Factors associated with self-perceived treatment-resistance in bipolar disorder.

Patients with bipolar disorder often report self-perceived treatment resistance. However, it is not known to what extent it is due to actual treatment resistance. The Juntendo University provides "Bipolar Disorder Treatment Rebuilding Program," in which patients with self-reported treatment resistant bipolar disorder are hospitalized for 2 weeks and undergo detailed examinations. In this study, we report our experience with the initial 43 patients hospitalized during the one and half years after the launch of the program. Among the patients who underwent full assessment, only one was regarded as having genuine treatment-resistant bipolar disorder without comorbidity. In other cases, ten were not diagnosed with bipolar disorder, 3 had organic brain diseases, 12 had comorbid mental disorders and its symptoms were regarded as treatment-resistant bipolar symptoms by the patients, and 18 did not receive adequate treatment because attendant physicians did not adhere to the treatment guidelines or patients did not adhere to the treatment because of lack of insight. The number of participants was not large, and selection bias hampered the generalization of the findings. Insight and adherence were assessed without the use of validated tools. We could not verify recovery after adequate treatment because of the limited hospitalization period. The findings suggest that most patients with self-perceived treatment-resistant bipolar disorder may not have genuine treatment-resistant bipolar disorder. These results shed light on the difficulties of public education of bipolar disorder and importance of providing appropriate services for diagnosis and treatment of bipolar disorder in the community.

Safety and real-world efficacy of lemborexant in the treatment of comorbid insomnia.

Aim: To investigate the real-world effectiveness and safety of lemborexan for treating comorbid insomnia associated with other psychiatric disorders, and whether lemborexant helps reduce the dose of benzodiazepines (BZs). Methods: This retrospective observational study was conducted on outpatients and inpatients treated by physicians of Juntendo University Hospital Mental Clinic between April 2020 and December 2021. Results: Data of 649 patients who were treated with lemborexant were eventually enrolled. About 64.5% of patients were classified as the responder group. Response rates of ≥60% were recorded for most psychiatric disorders. Upon administration of lemborexant, diazepam-equivalent dose of BZs had been significantly reduced in participants (3.7 ± 8.2 vs. 2.9 ± 7.9, p < 0.001). The results of logistic regression analysis showed that outpatient (odds ratios: 2.310; 95% confidence interval [CI]: 1.32-4.05), shorter duration of BZ use (<1 year) (odds ratios: 1.512; 95% CI: 1.02-2.25), no adverse events (odds ratios: 10.369; 95% CI: 6.13-17.54), larger reduction of diazepam-equivalent dose of BZs upon introducing lemborexant prescription (odds ratios: 1.150; 95% CI: 1.04-1.27), and suvorexant was the replacement drug (odds ratios: 2.983; 95% CI: 1.44-6.19), which were significant predictors of good response. Conclusion: Although this is a retrospective and observational study with many limitations, our study results suggest that lemborexant is effective and safe.

Whole-lesion histogram analysis of apparent diffusion coefficient for the assessment of non-mass enhancement lesions on breast MRI.

Objectives: To investigate the application of apparent diffusion coefficient (ADC) histogram analysis in differentiating between benign and malignant breast lesions detected as non-mass enhancement on MRI. Materials and Methods: A retrospective study was conducted for 25 malignant and 26 benign breast lesions showing non-mass enhancement on breast MRI. An experienced radiologist without prior knowledge of the pathological results drew a region of interest (ROI) outlining the periphery of each lesion on the ADC map. A histogram was then made for each lesion. Following a univariate analysis of 18 summary statistics values, we conducted statistical discrimination after hierarchical clustering using Ward's method. A comparison between the malignant and the benign groups was made using multiple logistic regression analysis and the Mann-Whitney U test. A P -value of less than 0.05 was considered statistically significant. Results: Univariate analysis for the 18 summary statistics values showed the malignant group had greater entropy (P < 0.001) and lower uniformity (P < 0.001). While there was no significant difference in mean and skewness values, the malignant group tended to show a lower mean (P = 0.090) and a higher skewness (P = 0.065). Hierarchical clustering of the 18 summary statistics values identified four values (10th percentile, entropy, skewness, and uniformity) of which the 10th percentile values were significantly lower for the malignant group (P = 0.035). Conclusions: Whole-lesion ADC histogram analysis may be useful for differentiating malignant from benign lesions which show non-mass enhancement on breast MRI.

