Remote Patient Monitoring for Neuropsychiatric Disorders: A Scoping Review of Current Trends and Future Perspectives from Recent Publications and Upcoming Clinical Trials.

Introduction: Telemedicine and remote patient monitoring are rapidly growing fields. This scoping review provides an update on remote patient monitoring for neuropsychiatric disorders from recent publications and upcoming clinical trials. Methods: Publications (PubMed and ICHUSHI; published January 2010 to February 2021) and trials (ClinicalTrials.gov and Japanese registries; active or recruiting by March 2021) that assessed wearable devices for remote management and/or monitoring of patients with neuropsychiatric disorders were searched. The review focuses on disorders with ≥3 publications. Results: We identified 44 publications and 51 active or recruiting trials, mostly from 2019 or 2020. Research on digital devices was most common for Parkinson's disease (11 publications and 19 trials), primarily for monitoring motor symptoms and/or preventing falls. Other disorders (3-5 publications each) included epilepsy (electroencephalogram [EEG] and seizure prediction), sleep disorder (sleep outcomes and behavioral therapies), multiple sclerosis (physical activity and symptoms), depression (physical activity, symptoms, and behavioral therapies), and amyotrophic lateral sclerosis (symptoms). Very few studies focused on newly emerging technologies (e.g., in-ear EEG and portable oximeters), and few studies integrated remote symptom monitoring with telemedicine. Discussion: Currently, development of digital devices for daily symptom monitoring is focused on Parkinson's disease. For the diseases reviewed, studies mostly focused on physical activity rather than psychiatric or nonmotor symptoms. Although the validity and usefulness of many devices are established, models for implementing remote patient monitoring in telehealth settings have not been established. Conclusions: Verification of the clinical effectiveness of digital devices combined with telemedicine is needed to further advance remote patient care for neuropsychiatric disorders.

Indication of intravaginal insemination for infertility treatment in couples with sexual dysfunction.

PURPOSE: To analyze the usefulness of intravaginal insemination (IVI) for the infertility treatment in couples with sexual dysfunction before applying assisted reproductive technology (ART). METHODS: Among 208 couples who presented sexual dysfunction, 144 couples underwent IVI procedures. The profiles of pregnant and non-pregnant patients were compared. RESULTS: Of 144 patients, 58 women conceived successfully (40.3% pregnancy rate). Between the pregnant and non-pregnant cases, the husband's age and infertility period were significantly higher (P = .0104) and longer (P = .0027) in the unsuccessful cases than the successful ones. The husbands who could not impregnate had a significantly higher ratio of sperm abnormalities (P = .0048). Among the 57 successful cases who underwent IVI treatment, 38 (66.7%) patients became pregnant within 3 times of the procedure, while 48 (84.2%) patients conceived within 6 times. CONCLUSION: The authors can propose the following inclusion IVI criteria for couples with sexual dysfunction: (a) younger husband (36 years old or less) which may be most important, (b) infertility duration of 3 years or less, (c) normal sperm condition, and (d) IVI trial for 3 times (maximum of 6 times). Since IVI appears to be a simple, noninvasive, and inexpensive way for couples with sexual dysfunction, it can be attempted before ART application.

Daily walking is effective for the management of pregnant women with gestational diabetes mellitus.

AIM: This study evaluated the usefulness of daily walking for gestational diabetes mellitus (GDM) management by analyzing the relationship between daily walking and glucose tolerance in pregnant women with GDM who were in the second trimester. METHODS: This longitudinal study was conducted at TOYOTA Memorial Hospital in Toyota, Japan, from January 2015 to June 2016. Pregnant women with GDM wore accelerometers on the waist for 7-12 weeks. RESULTS: Seventy-three women with GDM were included in the present study; data collected from 24 women were analyzed. The estimated number of steps walked daily showed a significant positive correlation (r = 0.798, P = 0.000) with energy expenditure related to physical activity. There was a significant negative correlation (r = -0.603, P = 0.014) between the post- to pre-research casual glucose level (CGL) ratio and the number of steps walked daily. No significant correlation (r = -0.004, P = 0.986) was detected between the ratio of hemoglobin A1c and the number of steps taken. When the study was completed, the 11 participants who walked ≥6000 steps/day showed significantly lower CGL (95 + 10 mg/dL [mean + SD]) than the 13 participants in the <6000 steps/day group (111 + 18 mg/dL) (P = 0.013). CONCLUSION: Simple walking for light intensity physical activity is effective for controlling the CGL in pregnant women with GDM. We recommend that pregnant women with GDM should walk a minimum of 6000 steps/day.

