Efficacy and Safety of Home-Based Cardiac Telemonitoring Rehabilitation in Patients After Transcatheter Aortic Valve Implantation: Single-Center Usability and Feasibility Study.

BACKGROUND: No consensus exists on the efficacy of home-based cardiac rehabilitation (CR) in patients who have undergone transcatheter aortic valve implantation (TAVI). Additionally, there are no reports on home-based cardiac telemonitoring rehabilitation (HBTR) in patients after TAVI. OBJECTIVE: We aimed to investigate the efficacy of HBTR in patients who have undergone TAVI. METHODS: This single-center preliminary study introduced HBTR to patients after TAVI, and the efficacy outcomes of the rehabilitation method were compared to that of a historical control cohort. The historical control cohort (control group) consisted of 6 consecutive patients who underwent ordinary outpatient CR after TAVI from February 2016 to March 2020. Patients who participated in the HBTR program were only recruited after the TAVI procedure and before discharge between April 2021 and May 2022. In the first 2 weeks after TAVI, patients underwent outpatient CR and were trained using telemonitoring rehabilitation systems. Thereafter, patients underwent HBTR twice a week for 12 weeks. The control group performed standard outpatient CR at least once a week for 12 to 16 weeks. Efficacy was assessed using peak oxygen uptake (VO2) prior to and after CR. RESULTS: Eleven patients were included in the HBTR group. All patients underwent 24 HBTR sessions during the 12-week training period, and no adverse events were observed. The control group participants performed 19 (SD 7) sessions during the training period, and no adverse events were observed. Participants in the HBTR and control groups had a mean age of 80.4 (SD 6.0) years and 79.0 (SD 3.9) years, respectively. In the HBTR group, preintervention and postintervention peak VO2 values were 12.0 (SD 1.7) mL/min/kg and 14.3 (SD 2.7) mL/min/kg (P=.03), respectively. The peak VO2 changes in the HBTR and control groups were 2.4 (SD 1.4) mL/min/kg and 1.3 (SD 5.0) mL/min/kg (P=.64), respectively. CONCLUSIONS: Home-based CR using a telemonitoring system is a safe outpatient rehabilitation method. Its efficacy is not inferior to that of standard CR in patients who have undergone TAVI. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs032200122; https://jrct.niph.go.jp/latest-detail/jRCTs032200122.

Hospital-acquired disability in older heart failure patients decreases independence and increases difficulties in activities of daily living.

AIMS: The aim of this study was to clarify whether worsening of independence in activities of daily living (ADL) and also difficulties in ADL are triggered by hospitalization in older patients with heart failure (HF) and whether difficulties in ADL can predict readmission for HF regardless of independence in ADL in these patients. METHODS AND RESULTS: We enrolled 241 HF patients in the present multi-institutional, prospective, observational study. The patients were divided according to age into the non-older patient group (<75 years, n = 137) and the older patient group (≥75 years, n = 104). The Katz index and the Performance Measure for Activities of Daily Living-8 (PMADL-8) were used to evaluate independence and difficulties in ADL, respectively. The endpoint of this study was rehospitalization for HF. Independence as indicated by the Katz index at discharge was significantly lower than that before admission only in the older patient group, and the value of the PMADL-8 at discharge was significantly higher than that before admission (P < 0.001). In all patients, after adjusting for the Katz index and other variables, PMADL-8 score was a significant predictor of rehospitalization for HF (hazard ratio 1.50; 95% confidence interval 1.07-2.13; P = 0.021). CONCLUSIONS: Worsening of both independence and difficulties in ADL was triggered by hospitalization in older HF patients, and difficulties in ADL were relevant factors for risk of rehospitalization regardless of independence in ADL. These findings indicate the importance of preventing not only decreased independence but also increased difficulties in ADL during and after hospitalization.

Relevant factors of leg strength at hospital discharge in patients hospitalized due to acute decompensated heart failure: multi-institutional prospective observational study.