Mediating Roles of Cognitive Complaints on Relationships between Insomnia, State Anxiety, and Presenteeism in Japanese Adult Workers.

Complaints of cognitive functions (CCFs), defined as subjective cognitive dysfunction, affect social function; additionally, for workers, this condition is an important factor in presenteeism and mediates the effect of depressive symptoms on presenteeism. This study aimed to investigate whether CCFs mediate the relationships among insomnia, state anxiety (SA), and presenteeism. Participants were 471 Japanese adult workers evaluated using the Athens Insomnia Scale, State-Trait Anxiety Inventory (Form Y), Cognitive Complaints in Bipolar Disorder Rating Assessment, and Work Limitations Questionnaire 8 to assess insomnia, SA, CCFs, and presenteeism, respectively. Path analysis was used to evaluate the correlations between variables. CCFs significantly mediated the associations among insomnia, SA, and presenteeism. To address the presenteeism associated with insomnia and SA, it may be useful to assess the mediating roles of CCFs.

Characteristics affecting cervical sagittal alignment in patients with chronic low back pain.

BACKGROUND: Sagittal spino-pelvic malalignment in patients with chronic low back pain (CLBP) have been reported in the past, which may also affect cervical spine lesions. The purpose of this study is to investigate the cervical alignment in patients with CLBP. METHOD: Of the patients who visited an orthopedic specialist due to low back pain lasting more than three months, 121 cases (average 71.5-years-old, 46 male and 75 female) with whole standing spinal screening radiographs were reviewed (CLBP group). Cervical parameters included cervical lordosis (CL), C2-C7 sagittal vertical axis (C2-7 SVA), and the T1 slope minus CL (T1S-CL). Cervical spine deformity was defined as C2-7 SVA >4 cm, CL <0°, or T1S-CL ≧20°. We compared the cervical alignment of these patients with 121 age and gender matched volunteers (control group). RESULTS: The prevalence of cervical spine deformity was significantly higher in the CLBP group than in the control group (20.7% vs. 10.7%, P = 0.034). The mean CL was smaller in the CLBP group than in the control group (16.1° vs. 21.4°, P = 0.002). The mean C2-7 SVA was 17.6 mm vs. 18.7 mm in the CLBP group and in the control group, respectively (P = 0.817). The mean T1S-CL was larger in the CLBP group than in the control group (9.1° vs. 3.5°, P < 0.001). Multivariate analysis showed that people with CLBP were more likely to have cervical deformities than people without CLBP (odds ratio 2.16, 95% confidence interval 1.006 to 4.637). CONCLUSIONS: This study results suggest that people with CLBP present with worse cervical sagittal alignment and higher prevalence of cervical spine deformities than age and gender matched volunteers with no CLBP. This means CLBP impacts cervical spine lesions negatively. LEVEL OF EVIDENCE: Ⅳ.

Victimization In Childhood Affects Depression In Adulthood Via Neuroticism：A Path Analysis Study.

BACKGROUND: Adverse experiences, such as low care, overprotection, or abuse in childhood increase the likelihood of depression via their effects on personality traits. Similarly, being victimized in childhood may affect the likelihood of depression via personality traits. In this case-control study, we hypothesized that being victimized in childhood is associated with depression in adulthood via its effect on neuroticism, and verified this hypothesis using path analysis. SUBJECTS AND METHODS: Eighty-two major depressive disorder (MDD) patients and 350 age-and-sex matched healthy controls completed self-administered questionnaires of demographic data, Patient Health Questionnaire-9, neuroticism, and victimization. The association between victimization, neuroticism, and depressive symptoms or having major depression was investigated by path analysis. RESULTS: Multiple group path analysis, in which depressive symptoms were considered as dependent variables, showed that the direct effect of victimization in childhood on depressive symptoms was not statistically significant in either healthy controls or MDD patients (standardized path coefficient: 0.079 and 0.084, respectively), but their indirect effects via neuroticism were statistically significant (standardized path coefficient: 0.059 and 0.141, respectively). Path analysis, in which the distinction between healthy controls and MDD patients was a dependent variable, showed that both direct effects and indirect effects of victimization in childhood via neuroticism on the distinction between healthy controls and MDD patients were statistically significant (standardized path coefficient: 0.186 and 0.164, respectively). LIMITATIONS: Recall bias and the relatively small number of MDD patients are limitations of this study. Because it was a case-control survey, this study could not make any conclusions regarding causal associations. CONCLUSION: This study suggests the possibility of causal associations between victimization in childhood and depressive symptoms or MDD in adulthood, and the mediation of this association by neuroticism.

