An autopsy case of pure nigropathy with TUBA4A nonsense mutation.

We showed the results of pathological and genetic investigation for an autopsy case who was evaluated as longstanding Parkinson's disease (PD) in alive. Neuropathological investigation showed "pure nigropathy" without Lewy and tau pathology, and genetic analyses using next-generation sequencing detected novel TUBA4A nonsence mutation. Subsequent physiological study added to strength the hypothesis that the variant is pathogenic one. Present case showed TUBA4A is not only responsible gene for amyotrophic lateral sclerosis/frontotemporal dementia but also PD associated pure nigropathy. Also we found minimal but significant tau pathology high possibly associated with long-term deep brain stimulation in subthalamic nucleus.

Bilateral Pallidal Stimulation with Directional Leads for Primary Focal Lingual Dystonia.

There have been limited studies regarding stereotactic and functional neurosurgery for lingual dystonia. Here, we report a patient with primary lingual dystonia who showed significant improvement after bilateral deep brain stimulation (DBS). A 42-year-old woman presented with a 5- to 6-year history of tongue protrusion; however, she lacked a significant medical or medication history before onset. She presented with gradually worsening symptoms and was diagnosed with idiopathic lingual dystonia. Her tongue was injected with botulinum toxin on 6 occasions; however, it had a limited effect. Oral medications were ineffective. She underwent DBS since her involuntary tongue movements were causing nocturnal breathing problems. Directional leads were bilaterally inserted into the internal segment of the globus pallidus (GPi). The directional part of each lead was inserted at the GPi bottom on both sides. The posteromedial contacts were used to deliver stimulation. After 1.5 years, the patient's Burke-Fahn-Marsden dystonia rating scale score improved from 9 to 1.5 and 2 to 1 for movement and disability, respectively. This case demonstrated the effectiveness of bilateral GPi-DBS. Placing the directional part of the lead in the GPi bottom could improve the stimulation effects.

[Stereotactic and Functional Neurosurgery: Complications and Countermeasures].

Stereotactic and functional neurosurgery(deep brain stimulation[DBS]and radiofrequency coagulation)is an established method of treatment for patients with Parkinson's disease, tremor, and/or dystonia. The surgery involves many pitfalls and is similar to other surgeries, requiring experience and skills. Here, we have discussed three categories of DBS-related complications, including surgical procedure-related and device-related complications, and stimulation-induced side effects. In addition, we have discussed the prevention and coping methods, including those not listed in the guidelines for stereotactic and functional neurosurgery.

Full recovery from drummer's dystonia with foot and arm symptoms after stereotactic ventro-oral thalamotomy: a case report.

Ventro-oral (Vo) thalamotomy is effective in patients with focal task-specific dystonias (FTSDs), but only in those with upper-limb symptoms. We describe a patient with drummer's dystonia who completely recovered after Vo thalamotomy. A 37-year-old man who started playing drums at 14 began having difficulty performing fine movements with his right foot when drumming at 22. He experienced right hand cramps while drumming 3 months before visiting our hospital. He was diagnosed with FTSD. Left Vo thalamotomy was performed, which led to complete improvement of symptoms. Vo thalamotomy may be effective for FTSD patients with upper- and lower-extremity symptoms.

Discovery and structure-guided fragment-linking of 4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxamide as a pyruvate kinase M2 activator.

Tumor cells switch glucose metabolism to aerobic glycolysis by expressing the pyruvate kinase M2 isoform (PKM2) in a low active form, providing glycolytic intermediates as building blocks for biosynthetic processes, and thereby supporting cell proliferation. Activation of PKM2 should invert aerobic glycolysis to an oxidative metabolism and prevent cancer growth. Thus, PKM2 has gained attention as a promising cancer therapy target. To obtain novel PKM2 activators, we conducted a high-throughput screening (HTS). Among several hit compounds, a fragment-like hit compound with low potency but high ligand efficiency was identified. Two molecules of the hit compound bound at one activator binding site, and the molecules were linked based on the crystal structure. Since this linkage succeeded in maintaining the original position of the hit compound, the obtained compound exhibited highly improved potency in an in vitro assay. The linked compound also showed PKM2 activating activity in a cell based assay, and cellular growth inhibition of the A549 cancer cell line. Discovery of this novel scaffold and binding mode of the linked compound provides a valuable platform for the structure-guided design of PKM2 activators.

A mushroom-derived amino acid, ergothioneine, is a potential inhibitor of inflammation-related DNA halogenation.

