[Endoscopic Surgery for Skull Base Tumors].

With the development of endoscopic and peripheral instruments, endonasal or transcranial endoscopic surgery for skull-base tumors has become more common. Preoperative simulation makes it relatively easy to understand the anatomical relationship between skull base tumors and the surrounding vital structures, which vary with each case. This may lead to the avoidance of complications and an improvement in the removal rate. Especially in cases of skull base tumors where multiple surgical approaches are possible, the three-dimensional model can be used to confirm the surgical field for each approach and consider the most appropriate. With the development of endovascular treatment and radiotherapy, experience in craniotomy has decreased. Young neurosurgeons need to develop skills to learn as efficiently as possible from their limited experience. Therefore, it is extremely useful to provide an environment that allows for easier preoperative simulations.

Effects of the combination of atomoxetine and oxybutynin in Japanese patients with obstructive sleep apnoea: A randomized controlled crossover trial.

BACKGROUND AND OBJECTIVE: The possibility of combination therapy with atomoxetine (ATO) and oxybutynin (OXY) has been suggested for obstructive sleep apnoea (OSA). However, the effectiveness of this treatment remains uninvestigated in Japanese OSA patients. Therefore, we performed a randomized, crossover, phase II, single-centre prospective trial to examine the effects of ATO-OXY therapy in Japanese OSA patients. METHODS: In total, 17 OSA patients participated in this study. The effects of one night of 80-mg ATO plus 5-mg OXY administration were compared with those of no medication administered before sleep. The primary and secondary outcomes comprised the apnoea-hypopnoea index (AHI) and nadir SpO2 , SpO2 drop time and sleep architecture, respectively. The safety endpoints included drug side effects and adverse events. RESULTS: The values of AHI, nadir SpO2 , 3% oxygen desaturation index (ODI), 4% ODI, and SpO2 drop time of <90% did not significantly differ between patients receiving ATO-OXY administration and no medication. Sleep architecture exhibited a significant change: ATO-OXY increased sleep stage N1 (p < 0.0001) and decreased stage N2 (p = 0.03), rapid eye movement (p < 0.0001) and sleep efficiency (p = 0.02). However, the subanalysis demonstrated an obvious decrease in AHI in five responder patients. Total sleep time and basal sleep efficiency tended to be lower in the responders compared with nonresponders (p = 0.065). No patients experienced severe adverse events or side effects. CONCLUSION: Overall, ATO-OXY therapy does not reduce AHI in Japanese OSA patients, although AHI was decreased in a proportion of patients. Future studies for identifying treatment response group characteristics are warranted.

Endoscopic endonasal approach to remove pediatric intraventricular tumors of the third ventricle.

PURPOSE: Pediatric intraventricular tumors of the third ventricle are among the most difficult-to-treat brain tumors. Recently, endonasal endoscopic surgery for suprasellar, third ventricle, and median clivus lesions has become the common procedure, and its indications are expanding to pediatric cases. We describe our strategy for endonasal endoscopic surgery for pediatric third ventricle tumors. METHOD: We report on surgical anatomies and our surgical procedures in detail, including case presentations. RESULT: Endoscopic endonasal surgery has the advantage of providing a wider view of the tumor site, hypothalamus, optic chiasm, and other critical structures. Good indications for the endoscopic endonasal approach for intra-third ventricular tumors are those arising from the floor of the third ventricle. In particular, craniopharyngioma, a typical pediatric suprasellar tumor, sometimes extends into the third ventricle, causing great operative difficulty. However, aggressive removal for long-term control while preserving memory and visual function is important. We perform surgery with a strategy of radically removing tumors without causing damage to visual or brain function, and we adopt the "4-hands technique by two neurosurgeons" in full endoscopic surgery to remove tumors safely and aggressively. CONCLUSION: We describe our strategy for endonasal endoscopic surgery for pediatric third ventricle tumors, especially those extending from the suprasellar region into the third ventricle, and present a representative case.

Extracting the latent needs of dementia patients and caregivers from transcribed interviews in japanese: an initial assessment of the availability of morpheme selection as input data with Z-scores in machine learning.

