Aging-Related Catatonia with Reversible Dopamine Transporter Dysfunction in Females with Depressive Symptoms: A Case Series.

OBJECTIVES: The authors describe five depressive patients with initially decreased striatal accumulation of dopamine transporter (DAT) single-photon emission computed tomography (SPECT), which improved in parallel with clinical symptoms. METHODS: Patients who exhibited decreased striatal accumulation and recovery of DATSPECT were identified among patients with the symptoms of depression. Their clinical and neuroimaging data were reviewed. RESULTS: Five patients were identified. All patients were presenile or senile women who presented with catatonia subsequent to symptoms of depression that remitted with treatment. DAT-SPECT showed a decreased striatal accumulation in all patients, which increased after treatment. Two patients had met the diagnostic criteria of probable dementia with Lewy bodies (DLB), but no longer did so after their symptoms improved. CONCLUSIONS: Reversible DAT dysfunction observed in this study suggests that reversible impairment of dopaminergic transmission in the striatum partly underlies catatonia. Careful consideration should be given to diagnosing DLB in patients with decreased DAT-SPECT accumulation, especially when catatonia is present.

Positional cloning and comprehensive mutation analysis of a Japanese family with lithium-responsive bipolar disorder identifies a novel DOCK5 mutation.

Bipolar disorder (BD) is a severe psychiatric disorder characterized by the recurrence of depressive and manic episodes. Its heritability is high, and many linkage and association studies have been performed. Although various linkage regions and candidate genes have been reported, few have shown sufficient reproducibility, and none have identified the pathogenic genes based on the results of the linkage analysis. To find functional variants that are expected to be rare and have strong genetic effects, we recruited ten healthy individuals, two individuals with unknown status, and six patients with BD or recurrent major depressive disorder (MDD) from a Japanese family consisting of 21 members. We performed a genome-wide linkage analysis using a 100K single-nucleotide polymorphism (SNP) array and microsatellite markers to narrow linkage regions within this family. Subsequently, we performed whole-exome sequencing for two patients with BD to identify genetic mutations in the narrowed linkage regions. Then, we performed co-segregation analysis for DNA variants obtained from the results of the exome sequencing. Finally, we identified a rare heterozygous mutation in exon 31 of DOCK5 (c.3170A>G, p.E1057G). Convergent functional genomics analysis revealed that DOCK5 was listed as one of the biomarkers for mood state and suicidality. Although DOCK5 is still a functionally unknown gene, our findings highlight the possibility of a pathological relationship between BD and DOCK5.

Positional cloning and comprehensive mutation analysis identified a novel KDM2B mutation in a Japanese family with minor malformations, intellectual disability, and schizophrenia.

The importance of epigenetic control in the development of the central nervous system has recently been attracting attention. Methylation patterns of lysine 4 and lysine 36 in histone H3 (H3K4 and H3K36) in the central nervous system are highly conserved among species. Numerous complications of body malformations and neuropsychiatric disorders are due to abnormal histone H3 methylation modifiers. In this study, we analyzed a Japanese family with a dominant inheritance of symptoms including Marfan syndrome-like minor physical anomalies (MPAs), intellectual disability, and schizophrenia (SCZ). We performed positional cloning for this family using a single nucleotide polymorphism (SNP) array and whole-exome sequencing, which revealed a missense coding strand mutation (rs1555289644, NM_032590.4: c.2173G>A, p.A725T) in exon 15 on the plant homeodomain of the KDM2B gene as a possible cause of the disease in the family. The exome sequencing revealed that within the coding region, only a point mutation in KDM2B was present in the region with the highest logarithm of odds score of 2.41 resulting from whole genome linkage analysis. Haplotype analysis revealed co-segregation with four affected family members (IV-9, III-4, IV-5, and IV-8). Lymphoblastoid cell lines from the proband with this mutation showed approximately halved KDM2B expression in comparison with healthy controls. KDM2B acts as an H3K4 and H3K36 histone demethylase. Our findings suggest that haploinsufficiency of KDM2B in the process of development, like other H3K4 and H3K36 methylation modifiers, may have caused MPAs, intellectual disability, and SCZ in this Japanese family.

