Search

In the late phase after Fontan surgery, organ dysfunction due to high central venous pressure (CVP) is a major clinical problem. We have described the cases of two patients with portosystemic shunts who exhibited hyperammonemia and high cardiac output associated with peripheral vasodilatation after Fontan surgery. A high CVP in these patients may have resulted in the formation of a portosystemic shunt. We performed coil embolization and balloon-occluded retrograde transvenous obliteration for each case. The possibility of a portosystemic shunt as a postoperative complication of Fontan surgery should always be considered. Early detection and therapeutic intervention seem necessary from the viewpoint of stabilizing the Fontan circulation and delaying the progression of liver disorder.

OBJECTIVE AND METHOD Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell lymphoma with poor prognosis. We retrospectively reviewed the medical records of 312 patients with aggressive ATL and analyzed the effect of chemotherapy dose intensity on prognosis in clinical practice. RESULT As first-line therapy, 62 patients underwent best supportive care (BSC) or single-agent chemotherapy, and 235 underwent intensive chemotherapy. The median survival time (MST) was 0.58 years in the 312 total patients, and 0.13 years and 0.75 years in the BSC/single-agent chemotherapy group and intensive chemotherapy group, respectively. The median average relative dose intensity (ARDI) of patients who received intensive chemotherapy was 60%. We divided patients into 3 groups according to ARDI. Those in the top tertile of ARDI (ARDI ≥ 75%, n = 82) had better overall survival compared with those in the intermediate tertile (45% ≤ ARDI

Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy and is associated with high morbidity and mortality. However, the role and significance of school screening for LVNC have not been fully elucidated. In this multicenter, retrospective cohort study, a total of 105 children with LVNC were included from 2000 to 2017. At the initial presentation, 44 patients (41.9%) were diagnosed by school screening. One (1.0%) patient underwent heart transplantation and four (3.8%) patients died during the study. Electrocardiogram data showed a high prevalence of fragmented QRS (33.4%) and J wave (15.7%). Treatments were needed in eight (18.2%) patients who were detected by school screening. The multivariable proportional hazards model showed T-wave abnormality on electrocardiogram in first graders was independent risk factors for major adverse cardiac events (odds ratio 4.94, p value = 0.0007). Moreover, dilation of the left atrium on chest X-ray and low ejection fraction on echocardiogram at the initial treatment were independent risk factors for treatment (odds ratio 1.7 × 107 and 22.3, p = 0.0362 and 0.0028, respectively). This study is the first report focusing on school screening in a large pediatric cohort with LVNC. With the use of abnormalities in electrocardiogram, school screening may be a good detector of and predictor for LVNC.

The prognosis of multiple myeloma (MM) has improved with the introduction of novel agents. These data are largely derived from clinical trials and might not reflect real-world patient outcomes accurately. We surveyed real-world data from 284 patients newly diagnosed with MM between 2010 and 2018 in Miyazaki Prefecture. The median follow-up period was 32.8 months. The median age at diagnosis was 71 years, with 68% of patients aged &gt, 65 years. The International Staging System (ISS) stage at diagnosis was I in 18.4% of patients, II in 34.1%, and III in 47.5%. Bortezomib-containing regimens were preferred as initial treatment, they were used in 147 patients (51.8%). In total, 80% of patients were treated with one or more novel agents (thalidomide, lenalidomide, or bortezomib). Among 228 patients who were treated with novel agents as an initial treatment, the overall response rate (partial response (PR) or better) to initial treatment was 78.4%, and the median time to next treatment (TTNT) was 11.6 months. In the multivariate analysis, PR or better responses to initial treatment were independently favorable prognostic factors for TTNT. The median survival time after initial therapy for patients with novel agents was 56.4 months and 3-year overall survival (OS) was 70.4%. In multivariate analysis, ISS stage I/II disease and PR or better response to initial treatment, and autologous stem cell transplantation (ASCT) were identified as independent prognostic factors for overall survival (OS).

Background The usefulness of electrocardiographic (ECG) voltage criteria for diagnosing hypertrophic cardiomyopathy (HCM) in pediatric patients is poorly defined.Methods and Results:ECGs at the 1st grade (mean [±SD] age 6.6±0.3 years) were available for 11 patients diagnosed with HCM at around the 7th grade (13.2±0.3 years). ECGs were available for another 64 patients diagnosed with HCM in the 1st (n=15), 7th (n=32), and 10th (n=17) grades. Fifty-one voltage criteria were developed by grade and sex using 62,841 ECGs from the general population. Voltage criteria were set at the 99.95th percentile (1/2,000) point based on the estimated prevalence of childhood HCM (2.9 per 100,000 [1/34,483]) to decrease false negatives. Conventional criteria were from guidelines for school-aged children in Japan. Of 11 patients before diagnosis, 2 satisfied conventional criteria in 1st grade; 5 (56%) of the remaining 9 patients fulfilled 2 voltage criteria (R wave in limb-lead I [RI]+S wave in lead V3 [SV3] and R wave in lead V3 [RV3]+SV3). Robustness analysis for sensitivity showed RV3+SV3 was superior to RI+SV3. For all patients after diagnosis, RI+SV4 was the main candidate. However, conventional criteria were more useful than voltage criteria. Conclusions Early HCM prediction was possible using RV3+SV3 in >50% of patients in 1st grade. Voltage criteria may help diagnose prediagnostic or early HCM, and prevent tragic accidents, although further prospective studies are required.