BACKGROUND: Given the increasing number of dementia patients worldwide, a new method was developed for machine learning models to identify the 'latent needs' of patients and caregivers to facilitate patient/public involvement in societal decision making. METHODS: Japanese transcribed interviews with 53 dementia patients and caregivers were used. A new morpheme selection method using Z-scores was developed to identify trends in describing the latent needs. F-measures with and without the new method were compared using three machine learning models. RESULTS: The F-measures with the new method were higher for the support vector machine (SVM) (F-measure of 0.81 with the new method and F-measure of 0.79 without the new method for patients) and Naive Bayes (F-measure of 0.69 with the new method and F-measure of 0.67 without the new method for caregivers and F-measure of 0.75 with the new method and F-measure of 0.73 without the new method for patients). CONCLUSION: A new scheme based on Z-score adaptation for machine learning models was developed to predict the latent needs of dementia patients and their caregivers by extracting data from interviews in Japanese. However, this study alone cannot be used to assign significance to the adaptation of the new method because of no enough size of sample dataset. Such pre-selection with Z-score adaptation from text data in machine learning models should be considered with more modified suitable methods in the near future.

TSC2 somatic mosaic mutation, including extra-tumor tissue, may be the developmental cause of solitary subependymal giant cell astrocytoma.

PURPOSE: Subependymal giant cell astrocytomas (SEGAs) are tumors that usually arise in the wall of one or the other lateral ventricle near a foramen of Monro, most often on a background of tuberous sclerosis complex (TSC). TSC has a variety of clinical manifestations caused by germline mutations of the TSC complex subunit 1 or 2 (TSC1, TSC2) genes. SEGAs without clinical manifestations of TSC are termed solitary SEGAs, which are hypothesized to be caused by tumor-only TSC1/2 mutations, or "forme fruste" of TSC with somatic mosaic mutations. However, it is difficult to distinguish between the two. Here, we report three patients with genetically investigated solitary SEGAs and review this rare manifestation. METHODS: SEGA was completely removed in two patients and partially removed in one. Genetic analyses were performed on the tumor tissue and on peripheral blood via DNA microarray, reverse-transcriptase polymerase chain reaction, and next-generation sequencing with ultra-deep sequencing of mutation points. RESULTS: All three patients had tumors with TSC2 somatic mutations and loss of heterozygosity (LOH). In one patient, the same TSC2 mutation was also detected in 1% of leukocytes in his blood. The tumors did not recur, and clinical manifestations of TSC did not develop during the 4-year follow-up. CONCLUSIONS: The genetic cause of solitary SEGAs may be a TSC2 mutation with LOH. In patients with solitary SEGA, mosaic mutations may present in other organs, and TSC may clinically manifest later in life; therefore, patients should be followed up for prolonged periods.

Risk factors for shoulder osteoarthritis with rotator cuff tear in the elderly general population.

HYPOTHESIS AND/OR BACKGROUND: The relationship between shoulder osteoarthritis (OA) and rotator cuff tear (RCT) is unclear. We hypothesized that there is a difference between the pathogenesis of OA complicating RCT and that of RCT complicating OA. In this study, our primary objective was to determine the prevalence of shoulder OA without RCT, RCT without OA, and OA with RCT in the general older population. Our secondary objective was to identify risk factors for the association with OA+RCT in shoulder OA alone or RCT alone, respectively. METHODS: We enrolled patients from the public health checkup conducted in Gunma prefecture (Japan) in 2014. Subjects' shoulder pain at rest, during motion, and at night was evaluated using a questionnaire. Moreover, active and passive range of motions (ROMs) in flexion, abduction, and external rotation were measured. For RCT parameters, we evaluated as no tear, partial-thickness supraspinatus (SSP) tear, full-thickness SSP tear, and SSP-infraspinatus tears. For further analysis, the shoulders were divided into three groups according to the presence of RCT and/or OA: OA, RCT, and OA + RCT groups. Risk factors for OA + RCT were identified in a logistic regression analysis. RESULTS: Overall, 944 of 1148 shoulders were eligible for inclusion. The prevalence rates of shoulder OA, RCT, and OA + RCT were 5.8%, 21.1%, and 4.2%, respectively. Furthermore, 650 shoulders were excluded, and 55, 199, and 40 shoulders had OA, RCT, and OA + RCT, respectively. There were significant differences for age, ROM of active external rotation, strength of abduction, external rotation, and morphology of the rotator tears. However, there were no significant differences for pain visual analog scale score, passive ROM, Simple Shoulder Test, and grades of OA. Older age decreased active ROM in external rotation, and the presence of both subscapularis and SSP-infraspinatus tears was a risk factor for the association of OA with an RCT shoulder. Older age, weaker power in external rotation, and affected dominant side were risk factors for the association of RCT with an OA shoulder. DISCUSSION AND/OR CONCLUSION: This study is the first to report risk factors by considering both shoulder OA and RCT in the general population. Our findings will be useful for the treatment and management of OA and RCT as well as for the prevention of these conditions in the older adults.