DNA analysis of benign adult familial myoclonic epilepsy reveals associations between the pathogenic TTTCA repeat insertion in SAMD12 and the nonpathogenic TTTTA repeat expansion in TNRC6A.

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disease characterized by adult-onset tremulous hand movement, myoclonus, and infrequent epileptic seizures. Recently, intronic expansion of unstable TTTCA/TTTTA pentanucleotide repeats in SAMD12, TNRC6A, or RAPGEF2 was identified as pathological mutations in Japanese BAFME pedigrees. To confirm these mutations, we performed a genetic analysis on 12 Japanese BAFME pedigrees. A total of 143 participants, including 43 familial patients, 5 suspected patients, 3 sporadic nonfamilial patients, 22 unaffected familial members, and 70 unrelated controls, were screened for expanded abnormal pentanucleotide repeats in SAMD12, TNRC6A, RAPGEF2, YEAT2, MARCH6, and STARD7. DNA samples were analyzed using Southern blotting, long-range polymerase chain reaction (PCR), repeat-primed PCR, and long-range PCR followed by Southern blotting. Of the 51 individuals with clinically diagnosed or suspected BAFME, 49 carried a SAMD12 allele with an expanded TTTCA/TTTTA pentanucleotide repeat. Genetic and clinical anticipation was observed. As in previous reports, the one patient with homozygous mutant alleles showed more severe symptoms than the heterozygous carriers. In addition, screening for expanded pentanucleotide repeats in TNRC6A revealed that the frequency of expanded TTTTA repeat alleles in the BAFME group was significantly higher than in the control group. All patients who were clinically diagnosed with BAFME, including those in the original family reported by Yasuda, carried abnormally expanded TTTCA/TTTTA repeat alleles of SAMD12. Patients with BAFME also frequently carried a TTTTA repeat expansion in TNRC6A, suggesting that there may be unknown factors in the ancestry of patients with BAFME that make pentanucleotide repeats unstable.

A patient with McLeod syndrome showing involvement of the central sensorimotor tracts for the legs.

BACKGROUND: McLeod syndrome is a rare X-linked recessive acanthocytosis associated with neurological manifestations including progressive chorea, cognitive impairment, psychiatric disturbances, seizures, and sensorimotor axonal polyneuropathy. However, no studies have investigated the functioning of central sensorimotor tracts in patients with McLeod syndrome. CASE PRESENTATION: A 66-year-old man had experienced slowly progressive chorea and gait disturbance due to lower limb muscle weakness since his early fifties. Blood examinations showed erythrocyte acanthocytosis and the reduction of Kell antigens in red blood cells. Brain magnetic resonance imaging showed atrophy of the bilateral caudate nuclei and putamen. The diagnosis of McLeod syndrome was confirmed by the presence of a mutation of the XK gene on the X chromosome. Somatosensory-evoked potential and transcranial magnetic stimulation studies demonstrated that the central sensory and motor conduction times were abnormally prolonged for the lower extremity but normal for the upper extremity. CONCLUSIONS: This is the first report of the involvement of the central sensorimotor tracts for the legs in a patient with McLeod syndrome. The clinical neurophysiological technique revealed the central sensorimotor tracts involvements clinically masked by neuropathy.

Mouse model of chorea-acanthocytosis exhibits male infertility caused by impaired sperm motility as a result of ultrastructural morphological abnormalities in the mitochondrial sheath in the sperm midpiece.

Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disease characterized by neurodegeneration in the striatum and acanthocytosis caused by loss-of-function mutations in the Vacuolar Protein Sorting 13 Homolog A (VPS13A) gene, which encodes chorein. We previously produced a ChAc-model mouse with a homozygous deletion of exons 60-61 in Vps13a, which corresponded to the human disease mutation. We found that male ChAc-model mice exhibited complete infertility as a result of severely diminished sperm motility. Immunocytochemical study revealed that chorein-like immunoreactivity is abundant only in the midpiece, mitochondria-rich region, of the sperm of wild type mice. They showed no significant differences from wild types in terms of the adenosine 5'-triphosphate (ATP) concentration of their sperm, sperm count, or sexual activity. Electron microscopy revealed abnormal ultrastructural morphology of the mitochondria in the midpiece of sperm from ChAc-model mice. These results suggest that chorein is essential in mouse sperm for the maintenance of ultrastructural mitochondrial morphology and sperm motility.