Although mindfulness-based stress reduction (MBSR) improves cognitive function, the mechanism is not clear. In this study, people aged 65 years and older were recruited from elderly communities in Chitose City, Japan, and assigned to a non-MBSR group or a MBSR group. Before and after the intervention, the Japanese version of the Montreal Cognitive Assessment (MoCA-J) was administered, and blood samples were collected. Then, neuron-derived extracellular vesicles (NDEVs) were isolated from blood samples, and microRNAs, as well as the target mRNAs, were evaluated in NDEVs. A linear mixed model analysis showed significant effects of the MBSR x time interaction on the MoCA-J scores, the expression of miRNA(miR)-29c, DNA methyltransferase 3 alpha (DNMT3A), and DNMT3B in NDEVs. These results indicate that MBSR can improve cognitive function by increasing the expression of miR-29c and decreasing the expression of DNMT3A, as well as DNMT3B, in neurons. It was also found that intracerebroventricular injection of miR-29c mimic into 5xFAD mice prevented cognitive decline, as well as neuronal loss in the subiculum area, by down-regulating Dnmt3a and Dnmt3b in the hippocampus. The present study suggests that MBSR can prevent neuronal loss and cognitive impairment by increasing the neuronal expression of miR-29c.

Background: Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy. Although it is associated with high morbidity and mortality, the related ion channel gene variants in children have not been fully investigated. This study aimed to elucidate the ion channel genetic landscape of LVNC and identify genotype-phenotype correlations in a large Japanese cohort. Methods: We enrolled 206 children with LVNC from 2002 to 2017 in Japan. LVNC was classified as follows: LVNC with congenital heart defects, arrhythmia, dilated phenotype, or normal function. In the enrolled patients, 182 genes associated with cardiomyopathy were screened using next-generation sequencing. Results: We identified 99 pathogenic variants in 40 genes in 87 patients. Of the pathogenic variants, 8.8% were in genes associated with channelopathies, 27% were in sarcomere genes, and 11.5% were in mitochondrial genes. Ion channel gene variants were mostly associated with the arrhythmia classification, whereas sarcomere and mitochondrial gene variants were associated with the dilated phenotype. Echocardiography revealed that the group with ion channel gene variants had almost normal LV ejection fraction and LV diastolic diameter Z scores. Fragmented QRS, old age, and an arrhythmia phenotype were the most significant risk factors for ventricular tachycardia ( P =0.165, 0.0428, and 0.0074, respectively). Moreover, the group with ion channel variants exhibited a greater risk of a higher prevalence of arrhythmias such as ventricular tachycardia, rather than congestive heart failure. Conclusions: This is the first study that focused on genotype-phenotype correlations in a large pediatric LVNC patient cohort with ion channel gene variants that were determined using next-generation sequencing. Ion channel gene variants were strongly correlated with arrhythmia phenotypes. Genetic testing and phenotype specification allow for appropriate medical management of specific LVNC targets.

Background Although Fanconi syndrome is rare in patients with epilepsy treated with sodium valproate (VPA), the prevalence might be higher in children with severe motor and intellectual disabilities (SMID). VPA-induced Fanconi syndrome usually has a favorable outcome, but the long-term outcome of renal tubular dysfunction in SMID patients remains unknown. The aim of this study was therefore to investigate the long-term outcome of renal proximal dysfunction in SMID children with Fanconi syndrome caused by VPA. Methods The records of six children with SMID and Fanconi syndrome caused by VPA were retrospectively reviewed to assess long-term proximal renal tubular function after discontinuation of VPA. All six patients had intractable epilepsy and required tube feeding. Results Proximal tubular dysfunction improved in almost all patients after VPA discontinuation, although abnormal uric acid reabsorption persisted in three patients. Five patients had hypocarnitinemia. After carnitine supplementation, one of these three patients with decreased ability to reabsorb uric acid had a normal serum level and improved fractional excretion of uric acid. Conclusions Secondary carnitine deficiency may cause prolonged tubular dysfunction in some SMID patients with VPA-induced Fanconi syndrome. Fanconi syndrome caused by VPA is a usually reversible dysfunction of the proximal tubules, but can be permanent. Although not effective for all patients, carnitine is recommended for patients with VPA-induced Fanconi syndrome, especially children with SMID.

A new entity, namely early/prefibrotic primary myelofibrosis (PMF), was introduced as a subtype of PMF in the 2016 revised World Health Organization (WHO) criteria for myeloproliferative neoplasms (MPN). It was diagnosed based on histopathological features of bone marrow (BM) biopsy specimens together with clinical parameters [leukocytosis, anemia, elevated lactate dehydrogenase (LDH) values, and splenomegaly]. The aim of this study was to evaluate the prevalence of early/prefibrotic PMF in patients who were previously diagnosed with ET, and to compare clinical features at diagnosis and outcomes between early/prefibrotic PMF and essential thrombocythemia (ET) patients. BM biopsy samples obtained at the time of ET diagnosis were available in 42 patients. Sample reevaluation according to the 2016 revised WHO criteria revealed that early/prefibrotic PMF accounted for 14% of patients who were previously diagnosed with ET, which was comparable to the rates in previous reports. Compared to patients with ET, patients with early/prefibrotic PMF had higher LDH values and higher frequencies of splenomegaly. Overall, myelofibrosis-free and acute myeloid leukemia-free survivals were comparable between the 2 groups. Accurate diagnosis is required to clarify the clinical features of Japanese ET patients.