Genetic risks of schizophrenia identified in a matched case-control study.

It has been suggested that dopaminergic neurotransmission plays important roles for the psychotic symptoms and probably etiology of schizophrenia. In our recent preliminary study, we demonstrated that the specific allele combinations of dopamine-related functional single nucleotide polymorphisms (SNPs), rs10770141, rs4680, and rs1800497 could indicate risks for schizophrenia. The present validation study involved a total of 2542 individuals who were age- and sex-matched in a propensity score matching analysis, and the results supported the statistical significances of the proposed genetic risks described in our previous reports. The estimated odds ratios were 1.24 (95% CI 1.06-1.45, p < 0.001) for rs4680, 1.73 (95% CI 1.47-2.02, p < 0.0001) for rs1800497, and 1.79 (95% CI 1.35-2.36, p < 0.0001) for rs10770141. A significant relationship was also revealed among these three polymorphisms and schizophrenia, with corresponding coefficients (p < 0.0001). In this study, we also present a new scoring model for the identification of individuals with the disease risks. Using the cut-off value of 2, our model exhibited sensitivity for almost two-thirds of all of the schizophrenia patients: odds ratio 1.87, 95% CI 1.59-2.19, p < 0.0001. In conclusion, we identified significant associations of dopamine-related genetic combinations with schizophrenia. These findings suggest that some types of dopaminergic neurotransmission play important roles for development of schizophrenia, and this type of approach may also be applicable for other multifactorial diseases, providing a potent new risk predictor.

Perception of and anxiety about COVID-19 infection and risk behaviors for spreading infection: an international comparison.

BACKGROUND: To control the spread of the new SARS-CoV-2 infection's disease (COVID-19), appropriate precautionary behaviors by the public should be promoted. There are international differences in public cognitive and behavioral pattern, attitudes toward information sources, and anxiety about COVID-19. Information about these differences could increase understanding of the patterns of epidemic-related anxiety and behavior, and would help optimize future policies for preventing the next wave of the epidemic. METHODS: To examine between-country differences in perception, attitude, and precautionary behaviors toward COVID-19, we conducted a cross-sectional study using an online questionnaire survey. Participants were adults who had been registered in Cross Marketing Group Inc. and living in the UK, Spain, or Japan. A total of 8,000 people stratified by age were recruited on a first-come, first-serve basis. Knowledge of and anxiety about COVID-19, the frequency of access and perceived credibility of several information sources, and the frequency of each precautionary behavior were examined on March 27-28, 2020, in Japan and April 17-21, 2020, in the UK and Spain. RESULTS: Knowledge, anxiety, and the frequency of precautionary behaviors were higher in the UK and Spain than in Japan. Participants with infected acquaintances were more concerned about COVID-19. However, participants in the UK rarely wore a medical mask. Participants in the UK and Spain were more eager to obtain information about COVID-19 than those in Japan. Participants in Spain tended not to trust official information and to believe specialists' comments instead. CONCLUSION: The rapidity of the spread of COVID-19, cultural background, and recent political situations seemed to contribute to the international differences here.

Pronation and palmar pinch improve the stability of the medial elbow joint space in high school baseball pitchers.

HYPOTHESIS: We aimed to investigate the contributions of grip, pronation, and pinch to stabilization of the medial elbow joint space; examine their relationship with muscle strength; and assess the effect of stabilization on the medial elbow joint space in baseball pitchers. METHODS: In this controlled laboratory study, we measured the medial elbow joint space using ultrasound during the following conditions: unloading; loading; and loading with grip, pronation, and pinch. To evaluate changes in the medial elbow joint space as a result of various conditions, 1-way repeated-measures analysis of variance and post hoc analysis for multiple comparisons were performed. To investigate whether strong or weak muscle strength improved the medial elbow joint space during the loaded condition, Pearson correlation analysis was performed. Finally, a post hoc power analysis was performed. RESULTS: We enrolled 121 pitchers. The medial elbow joint space in the loaded condition, loaded condition with full grip, and loaded condition with full pinch was significantly larger than that in the unloaded condition. The medial elbow joint space in the loaded condition with full grip, loaded condition with full pronation, and loaded condition with full palmar pinch was significantly smaller than that in the loaded condition. A post hoc power analysis showed that the power of the 1-way repeated-measures analysis of variance was 100%. The strengths of the full grip and palmar pinch were significantly correlated with a reduced gap distance of the medial elbow joint space (P < .001 for both). CONCLUSION: In high school baseball pitchers, pronation and palmar pinch contraction significantly improved the gap distance of the medial elbow joint space in the loaded condition and during grip contraction. Moreover, the grip and palmar pinch strengths were significantly correlated with stabilizing effects on the medial elbow joint space.