Chorein interacts with α-tubulin and histone deacetylase 6, and overexpression preserves cell viability during nutrient deprivation in human embryonic kidney 293 cells.

The autophagy pathway has recently been implicated in several neurodegenerative diseases. Recently, it was reported that chorein-depleted cells showed accumulation of autophagic markers and impaired autophagic flux. Here, we demonstrate that chorein overexpression preserves cell viability from starvation-induced cell death in human embryonic kidney 293 (HEK293) cells. Subsequent coimmunoprecipitation and reverse coimmunoprecipitation assays using extracts from chorein that stably overexpressed HEK293 cells revealed that chorein interacts with α-tubulin and histone deacetylase 6, a known α-tubulin deacetylater and central component of basal autophagy. Indeed, acetylated α-tubulin immunoreactivity was significantly decreased in chorein that stably overexpressed HEK293 cells. These results suggest that chorein/histone deacetylase 6/α-tubulin interactions may play an important role in starvation-induced cell stress, and their disruption may be one of the molecular pathogenic mechanisms of chorea-acanthocytosis.-Sasaki, N., Nakamura, M., Kodama, A., Urata, Y., Shiokawa, N., Hayashi, T., Sano, A. Chorein interacts with α-tubulin and histone deacetylase 6, and overexpression preserves cell viability during nutrient deprivation in human embryonic kidney 293 cells.

Phenotypic abnormalities in a chorea-acanthocytosis mouse model are modulated by strain background.

Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disease characterized by neurodegeneration in the striatum and acanthocytosis that is caused by mutations in the VPS13A gene. We previously produced a ChAc model mice encoding a human disease mutation with deletion of exons 60-61 in the VPS13A gene. The behavioral and pathological phenotypes of the model mice varied a good deal from individual to individual, indicating that differences between individuals may be caused by the content of a genetic hybrid 129/Sv and C57BL/6J strain background. To establish the effect of the genetic background on phenotype, we backcrossed the ChAc-model mice to different inbred strains: C57BL/6J and 129S6/Sv. Although no significant difference between ChAc-mutant mice and wild-type mice on the C57BL/6J background was observed, the ChAc-mutant mice on the 129S6/Sv showed abnormal motor function and behavior. Furthermore, we produced ChAc-mutant mice on two different inbred strains: BALB/c and FVB. Significant reduction in weight was observed in ChAc mutant mice on the FVB and 129S6 backgrounds. We found a marked increase in the osmotic fragility of red blood cells in the ChAc mutant mice backcrossed to 129S6/Sv and FVB. The phenotypes varied according to strain, with ChAc mutant mice on the FVB and 129S6 backgrounds showing remarkably abnormal motor function and behavior. These results indicate that there are modifying genetic factors of ChAc symptoms.

Seizures as presenting and prominent symptom in chorea-acanthocytosis with c.2343del VPS13A gene mutation.

OBJECTIVE: The aim of the study was to characterize the clinical features of nine patients in three families with chorea-acanthocytosis (ChAc) sharing the same rare c.2343del mutation in the VPS13A gene. METHODS: Genetic test results, clinical description, magnetic resonance imaging (MRI), and electroencephalography (EEG), as well as laboratory results are summarized. RESULTS: ChAc is a rare genetic disorder characterized by hyperkinetic movements, seizures, cognitive decline, neuropsychiatric symptoms, and acanthocytes on peripheral blood smear. This unique cohort of nine patients is characterized by seizures as a first and prominent symptom. In our patients, other features of ChAc appeared later, including tics, other movement disorders, dysarthria, and mild to moderate cognitive decline. SIGNIFICANCE: Patients with chorea-acanthocytosis carrying the described rare mutation can present with focal, treatment-resistant seizures.

The effects of olanzapine treatment on brain regional glucose metabolism in neuroleptic-naive first-episode schizophrenic patients.

