with Crow-Fukase syndrome].

We report a case of anaphylactoid shock occurring immediately after the initiation of second intravenous administration of high-dose immunoglobulin (IVIg) in a patient with Crow-Fukase syndrome. The patient was a 57-year-old woman, who was admitted to our hospital because of numbness and muscle weakness in the four extremities, difficulty in walking, and foot edema. On admission, her skin was dry and rough, and also showing scattered pigmentation, small hemangiomas, and hypertrichosis in both legs. She had distal dominant muscle weakness, more prominent in her legs, and was not able to walk. Deep tendon reflexes in her four extremities were markedly diminished or absent. She had a glove and stocking type of paresthesia, severe impairment of vibration, and absence of joint position sensation in her four extremities. On laboratory data, serum vascular endothelial growth factor (VEGF) was markedly elevated to 5,184 pg/ml (normal: below 220 pg/ml). Cerebrospinal fluid examination revealed cell counts of 2/microliter and protein level of 114 mg/dl. Abdominal echo showed marked hepatosplenomegaly. On peripheral nerve conduction study, both motor and sensory conduction velocity were undetectable in her legs. We diagnosed her condition as Crow-Fukase syndrome, and started IVIg of polyethyleneglycol-treated gamma-globulin (PEG-glob) at 400 mg/kg/day for 5 consecutive days for polyneuropathy. Since the first IVIg mildly improved muscle weakness, we tried the second IVIg of PEG-glob. However, immediately after the initiation of second IVIg of PEG-glob, she developed hypotention, dyspnea, cold sweating, cyanosis, and became lethargic. We immediately stopped IVIg and started first-aid treatment with epinephrine and corticosteroid for these symptoms. This treatment was successful and the patient fully recovered without any sequelae. Since serum IgE level remained unchanged and lymphocyte stimulation test (LST) was positive against the same rot number of PEG-glob, we diagnosed these symptoms as anaphylactoid shock. Based on the results of LST, we speculated that PEG-glob was the causative agent of anaphylactoid reaction. Anaphylactic or anaphylactoid reaction as adverse effects of IVIg is very rare, and to our knowledge, there are only 4 previous reports of anaphylactic or anaphylactoid reaction caused by IVIg. Therefore, we speculated that the prominent high level of serum VEGF in the present patient might play a significant contributory role in the development of anaphylactoid shock, since the vascular permeability of VEGF is 50,000 times stronger than that of histamine. We consider that it is necessary to carefully monitor IVIg of PEG-glob administration for polyneuropathy in patients with high level of serum VEGF, like Crow-Fukase syndrome.

[A case of acute autonomic, sensory and motor neuropathy (AASMN)--less favorable response of the autonomic dysfunctions to IVIg treatment].

We report a rare case of acute autonomic, sensory and motor neuropathy (AASMN). The patient, a 26-year-old woman, developed fever and common cold around January 20, 2001 and was admitted because of abdominal pain due to ileus on January 30. After admission, the patient complained of muscle weakness and numbness in the extremities, difficulty in seeing with the right eye, and dysuria. Neurologically, marked orthostatic hypotension, right tonic pupil, distal dominant moderate muscle weakness in extremities, areflexia in both lower limbs, glove and stocking type of paresthesia, and neurogenic atonic bladder were noted. Sensation to pin prick, light touch, temperature, and vibration were markedly impaired in upper limbs and below the level of the 5th thoracic cord. Cerebrospinal fluid examination revealed albumino-cytologic dissociation. Peripheral nerve conduction study revealed lower limb dominant axonal type impairment of sensory conduction and slight impairment of motor conduction velocity. Clinical autonomic testings revealed dysfunction of both sympathetic and parasympathetic systems. As having AASMN, she was given the intravenous high-dose immunoglobulin (IVIg) therapy twice. After IVIg, the sensory and motor symptoms improved remarkably, but pandysautonomia did not. To our knowledge, this is the first report of AASMN treated by IVIg, and the notable clinical feature in this case was the favorable motor and sensory recovery to IVIg, as opposed to poor autonomic outcome.