Deferasirox Might Be Effective for Microcytic Anemia and Neurological Symptoms Associated with Aceruloplasminemia: A Case Report and Review of the Literature.

The patient was a 64-year-old man presented with difficulty in walking, articulation, and swallowing, as well as cognitive impairment. He had refractory microcytic anemia and diabetes mellitus. His serum levels of iron, copper, and ceruloplasmin were low. Magnetic resonance imaging suggested iron deposition in the basal ganglia, thalami, cerebellar dentate nuclei, and cerebral and cerebellar cortices. He was diagnosed with aceruloplasminemia after a ceruloplasmin gene analysis. Iron chelation therapy with deferasirox improved his anemia and cerebellar symptoms, which included dysarthria and limb ataxia. The present study and previous reports indicate that cerebellar symptoms with aceruloplasminemia might respond to deferasirox in less than one year.

Tyrosol Reduces Amyloid-ß Oligomer Neurotoxicity and Alleviates Synaptic, Oxidative, and Cognitive Disturbances in Alzheimer's Disease Model Mice.

Soluble amyloid-ß (Aß) oligomers (AßOs), which elicit neurotoxicity and synaptotoxicity, are thought to play an initiating role in the pathology of Alzheimer's disease (AD). Since AßOs are a key therapeutic target, we attempted to identify natural agents that reduce AßO neurotoxicity. Using an assay system in which primary cultured neurons are treated with AßOs, we found that Rhodiola rosea extracts and one of its main constituents, tyrosol, significantly inhibited AßO-induced caspase-3 activation. We then assessed the in vivo efficacy of tyrosol by oral administration of the compound into AD model (5XFAD) transgenic and non-transgenic mice from either 2 or 4 to 7 months of age. In both paradigms, tyrosol treatment did not affect body weights of mice. Immunohistochemical analysis revealed that the immunoreactivity of spinophilin, a dendritic synaptic protein, was significantly reduced in three hippocampal subregions of vehicle-treated AD mice compared with non-transgenic mice, which was reversed in tyrosol-treated AD mice. Tyrosol treatment also prevented the enhancement of 4-hydroxy-2-nonenal immunoreactivity in the hippocampal CA3 region of AD mice. By contrast, tyrosol administration did not affect Aß accumulation, as evaluated by immunohistochemical and biochemical analyses. Moreover, the Barnes maze test showed that tyrosol administration modestly mitigated spatial memory impairment in AD mice. These findings collectively indicate that the natural agent tyrosol protects neurons against AßO neurotoxicity in vitro and ameliorates synaptic disturbance, oxidative stress responses, and cognitive impairment in vivo. We thus suggest that tyrosol is potentially an effective, safe, and unique drug candidate for AD.

High-sensitivity quantitative analysis reveals the non-linear relationship between the dose and deposition of diphenylarsinic acid in the rat central nervous system following its subchronic exposure.

In the year 2003, the residents of Kamisu, Japan, were exposed to pentavalent organic arsenic diphenylarsinic acid (DPAA[V]) via their normal drinking water. Following the exposure, they developed cerebellar and brainstem symptoms. Although the relatively high dose of DPAA(V) is assumed to have caused their symptoms, the relationship between the exposed dose of DPAA(V) and the level of their deposition in the central nervous system (CNS) remains unclear. Using liquid chromatography-tandem mass spectrometry, we examined the deposition of DPAA(V) and its pentavalent metabolites in the CNS tissues of Crl:CD(SD) rats following the administration of DPAA(V) for 28days. We found that the concentrations of DPAA(V) in the CNS were very high, given a dose of 5.0mg/kg/day. However, very low concentrations of DPAA(V) were detected at a dose of 0.3 or 1.2mg/kg/day, suggesting the absence of a linear dose-response relationship between the dose and deposition of DPAA(V). We also found that this non-linear relationship was commonly observed in various non-CNS tissues, including the excretory system. Our study showed for the first time the exact relationship between the dose and tissue deposition of the organic arsenic following its subchronic administration.

Liquorice-induced hypokalaemia in patients treated with Yokukansan preparations: identification of the risk factors in a retrospective cohort study.

OBJECTIVE: To evaluate serum potassium levels and rates of hypokalaemia in patients treated with liquorice-containing Japanese traditional Kampo-medicines Yokukansan (YK) and Yokukansan-ka-chinpihange (YKCH). DESIGN: Retrospective cohort study. SETTING: Patients receiving YK preparations for dementia and other psychiatric disorders in the University of Tsukuba Hospital in Japan. PARTICIPANTS: 389 patients (male/female: 174/215, 68.6±16.1 years) were treated with YK preparations for 231 days (range 6-2788 days). Patients whose potassium levels were <3.6 mEq/L before administration of YK preparations, and drug non-compliant patients, were excluded. MAIN OUTCOME MEASURE: The occurrence rate of hypokalaemia and assessment of the risk factors for YK preparation-induced hypokalaemia. RESULTS: Of the 389 patients treated with YK preparations, 94 (24.2%) developed hypokalaemia (potassium levels <3.6 mEq/L) 34 days (range 1-1600 days) after administration of the preparations. 36 (38.3%) patients had co-administration with lower potassium-inducing drugs (LPIDs; diuretics, glucocorticoids, mineralocorticoids and glycyrrhizin), which was more frequent in the patients without hypokalaemia (17.3%) (p<0.05). A Cox proportional hazard model identified four risk factors for hypokalaemia: YK administration (not YKCH) (HR 3.093, 95% CI 1.408 to 6.798), co-administration of LPIDs (HR 2.743, 95% CI 1.754 to 4.289), hypoalbuminaemia at baseline (HR 2.145, 95% 1.360 to 3.384), and full dosage administration (7.5 g/day) (HR 1.600, 95% CI 1.005 to 2.549). CONCLUSIONS: Serum potassium monitoring should be done at least monthly in patients with the following risk factors: LPID co-administration, YK administration, hypoalbuminaemia, and full dosage administration.

Galactorrhea in a Patient With Aquaporin-4 Antibody-positive Neuromyelitis Optica Spectrum Disorder: A Case Report and Review of the Literature.

This is the first report of a case of galactorrhea in a patient with neuromyelitis optica spectrum disorder (NMOSD) diagnosed on the basis of antiaquaporin-4 antibody seropositivity. The hypothalamus is becoming known as an area highly expressing aquaporin-4 and frequently involved in intracranial lesions of patients with neuromyelitis optica (NMO). We reviewed cases of hypothalamic endocrinopathy among patients with NMO, NMOSD, and the Japanese opticospinal form of MS. Among these cases, galactorrhea was the second most common symptom. Signs of hypothalamic endocrinopathies may be obscured by the grave neurological deficits caused by NMO. We recommend paying special attention to hypothalamic endocrinopathies among patients with NMO or NMOSD, irrespective of brain MRI findings.

Vestibular Function Impairment in Alzheimer's Disease.

BACKGROUND: Falls and fractures due to impaired balance in patients with Alzheimer's disease (AD) have an adverse effect on the clinical course of the disease. OBJECTIVE: To evaluate balance impairment in AD from the viewpoint of vestibular functional impairment. METHODS: The subjects were 12 patients with AD, 12 dementia-free elderly adults, and 12 younger adults. Vestibular function was assessed using a stepping test, caloric nystagmus, and a visual suppression (VS) test. RESULTS: The stepping test was abnormal in 9 of the 12 patients in the AD group. An abnormal stepping test was not associated with self-reported dizziness or tendency to fall. Significant VS abnormalities were present in the AD group. The suppression rate of VS was lower in AD patients with either a tendency to fall or constructional apraxia than in AD patients without either. The velocity of the rapid phase of caloric nystagmus before the VS test was similar in the AD group and the elderly control group. Significant abnormalities of both caloric nystagmus and VS were not present in either the elderly or the younger control groups. CONCLUSION: AD could involve impairments in the vestibular control of balance. The VS test is useful for assessing the tendency to fall in AD. Impairment of VS in AD might arise from cerebral vestibular cortex impairment rather than comorbid peripheral vestibular disorders.

Response to comment on "Drug screening for ALS using patient-specific induced pluripotent stem cells".

Our work and the study of Bilican et al. highlight the need for complementary assays to detect subtle phenotypic differences between control and mutant induced pluripotent stem cell lines.

Drug screening for ALS using patient-specific induced pluripotent stem cells.

Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which the motor neurons degenerate. The discovery of new drugs for treating ALS has been hampered by a lack of access to motor neurons from ALS patients and appropriate disease models. We generate motor neurons from induced pluripotent stem cells (iPSCs) from familial ALS patients, who carry mutations in Tar DNA binding protein-43 (TDP-43). ALS patient-specific iPSC-derived motor neurons formed cytosolic aggregates similar to those seen in postmortem tissue from ALS patients and exhibited shorter neurites as seen in a zebrafish model of ALS. The ALS motor neurons were characterized by increased mutant TDP-43 protein in a detergent-insoluble form bound to a spliceosomal factor SNRPB2. Expression array analyses detected small increases in the expression of genes involved in RNA metabolism and decreases in the expression of genes encoding cytoskeletal proteins. We examined four chemical compounds and found that a histone acetyltransferase inhibitor called anacardic acid rescued the abnormal ALS motor neuron phenotype. These findings suggest that motor neurons generated from ALS patient-derived iPSCs may provide a useful tool for elucidating ALS disease pathogenesis and for screening drug candidates.

Decreased expression of hypothalamic neuropeptides in Huntington disease transgenic mice with expanded polyglutamine-EGFP fluorescent aggregates.

Huntington disease is caused by polyglutamine (polyQ) expansion in huntingtin. Selective and progressive neuronal loss is observed in the striatum and cerebral cortex in Huntington disease. We have addressed whether expanded polyQ aggregates appear in regions of the brain apart from the striatum and cortex and whether there is a correlation between expanded polyQ aggregate formation and dysregulated transcription. We generated transgenic mouse lines expressing mutant truncated N-terminal huntingtin (expanded polyQ) fused with enhanced green fluorescent protein (EGFP) and carried out a high-density oligonucleotide array analysis using mRNA extracted from the cerebrum, followed by TaqMan RT-PCR and in situ hybridization. The transgenic mice formed expanded polyQ-EGFP fluorescent aggregates and this system allowed us to directly visualize expanded polyQ aggregates in various regions of the brain without performing immunohistochemical studies. We show here that polyQ-EGFP aggregates were intense in the hypothalamus, where the expression of six hypothalamic neuropeptide mRNAs, such as oxytocin, vasopressin and cocaine-amphetamine-regulated transcript, was down-regulated in the transgenic mouse brain without observing a significant loss of hypothalamic neurons. These results indicate that the hypothalamus is susceptible to aggregate formation in these mice and this may result in the down-regulation of specific genes in this region of the brain.