IMPORTANCE: Few studies with sufficient statistical power have shown the association of the z score of the coronary arterial internal diameter with coronary events (CE) in patients with Kawasaki disease (KD) with coronary artery aneurysms (CAA). OBJECTIVE: To clarify the association of the z score with time-dependent CE occurrence in patients with KD with CAA. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, collaborative retrospective cohort study of 44 participating institutions included 1006 patients with KD younger than 19 years who received a coronary angiography between 1992 and 2011. MAIN OUTCOMES AND MEASURES: The time-dependent occurrence of CE, including thrombosis, stenosis, obstruction, acute ischemic events, and coronary interventions, was analyzed for small (z score

Aim There has been no indicator that allows an early quantitative evaluation of the severity of a mamushi snake (Gloydius blomhoffii) bite. Because the number of severe mamushi bite cases is much fewer than non-severe cases, a formal case–control study is difficult. Therefore, we tried to generate a preliminary quantitative, real-time index for its severity by referring to published reports of severe mamushi bite cases. Methods We enrolled patients who presented with a mamushi bite and visited our outpatient clinic. Severe cases were collected from published works. Creatinine kinase levels and white blood cell counts of non-severe and severe cases were compared and analyzed. Results There was a lag time of 10 h before the creatinine kinase level began to rise. The speed of the increase was higher in severe cases than in non-severe cases, and severe cases were recognized as those showing speeds of above 250 IU/L/h. White blood cell counts increased earlier than creatinine kinase levels without any lag time. Severe cases were recognized as those with the counts of over 1,000 × (h) + 6,000 [/μL] before 5 h and 300 × (h) + 10,000 [/μL] after 5 h. Conclusion We herein present the creatinine kinase level and white blood cell count trends and demonstrate preliminary cut-off equations. The trends for both parameters serve as quantitative indicators of the severity of a mamushi bite until a large scale case–control study is achieved.

Polycythemia vera (PV) and essential thrombocythemia (ET) are associated with life-threatening thrombohemorrhagic events, and disease progression and development of non-hematological malignancies also reduce long-term survival. We retrospectively surveyed thrombohemorrhagic events and overall survival (OS) in 62 PV and 117 ET patients. The cumulative incidences of thrombohemorrhagic events in PV and ET patients were 11.3 and 10.3%, and the incidence rates were 2.42 and 1.85 per 100 person-years. The combined incidence rates of disease progression and development of non-hematological malignancies in PV and ET patients were 1.73 and 1.69 per 100 person-years. The incidence rates of thrombohemorrhagic events in our Japanese PV/ET patients were lower than those reported by most Western studies, but were comparable to those in the largest prospective observational study in ET patients. The combined incidence rates of disease progression and development of non-hematological malignancies were similar between Japanese and Western PV/ET patients. In ET patients, the conventional risk stratification model based on the presence of advanced age or history of thrombosis was useful to predict thrombosis risk, and both the conventional model and the International Prognostic Score of thrombosis in ET based on the above 2 risk factors plus increased leukocyte count could predict poor survival.

Mutation of the BMPR2 gene is the most common genetic cause of pulmonary arterial hypertension (PAH). Although there have been some reports of BMPR2 mutation carriers among PAH patients with congenital heart disease, there have been few reports of their treatment. Here, we describe a 13-year-old female BMPR2 mutation carrier who presented with heritable PAH and atrial septal defect (ASD). She complained of fatigue, and cardiac catheterization showed a mean pulmonary artery pressure (PAP) of 56 mmHg, a pulmonary vascular resistance (PVR) of 8 Wood units and a pulmonary to systemic blood flow ratio (Qp/Qs) of 1.3. Following 2 years of medication therapy, the mean PAP had decreased to 30 mmHg, the Qp/Qs had increased to 2.7, and her symptoms persisted. We closed the ASD interventionally, and her symptoms improved after closure. Medication therapy was continued. Four years after closure, the PAH had improved with a mean PAP of 20 mmHg and a PVR of 3.1 Wood units. To the best of our knowledge, this is the first report of PAH improvement following medication and ASD closure in a BMPR2 mutation carrier with heritable PAH. ASD closure following medication appears to be effective in some ASD patients with heritable PAH. Learning objective: Mutation of the BMPR2 gene is the most common genetic cause of pulmonary arterial hypertension (PAH). Heritable PAH with BMPR2 mutations has been reported to have a poorer prognosis once PAH has developed. Recent reports have described treatment of atrial septal defect (ASD) patients with PAH by surgical or interventional ASD closure following medication therapy. This case suggests that medication followed by ASD closure could also be effective for BMPR2 mutation carriers with ASD and heritable PAH.>

Objective The efficacy of mogamulizumab in adult T-cell leukemia/lymphoma (ATLL) was reported in a previous phase 2 study. Compared with patients in clinical trials, however, most patients in real-life settings have demonstrated worse outcomes. Method We retrospectively analyzed 96 patients with relapsed/refractory ATLL who received mogamulizumab treatment. Results Relapsed/refractory ATLL patients with a median age of 70 years received a median of five courses of mogamulizumab. Hematologic toxicity and skin rash were the most common adverse events, and both were manageable. Of 96 patients, 87 were evaluable for efficacy. The overall response rate was 36%, and the median progression-free survival (PFS) and overall survival (OS) from the start of mogamulizumab therapy were 1.8 and 4.0 months, respectively. Of the original 96 patients, only 25 fulfilled the inclusion criteria of the phase 2 study. Those who met the criteria demonstrated longer median PFS and OS durations of 2.7 and 8.5 months, respectively. The median OS from diagnosis in relapsed/refractory ATLL patients receiving mogamulizumab was 12 months, longer than the 5.8 months in a historical cohort without mogamulizumab. Conclusion In clinical practice, mogamulizumab exhibited antitumor activity in patients with relapsed/refractory ATLL, with an acceptable toxicity profile. Mogamulizumab therapy improved the OS of ATLL patients.