OBJECTIVE: The current study examined metabolic alterations associated with a positive response to olanzapine and identified brain regions associated with treatment-related improvement of symptoms in neuroleptic-naive first-episode schizophrenic patients using [18 F]fluoro-deoxy-glucose positron emission tomography analysis. METHODS: Neuroleptic-naive first-episode schizophrenic patients who showed good or poor clinical responses to olanzapine were assessed using the Positive and Negative Syndrome Scale. Data were analyzed using statistical nonparametric mapping. RESULTS: Before treatment, responders showed significantly increased metabolism in the superior temporal gyrus and cerebellum compared with healthy controls. Glucose metabolism in responders was significantly increased after treatment in the left precentral gyrus, left postcentral gyrus, and left paracentral lobule, and significantly decreased in the left hypothalamus. An analysis of the Positive and Negative Syndrome Scale symptoms associated with olanzapine treatment revealed that "suspiciousness/persecution" scores were positively correlated with metabolic changes in the right superior frontal gyrus. CONCLUSIONS: These findings provide evidence of the neural mechanisms underlying the effects of olanzapine on metabolism in the early stages of schizophrenia.

Comparison of the migration behavior of nanoparticles based on polyethylene glycol and silica using micellar electrokinetic chromatography.

Nanoparticles, spherical particles with diameters less than 100 nm, are promising theranostic devices for noninvasive diagnosis and therapy. In this study, nanoparticles composed of polyethylene glycol and silica were prepared, and their migration behavior was examined using capillary electrophoresis. The effects of the sodium dodecyl sulfate concentration in the electrolyte, the nanoparticle size, and the encapsulated molecule on the migration were examined. The addition of sodium dodecyl sulfate into the electrolyte had a significant effect on the electrophoretic mobility of polyethylene glycol nanoparticles, but a small effect on that of silica nanoparticles. As for the size effect, the mobility became a little faster for smaller nanoparticle sizes for both polyethylene glycol and silica nanoparticles. The encapsulated molecule affected the mobility of the nanoparticles through interactions between the encapsulated molecules and sodium dodecyl sulfate. We propose that the large effect of sodium dodecyl sulfate on the migration of the polyethylene glycol nanoparticles was due to the large spaces within the nanoparticles. These results indicate that nanoparticle migration is mainly determined by the nanoparticle components.

Evaluation of an aspiration-type semiautomatic cutting biopsy needle.

PURPOSE: The purpose of this study was to evaluate an aspiration-type semiautomatic cutting biopsy needle for biopsy of bovine tissue. MATERIAL AND METHODS: Aspiration-type semiautomatic cutting biopsy needles (18 gauge × 160 mm) with aspiration (Group A), aspiration-type semiautomatic biopsy needles without aspiration (Group Wo), or normal-type semiautomatic biopsy needles (18 gauge × 150 mm) (Group N) were used in 10 biopsies each of bovine liver or lung. The specimens were weighed with an electronic balance. RESULTS: Mean (standard deviation) weights for bovine liver specimens in Groups A, Wo, and N were 6.80 (0.615) mg, 5.62 (0.843) mg, and 4.19 (0.140) mg, respectively. Mean weights of bovine lung specimens from Groups A, Wo, and N were 2.98 (0.828) mg, 2.67 (0.832) mg, and 1.94 (0.864) mg, respectively. A significant difference was seen between the 3 groups for bovine liver. However, a significant difference was only seen between Groups A and N for bovine lung. CONCLUSION: Bovine liver and lung specimens obtained using the aspiration-type semiautomatic cutting biopsy needle were heavier than those obtained using the normal-type semiautomatic biopsy needle.

[Feasibility and Safety of Dexmedetomidine Sedation in Transarterial Embolization for Hepatocellular Carcinoma with Hepatitis C-Related Cirrhosis].