Intraoperative neuromonitoring during reverse shoulder arthroplasty.

BACKGROUND: The aim of this study was to evaluate the risk of nerve injury with neuromonitoring during reverse total shoulder arthroplasty. MATERIALS: This study included 15 shoulders of 15 patients (11 females and 4 males) who underwent reverse total shoulder arthroplasty. The mean age was 74.8 ± 4.4 years. Nine shoulders had cuff tear arthropathy, 4 had massive rotator cuff tears, 2 had osteoarthritis, and 1 had rheumatoid arthritis. The somatosensory evoked potentials of the median nerve, transcranial motor evoked potentials, and free-electromyograms from 6 upper-extremity muscles were measured intraoperatively. We defined a nerve alert as 50% amplitude attenuation or 10% latency prolongation of the somatosensory evoked potentials and transcranial motor evoked potentials and sustained neurotonic discharge on free-electromyogram. RESULTS: Thirty-one alerts were recorded in 11 patients. The axillary nerve was associated with 17 alerts. Eleven alerts occurred during the glenoid procedure and 5 alerts occurred during the humeral procedure. One patient who did not recover from the alert of the axillary nerve had clinically incomplete paralysis of the deltoid muscle. CONCLUSION: The present findings suggest that the axillary nerve was the nerve most frequently exposed to the risk of injury, especially during glenoid and humeral implantation.

Japanese adaptation of the Bad Sobernheim Stress Questionnaire-Brace for patients with adolescent idiopathic scoliosis.

BACKGROUND: Patients with adolescent idiopathic scoliosis (AIS) under brace treatment perceive stress, not only from scoliosis, but from wearing the brace itself. The Bad Sobernheim Stress Questionnaire-Brace (BSSQbrace) was developed to assess the level of psychological stress induced by brace treatment for AIS. However, a Japanese version of BSSQbrace had not yet been developed. METHODS: We developed a Japanese adaptation of the Bad Sobernheim Stress Questionnaire-Brace (JBSSQ-brace) through a guideline-based process to adapt assessment of the psychological effect of brace treatment for AIS in Japanese patients. We administered the JBSSQ-brace to 71 patients with AIS under brace treatment in our clinic. Internal consistency and reproducibility were analyzed using Cronbach's alpha and a test-retest method. RESULTS: We included 44 patients that responded adequately. JBSSQ-brace achieved excellent internal consistency (Cronbach's alpha = 0.84 for the first questionnaire, and 0.87 for the second) and substantial reproducibility (interclass correlation coefficient = 0.75). The average score for JBSSQ-brace was 16.5 and 16.8, and almost 40% of AIS patients felt a moderate-to-high stress from brace treatment. CONCLUSIONS: JBSSQ-brace is an effective instrument with which to evaluate the stress level from brace treatment in Japanese patients with AIS.

The prevalence of elbow osteoarthritis in Japanese middle-aged and elderly populations: the relationship between risk factors and function.

BACKGROUND: The aim was to investigate the prevalence of elbow osteoarthritis (OA) in populations aged 40 years or older and to clarify the risk factors and their relationship with elbow function. METHODS: The respondents were 354 residents of a single village who underwent general medical examinations in April 2016. The mean age was 67.2 years (range, 40-93 years), and 222 respondents (62.7%) were women. Anteroposterior radiographs of the bilateral elbow joints were obtained, and the subjects were classified into 4 groups (non-OA, mild OA, moderate OA, and severe OA) according to the modified Kellgren-Lawrence scale. With respect to risk factors for elbow OA, a logistic regression analysis was performed. RESULTS: Elbow OA was detected in 55.0% of the elbows. The prevalence of symptomatic elbow OA was 22.6%, and no correlation between elbow OA and daily function was observed. The risk of elbow OA increased according to age, with odds ratios for those in their 50s, 60s, 70s, and 80s or older against those in their 40s of 12.99, 11.26, 14.45, and 26.85, respectively. In addition, male sex and a history of elbow trauma were significant risk factors, with odds ratios of 2.57 and 9.26, respectively. CONCLUSIONS: The prevalence of elbow OA was 55.0%; the prevalence of symptomatic elbow OA was 22.6%; and the risk factors for elbow OA were older age, male sex, and a history of elbow trauma.