Uterus transplantation: Toward clinical application in Japan.

Background: In recent years, uterus transplantation (UTx) has been applied as the treatment for patients with uterine factor infertility worldwide. Thus, the clinical application of UTx in Japan should be considered through both the history of UTx technology development in the world and future prospects. Methods: Recent information on UTx was collected via a literature survey and the Internet. Results: Basic research using various animals has been done mainly since 2000. In 2014, the world's first UTx baby was born in Sweden. In total, 24 UTx procedures have been performed at 10 institutes in nine countries and five births were obtained (as of May, 2017). In Japan, the "Project Team for Uterus Transplantation" initiated UTx experiments in 2008 and the "Japan Society for Uterus Transplantation" was organized in March, 2014. In the rest of the world, the "International Society for Uterus Transplantation" was established in January, 2016. Conclusion: Uterus transplantation is still under development as a reproductive medicine tool and organ transplant procedure. A collaborative system that is not limited by facilities and specialties should strive to build an "all-Japan" team.

Feasibility study of the application of magnetic resonance elastography (MRE) to measure oral posture related changes in stiffness of zygomaticus major muscle.

PURPOSE: Development of a technique for measuring the mechanical properties of zygomaticus major (ZM) may aid advances in clinical treatments for correcting abnormal oral posture. The objective of this work was to demonstrate the feasibility of measuring the stiffness of ZM using an MR elastography technique that incorporates a custom local driver and a phase-gradient (PG) inversion. METHODS: 2D MRE investigations were performed for 3 healthy subjects using a vibration frequency of 90 Hz to test the prediction that the stiffness of ZM would be greater in the mouth-open compared to the mouth-closed position. MRE wave images were acquired along the long axis of ZM and processed using a 2D spatial-temporal directional filter applied in the direction of wave propagation along the long axis of the muscle. Stiffness measurements were obtained by applying the PG technique to a 1D-profile drawn in the phase image of the first harmonic of the wave images and a one-tailed paired t-test was used to compare the ZM stiffness between the two mouth postures (p < 0.05). RESULTS: The mean stiffness and standard deviation (SD) of ZM across the three participants in the mouth-closed and mouth-open postures was 6.75 kPa (SD 3.36 kPa) and 15.5 kPa (SD 5.15 kPa), respectively. Changes of ZM stiffness were significantly greater in the mouth-open than the mouth-closed posture (p = 0.038). CONCLUSION: The feasibility of using the PG MRE technique to measure stiffness changes in a small muscle such as ZM for different mouth postures has been demonstrated. Further investigations are required in a larger cohort of participants to investigate the sensitivity and reproducibility of the technique for potential clinical application as well as in health and beauty related studies.

Prescribing patterns and determinants for elderly patients with Parkinson's disease in Japan: a retrospective observational study using insurance claims databases.