This is the first report of a coronary artery with an anomalous origin from the proper sinus resulting in ischemic events in a child. Transthoracic echocardiogram, computed tomogram, and coronary angiogram revealed that, although the left main coronary trunk originated from the left sinus, its ostium was displaced horizontally and was located near the commissure between the left and noncoronary valve cusps. Moreover, it was associated with an acute take off angle and an intramural segment, which are known contributing features for ischemia in cases of anomalous origin of a coronary artery from the wrong sinus. Surgical intervention, involving the unroofing procedure, was employed successfully to eliminate the ischemic events. At the latest follow up, no chest pain was reported and the transthoracic echocardiogram showed no stenosis of the neo-ostium. Even in a coronary artery that originates from the proper sinus, an abnormal ostial location could be associated with an acute takeoff angle and an intramural segment. This finding is extremely rare but entails the risk of ischemia and sudden death.

Background: The second derivative of the photoplethysmogram (SDPTG) has been verified as a useful method for analyzing pulse wave form in adults; however, there have been few studies on the SDPTG in children. Methods: We examined age-related alteration of SDPTG (study 1) and the SDPTG response to a vasodilator (study 2). The subjects in study 1 were 36 healthy children aged 0.9–16.0 years. The subjects in study 2 were 13 children aged 5.4–18.9 years with a history of Kawasaki disease. Subjects received an i.v. infusion of 0.568 mg/kg dipyridamole. We assessed the SDPTG by d/a ratio, b/a ratio and aging index (AGI). Results: The d/a ratio increased with advance of age (r= 0.636, P < 0.001), and the b/a ratio and AGI decreased with advance of age (r=−0.343, P < 0.05 and r=−0.678, P < 0.001, respectively). The d/a ratio and AGI were correlated with height (r= 0.523, P < 0.01 and r=−0.623, P < 0.001, respectively), but the b/a ratio was not significantly correlated with height. In study 2, the d/a ratio increased significantly (P≤ 0.05), but the b/a ratio and AGI did not alter. Conclusions: The SDPTG indices in children show characteristic alterations with advance of age and react to a vasodilator.

Introduction We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective. Patients and Methods The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed. Results The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ+ T-cell and CD4+ regulatory T-cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation. Conclusion These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.

To identify the origin of urinary leukocytes in Kawasaki disease (KD) patients with pyuria, we prospectively studied clinical and laboratory findings of 23 KD patients. Patients were divided into three groups: patients without pyuria, patients with pyuria in both voided urine and bladder urine obtained by transurethral catheterization (bladder pyuria) and patients with pyuria only in voided urine (urethral pyuria). Pyuria in voided urine was found in ten of 23 KD patients (43.5%), with subsequent urine cultures proving sterile. Five out of ten patients with pyuria in voided urine also exhibited pyuria in bladder urine, whilst the remaining patients did not have pyuria in bladder urine. Urinary protein levels were higher in patients with bladder pyuria and in patients with urethral pyuria than in patients without pyuria. Urinary beta2-microglobulin concentrations and serum blood urea nitrogen (BUN) and creatinine levels were higher in patients with bladder pyuria than in patients with urethral pyuria or in patients without pyuria, although the serum BUN and creatinine levels of patients with bladder pyuria were within the normal ranges. These results suggest that some patients with KD develop sterile pyuria that originates from the urethra and/or the kidney as a result of mild and subclinical renal injury.

In contrast to the atrial septal defect (ASD) as a congenital interatrial shunt, the extracardiac interatrial tunnel is extremely rare. We report the first percutaneous closure of this entity during closure of a secundum ASD after careful investigation of ischemic risk in a 15-year-old girl. The extracardiac interatrial tunnel could entail interatrial shunt, and, if misidentified as an ASD, could result in lethal procedural complications during surgical or catheter interventions. In our case, the tunnel was also morphologically similar to the cardiac arterial/venous system. Therefore, careful investigation of its potential relationship with coronary circulation was required before its closure.

Hypothyroid status is believed to cause various metabolic changes in infants. However, it is interesting that even severely hypothyroid neonates, detected during mass neonatal screening, rarely show bradycardia, hypothermia, or inactivity. To study cardiac functions of screen-detected neonates with congenital hypothyroidism (CH), we recorded the electrocardiograms (ECG) of 53 screen-detected CH neonates before levothyroxine (LT4) replacement therapy, and 15 age-matched normal neonates for controls. The 53 CH neonates were divided into two groups according to initial serum thyroid hormone levels: a mildly hypothyroid group (n = 37), serum thyroid-stimulating hormone (TSH) less than 100 microIU/mL and free thyroxine (FT4) 0.6 ng/dl or more; and a severely hypothyroid group (n = 16), TSH 100 microIU/mL or more and FT4 less than 0.6 ng/dL. TSH, FT4, and other blood chemicals were measured on an autoanalyzer (Hitachi 7170). After blood sampling, the ECG was recorded during induced sleep by oral administration of triclofos sodium syrup. ECG parameters, including HR, PR, QRS, QT time and corrected QT time (QTc) were automatically obtained, using an auto-ECG analyzing system. The following results were obtained. No CH patients showed abnormal ECG findings. There was no significant difference of the mean heart rates (HRs) between the mildly hypothyroid (147.5 +/- 16.3 beats per minute) and the control group (148.3 +/- 12.1 beats per minute). The mean HR in the severely hypothyroid group (134.0 +/- 17.9 beats per minute, p = 0.007) was significantly low compared with the normal control group. However, all values were within normal ranges. QTc in the severely hypothyroid group (0.414 +/- 0.015, p = 0.033) was significantly shorter than in the control group (0.440 +/- 0.052). No statistical differences of PR, QRS, and QT time were noted among the three groups. All ECG parameters were within normal ranges. HR positively correlated with FT4 and log (FT4), and negatively with TSH and log (TSH). From these results we conclude that the deficiency of thyroid hormones does not affect ECG findings of congenitally hypothyroid neonates. This may be consistent with the unexpectedly mild signs and symptoms of screen-detected hypothyroid neonates.