Myeloperoxidase (MPO)-generated halogenating molecules, such as hypochlorous acid and hypobromous acid (HOBr), in inflammatory regions are postulated to contribute to disease progression. In this study, we showed that ergothioneine (EGT), derived from an edible mushroom, inhibited MPO activity as well as the formation of 8-bromo-2'-deoxyguanosine in vitro. The HOBr scavenging effect of EGT is higher than those of ascorbic acid and glutathione. We initially observed that the administration of Coprinus comatus, an edible mushroom containing a high amount of EGT, inhibited the UV-B-induced inflammatory responses and DNA halogenation, suggesting that EGT is a promising anti-inflammatory agent from mushrooms.

Phase II Trial of Intravenous Low-Dose Granulocyte Colony-Stimulating Factor in Acute Ischemic Stroke.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) has shown neuroprotective and neurogenerative activities in experimental studies, and our previous phase I clinical study suggested the safety and potential efficacy of low-dose G-CSF in acute ischemic stroke patients. The present phase II trial is aimed to evaluate the effect of G-CSF administration on neurological function and infarct volume, compared with a placebo group. METHODS: Forty-nine acute ischemic stroke patients (29 males, 20 females; 71 ± 10 years) within 24 hours after onset were recruited. Eligible patients were randomized 2:2:1 to receive G-CSF 150 µg/body/day, G-CSF 300 µg/body/day, and placebo, respectively. We evaluated clinical outcome in terms of the National Institutes of Health Stroke Scale, the modified Rankin Scale, and the Barthel Index at 90 days after onset, together with changes in infarct volume on magnetic resonance imaging. RESULTS: We found no serious adverse event, including change in leukocyte levels, which remained below 31,000/µL, at 150 and 300 µg G-CSF/body/day. Clinical outcome scores did not show any significant difference among the 3 groups. Chronological changes in infarct volume also showed no significant difference. CONCLUSIONS: G-CSF was well-tolerated at 150 and 300 µg/body/day in patients with acute ischemic stroke. However, administration of G-CSF at both 150 and 300 µg/body/day neither contributed to functional recovery nor reduced infarct volume at 3 months after onset, compared with the control group. The apparent lack of effectiveness may have been due to the small sample size. A trial of combination therapy with recombinant tissue plasminogen activator and G-CSF is planned.

Specific role of taurine in the 8-brominated-2'-deoxyguanosine formation.

At the sites of inflammation, hypohalous acids, such as hypochlorous acid and hypobromous acid (HOBr), are produced by myeloperoxidase. These hypohalous acids rapidly react with the primary amino groups to produce haloamines, which are relatively stable and can diffuse long distances and cross the plasma membrane. In this study, we examined the effects of taurine, the most abundant free amino acid in the leukocyte cytosol, on the hypohalous acid-dependent formation of 8-chloro-2'-deoxyguanosine (8-CldG) and 8-bromo-2'-deoxyguanosine (8-BrdG). The reaction of taurine with HOBr yielded taurine bromamine, which is the most stable among other bromamines of amino acids. Taurine also enhanced the bromination of only dG among the four 2'-deoxynucleosides, whereas it inhibited the 8-CldG formation. The specificity of taurine for the enhanced formation of halogenated dG is completely different from that of nicotine, an enhancer of chlorination. The amount of dibrominated taurine (taurine dibromamine) closely correlated with the formation of 8-BrdG, suggesting that taurine dibromamine might be a plausible mediator for the dG bromination in vivo.

[Complete remission of consciousness disturbances and spasticity due to a severe subarachnoid hemorrhage after intrathecal baclofen therapy: a case report].

Typically, intrathecal baclofen therapy(ITB)for spasticity is continuously required because the spasticity can recur if the ITB is stopped. Thus, an infusion pump for the ITB is permanently implanted. Some sporadic cases exhibiting remarkable improvements in their spasticity and consciousness disturbances have been reported after implanting the ITB pump. We experienced a rare case involving removal of the ITB pump after the spasticity resolved and the consciousness disturbances markedly improved. A 15-year-old girl developed a subarachnoid hemorrhage due to rupture of an aneurysm in the right anterior cerebral artery. Her initial Glasgow Coma Scale score was 4(E1V1M2). Trapping of the aneurysm and decompression craniotomy were performed. Subsequently, she underwent a tracheotomy, and a percutaneous gastrostomy(PEG)tube was implanted because of persistent consciousness disturbances. Cranioplasty and lumbar-peritoneal shunt for normal pressure hydrocephalus were performed after 1 month. An ITB pump was implanted to improve the spasticity observed mainly in the lower extremities 61 days after hemorrhage onset. Right hemiparesis remained due to Kernohan's notch. After transfer to the rehabilitation hospital, her consciousness disturbances and spasticity remarkably improved(1.9 to 1.0 and 3.5 to 1.0 on the Ashworth scale for the upper and lower extremities, respectively). The tracheostomy and PEG tubes were removed, and the baclofen dose was gradually reduced. She was completely off baclofen after 7 months, and she was discharged with a short leg brace and a cane for walking. The baclofen pump was then removed. In this case, temporary ITB improved the spasticity and consciousness disturbances.