BACKGROUND: Lower leg strength at hospital discharge is strongly associated with poor prognosis in older patients with acute decompensated heart failure (ADHF). Improving leg strength is important in acute-phase cardiac rehabilitation (CR). AIMS: This study aimed to clarify whether a change in leg strength occurs during hospitalization of older ADHF patients receiving CR and whether it affects leg strength at discharge. METHODS AND RESULTS: We enrolled 247 ADHF patients who underwent CR during hospitalization. They were divided into the non-older patient group (<75 years; n = 142) and older patient group (≥75 years; n = 105). Quadriceps isometric strength (QIS), body mass-corrected QIS (%BM QIS), and change in QIS during hospitalization (QIS ratio) were evaluated in all patients. Physical function in the stable phase was measured by the Performance Measure for Activities of Daily Living-8 (PMADL-8). The QIS value increased during hospitalization in the non-older patient group (30.0 ± 11.1 vs. 31.6 ± 10.9 kgf, P < 0.001) but did not increase in the older patient group (19.1 ± 6.3 vs. 19.5 ± 6.1 kgf, P = 0.275). Multiple regression analysis revealed that PMADL-8 significantly predicted %BM QIS at discharge in the non-older patient group (ß = -0.254, P = 0.004), whereas in the older patient group, QIS ratio and PMADL-8 significantly predicted %BM QIS at discharge (ß = 0.264, P = 0.008 for QIS ratio and ß = -0.307, P = 0.003 for PMADL-8). CONCLUSIONS: Leg strength was not improved in older ADHF patients during hospitalization even if they received CR, and this affected leg strength at discharge, suggesting that careful skeletal muscle intervention should be provided during hospitalization, and patients need to continue exercise after discharge.

New Formula to Predict Heart Rate at Anaerobic Threshold That Considers the Effects of ß-Blockers in Patients With Myocardial Infarction: MULTI-INSTITUTIONAL RETROSPECTIVE CROSS-SECTIONAL STUDY.

PURPOSE: It is recommended that patients with myocardial infarction (MI) be prescribed exercise by target heart rate (HR) at the anaerobic threshold (AT) via cardiopulmonary exercise testing (CPX). Although percent HR reserve using predicted HRmax (%HRRpred) is used to prescribe exercise if CPX or an exercise test cannot be performed, %HRRpred is especially difficult to use when patients take ß-blockers. We devised a new formula to predict HR at AT (HRAT) that considers ß-blocker effects in MI patients and validated its accuracy. METHODS: The new formula was created using the data of 196 MI patients in our hospital (derivation sample), and its accuracy was assessed using the data of 71 MI patients in other hospitals (validation sample). All patients underwent CPX 1 mo after MI onset, and resting HR, resting systolic blood pressure (SBP), and HRAT were measured during CPX. RESULTS: The results of multiple regression analysis in the derivation sample gave the following formula (R2 = 0.605, P < .001): predicted HRAT = 2.035 × (≥65 yr:-1, <65 yr:1) + 3.648 × (body mass index <18.5 kg/m2:-1, body mass index ≥18.5 kg/m2:1) + 4.284 × (ß1-blocker(+):-1, ß1-blocker(-):1) + 0.734 × (HRrest) + 0.078 × (SBPrest) + 36.812. This formula consists entirely of predictors that can be obtained at rest. HRAT and predicted HRAT with the new formula were not significantly different in the validation sample (mean absolute error: 5.5 ± 4.1 bpm). CONCLUSIONS: The accuracy of the new formula appeared to be favorable. This new formula may be a practical method for exercise prescription in MI patients, regardless of their ß-blocker treatment status, if CPX is unavailable.

Impact of perioperative change in physical function on midterm outcomes after transcatheter aortic valve implantation.