Background: This study aimed to determine real-world prescribing patterns and determinants for Japanese patients with Parkinson's disease (PD), with a focus on patients ≥75 years. Methods: This was a retrospective, observational, longitudinal study of patients with PD (≥30 years, ICD-10: G20 excluding Parkinson's syndrome) from three Japanese nationwide healthcare claim databases. Prescription drugs were tabulated using database receipt codes. Changes in treatment patterns were analyzed using network analysis. Factors associated with prescribing patterns and prescription duration were analyzed using multivariable analysis. Results: Of 18 million insured people, 39,731 patients were eligible for inclusion (≥75-year group: 29,130; <75-year group: 10,601). PD prevalence was 1.21/100 people ≥75 years. Levodopa was the most commonly prescribed anti-PD drug (total: 85.4%; ≥75 years: 88.3%). Network analysis of prescribing patterns showed that most elderly patients switched from levodopa monotherapy to adjunct prescription patterns, as did younger patients, but with less complexity. Elderly patients who newly initiated PD treatment remained on levodopa monotherapy longer than younger patients; factors significantly associated with levodopa prescriptions were older age and cognitive impairment. Commonly prescribed adjunct therapies were monoamine oxidase type B inhibitors, non-ergot dopamine agonists, and zonisamide, regardless of age. Droxidopa and amantadine were prescribed as adjunct levodopa therapy slightly more frequently among elderly patients; levodopa adjunct therapy was prescribed when the levodopa dose was 300 mg, regardless of age. Conclusion: Prescribing patterns for patients ≥75 years were levodopa centered and less complex than for those <75 years. Factors significantly associated with levodopa monotherapy and continued use of levodopa were older age and cognitive disorder. Clinical trial registration: UMIN Clinical Trials Registry, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000053425 (UMIN000046823).

Analytical and clinical validity of wearable, multi-sensor technology for assessment of motor function in patients with Parkinson's disease in Japan.

Continuous, objective monitoring of motor signs and symptoms may help improve tracking of disease progression and treatment response in Parkinson's disease (PD). This study assessed the analytical and clinical validity of multi-sensor smartwatch measurements in hospitalized and home-based settings (96 patients with PD; mean wear time 19 h/day) using a twice-daily virtual motor examination (VME) at times representing medication OFF/ON states. Digital measurement performance was better during inpatient clinical assessments for composite V-scores than single-sensor-derived features for bradykinesia (Spearman |r|= 0.63, reliability = 0.72), tremor (|r|= 0.41, reliability = 0.65), and overall motor features (|r|= 0.70, reliability = 0.67). Composite levodopa effect sizes during hospitalization were 0.51-1.44 for clinical assessments and 0.56-1.37 for VMEs. Reliability of digital measurements during home-based VMEs was 0.62-0.80 for scores derived from weekly averages and 0.24-0.66 for daily measurements. These results show that unsupervised digital measurements of motor features with wrist-worn sensors are sensitive to medication state and are reliable in naturalistic settings.Trial Registration: Japan Pharmaceutical Information Center Clinical Trials Information (JAPIC-CTI): JapicCTI-194825; Registered June 25, 2019.

Treatment Satisfaction and Its Influencing Factors in Parkinson's Disease: A Web-Based Survey of Patients and Physicians in Clinical Practice in Japan.

OBJECTIVE: This study aimed to gain an understanding of patient and physician satisfaction with overall treatment and routine consultations for Parkinson's disease in clinical practice. METHODS: This observational, cross-sectional, web-based survey was conducted in Japan from February to March 2019. Eligible patients with Parkinson's disease (N = 186) and physicians who treat patients with Parkinson's disease (N = 331) were asked to evaluate their satisfaction with treatment, consultation, symptom control, and use of a symptom diary. RESULTS: Patients had a mean age of 62.7 years, 54.8% were male, and most (75.8%) had Hoehn and Yahr stage ≥3 symptoms. Physicians were mostly male (93.1%) and had treated 52 patients with Parkinson's disease in the last 6 months, and 34.1% were certified neurologists. There were significant gaps between patient and physician satisfaction with treatment and consultations. Patient and physician satisfaction with overall treatment was significantly lower for patients with Hoehn and Yahr stage ≥3 symptoms than stage 1-2 symptoms (patients: 53.9% vs. 71.1%; physicians: 43.2% vs. 69.7%, respectively). The proportion of patients who were satisfied with symptom control was lower than that of physicians (26.4% vs. 51.5%). Influencing factors for patient satisfaction with treatment were nonmotor symptoms (e.g., insomnia and depression). Satisfaction tended to be higher for patients and physicians when symptom diaries were used. CONCLUSION: Significant gaps in perceptions of treatment and consultation exist between patients and physicians in Parkinson's disease. Physicians should participate in shared decision making with their patients and consider strategies for management of nonmotor symptoms and nonpharmacological therapies and encourage the use of symptom diaries.