BACKGROUND: Dexmedetomidine (Precedex®)is an agonist of a2-adrenergic receptors in certain parts of the brain. It was approved for "procedural sedation in the non-intubation in under local anesthesia" in June 2013 in Japan. However, because of metabolism delay, dexmedetomidine has to be administered carefully to patients with liver dysfunction. PURPOSE: To evaluate the feasibility and safety of sedation using dexmedetomidine in percutaneous arterial chemoembolization for hepatocellular carcinoma with liver dysfunction. METHODS: Thirty consecutive cases of percutaneous arterial chemoembolization for hepatocellular carcinoma with hepatitis C-related cirrhosis(male, 23; female, 7; age, 74±5.9; weight, 62.7±12.3 kg; Child-Pugh A, 23; Child-Pugh B, 7)were analyzed retrospectively. Dexmedetomidine was administered at 3 mg/kg/h for 15 minutes as the initial loading dose and at 0.4 mg/kg/h as the maintenance dose. The sedation level was evaluated using the Ramsay sedation scale. RESULTS: In 30 of 30 cases, percutaneous arterial chemoembolization therapy could be performed with dexme- detomidine sedation. In 27 of 30 cases, the procedure was completed with the maintenance dose of 0.4 mg/kg/h. In 3 of 30 cases, the maintenance dose was increased to 0.6 mg/kg/h because of patient body motion. The mean administration time of dexmedetomidine was 82±30 minutes. The level of sedation measured with the Ramsay sedation scale at the end of the procedure was 3 points in 29 cases and 5 points in one case. Adverse events occurred in 3 of 30 cases. Intravenous drip leakage occurred in one case, vertigo occurred in one case, and vomiting occurred in one case. There were no adverse events requiring treatment. CONCLUSION: Sedation with dexmedetomidine in percutaneous arterial chemoembolization for hepatocellular carcinoma with liver dysfunction was feasible and safe.

Radiation dose of nurses during IR procedures: a controlled trial evaluating operator alerts before nursing tasks.

PURPOSE: To compare radiation exposure of nurses when performing nursing tasks associated with interventional procedures depending on whether or not the nurses called out to the operator before approaching the patient. MATERIALS AND METHODS: In a prospective study, 93 interventional radiology procedures were randomly divided into a call group and a no-call group; there were 50 procedures in the call group and 43 procedures in the no-call group. Two monitoring badges were used to calculate effective dose of nurses. In the call group, the nurse first told the operator she was going to approach the patient each time she was about to do so. In the no-call group, the nurse did not say anything to the operator when she was about to approach the patient. RESULTS: In all the nursing tasks, the equivalent dose at the umbilical level inside the lead apron was below the detectable limit. The equivalent dose at the sternal level outside the lead apron was 0.16 µSv ± 0.41 per procedure in the call group and 0.51 µSv ± 1.17 per procedure in the no-call group. The effective dose was 0.018 µSv ± 0.04 per procedure in the call group and 0.056 µSv ± 0.129 per procedure in the no-call group. The call group had a significantly lower radiation dose (P = .034). CONCLUSIONS: Radiation doses of nurses were lower in the group in which the nurse called to the operator before she approached the patient.

Simultaneous analysis of nanoparticles and small molecules by high-performance liquid chromatography using a silica monolithic column.

A high-performance liquid chromatography method using a commercially available silica monolithic column for the simultaneous analysis of nanoparticles and small molecules was developed. The method uses the micrometer-sized flow-through pores and nanometer-sized mesopores of the monolithic column for separation: first, size separation of nanoparticles was performed by the micrometer-sized pores using the hydrodynamic mode, and then small molecules were separated by the nanometer-sized pores using the normal-phase mode. The method was used to evaluate and compare three existing methods for purifying nanoparticles and to analyse nanoparticle stability. The bimodal structure of the monolithic column is promising for the simultaneous separation of nanoparticles and small molecules.

The Role of Chorein Deficiency in Late Spermatogenesis.

VPS13A, also known as chorein, whose loss of function causes chorea-acanthocytosis (ChAc), is characterized by Huntington's-disease-like neurodegeneration and neuropsychiatric symptoms in addition to acanthocytosis in red blood cells. We previously reported that ChAc-model mice with a loss of chorein function exhibited male infertility, with asthenozoospermia and mitochondrial dysmorphology in the spermatozoa. Here, we report a novel aspect of chorein dysfunction in male fertility, particularly its role in spermatogenesis and mitochondrial integrity. An increase in anti-malondialdehyde antibody immunoreaction within the testes, predominantly observed at the advanced stages of sperm formation in chorein-deficient mice, suggests oxidative stress as a contributing factor to mitochondrial dysfunction and impaired sperm maturation. The chorein immunoreactivity in spermatids of wild-type mice accentuates its significance in sperm development. ChAc-model mice exhibit mitochondrial ultrastructural abnormalities, specifically during the late stages of sperm maturation, suggesting a critical timeframe for chorein's action in spermiogenesis. We observed an increase in TOM20 protein levels, indicative of disrupted mitochondrial import mechanisms. The concurrent decrease in metabolic enzymes such as IDH3A, LDHC, PGK2, and ACAT1 suggests a complex chorein-mediated metabolic network that is essential for sperm vitality. Additionally, heightened separation of cytoplasmic droplets from sperm highlights the potential membrane instability in chorein-deficient spermatozoa. Metabolomic profiling further suggests a compensatory metabolic shift, with elevated glycolytic and TCA-cycle substrates. Our findings suggest that chorein is involved in anti-ferroptosis and the maturation of mitochondrial morphology in the late stages of spermatogenesis, and its deficiency leads to asthenozoospermia characterized by membrane instability, abnormal cytosolic glycolysis, abnormal mitochondrial function, and a disrupted TCA cycle. Further analyses are required to unravel the molecular mechanisms that directly link these findings and to elucidate the role of chorein in spermatogenesis as well as its broader implications.