Preoperative frailty diminishes the potential for functional recovery after transcatheter aortic valve implantation (TAVI). However, perioperative changes in physical status and their impact on prognosis after TAVI have not previously been reported. Therefore, this study aimed to investigate whether perioperative changes in physical function affect prognosis in patients undergoing TAVI. We retrospectively reviewed 257 patients who underwent TAVI. The Short Physical Performance Battery (SPPB), an objective physical status assessment tool, was evaluated pre- and post-TAVI. Patients were divided into two groups: (i) patients whose SPPB score declined in the perioperative period (the decline group) and (ii) patients whose SPPB score did not decline in the perioperative period (the non-decline group). The primary endpoint was unplanned hospitalization owing to heart failure or cardiovascular death following TAVI. The mean follow-up period was 385 ± 151 days, mean age was 83.2 ± 5.8 years, and 67% of the patients were women. Sixteen patients required readmission owing to heart failure, and seven experienced cardiovascular-related death. Kaplan-Meier analysis revealed that the event-free rate was significantly lower in the decline group (log-rank, p = 0.006). A stepwise multivariate logistic regression analysis showed that a perioperative change in SPPB was significantly associated with primary endpoints (odds ratio, 1.51; 95% confidence interval, 1.12-2.04). Perioperative change in physical function was an independent risk factor for heart failure, hospitalization, or cardiovascular death following TAVI.

Prognostic value of Mini Nutritional Assessment-Short Form with aortic valve stenosis following transcatheter aortic valve implantation.

AIMS: Older adults at risk for malnutrition are known to have a high mortality rate. This study aimed to investigate whether the Mini Nutritional Assessment-Short Form (MNA-SF) could predict midterm mortality in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: We applied the MNA-SF in 288 patients who had undergone TAVI from January 2016 to June 2019 at the St. Marianna University School of Medicine hospital. Using the MNA-SF cut-off value to indicate the risk of malnutrition, patients were divided into two groups, namely, those with an MNA-SF score ≤11 (impaired MNA-SF group) and those with an MNA-SF score ≥12 (maintained MNA-SF group). We used this value to investigate the association between the MNA-SF and all-cause mortality. Overall, 188 (65%) and 100 (35%) patients comprised the impaired MNA-SF and maintained MNA-SF groups, respectively, and 41 patients died after TAVI (mean follow-up duration, 458 ± 315 days). Kaplan-Meier analyses showed that patients in the impaired MNA-SF group had a significantly higher incidence of all-cause mortality (hazard ratio 2.67; 95% confidence interval 1.29-6.21; P = 0.01). Multivariate Cox regression analyses showed that the MNA-SF score was an independent predictor of all-cause mortality after adjusting for the Society of Thoracic Surgeons risk score, Katz Index, and brain natriuretic peptide test results (hazard ratio 1.14; 95% confidence interval 1.01-1.28; P = 0.04). CONCLUSIONS: The MNA-SF was useful to screen for the risk of malnutrition in patients with TAVI and in predicting midterm prognoses in patients undergoing TAVI and could predict patient mortality after the procedure.

Effects of αß-Blocker Versus ß1-Blocker Treatment on Heart Rate Response During Incremental Cardiopulmonary Exercise in Japanese Male Patients with Subacute Myocardial Infarction.

A simplified substitute for heart rate (HR) at the anaerobic threshold (AT), i.e., resting HR plus 30 beats per minute or a percentage of predicted maximum HR, is used as a way to determine exercise intensity without cardiopulmonary exercise testing (CPX) data. However, difficulties arise when using this method in subacute myocardial infarction (MI) patients undergoing beta-blocker therapy. This study compared the effects of αß-blocker and ß1-blocker treatment to clarify how different beta blockers affect HR response during incremental exercise. MI patients were divided into αß-blocker (n = 67), ß1-blocker (n = 17), and no-ß-blocker (n = 47) groups. All patients underwent CPX one month after MI onset. The metabolic chronotropic relationship (MCR) was calculated as an indicator of HR response from the ratio of estimated HR to measured HR at AT (MCR-AT) and peak exercise (MCR-peak). MCR-AT and MCR-peak were significantly higher in the αß-blocker group than in the ß1-blocker group (p < 0.001, respectively). Multiple regression analysis revealed that ß1-blocker but not αß-blocker treatment significantly predicted lower MCR-AT and MCR-peak (ß = -0.432, p < 0.001; ß = -0.473, p < 0.001, respectively). Based on these results, when using the simplified method, exercise intensity should be prescribed according to the type of beta blocker used.