Stereotactic neurosurgery for writer's cramp: report of two cases with an overview of the literature.

BACKGROUND: Writer's cramp is a specific movement disorder with hand muscle cramps in writing, being classified into focal and action-specific dystonia. Stereotactic surgery, such as thalamotomy and deep brain stimulation (DBS), has been reported for writer's cramp; however, the number of reported cases is still scarce and surgical procedures are also controversial. OBJECTIVES: In this study, therefore, we present 2 patients who underwent thalamotomy for writer's cramp and systematically review the literature on stereotactic surgery for writer's cramp. METHODS: Case reports and literature review are presented. RESULTS: Both patients underwent ventral oral nucleus (Vo) thalamotomy safely. Their symptoms completely disappeared after surgery and did not recur during follow-up periods. In the literature, a total of 31 cases were surgically treated for writer's cramp. Stereotactic surgery included thalamotomy in 25 cases and DBS in 6. The target included the Vo in 17 cases, the ventral intermediate nucleus (Vim) in 3, and both Vo and Vim in 7. Both procedures markedly improved or resolved the symptoms. Transient neurological deficits were observed in 16.0% of patients after thalamotomy. CONCLUSIONS: The Vo may be the most effective target to treat writer's cramp. Both thalamotomy and DBS are feasible and effective, but thalamotomy would be a better option, especially in younger or high-risk patients.

Neuronal activity topography parameters as a marker for differentiating vascular cognitive impairment in carotid stenosis.

Previously, we reported on the differentiation between patients with Alzheimer disease and normal controls using a quantitative electroencephalographic technique called neuronal activity topography (NAT). In this technique, cerebral neuronal activities are characterized by the signal intensity and coherence (sNAT and vNAT, respectively). In the present study, we examined 47 patients with vascular cognitive impairment in carotid stenosis and 52 normal controls. All subjects underwent electroencephalography in a resting state with closed eyes for 5 minutes. Electroencephalographic markers of the differential likelihood, that is, the sensitivity-versus-specificity characteristics, sL(x:VCI-NLc) and vL(x:VCI-NLc), were assessed with neuronal activity topography and were compared between the 2 groups. sL(x:VCI-NLc) and vL(x:VCI-NLc) crossed each other at a cutoff value of the differential likelihood. Separation of the patients and controls was made with a sensitivity of 92% and 88%, as well as a false-positive rate of 8% and 12% for sL(x:VCI-NLc) and vL(x:VCI-NLc), respectively. Using sNAT, we accurately differentiated 92% patients with vascular cognitive impairment. We recommend that sNAT, rather than vNAT, should be used in detecting vascular cognitive impaired patients.

The first-in-human phase I study of a brain-penetrant mutant IDH1 inhibitor DS-1001 in patients with recurrent or progressive IDH1-mutant gliomas.

BACKGROUND: Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001. METHODS: This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose-escalation used a modified continual reassessment method. RESULTS: The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cutoff. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least 1 grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples. CONCLUSIONS: DS-1001 was well tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272).

Cerebrospinal Fluid Leakage to the Chest Subcutaneous Pocket Due to Aggressive Brain Edema around the Leads for Deep Brain Stimulation: A Case Report and Literature Review.

Cerebral edema around the lead has been reported as a complication of deep brain stimulation; however, the causes remain unknown. Herein, we present a rare case of sudden cerebral edema around the lead occurring after deep brain stimulation. This was accompanied by cerebrospinal fluid (CSF) leakage into the subcutaneous thoracic pocket around the implantable pulse generator in a 53-year-old man with Parkinson's disease. No such case has been reported thus far. Lumbar drainage was performed to improve CSF leakage. The cerebral edema initially responded to steroids, but then it stopped responding to treatment. The edema appeared alternately on the left and right sides, and cyst formation was noted around the left lead. There are some reports of cyst formation around the lead; however, in our case, images were used to monitor the edema and cyst from their appearance to their disappearance. Our data suggest that cyst formation and cerebral edema are related.