Percutaneous transluminal pulmonary valvuloplasty may be indicated in not only isolated pulmonary valve stenosis, but also complex congenital heart diseases. Because palliative surgery for increasing pulmonary blood flow entails a risk of scar formation and immediate postoperative complications, catheter intervention is preferred, if possible. However, an acute-angled, twisted, or tortuous access route or a small valve orifice occasionally makes it difficult for the catheter to reach or cross the target. We succeeded in performing this intervention for such a complex stenosis effectively and safely in a patient with tricuspid atresia, ventricular septal defect (VSD), and severe pulmonary valve stenosis, thereby evading surgery. In previous reports, the catheter for this cardiac anomaly was accessed via the femoral vein. In the present case, the catheter was advanced through the femoral artery via the aorta, left ventricle, VSD, and right ventricle to the pulmonary valve, using a micro-catheter in a telescopic manner, in combination with a coronary balloon dilatation catheter. This maneuver, which has not been reported previously, made it much easier to perform the procedure as compared to the femoral vein approach, despite the acute turn and the pinhole orifice. Moreover, reported complications of the femoral vein approach, including bradycardia, hypotension, and valve regurgitation, were not observed in this case. We conclude that the femoral artery approach can be a safe and effective alternative in patients for whom a more conventional procedure has been unsuccessful. © 2013 Wiley Periodicals, Inc.

Introduction Adult T-cell leukemia/lymphoma (ATLL) is an aggressive peripheral T cell neoplasm that is resistant to conventional chemotherapy and carries a poor prognosis. The effect of mogamulizumab, an immunoglobulin (Ig) G1 monoclonal antibody targeting CCR4 for ATLL cells, was reported in a previous phase 2 study in which mogamulizumab monotherapy was evaluated in relapsed ATLL patients. The overall response rate (ORR), median progression-free survival (PFS) and median overall survival (OS) were 50%, 5.2 and 13.7 months, respectively. It was not stated whether these values were derived in the real world or in clinical practice. Here we evaluate the clinical impact of mogamulizumab treatment in CCR-4-positive aggressive ATLL patients in clinical practice. Patients and methods We retrospectively analyzed 101 CCR-4-positive ATLL patients who received at least one cycle of mogamulizumab infusion between March, 2012 and April, 2016 in 7 facilities in Miyazaki prefecture, an HTLV-1 endemic area in Southwestern Japan. The ORR, PFS, OS and adverse effects (AEs) were evaluated. We next compared OS in patients with at least one course of mogamulizumab therapy with that in historical control patients without mogamulizumab therapy. Results Of the 101 patients, 92 were evaluable for treatment response, survival and AEs. The median age was 70 years old (range; 45 to 90), and 52 patients (51%) were more than 70 years old. According to Shimoyama's criteria, 66 patients were classified as acute type, 32 as lymphoma type, and 3 as chronic type. All 3 chronic-type ATLL patients had at least one unfavorable risk factor. Of the 101 patients, 96 had refractory or relapsed ATLL when mogamulizumab treatment was started, and the prior treatments consisted of VCAP-AMP-VECP, CHOP, DeVIC or CHASE therapy, with an average of 2 courses. In the 5 remaining cases, mogamulizumab was administered as the initial therapy for ATLL. Mogamulizumab was administered as monotherapy in 87 cases (86%), and as combination therapy with other drugs in 14 cases (14%). The ORR was 37%, including a complete remission rate of 19%. The median PFS and OS were 1.8 and 4.2 months, respectively. Among the 101 patients treated with mogamulizumab, only 26 (26%) fulfilled the inclusion criteria of the phase 2 clinical study. Among patients who met those inclusion criteria, the median PFS and OS were 6.0 and 8.4 months, respectively. The use of mogamulizumab improved OS in clinical practice. The median OS of patients receiving mogamulizumab therapy was 12 months, whereas that of patients who did not receive mogamulizumab in the historical cohort was 8.4 months. Hematologic toxicity and skin rash were the most common AEs, and both were manageable Conclusion Mogamulizumab therapy showed clinically meaningful activity in ATLL patients, with an acceptable toxicity in clinical practice. Disclosures No relevant conflicts of interest to declare.

Background Several coronary artery Z score models have been developed. However, a Z score model derived by the lambda-mu-sigma (LMS) method has not been established. Methods Echocardiographic measurements of the proximal right coronary artery, left main coronary artery, proximal left anterior descending coronary artery, and proximal left circumflex artery were prospectively collected in 3,851 healthy children ≤18 years of age and divided into developmental and validation data sets. In the developmental data set, smooth curves were fitted for each coronary artery using linear, logarithmic, square-root, and LMS methods for both sexes. The relative goodness of fit of these models was compared using the Bayesian information criterion. The best-fitting model was tested for reproducibility using the validation data set. The goodness of fit of the selected model was visually compared with that of the previously reported regression models using a Q-Q plot. Results Because the internal diameter of each coronary artery was not similar between sexes, sex-specific Z score models were developed. The LMS model with body surface area as the independent variable showed the best goodness of fit; therefore, the internal diameter of each coronary artery was transformed into a sex-specific Z score on the basis of body surface area using the LMS method. In the validation data set, a Q-Q plot of each model indicated that the distribution of Z scores in the LMS models was closer to the normal distribution compared with previously reported regression models. Finally, the final models for each coronary artery in both sexes were developed using the developmental and validation data sets. A Microsoft Excel–based Z score calculator was also created, which is freely available online (http://raise.umin.jp/zsp/calculator/). Conclusions Novel LMS models with which to estimate the sex-specific Z score of each internal coronary artery diameter were generated and validated using a large pediatric population.