Rasagiline as Adjunct to Levodopa for Treatment of Parkinson's Disease: A Systematic Review and Meta-Analysis.

Background: Rasagiline is a selective, irreversible monoamine oxidase type B inhibitor used as monotherapy in early Parkinson's disease and as an adjunct therapy to levodopa in Parkinson's disease with motor fluctuations. Objectives: This meta-analysis aimed to provide updated evidence on the efficacy for motor and nonmotor symptoms and the safety of rasagiline/levodopa versus levodopa in patients with Parkinson's disease experiencing motor fluctuations. Methods: A systematic literature search was conducted (January 18-19, 2021) using PubMed, Cochrane Library, EMBASE, Web of Science, and Google Scholar to identify randomized controlled trials comparing rasagiline/levodopa versus placebo/levodopa in patients with Parkinson's disease experiencing motor fluctuations. Outcomes included change in wearing-off time, Unified Parkinson's Disease Rating Scale (UPDRS)/Movement Disorder Society-UPDRS (MDS-UPDRS) II and III scores, treatment-emergent adverse events (TEAEs), and Parkinson's Disease Questionnaire (PDQ-39) summary index score. A random effect model was used to estimate the treatment effects. Results: Six studies were included (1912 patients). Significant improvements in wearing-off time (standardized mean difference [SMD]: -0.50, 95% confidence interval [CI]: -0.92 to -0.09, p = 0.002), levodopa dosage (SMD: -0.18, 95% CI: -0.35 to -0.01, p = 0.041), UPDRS/MDS-UPDRS II (SMD: -0.39, 95% CI: -0.52 to -0.25, p < 0.0001), UPDRS/MDS-UPDRS III (SMD: -0.30, 95% CI: -0.44 to -0.16, p < 0.0001), and PDQ-39 summary index score (SMD: -0.21, 95% CI: -0.37 to -0.04, p = 0.013) were observed with rasagiline/levodopa versus placebo/levodopa. The incidence of TEAEs did not differ between treatments (risk ratio: 1.13, 95% CI: 0.98-1.30, p = 0.093). Conclusions: This meta-analysis further indicated the superiority of rasagiline/levodopa in improving motor and nonmotor symptoms of Parkinson's disease, with a similar safety profile to that of levodopa in Parkinson's disease with motor fluctuations.

Prescription pattern of anti-Parkinson's disease drugs in Japan based on a nationwide medical claims database.

INTRODUCTION: Parkinson's disease (PD) treatment should follow guidelines and be tailored to each patient. Large database analyses can provide insights into prescribing patterns. METHODS: Retrospective, cross-sectional study of patients (≥30 years) with PD diagnosis (ICD-10; schizophrenia/cerebrovascular disease excluded) using health insurance claims data (April 2008-December 2016) from the Japan Medical Data Vision database. Prescription patterns of anti-PD drugs were analysed by patient age and sex, calendar year, and overall. RESULTS: The analysis comprised 155,493 PD patient-years (56.1% women, mean 73.4 years). Patient number increased each year, mainly because of database expansion. L-dopa as monotherapy was the most common prescription (22.7% of patient-years); non-ergot dopamine agonists (DAs) were also common (7.6% as monotherapy, 6.8% with L-dopa). Monotherapy was prescribed for ~50% of patient-years, two drugs for 14.1%, and at least three drugs for 18.4%. Consistent with Japanese guidelines, L-dopa was mostly prescribed to older patients (≥60 years), whereas non-ergot DAs were mostly prescribed to middle-aged patients (peak at 50-69 years). Between 2008 and 2011, L-dopa prescription decreased while that of non-ergot DAs increased; this pattern reversed between 2012 and 2016. CONCLUSION: These results indicate that Japanese clinicians are adhering to Japanese guidelines and tailoring anti-PD treatment to individual patients.

Adherence to treatment guideline recommendations for Parkinson's disease in Japan: A longitudinal analysis of a nationwide medical claims database between 2008 and 2016.