Influence of trait anxiety, child maltreatment, and adulthood life events on depressive symptoms.

BACKGROUND: Various personality traits mediate the association between childhood stress and depressive symptoms in adulthood. The aim of this study was to clarify the indirect effects of the experience of child maltreatment on depressive symptoms and appraisal of life events in adulthood through trait anxiety. SUBJECTS AND METHODS: A total of 404 participants who were volunteer subjects from the community were studied using the following self-administered questionnaire surveys: Patient Health Questionnaire-9, which measures depressive symptoms; State-Trait Anxiety Inventory Form Y, which measures trait anxiety; the Child Abuse and Trauma Scale, which measures child maltreatment; and Life Experiences Survey, which measures negative and positive appraisal of adulthood life events. RESULTS: Structural equation modeling demonstrated that the experience of child maltreatment increased depressive symptoms in adulthood as well as the negative appraisal of life events in adulthood through an increase in trait anxiety. Furthermore, trait anxiety affected depressive symptoms in adulthood through its influence on the negative appraisal of adulthood life events. The following indirect effect was also significant: the experience of child maltreatment increased the negative appraisal of adulthood life events via trait anxiety and subsequently influenced adult depressive symptoms. LIMITATIONS: The subjects of this study are volunteer subjects from the community including healthy people, and hence the results may not be generalizable to major depressive patients. Recall bias should be considered when interpreting the results. Because this study is a cross-sectional study, the causality between the experience of child maltreatment and depression is not clear. CONCLUSION: This study suggests that trait anxiety may play a mediating role in the influence of the experience of child maltreatment on depressive symptoms in adulthood and negative appraisal of adulthood life events.

A multicenter, observational study of metastatic breast cancer patients who were treated with eribulin mesylate or taxane-based regimens.

AIM: This multicenter, observational study aimed to investigate the survival benefit of eribulin as well as that of taxane-based regimens in Japanese patients with metastatic breast cancer (MBC) in a real-world setting. METHODS: This study enrolled women with MBC who received eribulin or taxane-based regimens with or without bevacizumab in routine clinical practice from July 2011 to March 2014. Patients were followed until September 2015. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), post-progression survival (PPS) and adverse events. Efficacy findings were adjusted according to demographics. RESULTS: In total, 216 patients receiving eribulin monotherapy (n = 101), taxane monotherapy (n = 73) or taxane plus bevacizumab (n = 42) were followed for a median time of 15.4 months. Median OS, PFS and PPS were 22.3, 8.1 and 14 months in the eribulin monotherapy group; 13.2, 3.6 and 7.6 months in the taxane monotherapy group; and 12.9, 5.7 and 6.3 months, in the taxane plus bevacizumab group, respectively. The incidence of neutropenia was 67.3, 41.1 and 16.7%, and the incidence of grade 4 neutropenia was 1.0, 8.2 and 7.1% in the eribulin monotherapy, taxane monotherapy and taxane plus bevacizumab groups, respectively. One patient (1.0%) discontinued eribulin and 18 patients (15.7%) discontinued taxane-based regimens because of adverse events. CONCLUSION: In Japanese MBC patients in a real-world setting, eribulin showed a survival benefit and tolerability similar to that in previous reports.

Serum TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer.