Comparison of impedance measured by the forced oscillation technique and pulmonary functions, including static lung compliance, in obstructive and interstitial lung disease.

Objective: To examine whether the parameters of impedance measured by the broadband frequency forced oscillation technique (FOT) were reflected by changes in lung compliance induced by emphysema and fibrosis, we retrospectively compared the parameters of FOT and pulmonary functions, including static lung compliance (Cst), in obstructive lung disease (OLD) and interstitial lung disease (ILD). Patients and methods: The data of 18 patients with OLD (16 with COPD, two with asthma COPD overlap), 11 with ILD, and 24 healthy volunteers, whose respiratory impedance was measured using a MostGraph-01 and other pulmonary functions including Cst and lung resistance (RL) were measured on the same day and were retrospectively collected and compared. Results: The parameters of resistance, reactance, and resonant frequency showed good correlations with ventilation unevenness (r=0.63, -0.89, 0.77, respectively) and lung elastic resistance (r=0.59, -0.80, 0.73, respectively) in all groups (N=53). These indices were significant determinants of increased respiratory resistance and more negative shift of respiratory reactance (Xrs) at lower frequency (P<0.001). Decreased functional residual capacity was also a determinant of Xrs at 5 Hz (X5) (P<0.05). The differences in mean X5 in the expiratory phase relative to those in the inspiratory phase (within-breath changes in X5) were associated with airflow obstruction (P<0.002) and lung elastic resistance (P<0.001). However, no significant correlations between Cst and any parameters of respiratory impedance were observed. Conclusions: These findings suggest that the impedance parameters measured by FOT are reflected by airway obstruction, ventilation unevenness, and lung resistance, but hardly reflected by changes in lung compliance due to emphysema or fibrosis in both CLD and ILD.

Effect of carvedilol on heart rate response to cardiopulmonary exercise up to the anaerobic threshold in patients with subacute myocardial infarction.

Resting heart rate (HR) plus 20 or 30 beats per minute (bpm), i.e., a simplified substitute for HR at the anaerobic threshold (AT), is used as a tool for exercise prescription without cardiopulmonary exercise testing data. While resting HR plus 20 bpm is recommended for patients undergoing beta-blocker therapy, the effects of specific beta blockers on HR response to exercise up to the AT (ΔAT HR) in patients with subacute myocardial infarction (MI) are unclear. This study examined whether carvedilol treatment affects ΔAT HR in subacute MI patients. MI patients were divided into two age- and sex-matched groups [carvedilol (+), n = 66; carvedilol (-), n = 66]. All patients underwent cardiopulmonary exercise testing at 1 month after MI onset. ΔAT HR was calculated by subtracting resting HR from HR at AT. ΔAT HR did not differ significantly between the carvedilol (+) and carvedilol (-) groups (35.64 ± 9.65 vs. 34.67 ± 11.68, P = 0.604). Multiple regression analysis revealed that old age and heart failure after MI were significant predictors of lower ΔAT HR (P = 0.039 and P = 0.013, respectively), but not carvedilol treatment. Our results indicate that carvedilol treatment does not affect ΔAT HR in subacute MI patients. Therefore, exercise prescription based on HR plus 30 bpm may be feasible in this patient population, regardless of carvedilol use, without gas-exchange analysis data.

Structural equation modeling approach between salience network dysfunction, depressed mood, and subjective quality of life in schizophrenia: an ICA resting-state fMRI study.