BACKGROUND: Adherence to the 2011 Japanese guidelines for treatment of Parkinson's disease (PD) in real-life practice is unknown. METHODS: In this retrospective longitudinal observational study, we examined patterns and trends in anti-PD drug prescriptions in 20,936 patients (≥30 years of age with newly diagnosed PD [International Classification of Diseases-Tenth code G20 or PD Hoehn and Yahr scale 1-5] and one or more prescriptions) using nationwide registry data between 2008 and 2016. Data are presented as descriptive statistics. RESULTS: Half (49.6%) of the patients received levodopa (L-dopa) monotherapy, followed by non-ergot dopamine agonists (DA) prescribed as monotherapy (8.3%) or with L-dopa (8.1%). Consistent with the guidelines, 75% of patients were prescribed within 13 days of initial diagnosis; L-dopa monotherapy was the most prescribed drug in patients ≥70 years of age, whereas non-ergot DA monotherapy was more likely to be prescribed than L-dopa in patients between 30 and 50 years of age. Inconsistent with the guidelines, L-dopa monotherapy was the most prescribed drug in patients between 51 and 69 years of age. Over the course of 4 years of treatment, the prescription rate of L-dopa monotherapy and non-ergot DA monotherapy decreased by 63.7% and 44.1%, respectively, whereas that of L-dopa and non-ergot DA combination therapy increased by 103.7%. Combination therapy with L-dopa, non-ergot DA, and monoamine oxidase-B inhibitors was gradually increased at a later stage. CONCLUSION: These results highlight that the state of PD treatment in Japan adheres to most of the recommendations in the 2011 national guidelines, but also precedes the 2018 guidelines.

Factors associated with symptoms of depression among pregnant women with gestational diabetes mellitus in Japan.

The objective of this study was to explore the factors associated symptoms of depression among pregnant women with gestational diabetes mellitus (GDM) in Japan. This cross-sectional study was conducted at a hospital in Toyota, Japan, from January 2015 to June 2016. Pregnant women who visited the hospital and were diagnosed with GDM in the second trimester were enrolled. We analyzed depression symptoms using the Centers for Epidemiological Studies Depression Scale (CES-D) and considered related factors of depression symptoms, such as dietary intake and daily walking. Dietary intake during the past month was assessed using a brief self-administered diet history questionnaire, and daily walking was assessed using an accelerometer. The prevalence rate for GDM was 8.8%, and 25 pregnant women with GDM were analyzed. The CES-D was not significantly correlated with pre-pregnancy BMI, postprandial plasma glucose, hemoglobin A1c, and the number of steps walked. In contrast, a significant negative correlation was observed between the CES-D score and intake of fish with bones, simmered fish, pickles, green leaves, mushrooms, and green tea. Furthermore, a significant positive correlation was found between Coke® and CES-D scores. For nutrient intake, a significant negative correlation was found between the CES-D score and vitamin K, folate, and ß-carotene levels. The present study suggests that depression symptoms among pregnant women with GDM in the second trimester may be associated with diet.

Cell Type Specific Representation of Vibro-tactile Stimuli in the Mouse Primary Somatosensory Cortex.

Although the processing of whisker deflections in the barrel area of the rodent primary somatosensory cortex (S1) has been studied extensively, how cutaneous vibro-tactile stimuli are processed in the rodent S1 outside the barrel area has not been fully examined. Particularly, the cell-type specific representation of multiple vibration frequencies in genetically identified inhibitory cells in the S1 has not been examined. Using two-photon calcium imaging, we examined the responses to vibration stimuli of excitatory and inhibitory neurons in the S1 hind limb area of male and female mice. The excitatory cells showed relatively sharp selectivity to vibration stimuli, whereas the inhibitory cells exhibited less selectivity. The excitatory and inhibitory cells with different preferred stimuli were intermingled in a "salt and pepper" manner. Furthermore, the noise correlation tended to be especially strong in excitatory-inhibitory and inhibitory-inhibitory cell pairs that have similar stimulus selectivity. These results suggest that excitatory cells tend to represent specific stimulus information and work together with similarly tuned inhibitory cells as a functionally connected network.