The masseter muscle of developing male and female mice were stained immunohistochemically with a monoclonal antibody specific to androgen receptors (ral IgG). From day 5 to 20 after birth, very weak reactions were detectable in the nuclei of masseter muscle from male and female mice. With the progression of weaning, the intensity of the reaction increased gradually in the muscle from both males and females. On the 30th postnatal day, a relatively strong reaction was observed in the masseter muscles, and by postnatal day 40 the reaction became much stronger. No sexual difference in the intensity of the reaction to androgen receptors was observed

The effects of progesterone (Pro), 5 alpha-dihydrotestosterone (DHT), 17 beta-estradiol (E2), T3, and dexamethasone (Dex), given alone or in combination, on induction of epidermal growth factor (EGF) and proteinase isozymes in the submandibular glands of hypophysectomized mice were examined. Each hormone, except E2, acting alone had essentially comparable inductive effects on EGF concentrations and on total proteinase activity. E2 alone had no inductive effect at all. Pro acted synergistically with T3, but its inductive effect was diminished when given with Dex. E2 was not synergistic with T2, and it inhibited the effect of Dex; it also partially blocked the action of DHT on induction of proteinase activity but not of EGF. Simultaneous administration of all five hormones restored total proteinase activity completely but EGF levels to only 50% of values for intact males, respectively. Submandibular proteinases were resolved by isoelectric focusing into four isozymes: proteinase F (pI 4.8), proteinase D (pI 5.8), proteinase A (pI 6.2), and proteinase P (pI 10.0). Pro alone slightly increased levels of proteinase F but greatly raised levels of the other three isozymes. This inductive action was augmented when Pro was given with T3 but blocked when it was given with Dex. E2 alone not only failed to induce any of the isozymes, but even further reduced levels of proteinase F. It also decreased the inductive effects of T3 on these isozymes, and with Dex completely blocked induction of proteinases D, A, and P. E2 plus DHT suppressed proteinase F levels and only induced proteinase A. All five hormones together reestablished the isozyme profile seen in intact males. These results show that Pro by itself is as capable as androgens, thyroid hormone, or glucocorticoid in regulating expression of these submandibular polypeptides, and that its action can be modulated by other pituitary-dependent hormones. In addition, they demonstrate that E2 does not regulate their expression, and that it has an inhibitory effect on the inductive action of other hormones. Last, they indicate that these various hormones may regulate expression of EGF and of each of the individual proteinase isozymes differently.

An established pulp cell line (RPC-C2A) was used to study the regulatory effect of insulin on dentinogenesis. Insulin increased alkaline phosphatase activity and the incorporation of [2,3-3H]-proline into collagenase-digestible protein, whereas [3H]-thymidine incorporation by the cells was inhibited by insulin. The enhancing effect of insulin on alkaline phosphatase activity was inhibited by epidermal growth factor (EGF) or transforming growth factor-beta (TGF-beta). The stimulatory effect of insulin on collagen synthesis was also inhibited when insulin was combined with EGF, but was accelerated by the addition of TGF-beta. Inhibitory effects of insulin on the [3H]-thymidine incorporation were potentiated by EGF, though EGF alone strongly increased the effect; whereas the addition of TGF-beta had no significant effect on the insulin action. These findings suggest that insulin may be concerned with the differentiation of pulp cells in dentinogenesis and that EGF or TGF-beta regulate the insulin effects.

The effects of androgen, glucocorticoid, and thyroid hormones on levels of proteinase isozymes and epidermal growth factor (EGF) in the submandibular glands of hypophysectomized (Hypox) mice were investigated. Total proteinase activity in males was decreased by hypophysectomy and increased by single or combined injection of the three hormones into these mice. 5 alpha-Dihydrotestosterone (DHT) had the strongest effect, and dexamethasone (Dex) the least. By isoelectric focusing, proteinases extracted from the submandibular gland of untreated male and female mice were fractionated into four isozymes with pI values of 4.8 (proteinase-F), 5.8 (proteinase-D), 6.2 (proteinase-A), and 10.0 (proteinase-P). In Hypox mice (both sexes), there was only a single isozyme, proteinase-F. Proteinase-D, -A, and -P were induced in the submandibular gland of Hypox males by injections of DHT, Dex, and/or T3; the percent ratio of activity of each of these isozymes induced by these hormones, given either singly or in combination, was almost parallel among the three isozymes. Synergistic effects were observed between T3 and Dex, and additive effects between T3 and DHT. The increase in proteinase isozyme activities by concomitant injections of T3 and Dex was about 2 times more than the additive values. The changes in proteinase-F upon hormone injection were complicated. In females, the enzyme activity was decreased by hypophysectomy and increased by DHT administration. In males, on the other hand, it was increased by hypophysectomy and suppressed by T3 or T3 plus steroid hormones. The EGF level in the submandibular gland was decreased to about 1/800th (males) or 1/90th (females) of its normal level by hypophysectomy. Its level in the Hypox animal was greatly increased by all three hormones, given singly or in combination. Synergism was also observed between T3 and steroid hormones; DHT plus T3 and T3 plus Dex induced EGF 6 times and 9 times, respectively, more than the additive values. These values were much greater than those for the induction of proteinase-D, -A, and -P by combined injections of T3 and steroids. The present results suggest that the genes coding for proteinase-A, -D, and -P are located close to each other and that the onset of their expression may be controlled by the same regulatory mechanism. By contrast, the gene for proteinase-F may be mapped to a different locus or regulated differently. The mechanism of induction of EGF by T3, DHT, and Dex appears to be similar to but not completely the same as that for proteinase-D, -A, and -P.