PURPOSE: Quality of life (QOL) is an important clinical outcome for patients with schizophrenia, and recent studies have focused on subjective QOL. We evaluated the causal relationship between psychosocial aspect of subjective QOL, symptoms, cognitive functions, and salience network (SN) dysfunction in schizophrenia using structural equation modeling (SEM). PATIENTS AND METHODS: We performed a cross-sectional study of 21 patients with symptomatically stabilized schizophrenia and 21 age-, sex-, and education level-matched healthy controls who underwent resting-state functional magnetic resonance imaging. We evaluated SN dysfunction in schizophrenia using independent component analysis (ICA). We rated participant psychopathology using the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), and the Calgary Depression Scale for Schizophrenia (CDSS). We rated psychosocial aspect of subjective QOL using the Schizophrenia Quality of Life Scale (SQLS) psychosocial subscale. We applied SEM to examine the relationships between SN dysfunction, PANSS positive and negative scores, CDSS total scores, BACS composite scores, and SQLS psychosocial subscale scores. RESULTS: In second-level analysis after group ICA, patient group had significant lower right pallidum functional connectivity (FC) within the SN than the controls did (Montreal Neurological Institute [MNI] [x y z] = [22 -2 -6]) (p = 0.027, family-wise error [FWE] corrected). In SEM, we obtained a good fit for an SEM model in which SN dysfunction causes depressed mood, which in turn determines psychosocial aspect of subjective QOL (chi-squared p = 0.9, root mean square error of approximation (RMSEA) < 0.001, comparative fit index [CFI] = 1.00, and standardized root mean square residual [SRMR]= 0.020). CONCLUSION: We found a continuous process by which SN dysfunction causes depressed moods that determine psychosocial aspect of subjective QOL in schizophrenia. This is the first report that offers a unified explanation of functional neuroimaging, symptoms, and outcomes. Future studies combining neuroimaging techniques and clinical assessments would elucidate schizophrenia's pathogenesis.

Rapid ABO genotyping by high-speed droplet allele-specific PCR using crude samples.

BACKGROUND: ABO genotyping has common tools for personal identification of forensic and transplantation field. We developed a new method based on a droplet allele-specific PCR (droplet-AS-PCR) that enabled rapid PCR amplification. We attempted rapid ABO genotyping using crude DNA isolated from dried blood and buccal cells. METHODS: We designed allele-specific primers for three SNPs (at nucleotides 261, 526, and 803) in exons 6 and 7 of the ABO gene. We pretreated dried blood and buccal cells with proteinase K, and obtained crude DNAs without DNA purification. RESULTS: Droplet-AS-PCR allowed specific amplification of the SNPs at the three loci using crude DNA, with results similar to those for DNA extracted from fresh peripheral blood. The sensitivity of the methods was 5%-10%. The genotyping of extracted DNA and crude DNA were completed within 8 and 9 minutes, respectively. The genotypes determined by the droplet-AS-PCR method were always consistent with those obtained by direct sequencing. CONCLUSION: The droplet-AS-PCR method enabled rapid and specific amplification of three SNPs of the ABO gene from crude DNA treated with proteinase K. ABO genotyping by the droplet-AS-PCR has the potential to be applied to various fields including a forensic medicine and transplantation medical care.

Role of the Programmed Death-1 (PD-1) pathway in regulation of Theiler's murine encephalomyelitis virus-induced demyelinating disease.

Programmed death-1 (PD-1) belongs to the CD28 family of co-stimulatory and co-inhibitory molecules and regulates adaptive immunity. This molecule induces the development of regulatory T cells, T cell tolerance, or apoptosis. We examined the role of PD-1 pathway in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) mice. Up-regulation of PD-1 and PD-1 ligand-1 (PD-L1) mRNA expression in bone marrow-derived dendritic cells were induced by TMEV infection in vitro. Furthermore, PD-1 and PD-L1 mRNA expression was increased in the spinal cords of the TMEV-infected mice in vivo. Treatment with a blocking monoclonal antibody (mAb) against PD-1, especially during the effector phase, resulted in significant deterioration of the TMEV-IDD both clinically and histologically. Flow cytometric analysis revealed a dramatically increase of CD4(+) T cells producing Th1 cytokines such as IFN-γ and TNF-α in the spinal cord of anti-PD-1 mAb-treated mice. These results indicate that the PD-1 pathway plays a pivotal regulatory role in the development of TMEV-IDD.

