Late relapse of anti-N-methyl-d-aspartate receptor encephalitis with amusia and transiently reduced uptake in 123I-iomazenil single-photon emission computed tomography.

INTRODUCTION: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis has a high relapse rate at approximately 10-20%. Most relapses occur within 2 years from onset, and 5 years after onset is rare. We report a case of anti-NMDAR encephalitis relapse with amusia 10 years after the initial encephalitis and discuss the usefulness of 123I-iomazenil single-photon emission computerized tomography (IMZ-SPECT) for its diagnosis. CASE: A 13-year-old left-handed girl presented with a depressed level of consciousness and focal to bilateral tonic-clonic seizures. Cerebrospinal fluid (CSF) analysis showed a mildly increased white blood cell count, elevated neopterin levels, and positive oligoclonal bands. Brain MRI was normal. IMZ-SPECT revealed reduced uptake in the right frontoparietal region. She received intravenous pulse methylprednisolone (IVMP) and high-dose intravenous immunoglobulin for autoimmune encephalitis; her symptoms resolved without neurological deficits. At 23 years old, she had mild right-sided numbness, dysarthria, amusia, and tonic-clonic seizures. Although the CSF analysis and brain MRI were normal, IMZ-SPECT revealed reduced uptake, indicating a relapse of encephalitis. IVMP administration resolved the symptoms. After discharge, the initial and relapse CSF analysis revealed anti-NMDAR antibodies. CONCLUSION: An anti-NMDAR encephalitis relapse 10 years after onset has never been reported. IMZ-SPECT may help in the diagnosis of anti-NMDAR encephalitis.

Drug screening with a novel tumor-derived cell line identified alternative therapeutic options for patients with atypical teratoid/rhabdoid tumor.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare intracranial tumor occurring predominantly in young children. The prognosis is poor, and no effective treatment is currently available. To develop novel effective therapies, there is a need for experimental models for AT/RT. In this research, we established a cell line from a patient's AT/RT tissue (designated ATRT_OCGH) and performed drug screening using 164 FDA-approved anti-cancer agents, to identify candidates for therapeutic options. We found that bortezomib, a proteasome inhibitor, was among the agents for which the cell line showed high sensitivity, along with tyrosine kinase inhibitors, topoisomerase inhibitors, and histone deacetylase inhibitors, which are known to exert anti-AT/RT effects. Concomitant use of panobinostat potentiated the inhibitory effect of bortezomib on AT/RT cell proliferation. Our findings may provide a rationale for considering combination therapy of panobinostat and bortezomib for treatment of AT/RT.

Efficacy of preoperative amino acid supplements on postoperative physical function and complications in open heart surgery patients: A study protocol for a randomized controlled trial.

BACKGROUND: Elderly patients undergoing cardiac surgery often show poor nutritional status, muscle wasting, and sarcopenia, which are reported to affect postoperative functional recovery and incidence of complications. Amino acids are essential in maintaining nutritional status, synthesizing muscle protein, and promoting beneficial energy balance of the heart muscle. ß-Hydroxy ß-methylbutyric acid (HMB) is a leucine metabolite known to increase muscle protein synthesis and inhibit protein catabolism; it has been used to more effectively support patients with muscle wasting due to wearing diseases. However, the efficacy of amino acid administration comprising HMB in patients undergoing open heart surgery remains unclear. This study aims to examine whether preoperative short-term aggressive amino acid administration helps support postoperative recovery of physical function and prevent complications. METHODS: This is a single-center prospective randomized controlled trial (UMIN000030490). Patients aged ≥65 years who will be hospitalized for medical examination before cardiac surgery will be recruited. The participants will be randomly assigned to the experimental or control group. The experimental group will be administered with an amino acid supplement with HMB 1200mg, l-glutamine 7000mg, and l-arginine 7000mg once or twice per day depending on the degree of renal dysfunction, for 14-28 days preoperatively. The control group will not receive any nutritional intervention. The main outcome will be a change in the 6-min walking test distance pre- and postoperatively as a sign of functional recovery. Secondary outcomes such as the incidence of complications; physical, nutritional, and psychological states; mortality; and length of hospital stay will also be evaluated. CONCLUSION: This clinical study will determine the effects of preoperative short-term oral amino acid supplementation with HMB, l-glutamine, and l-arginine on postoperative physical function in elderly patients undergoing cardiac surgery.

A case of epilepsy induced by eating or by visual stimuli of food made of minced meat.

We report a 34-year-old woman with eating epilepsy induced not only by eating but also seeing foods made of minced meat. In her early 20s of age, she started having simple partial seizures (SPS) as flashback and epigastric discomfort induced by particular foods. When she was 33 years old, she developed SPS, followed by secondarily generalized tonic-clonic seizure (sGTCS) provoked by eating a hot dog, and 6 months later, only seeing the video of dumpling. We performed video electroencephalogram (EEG) monitoring while she was seeing the video of soup dumpling, which most likely caused sGTCS. Ictal EEG showed rhythmic theta activity in the left frontal to mid-temporal area, followed by generalized seizure pattern. In this patient, seizures were provoked not only by eating particular foods but also by seeing these. This suggests a form of epilepsy involving visual stimuli.

Pediatric thalamic glioma with H3F3A K27M mutation, which was detected before and after malignant transformation: a case report.

PURPOSE: Histone H3.3 (H3F3A) mutation in the codon for lysine 27 (K27M) has been found as driver mutations in pediatric glioblastoma and has been suggested to play critical roles in the pathogenesis of thalamic gliomas and diffuse intrinsic pontine gliomas. We report a case of thalamic glioma with H3F3A K27M mutation, which was detected in both the primary tumor diagnosed as diffuse astrocytoma obtained during the first surgery and also in the tumor diagnosed as anaplastic astrocytoma obtained at the second surgery. CASE PRESENTATION: A 14-year-old girl presented with mild headache. Magnetic resonance imaging (MRI) showed a small intraaxial lesion in the left thalamus, which increased in size. Stereotactic tumor biopsy was performed 2 years after the initial diagnosis, and a pathological diagnosis of diffuse astrocytoma (WHO grade 2) was made. The tumor grew further and showed contrast enhancement on MRI despite 16 months of chemotherapy. Surgical removal via the transcallosal approach was then performed, and postoperative pathological diagnosis was anaplastic astrocytoma (WHO grade 3), indicating malignant transformation of the tumor. Molecular diagnosis of tumor tissue obtained at first and second surgeries revealed H3F3A K27M mutation in both primary and secondary specimens. CONCLUSION: This report demonstrates minute neuroradiological and pathological features of malignant transformation from thalamic low grade glioma with H3F3A K27M mutation. It is noteworthy that this mutation was found in this case when the tumor was still a low-grade glioma. Tissue sampling for genetic analysis is useful in patients with thalamic gliomas to predict the clinical course and efficacy of treatments.

[Para-Aortic Lymphadenectomy and Subsequent Chemotherapy after Resection of the Primary Lesion for Poorly Differentiated Adenocarcinoma of the Sigmoid Colon - A Case Report].

The patient was a 68-year-old male who had bloody stools. A colonoscopy revealed a sigmoid colon stricture, and a histological examination confirmed the presence of a poorly differentiated adenocarcinoma.Computed tomography revealed the involvement of a para-aortic lymph nodes, without other metastatic lesions. The patient underwent a sigmoidectomy (with regional lymph node dissection) and a para-aortic lymph node biopsy to prove the histological conformation. Subsequently, he was provided with 6 courses of modified FOLFOX6(mFOLFOX6) chemotherapy, resulting in a marked decrease in para-aortic lymph node involvement. He subsequently underwent a para-aortic lymphadenectomy. The resected specimen was mostly composed of fibrous degenerative tissue; viable cancer cells were observed only in a 2-mm² area. The patient was provided with 6 more courses of mFOLFOX6 chemotherapy, and has since been free of recurrence (for 6 years and 1 month after the second surgery).

Protocadherin 17 regulates presynaptic assembly in topographic corticobasal Ganglia circuits.

Highly topographic organization of neural circuits exists for the regulation of various brain functions in corticobasal ganglia circuits. Although neural circuit-specific refinement during synapse development is essential for the execution of particular neural functions, the molecular and cellular mechanisms for synapse refinement are largely unknown. Here, we show that protocadherin 17 (PCDH17), one of the nonclustered δ2-protocadherin family members, is enriched along corticobasal ganglia synapses in a zone-specific manner during synaptogenesis and regulates presynaptic assembly in these synapses. PCDH17 deficiency in mice causes facilitated presynaptic vesicle accumulation and enhanced synaptic transmission efficacy in corticobasal ganglia circuits. Furthermore, PCDH17(-/-) mice exhibit antidepressant-like phenotypes that are known to be regulated by corticobasal ganglia circuits. Our findings demonstrate a critical role for PCDH17 in the synaptic development of specific corticobasal ganglia circuits and suggest the involvement of PCDH17 in such circuits in depressive behaviors.

Inhibition of COX-2 expression by topical diclofenac enhanced radiation sensitivity via enhancement of TRAIL in human prostate adenocarcinoma xenograft model.

BACKGROUND: COX-2 inhibitors have an antitumor potential and have been verified by many researchers. Treatment of cancer cells with external stressors such as irradiation can stimulate the over-expression of COX-2 and possibly confer radiation resistance. In this study, we tested if topical diclofenac, which inhibits both COX-1 and COX-2, administration rendered prostate tumor cells sensitize to the effects of radiation. METHODS: LNCaP-COX-2 and LNCaP-Neo cells were treated with 0 to 1000 µM diclofenac. Next, a clonogenic assay was performed in which cells were subjected to irradiation (0 to 4 Gy) with or without diclofenac. COX-2 expression and other relevant molecules were measured by real-time PCR and immunohistochemistry after irradiation and diclofenac treatment. In addition, we assessed the tumor volumes of xenograft LNCaP-COX-2 cells treated with topical diclofenac with or without radiation therapy (RT). RESULTS: LNCaP-COX-2 and LNCaP-Neo cell lines experienced cytotoxic effects of diclofenac in a dose related manner. Clonogenic assays demonstrated that LNCaP-COX-2 cells were significantly more resistant to RT than LNCaP-Neo cells. Furthermore, the addition of diclofenac sensitized LNCaP-COX-2 not but LNCaP-Neo cells to the cytocidal effects of radiation. In LNCaP-COX-2 cells, diclofenac enhanced radiation-induced apoptosis compared with RT alone. This phenomenon might be attributed to enhancement of RT-induced TRAIL expression as demonstrated by real-time PCR analysis. Lastly, tumor volumes of LNCaP-COX-2 cells xenograft treated with diclofenac or RT alone was >4-fold higher than in mice treated with combined diclofenac and radiation (p<0.05). CONCLUSIONS: These in vitro and in vivo findings suggest that conventional COX inhibitor, diclofenac enhances the effect of RT on prostate cancer cells that express COX-2. Thus, diclofenac may have potential as radiosensitizer for treatment of prostate cancer.

[Pharmacotherapy of anxiety disorders].

Until the 1980s, benzodiazepines were first-line drugs used to treat anxiety disorders. However, benzodiazepines present some limitations: they are ineffective for some subtypes of anxiety disorders. Moreover, they entail side effects such as dependency, somnolence, and memory disturbances. Since 1980s, several clinical trials have shown that selective serotonin reuptake inhibitors (SSRIs), which have no dependency, are effective for most subtypes of anxiety disorders. Consequently, SSRIs are now anti-anxiety drugs as well as antidepressants. In a recent guideline for the pharmacological treatment of anxiety disorders developed by the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force, SSRIs are first-line drugs for the treatment of most subtypes of anxiety disorders. However, SSRIs do not improve symptoms in all patients with anxiety disorders. Therefore, benzodiazepines and tricyclic antidepressants are used even now for the treatment of anxiety disorder. Furthermore, off-label pharmacotherapies, supportive and other psychotherapies, and psychoeducation are applied to the treatment of anxiety disorders. Pharmacotherapy is part of integrative therapy of anxiety disorders. The treatment and pathogenesis of treatment-resistant anxiety disorders have not been elucidated sufficiently. Future studies must be conducted to elucidate the pathogenesis and to develop a new treatment for treatment-resistant anxiety disorders. In contrast to those for other emotions, the neurocircuits related to anxiety and fear have been clarified in detail. The author and others have investigated the mechanisms and target brain regions of the anti-anxiety action of SSRIs using an animal model of anxiety: conditioned fear stress. Results show that SSRIs inhibit glutamatergic neurons of the amygdala through increased extracellular serotonin levels. This inhibition engenders anti-anxiety action. Benzodiazepines also inhibit the amygdala, thereby reducing fear or anxiety. The inhibitory action on the amygdala might be a common mechanism of anti-anxiety action of SSRIs and benzodiazepines.

Lamotrigine blocks apoptosis induced by repeated administration of high-dose methamphetamine in the medial prefrontal cortex of rats.

Lamotrigine (LTG) is sometimes co-administered with antipsychotic drugs for the treatment of schizophrenia. Nevertheless, the pharmacological basis of LTG use for schizophrenia has not been reported. Our group recently proposed a new psychostimulant animal model that might reflect the progressive pathophysiology of schizophrenia. Results obtained using that model show that LTG blocks the initiation and expression of repeated high-dosage methamphetamine-induced prepulse inhibition deficit in rats (Nakato et al., 2010, Neurosci. Lett. [25]). Using the model, the effect of LTG (30 mg/kg) on methamphetamine (METH, 2.5 mg/kg)-induced increases in extracellular glutamate levels in the medial prefrontal cortex (mPFC) was examined in this study. Then the effect of repeated co-administration of LTG (30 mg/kg) on repeated METH (2.5 mg/kg)-induced apoptosis in this region of rats was investigated. Results show that LTG (30 mg/kg) blocked the METH (2.5 mg/kg)-induced glutamate increase in the mPFC. Repeated co-administration of LTG (30 mg/kg) blocked the development of apoptosis induced by repeated administration of METH (2.5 mg/kg) in the mPFC. The LTG blocks histological abnormalities induced by repeated administration of METH, which suggests a mechanism of LTG that protects against progressive pathophysiology in schizophrenia.