Breast cancer remains a common malignancy in women, but the take-up for breast cancer screening programs in Japan is still low, possibly due to its perceived inconvenience. TFF1 and TFF3 are expressed in both breast cancer tissue and normal breast. Serum trefoil proteins were reported as cancer screening markers for gastric, prostate, lung, pancreatic cancer and cholangio carcinoma. The purpose of this study was to examine whether serum trefoil proteins could be screening biomarkers for breast cancer. Serum trefoil proteins in 94 breast cancer patients and 84 health check females were measured by ELISA. Serum TFF1 and TFF3 were significantly higher and serum TFF2 was significantly lower in breast cancer patients. Area under the curve of receiver operating characteristic of TFF1, TFF2, and TFF3 was 0.69, 0.83, and. 0.72, respectively. AUC of the combination of TFF1, TFF2, and TFF3 was 0.96. Immunohistochemically, TFF1 expression was positive in 56.5% and TFF3 was positive in 73.9% of breast cancers, while TFF2 was negative in all tumors. Serum TFF1 had positive correlation with expression of TFF1 in breast cancer tissue. Serum concentrations of TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer.

QM/MM Geometry Optimization on Extensive Free-Energy Surfaces for Examination of Enzymatic Reactions and Design of Novel Functional Properties of Proteins.

Many remarkable molecular functions of proteins use their characteristic global and slow conformational dynamics through coupling of local chemical states in reaction centers with global conformational changes of proteins. To theoretically examine the functional processes of proteins in atomic detail, a methodology of quantum mechanical/molecular mechanical (QM/MM) free-energy geometry optimization is introduced. In the methodology, a geometry optimization of a local reaction center is performed with a quantum mechanical calculation on a free-energy surface constructed with conformational samples of the surrounding protein environment obtained by a molecular dynamics simulation with a molecular mechanics force field. Geometry optimizations on extensive free-energy surfaces by a QM/MM reweighting free-energy self-consistent field method designed to be variationally consistent and computationally efficient have enabled examinations of the multiscale molecular coupling of local chemical states with global protein conformational changes in functional processes and analysis and design of protein mutants with novel functional properties.

Molecular Mechanism of Wide Photoabsorption Spectral Shifts of Color Variants of Human Cellular Retinol Binding Protein II.

Color variants of human cellular retinol binding protein II (hCRBPII) created by protein engineering were recently shown to exhibit anomalously wide photoabsorption spectral shifts over ∼200 nm across the visible region. The remarkable phenomenon provides a unique opportunity to gain insight into the molecular basis of the color tuning of retinal binding proteins for understanding of color vision as well as for engineering of novel color variants of retinal binding photoreceptor proteins employed in optogenetics. Here, we report a theoretical investigation of the molecular mechanism underlying the anomalously wide spectral shifts of the color variants of hCRBPII. Computational modeling of the color variants with hybrid molecular simulations of free energy geometry optimization succeeded in reproducing the experimentally observed wide spectral shifts, and revealed that protein flexibility, through which the active site structure of the protein and bound water molecules is altered by remote mutations, plays a significant role in inducing the large spectral shifts.

[Marked response to oral administration of UFT and leucovorin for liver metastases from colon cancer in an elderly patient].

A83 -year-old man was admitted to our hospital for the treatment of advanced ascending colon cancer with liver metastases. He had initially undergone an ileocecal resection for ascending colon cancer. Subsequently, we started oral administration of UFT/LV(UFT 400mg/day, LV 75 mg/day, and 4 weeks of therapy followed by a week suspension of treatment). After 3 courses, his tumors responded well to treatment, and CT showed marked regression of liver metastases. After 10 courses, liver metastases had almost disappeared. Two years passed without any adverse events since UFT/LV therapy was started. These findings suggest that UFT/LV therapy is very safe and effective for elderly patients with unresectable colorectal cancer.

Safety and short-term therapeutic effects of miriplatin-lipiodol suspension in transarterial chemoembolization (TACE) for hepatocellular carcinoma.