Downregulation of water channel aquaporin-4 in rats with experimental autoimmune encephalomyeritis induced by myelin basic protein.

Characteristics of myelin basic protein (MBP)-induced experimental autoimmune encephalomyelitis (EAE) include acute edema and infiltration of mononuclear cells (MNCs) in the microvessels of central nervous system (CNS). Aquaporin-4 (AQP4) is a water channel protein expressed in astrocytes foot process throughout the CNS. We performed immunostaining, western blotting and semi-quantitative real-time RT-PCR of AQP4 and glial fibrillary acidic protein (GFAP) in CNS from rats immunized with MBP. Immunohistochemical analysis revealed that AQP4 is down-regulated in MNCs infiltrated microvessels of rats with EAE. Furthermore, western blotting and real-time RT-PCR analyses showed that AQP4 was significantly decreased at the stage of severe EAE compared with control rats. On the other hand, expression of GFAP-protein was significantly increased after stage of severe EAE. Our findings suggest that AQP4 may be involved in forming edema in the inflammatory lesions of EAE accompanying with up-regulation of reactive astrocyte.

Determination of the effectiveness of accelerometer use in the promotion of physical activity in cardiac patients: a randomized controlled trial.

OBJECTIVE: To investigate the effect of the self-monitoring of physical activity by hospitalized cardiac patients attending phase I cardiac rehabilitation (CR). DESIGN: Randomized controlled trial. SETTING: University hospital CR program. PARTICIPANTS: CR patients (N=126) with a mean age of 59.1 years. INTERVENTIONS: Patients were randomly assigned to the self-monitoring group (group A, n=63) or the control group (group B, n=63). Along with CR, group A patients performed self-monitoring of their physical activity at the beginning of a phase I CR program (acute in-hospital phase for inpatients) and ending just before they began a phase II CR program (postdischarge recovery phase for outpatients). MAIN OUTCOME MEASURES: Physical activity (averages of daily number of steps taken and daily energy expenditure for 1wk) as measured by accelerometer was assessed in both groups at baseline (t1) and before the beginning of phase II CR (t2). RESULTS: Although there were no significant differences in physical activity values between groups A and B at t1, values of group A at t2 were significantly higher than those of group B (8609.6 vs 5512.9 steps, P<.001; 242.6 vs 155.9kcal, P<.001). CONCLUSIONS: Self-monitoring of patient physical activity from phase I CR might effectively increase the physical activity level in preparation for entering a phase II CR program. Results of the present study could contribute to the development of new strategies for the promotion of physical activity in cardiac patients.

Relation between physical activity and exercise capacity of ≥5 metabolic equivalents in middle- and older-aged patients with chronic heart failure.

PURPOSE: Patients with exercise capacity of <5 metabolic equivalents (METs) are considered to have a high risk of death. The aim of this study was to determine age-related differences in physical activity associated with an exercise capacity of ≥5 METs in chronic heart failure (CHF) outpatients. METHODS: We enrolled 157 stable CHF patients (79.6% men, age 60.3 ± 11.5 years). Patients were divided into two age-based groups (middle-aged, <65 years, n = 97) and (older-aged, ≥65 years, n = 60). Peak oxygen uptake (peak (V)O(2)) was assessed by cardiopulmonary exercise testing. We further divided patients into groups according to exercise capacity: ≥5 METs and <5 METs. Physical activity was assessed by measuring the average number of steps/day for 1 week with an electronic pedometer. RESULTS: Receiver-operating characteristic curves were used to select cutoff values for steps associated with an exercise capacity of ≥5 METs in the middle- and older-aged patients. Cutoff values of 6045 steps in the middle-aged and 6070 steps in the older-aged patients were determined. CONCLUSIONS: Both middle- and older-aged CHF patients with exercise capacity of ≥5 METs completed approximately 6000 steps/day. This could become a target amount for minimal physical activity that could contribute to increased exercise capacity in CHF patients. IMPLICATIONS FOR REHABILITATION: • Middle-aged and older-aged chronic heart failure (CHF) patients with a measured exercise capacity of ≥5 METs completed approximately 6000 steps/day as measured by electronic pedometer. • This amount of steps could become a target amount for minimal physical activity that could contribute to increased exercise capacity in CHF patients.