発育中のラットの実験的骨創傷の治癒と発育に対するtestosterone propionate (TP) の影響とTPに対するcyproterone acetate (CPA) の拮抗作用を検討した。ラットの睾丸を3週齢で除去し, 1週間後に頭頂骨に創傷孔を形成し, TP (1, 2, 5mg/kg) およびCPA (5, 10, 20, 40mg/kg) の単独または併用 (TP 1mg/kg+CPA 10mg/kg, TP 2mg/kg+CPA 20mg/kg) 2週間皮下投与を行い, 体重, 頭頂骨創傷孔面積, 大腿骨長径および臓器重量を測定した。また, TP2mg/kgおよびCPA20mg/kgの単独・併用投与についてはさらにcalcium (Ca) 量, hydroxyproline (HP) 量を測定した。その結果, 1) 睾丸除去群は非除去群に比較して有意に体重が減少し, TP投与群では用量依存的な体重の増加がみられ, CPA投与群では10, 20, 40mg/kgで逆に有意の減少がみられた。TP+CPAの併用投与群ではCPAはTPの作用に拮抗した。2) 骨創傷孔面積の縮小は睾丸除去後, 非除去群に比べて有意に遅延し, TP投与は創傷孔面積の縮小を用量依存的に促進し, 睾丸除去による創傷治癒遅延を有意に抑制した。3) TPの競合拮抗薬であるCPAの単独投与は高用量で創傷孔面積縮小促進が有意にみられた。TPとの併用によりCPAはTPの抑制作用に拮抗傾向を示し, 睾丸除去群の値に近ずいた。4) 睾丸除去群は非除去群に比較して有意に大腿骨長径の発育が遅延し, TP投与群では長径の発育の促進がみられ, 特に2および5mg/kgで著しかった。TP+CPAの併用投与群ではCPAはTPの作用に拮抗した。5) 頭頂骨創傷部のHP量は睾丸除去により有意に減少し, TP投与によりこの減少は抑制され, CPAはTPの作用に拮抗した。同様の傾向はCa量および頭頂骨非創傷部のHP量およびCa最でもみられたが, 創傷部HP量の変化ほど明瞭ではなかった。6) 前立腺, 精嚢, 肛門挙筋のいずれの相対湿重量も睾丸除去による減少, TPによる増加, CPAのTPに対する拮抗作用が明瞭に認められた。以上のことから, 骨創傷治癒および発育にTPは促進的に働き, CPAはagonistantagonistとしての作用をもつことが示唆された。

発育中ラットの頭頂骨に形成した創傷孔の治癒と大腿骨の発育におよぼすdexamethasoneとindomethacinの影響を調べた。薬物は0.5, 1, 2mg/kgを日曜日を除く1日1回, 1, 2または4週間皮下投与し, 頭頂骨はalizarin red S染色を行って創傷孔部分の非染色部を未石灰化部としてその面積を測定した。また, 大動脈にIndia inkを注入して創傷孔の血管の再生状態を観察した。また, 軟X線写真を撮影してフィルム上の大腿骨の長径と幅径を測定し, 大腿骨のフィルム上の黒化度をmicrodensitometerで判定した。その結果, 1. Dexamethasone, indomethacinはともに創傷孔未石灰化面積の縮小を遅延するが, その作用は前者の方が強かった。2. Dexamethasone 1週間投与では創傷孔中の血管の新生をあまり抑制しなかったが, その後の骨の再生にともなう血管量の正常な減退がdexamethasone2週間投与で強く抑制されたことから, daxamethasoneは血管の再構築を抑制して骨の再生・創傷治癒遅延を起こしていることが考えられる。Indomethacinではその作用が弱かった。3. 大腿骨の長径と幅径の発育は, dexamethasone投与によって著しく抑制され, indomethacinの作用は弱かった。大腿骨の発育にともなう軟X線写真フィルムの黒化度の低下は, 両薬物によって明瞭に抑制された。さらにdexamethasone2週間投与では黒化度の高進がみられたが, indomethacinではみられなかった。これらの結果は, 骨創傷治癒と骨発育におけるdexamethasoneの遅延作用はindomethacinのそれより強く両薬物の作用動態度もやや異なることを示していると考えられる。

Although hyponatremia frequently occurs in Kawasaki disease (KD), the clinical characteristics of KD patients with hyponatremia and the pathogenesis of hyponatremia in KD remain unknown. The aims of this study were to define the clinical characteristics of KD patients with hyponatremia (serum sodium

The effects of procaine, Ca, Mg and K on the release of transmitter from the cholinergic sweat nerve endings in the forearm skin were studied. Sweating was visualized by the iodine-starch method of Wada and Takagaki. At a concentration of 10-7, intradermal injections of eserine did not produce a local sweating in a cool environment, but they became effective in eliciting sweat response on the injection wheals by entering a warm or hot environment. Local sweat responses to eserine in 10-6 and 10-5 were also intensified on exposure to heat. Procaine in 10-4 inhibited the sweat responses to eserine very probably by affecting the acetylcholine release from the sweat nerve endings. It was found that Ca ions contained in Krebs solution are important in the process of the acetylcholine release and excessive Ca facilitates this release. In contrast, Mg and K ions present in Krebs solution were without any effect. But, when Mg was in excess relative to Ca, it was observed that Mg antagonized the effect of Ca. The antagonism between Mg and Ca was demonstrated also in the case of spontaneous thermoregulatory sweating. The effect of Ca on the acetylcholine release seems to be antagonized by Mg in a ratio of approximately 1:2 in molality.