AIM: To determine the safety and usefulness of a novel anticancer drug, miriplatin, in transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma. PATIENTS AND METHODS: Patients (n=115) who underwent TACE with miriplatin-lipiodol suspension (miriplatin group), and control patients (n=131) who underwent TACE with cisplatin-lipiodol suspension (CDDP group) took part in this study. RESULTS: The overall incidence of adverse events was significantly lower in the miriplatin group. The percentage of patients attaining treatment effect 4 in both groups was not significantly different. The proportion exhibiting a >50% decrease in positive tumor markers following TACE was significantly greater in the CDDP group for alpha-fetoprotein, but not significantly different for des-gammma-carboxy prothrombin. CONCLUSION: Miriplatin-lipiodol suspension was associated with reduced intensity of adverse events and had comparable short-term therapeutic effects to cisplatin-lipiodol suspension, thereby indicating its usefulness in TACE.

Expression and functional characterization of choline transporter in human keratinocytes.

Choline is essential for synthesis of the major membrane phospholipid phosphatidylcholine. Moreover, it serves as a precursor for synthesis of the neurotransmitter acetylcholine (ACh). Keratinocytes of the epidermis synthesize and release ACh. The uptake of choline is the rate-limiting step in both ACh synthesis and choline phospholipid metabolism, and it is a prerequisite for keratinocyte proliferation. However, the nature of the choline transport system in keratinocytes is poorly understood. In this study, we examined the molecular and functional characterization of choline uptake into cultured human keratinocytes. Choline uptake into keratinocytes was independent of extracellular Na(+), saturable, and mediated by a single transport system with an apparent Michaelis-Menten constant of 12.3 muM. Choline uptake was reduced when the keratinocyte membrane potential was depolarized by high K(+). These results provide evidence that the choline transport activity is potential-sensitive. Various organic cations inhibit the choline transport system. RT-PCR demonstrated that keratinocytes expressed mRNA for choline transporter-like protein 1 (CTL1), mainly the CTL1a subtype. The present biochemical and pharmacological data suggest that CTL1a is functionally expressed in human keratinocytes and is responsible for the uptake of choline and organic cations in these cells.

Morphologic study of nipple-areola complex in 600 breasts.

To investigate the morphologic characteristics of the nipple-areola complex, the diameter of the nipple-areola complex and the height of the nipple in 300 adult women (600 breasts) were measured using micrometer calipers. Furthermore, the morphologic characteristics were classified into four types by visual observation. Mean diameter of the areola was 4.0 cm, mean diameter of the nipple was 1.3 cm, and mean height of the nipple was 0.9 cm. From the morphologic point of view, the elevated plateau type without constriction (IIs) was most commonly found, being present in 60.2% of breasts. Inverted nipples (III) were found in 3.5% and unclassified type (IV) such as multiple or divided nipples was found in 0.3%. Because women have become sensitive about the appearance of their breasts and there is increasing cosmetic interest following surgery for breast carcinoma, operations on the nipple-areola complex are now common. When a surgeon counsels a patient and designs a reconstruction method prior to operation, these data may be helpful.

Axillary mass suspected to be occult breast carcinoma: a case study of skipped axillary lymph node metastasis from endometrial carcinoma in which core-needle biopsy was useful for diagnosis.

A 55-year-old Japanese woman presented with metrorrhagia and was diagnosed with endometrial carcinoma. Chest computed tomography (CT), ultrasonography (US) and magnetic resonance imaging (MRI) showed a left axillary mass. Regarding the diagnosis of the axillary mass, lymph node metastasis from the uterus was first suspected. Metastasis from the breast, lung, thyroid or stomach was considered next. On a general search including positron emission tomography (PET)-CT, there was no abnormality except endometrial carcinoma and the left axillary mass. Skipped axillary lymph node metastasis of endometrial carcinoma is extremely rare, with a reported incidence of 0.03% of endometrial carcinoma cases. The differential diagnosis was double carcinoma of the uterus and breast. We carried out US-guided core needle biopsy (CNB) of the axillary mass, and the histopathological findings suggested axillary lymph node metastasis from endometrioid carcinoma. US-guided CNB is a valid method for accurate diagnosis of an axillary mass.