High affinity receptor labeling based on basic leucine zipper domain peptides conjugated with pH-sensitive fluorescent dye: Visualization of AMPA-type glutamate receptor endocytosis in living neurons.

Techniques to visualize receptor trafficking in living neurons are important, but currently available methods are limited in their labeling efficiency, specificity and reliability. Here we report a method for receptor labeling with a basic leucine zipper domain peptide (ZIP) and a binding cassette specific to ZIP. Receptors are tagged with a ZIP-binding cassette at their extracellular domain. Tagged receptors expressed in cultured cells were labeled with exogenously applied fluorescently labeled ZIP with low background and high affinity. To test if ZIP labeling is useful in monitoring endocytosis and intracellular trafficking, we next conjugated ZIP with a pH-sensitive dye RhP-M (ZIP-RhP-M). ZIP binding to its binding cassette was pH-resistant and RhP-M fluorescence dramatically increased in acidic environment. Thus AMPA-type glutamate receptors (AMPARs) labeled by ZIP-RhP-M can report receptor endocytosis and subsequent intracellular trafficking. Application of ZIP-RhP-M to cultured hippocampal neurons expressing AMPARs tagged with a ZIP-binding cassette resulted in appearance of fluorescent puncta in PSD-95-positive large spines, suggesting local endocytosis and acidification of AMPARs in individual mature spines. This spine pool of AMPARs in acidic environment was distinct from the early endosomes labeled by transferrin uptake. These results suggest that receptor labeling by ZIP-RhP-M is a useful technique for monitoring endocytosis and intracellular trafficking. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.

Daily walking decreases casual glucose level among pregnant women in the second trimester.

The objective of this study was to explore the relationship between carbohydrate metabolism and the number of steps walked daily, as evaluated by accelerometer, among Japanese women in the second trimester of pregnancy. This longitudinal study was conducted at a university hospital in Tokyo, Japan, from August 2012 to January 2013. Healthy pregnant women at 14 to 18 gestational weeks were recruited. Participants wore accelerometers on the waist for 4 weeks. Casual glucose and hemoglobin A1c (HbA1c) levels were compared between two groups based on whether participants habitually walked ≥ 6,000 steps/day or < 6,000 steps/day. Fifty-one pregnant women were included in the present study; data from 35 were analyzed. There were 22 women in the group that habitually walked ≥ 6,000 steps/day and 13 in the group habitually walking < 6,000 steps/day. Although the median serum casual glucose level at the end of the investigation was 90.0 mg/dL in the group walking < 6,000 steps/day, the level in the group walking ≥ 6000 steps/day was 83.5 mg/dL (p = 0.01). HbA1c levels were not significantly different between the two groups. Our results suggest that walking as a daily habitual physical activity is effective for controlling casual glucose levels in the second trimester of pregnancy.

Permeability characteristics of endocrine-disrupting chemicals using an in vitro cell culture model, Caco-2 cells.

The purpose of this study was to evaluate the permeability characteristics of endocrine disrupting chemicals utilizing epithelial monolayers of Caco-2 cells. The drugs tested in this study were bisphenol A (BPA), tert-octylphenol (tOP), tert-butylphenol (tBP), di(2-ethylhexyl)phthalate (DOP), dibutylphthalate (DBP), and butylbenzylphthalate (BBP), all of which are used in plastic materials. The Caco-2 cell line was grown on cell culture inserts with polyethylene terephthalate membranes, and Hank's balanced salt solution (HBSS, pH 7.4) was used for the transport experiments. The barrier properties were assessed by measuring transepithelial electrical resistance (TEER) using a volt ohmmeter, and transport of these endocrine disrupting chemicals was examined in both directions. The permeated amounts of these chemicals within 180 min in the apical to basolateral (A-to-B) and the basolateral to apical (B-to-A) directions without verapamil, a P-glycoprotein (P-gp) inhibitor, were in the rank order of tBP > tOP > BPA > DOP > DBP > BBP and BPA >> tBP > tOP > DOP > DBP > BBP, respectively. In the presence of 100 microM verapamil, the permeated amounts of BPA, tOP and tBP within 180 min in the B-to-A direction decreased by 12-, 2.6- and 3.1-fold, respectively. In the case of phthalate esters, the permeated amount of DOP within 180 min in the B-to-A direction decreased by 1.6-fold, while that of DBP and BBP showed no significant changes. The ratios of apparent permeability coefficient of B-to-A against A-to-B, P(app) ratios, for BPA, tOP and tBP were markedly decreased in the presence of 100 microM verapamil. These findings indicated that both BPA and alkyl phenols are substrates of the P-gp located in the apical side of Caco-2 cells, and suggested that the P-gp in the small intestine may act as an organic barrier against BPA and alkyl phenols.