Li-ion diffusion in Li intercalated graphite C6Li and C12Li probed by µ+SR.

In order to study a diffusive behavior of Li+ in Li intercalated graphites, we have measured muon spin relaxation (µ+SR) spectra for C6Li and C12Li synthesized with an electrochemical reaction between Li and graphite in a Li-ion battery. For both compounds, it was found that Li+ ions start to diffuse above 230 K and the diffusive behavior obeys a thermal activation process. The activation energy (Ea) for C6Li is obtained as 270(5) meV, while Ea = 170(20) meV for C12Li. Assuming a jump diffusion of Li+ in the Li layer of C6Li and C12Li, a self-diffusion coefficient DLi at 310 K was estimated as 7.6(3) × 10-11 (cm2 s-1) in C6Li and 14.6(4) × 10-11 (cm2 s-1) in C12Li.

Does successful rotator cuff repair improve muscle atrophy and fatty infiltration of the rotator cuff? A retrospective magnetic resonance imaging study performed shortly after surgery as a reference.

BACKGROUND: Muscle atrophy and fatty infiltration in the rotator cuff muscles are often observed in patients with chronic rotator cuff tears. The recovery from these conditions has not been clarified. METHODS: Ninety-four patients were included in this study. The improvement in muscle atrophy and fatty infiltration in successfully repaired rotator cuff tears was evaluated by magnetic resonance imaging at 1 year and 2 years after surgery and was compared with muscle atrophy and fatty infiltration observed on magnetic resonance imaging at 2 weeks after surgery to discount any changes due to the medial retraction of the torn tendon. The patients' muscle strength was evaluated in abduction and external rotation. RESULTS: Muscle atrophy and fatty infiltration of the supraspinatus were significantly improved at 2 years after surgery in comparison to 2 weeks after surgery. The subjects' abduction and external rotation strength was also significantly improved at 2 years after surgery in comparison to the preoperative values. Patients whose occupation ratio was improved had a better abduction range of motion, stronger abduction strength, and higher Constant score. Patients whose fatty infiltration was improved had a better range of motion in flexion and abduction, whereas the improvements of muscle strength and the Constant score were similar in the group that showed an improvement of fatty infiltration and the group that did not. CONCLUSION: Muscle atrophy and fatty infiltration can improve after rotator cuff repair. The strengths of abduction and external rotation were also improved at 2 years after surgery.

[A Curatively Resected Case of Lateral Lymph Node Metastasis Five-Years after Initial Surgery for Rectal Cancer].

A 74-year-old male had undergone laparoscopic abdominoperineal resection for lower rectal cancer in July 2009. The pathological diagnosis was T2, N0, M0, pStage I (TNM 7th). Because of pathological venous invasion, adjuvant chemotherapy with Tegafur-uracil(UFT)plus Leucovorin for a year was performed. A CT examination revealed slowly growing peripheral right internal iliaclymph node. PET-CT demonstrated a 20mm right lateral lymph node(LLN)metastasis without other distant metastases. On diagnosis of solitary LLN metastasis of rectal cancer, the patient underwent surgical lymph node resection in September 2014. The pathological diagnosis was lymph node metastasis from rectal cancer. Subsequently, the patient received mFOLFOX6 adjuvant chemotherapy for 6 months. The patient remains alive without any recurrence 31 months after the second surgical treatment. lt is important to consider that LLN metastasis of Stage I rectal cancer might still occur a long time after the curative operation.

The morphologic change of the ulnar collateral ligament of elbow in high school baseball pitchers, with and without symptoms, by sonography.