Comparison of estrogen receptor, progesterone receptor and Her-2 status in breast cancer pre- and post-neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NAC) is now a relatively standard treatment for breast carcinoma. However, some tumors are known to develop resistance to chemotherapies. We investigated whether the status of estrogen receptor (ER), progesterone receptor (PR) and Her-2 expressions in breast cancer cases prior to NAC could be changed after NAC. We used immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods. No differences were found in ER or Her-2 status, but a significant difference was found in PR status. Changes in Her-2 status were suspected in four specimens after NAC (3+ to 1+ for 3 patients, and 1+ to 3+ for one patient) according to the IHC results. However, in all four of these cases, FISH of the resections showed no change. When IHC indicates a change in Her-2 expression after NAC, FISH is recommended.

Segmental enhancement on breast MR images: differential diagnosis and diagnostic strategy.

The histopathological variations of segmental enhancement on breast magnetic resonance imaging (MRI) were investigated, with the aim of identifying imaging characteristic clues to their differential diagnosis. We reviewed 70 breast MRI examinations demonstrating segmental enhancement, classified them based on their histopathology, and assessed their MRI findings as follows: (1) confluent or not confluent, (2) late enhancement pattern, and the absence or presence of (3) clustered ring enhancements and (4) surrounding high signal intensity (SI) on T2-weighted imaging. Thirteen lesions (18.5%) were benign, eight (11.5%) were high risk, 25 (36%) were ductal carcinoma in situ (DCIS) and 24 (34%) were infiltrating mammary carcinomas (IMC). Clustered ring enhancements were demonstrated in 74% of malignancies (high risk, DCIS and IMC) but no benign lesions (P=0.0001). The surrounding high SI on T2-weighted imaging was seen in four of five IMC with marked lymphatic involvement. Clustered ring enhancement was not demonstrated in six of seven IMC of tubular and/or lobular types. Segmental enhancement was seen in not only DCIS but also IMC, high-risk and benign lesions. Clustered ring enhancement and surrounding high SI on T2-weighted imaging were clues to their differential diagnosis and helpful to decide their diagnostic strategy.

Comparison of magnetic resonance imaging, multidetector row computed tomography, ultrasonography, and mammography for tumor extension of breast cancer.

INTRODUCTION: Breast imaging modalities can assess the tumor extent and adequacy of excision, but there have been no reports comparing magnetic resonance (MR) imaging, multidetector row computed tomography (MDCT), ultrasonography (US) and mammography (MMG) for the tumor extent of breast cancer. We prospectively assessed the accuracy of MR imaging, MDCT, US and MMG for preoperative assessment of the tumor extent of breast cancer. METHODS: Preoperative MR imaging, MDCT, US and MMG were performed for 210 breasts with breast cancer. The MR and MDCT images were independently interpreted by one of two radiologists with knowledge of the clinical and MMG findings. The US was performed with knowledge of the clinical and MMG findings by one of five US technologists. The correlation of the results of these examinations with histological findings was examined. RESULTS: Of the 210 index breast tumors, 210 (100%) could be detected on MR, 208 (99%) were detected on MDCT, 209 (99.5%) were detected on US, and 195 (93%) were detected on MMG. For evaluating local tumor extent, the accuracy of MR imaging (76%) was significantly higher than those of MDCT, US, and MMG (71%, 56%, and 52%, respectively) (P = 0.001, P < 0.0001, and P < 0.0001). MDCT was significantly more accurate than US (P < .0001) or MMG (P < .0001), and US was significantly more accurate than MMG (P = 0.004). MR imaging and US had substantial risk (11% and 17%) of overestimation of the tumor extent. Regarding ductal carcinoma in situ (DCIS), for non-comedo DCIS, the accuracies of MR imaging (89%), MDCT (72%), and US (61%) were significantly higher than the 22% accuracy of MMG (P < 0.0001, P = 0.012, and P = 0.016), but for comedo DCIS, there were no significant differences among the four breast imaging modalities. CONCLUSION: MR imaging was the most accurate breast imaging modality for the tumor exten of breast cancer, although MR imaging had a substantial of risk of overestimation. MR imaging, MDCT and US can complement MMG for the preoperative evaluation of patients who are candidates for breast-conserving surgery.