No relation between folate and homocysteine levels and depression in early pregnant women.

The objective in this study was to evaluate the association between folate and homocysteine (Hcy) levels and depressive symptoms in early pregnancy. A cross-sectional study was conducted with 86 pregnant women in the first trimester. A Japanese version of the Center for Epidemiologic Studies Depression (CES-D) scale was used to screen for depression. Non-fasting blood samples were collected from the women to measure folate and Hcy levels. Fifty-three (61.6%) women scored at or above a clinical cut-off of 16, and were classified with depression. In logistic regression analyses, no significant associations were observed between the incidence of depression in the first trimester and elevated Hcy and deficiencies of serum folate, folate intake, vitamin B6 intake and vitamin B12 intake. Folate and Hcy concentrations, and folate consumption, may not be protective against depression in early pregnancy.

Lupus antibodies to the HMGB1 chromosomal protein: epitope mapping and association with disease activity.

The high mobility group box 1 (HMGB1) protein is a non-histone chromosomal protein that acts as a potent proinflammatory cytokine when actively secreted from LPS- or TNF-activated macrophages, monocytes, and other cells. Anti-HMGB1/2 antibodies have been previously identified in sera from a high proportion of patients with autoimmune diseases. In this study, we examined anti-HMGB1 antibody titers in sera of patients with systemic rheumatic diseases and the correlations between the presence of anti-HMGB1 antibodies and disease activity in systemic lupus erythematosus (SLE) patients by enzyme-linked immunosorbent assay and western blotting. We detected increases in both the levels and the frequency of anti-HMGB1 antibodies in sera from SLE and polymyositis/dermatomyositis (PM/DM) patients, and observed that the presence of anti-HMGB1 antibodies positively correlates with SLE disease activity index. Through epitope mapping, we found that multiple HMGB1 epitopes were recognised in SLE sera, with the major epitope mapping to box A. Another epitope, the joiner region of HMGB1, was preferentially recognized by SLE sera, but not by PM/DM sera. Collectively, these observations suggest that the presence of anti-HMGB1 antibodies correlates with disease activity in SLE patients.

Alteration of phosphatidylinositol 3-kinase cascade in the multilobulated nuclear formation of adult T cell leukemia/lymphoma (ATLL).

Adult T cell leukemia/lymphoma (ATLL) has been characterized as one of the most aggressive human neoplasias and its incidence is thought to be caused by both genetic and epigenetic alterations to the host cellular genes of T cells infected with human T cell leukemia virus type I (HTLV-I). A multilobulated nuclear appearance is an important diagnostic marker of ATLL, and we have now identified that the molecular mechanisms underlying these formations occur through microtubule rearrangement via phosphatidylinositol 3-kinase (PI3-kinase) activation by AILIM/ICOS signaling. We also show that PTEN and/or SHIP-1, which are PIP3 inositol phosphatases that inhibit the activation of downstream effectors of the PI3-kinase cascade, are disrupted in both ATLL neoplasias and in multilobulated nuclei-forming Jurkat cells. This down-regulation of PTEN was found to be essential for the formation of ATLL-type nuclear lobules. Furthermore, PI3-kinase and PTEN activities were observed to be closely associated with cellular proliferation. Thus, our results suggest that alteration of PI3-kinase signaling cascades, as a result of the down-regulation of inositol phosphatases, induces ATLL-type multilobulated nuclear formation and is also associated with the cellular proliferation of malignant T cell leukemias/lymphomas.