Chemical and immunochemical detection of 8-halogenated deoxyguanosines at early stage inflammation.

Myeloperoxidase (MPO) generates reactive halogenating species that can modify DNA. The aim of this study was to investigate the formation of 8-halogenated 2'-deoxyguanosines (8- halo-dGs) during inflammatory events. 8-Bromo-2'-dG (8-BrdG) and 8-chloro-2'-dG (8-CldG) were generated by treatment of MPO with hydrogen peroxide at physiological concentrations of Cl(-) and Br(-). The formation of 8-halo-dGs with other oxidative stress biomarkers in lipopolysaccharide-treated rats was assessed by liquid chromatography tandem mass spectrometry and immunohistochemistry using a novel monoclonal antibody (mAb8B3) to 8-BrdG-conjugated keyhole limpet hemocyanin. The antibody recognized both 8-BrdG and 8-CldG. In the liver of lipopolysaccharide-treated rats, immunostaining for 8-halo-dGs, halogenated tyrosines, and MPO were increased at 8 h, whereas those of 8-oxo-2'-dG (8-OxodG) and 3-nitrotyrosine were increased at 24 h. Urinary excretion of both 8-CldG and 8-BrdG was also observed earlier than those of 8-OxodG and modified tyrosines (3-nitrotyrosine, 3-chlorotyrosine, and 3- bromotyrosine). Moreover, the levels of the 8-halo-dGs in urine from human diabetic patients were 8-fold higher than in healthy subjects (n = 10, healthy and diabetic, p < 0.0001), whereas there was a moderate difference in 8-OxodG between the two groups (p < 0.001). Interestingly, positive mAb8B3 antibody staining was observed in liver tissue from hepatocellular carcinoma patients but not in liver tissue from human cirrhosis patients. These data suggest that 8-halo-dGs may be potential biomarkers of early inflammation.

Bilateral subthalamic deep brain stimulation for camptocormia associated with Parkinson's disease.

BACKGROUND: Few multiple case studies of the effects of deep brain stimulation for camptocormia associated with Parkinson's disease have been reported. Although deep brain stimulation was in some cases not effective against camptocormia, it is unclear in which types of patients it was effective in treating camptocormia. OBJECTIVE: We treated 4 Parkinson's disease patients with camptocormia and evaluated their paraspinal muscle status by computed tomography to specify the characteristics of cases of effective treatment. METHODS: The 2 female and 2 male patients in this study were 60-69 years old, with a disease duration from onset to surgery of 7-13 years and a follow-up period of 18-40 months. The electrodes were implanted bilaterally in the subthalamic nuclei. RESULTS: Camptocormia was improved in 3 cases, and was unchanged in the remaining case although other parkinsonian symptoms improved. The computed tomography number of paraspinal muscle in the unimproved patient was much smaller than that in the improved patients. CONCLUSIONS: A relationship may exist between improvement of camptocormia and severity of paraspinal muscle degeneration.

Foreign body granuloma around implantable pulse generator for deep brain stimulation: Two case reports.

We report two cases of granuloma that occurred around an implantable pulse generator (IPG) for deep brain stimulation. Both cases showed no signs of infection and disappeared after moving the IPG and removing the granulation. If a noninfectious mass is formed, the relocation of IPG may improve it.

Molecular cloning and expression study on Toll-like receptor 5 paralogs in Japanese flounder, Paralichthys olivaceus.

Toll-like receptor (TLR) 5 is responsible for the bacterial flagellin recognition in vertebrates. Synergistic role of TLR 5 membrane form (TLR 5M) and TLR 5 soluble form (TLR 5S) have been reported from the study on rainbow trout. This system is regarded as the unique system in teleost fish. However, systemic response of TLR 5 genes in teleost fish has not been fully understood. Hence, we cloned Japanese flounder (Paralichthys olivaseus) TLR 5M and TLR 5S genes and their expressions were analyzed. The coding region of Japanese founder TLR 5M and TLR 5S cDNA were 2670 bp and 1923 bp, encoding 889 and 640 amino acid residues, respectively. The Japanese flounder TLR 5M was composed of an extracellular leucine rich repeats (LRRs), a transmembrane and an intracellular Toll/interleukin-1 receptor (TIR) domains, whereas TLR 5S possessed only the LRR domain. TLR 5M was highly expressed in the gill, head kidney, heart and liver. TLR 5S was highly expressed in the brain, head kidney and heart. Flagellin stimulation (1 and 5 microg/ml) led to strong gene expression of TLR 5S in peripheral blood leukocytes (PBLs) and liver cells. In contrast to TLR 5S, TLR 5M was down-regulated until 3 h after flagellin stimulation in PBLs and liver cells. The flagellin stimulation also resulted in the production of the flounder IL-1beta and IL-6 from the liver cells and PBLs. The gene expression of TLR 5M was highly induced in the liver, while TLR 5S gene expression was drastically increased in the intestine following challenge with Edwardsiella tarda. Increased number of TLR 5M- and 5S-expressing cell populations were detected by in situ hybridization in the lamina propria of the intestine and liver after E. tarda infection, respectively. These results imply that the expression of these TLR 5 paralogs in Japanese flounder are differently regulated in the whole body and play important roles in the immune response against bacterial pathogens.

The Hanger Reflex: An Inexpensive and Non-invasive Therapeutic Modality for Dystonia and Neurological Disorders.

The hanger reflex is a phenomenon characterized by the involuntary rotation of the head when a wire hanger is worn around the head such that a force is applied to the frontal temporal area by the longer side of the hanger. The application of a shearing force on the skin is thought to be the cause of this phenomenon. Attempts have been made to treat cervical dystonia using equipment designed to induce the hanger reflex. This reflex may have implications in the treatment of headaches, cervical pain, and adhesive capsulitis. The hanger reflex is seen not only in the head region but is also in other parts of the body. Thus, it could be used in the treatment of systemic dystonias. The hanger reflex may help develop inexpensive and non-invasive treatment for dystonia or other neurological diseases and is expected to be the focus of research in the future.

Pilot Study for Considering Subthalamic Nucleus Anatomy during Stimulation Using Directional Leads.

OBJECTIVE: Directional leads are used for deep brain stimulation (DBS). Two of the four contacts of the leads are divided into three parts, enabling controlled stimulation in a circumferential direction. The direction of adverse effects evoked by DBS in the subthalamic nucleus (STN) and stimulation strategies using directional leads were evaluated. METHODS: Directional leads were implanted into the bilateral STN of six parkinsonian patients (1 man, 5 women; mean age 66.2 years). The contact centers were located within the upper border of the STN, and the locations were identified electrically using microrecordings. Adverse effects were evaluated with electrical stimulation (30 µs, 130 Hz, limit 11 mA) using the directional part of each lead after surgery, and the final stimulation direction was investigated. Unified Parkinson's disease rating scale (UPDRS) scores were evaluated before and after DBS. RESULTS: Fifty-six motor and four sensory symptoms were evoked by stimulation; no adverse effect was evoked in 14 contacts. Motor and sensory symptoms were evoked by stimulation in the anterolateral direction and medial to posterolateral direction, respectively. Stimulation in the posteromedial direction produced adverse effects less frequently. The most frequently used contacts were located above the STN (63%), followed by the upper part of the STN (32%). The mean UPDRS part III and dyskinesia scores decreased after DBS from 30.2 ± 11.7 to 7.2 ± 2.9 and 3.3 ± 2.4 to 0.5 ± 0.8, respectively. CONCLUSION: The incidence of adverse effects was low for the posteromedial stimulation of the STN. Placing the directional part of the lead above the STN may facilitate the control of dyskinesia.

Improvement of Writer's Cramp from an Old Lesion in the Contralateral Hemisphere with Transient Gait Disturbance After Thalamotomy.

BACKGROUND: Stereotactic ventro-oral thalamotomy has been performed in cases of focal task-specific dystonia, including writer's cramp, with excellent outcomes. However, no reports have revealed the outcome of ventro-oral thalamotomy in a patient with a contralateral cerebral lesion. We describe a patient with left-hand writer's cramp with an old lesion in the left hemisphere and transient gait disturbance after right ventro-oral thalamotomy. CASE DESCRIPTION: A 43-year-old man had a hemorrhage in the left basal ganglia due to cerebral arteriovenous malformation at 22 years of age, and right hemiparesis remained as a sequela. He developed left-handed writing ability; however, he became aware of the stiffness of his left hand and difficulty in writing. Writer's cramp was diagnosed. Medical treatments were not effective, and right ventro-oral thalamotomy was performed. Although his writing ability improved, he could not walk. After performing rehabilitation, his walking completely improved, reaching the level before surgery, after 3 months, and his writer's cramp was completely cured. CONCLUSIONS: In patients with basal nucleus lesions, gait disturbance may appear transiently after contralateral thalamotomy. It is crucial to fully explain the potential complications, particularly in relation to temporal gait disturbances, and obtain informed consent.