Machine learning analysis of pathological images to predict 1-year progression-free survival of immunotherapy in patients with small-cell lung cancer.

BACKGROUND: In small-cell lung cancer (SCLC), the tumor immune microenvironment (TIME) could be a promising biomarker for immunotherapy, but objectively evaluating TIME remains challenging. Hence, we aimed to develop a predictive biomarker of immunotherapy efficacy through a machine learning analysis of the TIME. METHODS: We conducted a biomarker analysis in a prospective study of patients with extensive-stage SCLC who received chemoimmunotherapy as the first-line treatment. We trained a model to predict 1-year progression-free survival (PFS) using pathological images (H&E, programmed cell death-ligand 1 (PD-L1), and double immunohistochemical assay (cluster of differentiation 8 (CD8) and forkhead box P3 (FoxP3)) and patient information. The primary outcome was the mean area under the curve (AUC) of machine learning models in predicting the 1-year PFS. RESULTS: We analyzed 100,544 patches of pathological images from 78 patients. The mean AUC values of patient information, pathological image, and combined models were 0.789 (range 0.571-0.982), 0.782 (range 0.750-0.911), and 0.868 (range 0.786-0.929), respectively. The PFS was longer in the high efficacy group than in the low efficacy group in all three models (patient information model, HR 0.468, 95% CI 0.287 to 0.762; pathological image model, HR 0.334, 95% CI 0.117 to 0.628; combined model, HR 0.353, 95% CI 0.195 to 0.637). The machine learning analysis of the TIME had better accuracy than the human count evaluations (AUC of human count, CD8-positive lymphocyte: 0.681, FoxP3-positive lymphocytes: 0.626, PD-L1 score: 0.567). CONCLUSIONS: The spatial analysis of the TIME using machine learning predicted the immunotherapy efficacy in patients with SCLC, thus supporting its role as an immunotherapy biomarker.

Chorein, the protein responsible for chorea-acanthocytosis, interacts with ß-adducin and ß-actin.

Chorea-acanthocytosis (ChAc) is an autosomal, recessive hereditary disease characterized by striatal neurodegeneration and acanthocytosis, and caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene. VPS13A encodes chorein whose physiological function at the molecular level is poorly understood. In this study, we show that chorein interacts with ß-adducin and ß-actin. We first compare protein expression in human erythrocyte membranes using proteomic analysis. Protein levels of ß-adducin isoform 1 and ß-actin are markedly decreased in erythrocyte membranes from a ChAc patient. Subsequent co-immunoprecipitation (co-IP) and reverse co-IP assays using extracts from chorein-overexpressing human embryonic kidney 293 (HEK293) cells, shows that ß-adducin (isoforms 1 and 2) and ß-actin interact with chorein. Immunocytochemical analysis using chorein-overexpressing HEK293 cells demonstrates co-localization of chorein with ß-adducin and ß-actin. In addition, immunoreactivity of ß-adducin isoform 1 is significantly decreased in the striatum of gene-targeted ChAc-model mice. Adducin and actin are membrane cytoskeletal proteins, involved in synaptic function. Expression of ß-adducin is restricted to the brain and hematopoietic tissues, corresponding to the main pathological lesions of ChAc, and thereby implicating ß-adducin and ß-actin in ChAc pathogenesis.