Relation between sleep quality and physical activity in chronic heart failure patients.

To determine self-reported sleep quality-related differences in physical activity (PA) and health-related quality of life (HRQOL) and target values of PA for high-quality sleep in chronic heart failure (CHF) outpatients, 149 CHF outpatients (mean age 58 years) were divided into two groups by sleep-quality level determined via self-reported questionnaire: shallow sleep (SS) group (n = 77) and deep sleep (DS) group (n = 72). Steps were assessed by electronic pedometer, HRQOL was assessed with the Short Form 36 (SF-36) survey, and data were compared between groups. PA resulting in high-quality sleep was determined by receiver-operating characteristics curves. All SF-36 subscale scores except that of bodily pain were significantly decreased in the SS versus DS group. A cutoff value of 5723.6 steps/day and 156.4 Kcal/day for 1 week were determined as target values for PA. Sleep quality may affect PA and HRQOL, and attaining target values of PA may improve sleep quality and HRQOL of CHF outpatients. Patents relevant to heart failure are also discussed in this article.

Ameliorating effects of anti-Dll4 mAb on Theiler's murine encephalomyelitis virus-induced demyelinating disease.

We examined the role of Notch ligand Delta-like 4 (Dll4) in the development of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD). Treatment with mAb to Dll4, especially during the effector phase, resulted in significant suppression of the disease development both clinically and histologically. The number of infiltrating mononuclear inflammatory cells in the spinal cords was also decreased in mice treated with anti-Dll4 mAb. Semi-quantitative analysis of mRNA by using real-time PCR revealed that mRNAs of T(h)1-derived cytokines such as IFN-gamma and T(h)17-derived cytokines such as IL-17 were decreased in mice treated with anti-Dll4 mAb, whereas those of T(h)2-derived cytokines such as IL-4 and IL-10 were not. Flow cytometric analysis of cytokines indicated that there were no significant differences between mAb-treated mice and control mice in the relative frequency of splenic T(h)1 and T(h)2. However, absolute cell numbers of T(h)1-derived cytokine-producing cells in spinal cord were markedly decreased in mice treated with anti-Dll4 mAb in effector phase compared with control mice treated with non-specific IgG. These data suggest that Dll4 is critically involved in the pathogenesis of TMEV-IDD and that antibodies to Dll4 could be used as a novel therapeutic treatment of demyelinating diseases such as human multiple sclerosis.

Effects of anti-CD70 mAb on Theiler's murine encephalomyelitis virus-induced demyelinating disease.

Ligation of CD27, a member of the tumor necrosis factor (TNF) receptor family, by its ligand CD70 is thought to be important in T cell activation, expansion and survival, B cell activation, and NK cell activation. We examined the role of CD70 in Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) mice. Blocking of CD70 in effector phase by anti-CD70 monoclonal antibody (mAb) suppressed the development of TMEV-IDD. The number of IFN-gamma- or TNF-alpha-producing cells in the spleen and mRNA levels of IFN-gamma and TNF-alpha in spinal cord were decreased in mice treated with anti-CD70 mAb at the effector phase. In contrast, treatment with anti-CD70 mAb in induction phase failed to reduce these responses, compared to nonspecific IgG-treated control mice. These data suggest that CD70 is critically involved in the pathogenesis of TMEV-IDD and that antibodies against CD70 could be a novel therapeutic approach in the clinical treatment of demyelinating diseases such as human multiple sclerosis.