BACKGROUND: Few reports in the literature relate morphologic changes of the ulnar collateral ligament (UCL) to prior elbow symptoms. This study used ultrasonography (US) to assess the ulnohumeral joint space width, with and without stress, and elucidate morphologic changes of the UCL of the elbow in high school pitchers with and without a history of elbow symptoms. METHODS: Each of 122 high school baseball pitchers who underwent US of the medial aspect of both elbows completed a self-administered questionnaire related to the self-satisfaction score (0-100) for pitching performance and throwing-related elbow joint pain sustained during the prior 3 years. We conducted gravity stress US elbow examination with 30° of flexion with and without valgus stress. Comparisons of the UCL thickness and ulnohumeral joint space width, with and without valgus stress, were made among the 122 high school pitchers with and without a history of elbow symptoms. RESULTS: Pitchers with an elbow symptom history exhibited a greater difference between the UCL thickness on the throwing side than those with no elbow symptom history (P = .0013). A negative significant association was found between UCL thickness on the pitching side and the self-evaluation score for pitching performance (r = -0.20, P = .04). CONCLUSIONS: US assessment demonstrated that the UCL in the dominant side with elbow symptom history was thicker than that with no elbow symptom history. The UCL thickness might reflect the prior pitching condition of high school baseball pitchers.

Increased serum levels of serine enantiomers in patients with depression.

OBJECTIVE: Glutamatergic neurotransmission via the N-methyl-d-aspartate (NMDA) receptor is integral to the pathophysiology of depression. This study was performed to examine whether amino acids related to NMDA receptor neurotransmission are altered in the serum of patients with depression. METHOD: We measured the serum levels of d-serine, l-serine, glycine, glutamate and glutamine in patients with depression (n=70), and age-matched healthy subjects (n=78). RESULTS: Serum levels of d-serine and l-serine in patients with depression were significantly higher than those of healthy controls (p<0.001). In contrast, serum levels of glycine, glutamate and glutamine did not differ between the two groups. Interestingly, the ratio of l-serine to glycine in patients was significantly higher than that of healthy controls (p<0.001). CONCLUSION: This study suggests that serine enantiomers may be peripheral biomarkers for depression, and that abnormality in the d-serine-l-serine-glycine cycle plays a role in the pathophysiology of depression.

Association between neck and shoulder pain, back pain, low back pain and body composition parameters among the Japanese general population.

BACKGROUND: Neck and shoulder pain, back pain and low back pain are common symptoms in Japanese subjects, and it is important to elucidate the pathology and associated factors of these pains due to their frequency and impact on the quality of life (QOL) and activities of daily living (ADL). The purpose of the present study was to investigate whether body composition is associated with these pains. METHODS: We collected the data of 273 Japanese subjects regarding the presence and the visual analogue scale (VAS) of neck and shoulder pain, back pain, low back pain and body composition parameters calculated using bioelectrical impedance analysis (BIA) technology. Furthermore, we investigated the association between these pains and the body composition using statistical methods. RESULTS: According to a multivariate analysis adjusted for age and gender, lower total body water ratio was significantly associated with the presence of neck and shoulder pain at present (P < 0.05); additionally, total body muscle mass (standardized ß = -0.26, 95 % CI, -0.17 - -0.008, P < 0.05), total body water (standardized ß = -0.27, 95 % CI, -0.23 - -0.04, P < 0.01), appendicular muscle mass (standardized ß = -0.29, 95 % CI, -0.36 - -0.04, P < 0.05), and the appendicular muscle mass index (AMI) (standardized ß = -0.24, 95 % CI, -1.18 - -0.20, P <0.01) were negatively correlated with the VAS of neck and shoulder pain, whereas no body composition parameters were significantly associated with back pain, low back pain at present and any type of chronic pain. CONCLUSIONS: The present study demonstrated that some body composition parameters regarding body water and body muscle were associated or correlated with the presence or intensity of neck and shoulder pain.

Treatment of puberty trichotillomania with low-dose aripiprazole.

The present case is of a 14-year-old female with trichotillomania (TTM) that was treated with a low dose of aripiprazole (ARP) 1.5 mg/day. To our knowledge, this is the first published report to show an improvement of pubertal TTM using an ultra-low dose of ARP. In this case, a 50-mg fluvoxamine monotherapy for 2 years and a subsequent 4-month comprehensive cognitive behavioral therapy (CBT) monotherapy did not improve her hair-pulling symptoms. However, the treatment with a low-dose ARP of 1.5 mg/day dramatically improved her TTM symptoms without extrapyramidal symptoms. In this regard, low-dose ARP treatment for TTM might be a safe alternative to antidepressants, which carry the risk of agitation with suicidal ideation in adolescents.

Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria.

Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 µM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 µM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs.