Daisuke Kato

Efficacy of docetaxel as a second-line chemotherapy for thymic carcinoma.

Thymic carcinoma is a rare and aggressive tumor, and the efficacy of second-line chemotherapy is still unclear. Here, we reported a case of thymic carcinoma that responded well to the administration of docetaxel alone as a second-line chemotherapy. A 64-year-old woman was diagnosed with thymic carcinoma (squamous cell type) with bone metastasis, and she, therefore, received nedaplatin combined with etoposide and ifosfamide. She responded partially, after which she received irradiation for bone metastasis. Two months after chemotherapy, the thymic carcinoma exhibited gradual regrowth and she experienced shoulder pain. We treated this with docetaxel alone (60 mg/m2 every 4 weeks). After three courses of docetaxel, we observed a partial response and her shoulder pain disappeared. This case demonstrated that docetaxel is effective as a second-line chemotherapy for thymic carcinoma.

Paranodal dissection in chronic inflammatory demyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1 antibodies

Objective To investigate the morphological features of chronic inflammatory demyelinating polyneuropathy (CIDP) with autoantibodies directed against paranodal junctional molecules, particularly focusing on the fine structures of the paranodes. Methods We assessed sural nerve biopsy specimens obtained from 9 patients with CIDP with anti-neurofascin-155 antibodies and 1 patient with anti-contactin-1 antibodies. 13 patients with CIDP without these antibodies were also examined to compare pathological findings. Results Characteristic light and electron microscopy findings in transverse sections from patients with anti-neurofascin-155 and anti-contactin-1 antibodies indicated a slight reduction in myelinated fibre density, with scattered myelin ovoids, and the absence of macrophage-mediated demyelination or onion bulbs. Teased-fibre preparations revealed that segmental demyelination tended to be found in patients with relatively higher frequencies of axonal degeneration and was tandemly found at consecutive nodes of Ranvier in a single fibre. Assessment of longitudinal sections by electron microscopy revealed that detachment of terminal myelin loops from the axolemma was frequently found at the paranode in patients with anti-neurofascin-155 and anti-contactin-1 antibody-positive CIDP compared with patients with antibody-negative CIDP. Patients with anti-neurofascin-155 antibodies showed a positive correlation between the frequencies of axo–glial detachment at the paranode and axonal degeneration, as assessed by teased-fibre preparations (p<0.05). Conclusions Paranodal dissection without classical macrophage-mediated demyelination is the characteristic feature of patients with CIDP with autoantibodies to paranodal axo–glial junctional molecules.

Suppressed phosphorylation of collapsin response mediator protein-2 in the hippocampus of HCNP precursor transgenic mice

We previously reported a novel peptide, Hippocampal Cholinergic Neurostimulating Peptide (HCNP), which induces acetylcholine synthesis by increasing the amount of choline acetyltransferase (ChAT) in medial septal nuclei. The HCNP precursor protein (HCNP-pp), composed of 186 amino acids, is an inhibitory factor of the c-Raf/MEK cascade and may be involved in fetal rat brain development via the inhibition of phosphorylation of Erk. To clarify the involvement of HCNP in hippocampal cholinergic circuitry, we previously generated HCNP-pp transgenic (HCNP-pp Tg) mice using the promoter of the α subunit of Ca(2+) calmodulin-dependent protein kinase II (CaMKIIα). These mice showed increased levels of ChAT in medial septal nuclei at 12 weeks of age, and the phenotype of depressive mood at 30 weeks of age. Here, through proteomic analysis we investigated the alteration of protein expression in the hippocampus of HCNP-pp Tg mice compared with wild-type littermate mice. We demonstrate that the activation of collapsin response mediator protein-2 (CRMP-2) is increased in the transgenic mice at 12 weeks of age when compared with wild-type littermate mice.

Suppression of Astrocyte Lineage in Adult Hippocampal Progenitor Cells Expressing Hippocampal Cholinergic Neurostimulating Peptide Precursor in an In Vivo Ischemic Model

Hippocampal cholinergic neurostimulating peptide (HCNP) is known to promote differentiation of septohippocampal cholinergic neurons. The HCNP precursor protein (HCNP-pp) may play several roles, for example, as an ATP-binding protein, a Raf kinase inhibitor protein, and a phosphatidylethanolamine-binding protein, as well as a precursor for HCNP. This study therefore aimed to elucidate the involvement of HCNP-pp in specific neural lineages after stroke using a hypoxic–ischemic (HI) rat model of brain ischemia. The specific neural lineages in the hippocampus were investigated 14 days after ischemia. Some bromodeoxyuridine (BrdU)+ neural progenitor cells in the hippocampus of hypoxic, HI, or sham-operated rats expressed HCNP-pp. Almost half of the BrdU+/HCNP-pp+ cells also expressed the oligodendrocyte lineage marker 2′,3′-cyclic nucleotide 3′-phosphodiesterase, whereas only a few BrdU+/HCNP-pp+ cells in the hippocampus in HI brains expressed the neuronal lineage marker, doublecortin (DCX). Interestingly, no BrdU+/HCNP-pp+ progenitor cells in hypoxic, HI, or sham-operated brains expressed the astrocyte lineage marker, glial fibrillary acidic protein. Together with previous in vitro data, the results of this study suggest that the expression level of HCNP-pp regulates the differentiation of neural progenitor cells into specific neural lineages in the HI hippocampus, indicating that neural stem cell fate can be controlled via the HCNP-pp mediating pathway.

Combination of ketogenic diet and stiripentol for super-refractory status epilepticus: A case report

Super-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues for at least 24 h after initiation of general anaesthetic medications, including cases in which SE recurs on reduction or withdrawal of anaesthesia [1]. Given the severity of SRSE, there is a critical need for new therapies to halt ongoing seizure activity. Because neuronal excitation is regulated by energy metabolism, SRSE can be suppressed by inhibiting metabolic pathways. A ketogenic diet (KD) has been proven to be effective in critically ill adults with SRSE [2]; however, the mechanisms by which KD prevents seizures remain unknown. It has recently been found that one of the mechanisms that KD works on is a metabolic pathway via lactate dehydrogenase (LDH) and that LDH may be inhibited by stiripentol (STP) [3]. Here, we report that a combination of KD and STP appeared to constitute effective treatment of a patient with SRSE underlying anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. A 20-year-old Japanese woman presented with a week of headaches followed by impaired consciousness. On admission, she exhibited abnormal behaviours, including altered manner of speaking and shouting loudly. She was unable to follow commands and became unresponsive to external stimuli. An electroencephalogram (EEG) showed generalized rhythmic delta frequency activity at 1 Hz with superimposed, frontally predominant bursts of rhythmic beta frequency activity (extreme delta brushes) (Fig. 1(A-1)). Her cerebrospinal fluid demonstrated mild pleocytosis (74 cells per mm) with a slightly elevated IgG index (1.01). Glucose and protein concentrations were normal. She was diagnosed as having NMDAR encephalitis (positive anti-NMDAR antibody result) with bilateral ovarian teratomas (pelvic CT findings) (Fig. 1(B)). Her symptoms were not alleviated by bilateral ovariectomy and immunotherapy (plasma exchange, intravenous immunoglobulin at 400 mg/kg over 5 days and intravenous methylprednisolone at 1000 mg over 3 days). Additionally, her seizures were unresponsive to conventional antiepileptic drugs (AEDs) such as valproate, carbamazepine, phenytoin, clonazepam, phenobarbital, and levetiracetam. Further, these treatments repeatedly resulted in a generalized rash accompanied by fever, leukopenia, and acute hepatitis and they were accordingly ceased.

Phosphorylation of collapsin response mediator protein-2 regulates its localization and association with hippocampal cholinergic neurostimulating peptide precursor in the hippocampus

Hippocampal cholinergic neurostimulating peptide (HCNP) induces the synthesis of acetylcholine in the medial septal nucleus in vitro and in vivo. The precursor, HCNP-pp, is a multifunctional protein participating in important signaling pathways, such as MAPK/ERK kinase (MEK) and G-protein-coupled receptor kinase 2 (GRK2). We recently demonstrated that HCNP-pp colocalizes with collapsin response mediator protein-2 (CRMP-2) at presynaptic terminals in the hippocampus, suggesting that HCNP-pp may play an important role in presynaptic function in association with CRMP-2. To clarify the involvement of phosphorylation in regulating the interaction between HCNP-pp and CRMP-2, we investigated the colocalization of HCNP-pp with unphosphorylated- and/or phosphorylated-CRMP-2 (pCRMP-2) at presynaptic terminals. We further determined if the phosphorylation of CRMP-2 affects the binding between those proteins. Here, we demonstrate that HCNP-pp predominantly colocalizes and associates with unphosphorylated and/or pSer-522-CRMP-2 at presynaptic terminals in the hippocampus. Interestingly, HCNP-pp does not associate with pThr-509/514-CRMP-2, which is primarily localized at postsynaptic terminals. These findings suggest that HCNP-pp, in association with unphosphorylated and/or pSer522-CRMP-2, plays an important role in presynaptic function in the mature hippocampus.

Co-localization of hippocampal cholinergic neurostimulating peptide precursor with collapsin response mediator protein-2 at presynaptic terminals in hippocampus

Hippocampal cholinergic neurostimulating peptide (HCNP) induces the synthesis of acetylcholine in medial septal nucleus in vitro and in vivo. HCNP precursor protein (HCNP-pp) is a multifunctional protein that participates in a number of signaling pathways, including MAPK/extracellular signal and G-protein-coupled receptor kinase 2. We recently demonstrated that the amount of collapsin response mediator protein-2 (CRMP-2) is increased in hippocampus of HCNP-pp transgenic mice. To clarify the interaction between HCNP/HCNP-pp and CRMP-2 and its role in synaptic function, we investigated whether HCNP-pp is localized to the synapse and if it affects protein expression. Here, we demonstrate that HCNP-pp co-localizes with CRMP-2 at presynaptic terminals. Furthermore, HCNP-pp overexpression increases synaptophysin levels. These findings suggest that HCNP-pp, in association with CRMP-2, plays an important role in presynaptic function in the hippocampus.

Utility of the fluid-attenuated inversion recovery sequence in detecting a hyperintense putaminal rim in multiple system atrophy-parkinsonism: a preliminary study.

Objective: To investigate the utility of fluid-attenuated inversion recovery (FLAIR) imaging for diagnosing multiple system atrophy-parkinsonism (MSA-P). Methods: We retrospectively evaluated 49 subjects (19 with MSA-P including 11 with early-stage disease, 15 with Parkinson’s disease and 15 matched controls) in order to compare the diagnostic value of FLAIR imaging to detect a hyperintense putaminal rim (HPR) with that of T2-weighted (T2W) imaging. Results: Compared with T2W imaging, FLAIR imaging detected HPR more conspicuously in the 19 MSA-P patients (p = 0.01); this trend was also observed in 11 early-stage MSA-P patients (p = 0.01). Furthermore, FLAIR imaging tended to increase sensitivity of detecting HPR compared with T2W imaging (all patients: 89 vs. 58%, p = 0.07; early-stage patients: 100 vs. 55%, p = 0.06). Conclusions: FLAIR imaging might be more useful for detecting HPR in MSA-P patients, even though they are at an early stage.

Activity-dependent functions of non-electrical glial cells

Electrical activity is essential for brain function. However, neurons, the electrically active cells, are less numerous than the non-electrical glial cells in the central nervous system. The non-electrical components modify the function of neural circuits, depending on the electrical neuronal activity, by wrapping synapses, myelinating axons and phagocytozing the neuronal components. Moreover, recent evidence has suggested that they contribute to neurological and psychiatric disease by regulating neuronal circuits, ultimately affecting their behaviour. In this review, we highlight the physiological functions of glial cells, particularly the electrical activity-dependent processes, to provide further insight into their role in brain function.

Stiripentol for the treatment of super‐refractory status epilepticus with cross‐sensitivity

Cross‐sensitivity of rash has been reported between various antiepileptic drugs (AEDs). However, few studies have determined the frequency and management of cross‐sensitivity in patients with super‐refractory status epilepticus (SRSE).