Esteroprotease, an androgen-dependent enzyme of the mouse submandibular gland, was increased by injection of tri-iodothyronine (T3) in mice with testicular feminization (Tfm) which are genetically deficient in androgen receptors. Histochemical and electron microscopic studies also demonstrated increases of RNA and serous-like granules in cells of the convoluted tubules of the gland. These findings suggest that the esteroprotease gene in Tfm mice is normal and that T3 can induce both esteroprotease and serous-like granules independently of androgen.

The administration of cortisol acetate and dexamethasone to castrated–adrenalectomized mice increased the submandibular gland weight, the granular duct cell size of the gland and the number of androgen-dependent granules detected with the staining for tryptophan in the duct cell. These changes were not as pronounced as when testosterone propionate was given. Similar effects on the duct cells and an increase in androgen-dependent esteroprotease activity of the submandibular glands were observed in castrated mice, but not in mice with testicular feminization which are genetically deficient in androgen receptors. These results suggest that glucocorticoids exert a certain degree of androgenic action on the granular duct cell through androgen receptors when androgens are absent or deficient.

The area of wound holes made in the parietal bone of 4-week-old rats was measured at 1, 2 and 4 weeks after the operation using Alizarin red S staining without the use of histological sections. Dexamethasone and indomethacin were administered s.c. after the operation every day except Sunday. The inhibitory action of dexamethasone on bone wound healing was stronger than that of indomethacin, as was its inhibitory action on skin wound healing. Inhibition of the age-related decrease in radiolucency of femurs and some changes in serum calcium level were also observed by dexamethasone administration, but not by indomethacin. These results suggest that dexamethasone inhibits bone wound healing through its effects on calcium metabolism in addition to its general inhibitory action on wound healing which is shared with indomethacin. Dexamethasone also strongly inhibited the decrease in Alcian blue stainability which occurs with an increase in age, both in the normal portion and in the wound hole portion of the calvaria, whereas indomethacin showed a weak inhibitory effect only in the wound hole portion. This result suggests that one of the mechanisms by which dexamethasone inhibits bone wound healing may be based on the retardation of mineralization caused by the inhibition of removal of acid mucopolysaccharide.

1) 6-Ketoprogesterone (6 kp) can not demonstrate the progestin effects by Hooker-Forbes' method.2) 6Kp has little androgenic and estrogenic action.3) 6Kp has myotrophic (anabolic) action almost as strong as progesterone.4) 6Kp has the hypertrophic action on the preputial gland which is almost equivalent to that of 17 (α)-hydroxyprogesterone, 17 (α)-methyl-Δ5-androstene-3 (β)-17 (β)-diol.5) 6Kp (large dose), has depressant effect on the central nervous system, resembling progesterone in variation with sex and lack of excitation at the induction of anesthesia, displays one-sixth to one-seventh of its potency.6) The spinal reflex is accelerated by 6kp similar to progesterone.7) 6kp has little influence on blood pressure.8) The steroid, which is produced in the placenta and which has myotrophic, anabolic action and hypertrophic effect on the preputial gland without androgenic action, is possibly 6kp or its related compound.9) The vaginal smear cycle in the rat is under the control of estrogen and progesterone.

The effects of thyroid hormone, androgen, glucocorticoid, and mineralocorticoid on Na+,K+-ATPase activity and on levels of its alpha-subunit protein (alpha 1 isoform) in mouse submandibular gland (SMG) were studied by enzyme assay for ouabain-sensitive ATP hydrolysis, by quantitative densitometric scanning of Western blots, and by immunohistochemistry. To define the specific regulatory effects of various pituitary-dependent hormones on expression of Na+,K+-ATPase in the SMG, we treated hypophysectomized (hypox) male mice with triiodo-L-thyronine (T3), 5 alpha-dihydrotestosterone (DHT), dexamethasone (Dex), and aldosterone (Ald), injected singly or in combination. Na+,K+-ATPase was confined to the duct system of the SMG. In intact mice there was a gender difference in SMG Na+,K+-ATPase, with levels of the enzyme's activity and of its alpha 1-subunit being less in the glands of males. In males, hypophysectomy caused a rise in levels of Na+,K+-ATPase activity and in levels of the alpha 1-subunit protein of this enzyme, and in intensity of immunocytochemical staining for this subunit but there were no such changes in the SMG of hypox females. Changes caused by hormonal replacement to hypox males in Na+,K-ATPase activity, levels of its alpha 1-subunit, or the intensity of immunocytochemical staining for this subunit were complex. Ald had no effect. T3 or dexamethasone, given alone, induced Na+,K+-ATPase activity above control values (hypox males) and increased levels of its alpha 1-subunit protein and immunohistochemical staining for this subunit. By contrast, DHT did not cause a decline in any of these parameters. However, when treatment with T3 was combined with administration of Dex or DHT, enzymatic activity of Na+,K+-ATPase decreased but levels of the alpha 1-subunit protein and immunohistochemical staining for this subunit increased. Therefore, inductions of the alpha 1-subunit of this enzyme are not always correlated with increases in levels of activity of Na+,K+-ATPase, and we propose that both enzymatic and immunochemical analyses are essential for evaluation of hormonal regulation of Na+,K+-ATPase in salivary gland and in other tissues.