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Objective: To determine clinical features of very low birth weight infants (VLBWIs) who had developed epilepsy by age 3 years., Study Design: Multicenter cohort study using the Neonatal Research Network of Japan database. We analyzed clinical variables of 8431 VLBWIs who had recorded data of neurological sequelae at age 3 years. Logistic regression identified the association between variables and development of epilepsy., Result: One hundred and forty-three (1.7%) infants developed epilepsy, 683 (8.1%) showed cerebral palsy (CP), and 1114 (13.2%) had psychomotor delay. Epilepsy was associated with history of sepsis [adjusted odds ratio (AOR) 3.23], severe intraventricular hemorrhage (IVH; AOR 5.13), and cystic periventricular leukomalacia (PVL; AOR 12.7). Severe IVH and cystic PVL were also frequently associated with CP and psychomotor delay., Conclusion: Severe IVH and cystic PVL are strongly associated with development of epilepsy, as well as other neurological sequelae, and are potential critical therapeutic targets.

Background: To investigate the hematological features of infants with bronchopulmonary dysplasia (BPD) and their relationships with clinical severity., Methods: This prospective observational study enrolled 73 BPD patients from a total of 331 infants with a birth weight of <1500 g from 2005 to 2013. The clinical severity of BPD was defined by the duration of oxygen supplementation and positive pressure ventilation (PPV) in line with the diagnostic criteria of BPD. The hematological status and cytokine levels were surveyed from blood samples at birth and at 2 and 4 weeks of life., Results: Thirty-four (46.6%) cases were classified as "moderate-to-severe" BPD. Small-for-gestational-age (SGA) was associated with the severity of BPD (OR: 5.05; 95% CI: 1.45 to 17.2). The CRP level at 2 weeks (partial regression coefficient [rc]: 21.8; 4.01 to 39.7) and the neutrophil count at 4 weeks (0.005; 0.001 to 0.007) were positively correlated with the oxygenation period. The PPV period was found to be correlated with the CRP level at 2 weeks (27.2; 14.9 to 39.5), and the neutrophil count (0.003; 0.001 to 0.004) at 4 weeks., Conclusion: The aggravation of BPD was associated with both SGA at birth and inflammation during neonatal period., (Copyright © 2019. Published by Elsevier B.V.)

Abstarct: OBJECTIVE: The diagnosis of neonatal-onset protein C (PC) deficiency is challenging. This study aimed to establish the neonatal screening of heritable PC deficiency in Japan., Study Design: We determined the changes in plasma activity levels of PC and protein S (PS) in healthy neonates, and studied newborn patients with PROC mutation in the Japanese registry., Result: Physiological PC and PS levels increased with wide range. The PC/PS-activity ratios converged after birth. The PC/PS-activity ratios of 19 patients with biallelic mutations, but not, 9 with monoallelic mutation, were lower than those of 13 without mutation. The logistic regression analyses established a formula including two significant variables of PC activity (cut-off < 10%, odds ratio = 30.0) and PC/PS-activity ratio (cut-off < 0.35, odds ratio = 22.7), with 93% sensitivity and 44% specificity for determining patients with mutation(s)., Conclusion: The PC/PS-activity ratio is an effective parameter for the genetic screening of neonatal-onset PC-deficiency in Japanese population.

To investigate if ipragliflozin, a novel sodium-glucose co-transporter 2 inhibitor, alters body composition and to identify variables associated with reductions in visceral adipose tissue in Japanese patients with type 2 diabetes mellitus. This prospective observational study enrolled Japanese participants with type 2 diabetes mellitus. Subjects were administered ipragliflozin (50 mg/day) once daily for 16 weeks. Body composition, visceral adipose tissue volume and plasma variables were measured at 0, 8, and 16-weeks. The subjects' lifestyle habits including diet and exercise were evaluated at baseline and 16 weeks. The primary endpoint was defined as the decrease of visceral adipose tissue mass. Twenty-four of 26 enrolled participants completed the study. The visceral adipose tissue decreased significantly (110 ± 33 to 101 ± 36 cm(2), p = 0.005) as well as other parameters for metabolic insufficiency including hemoglobin A1c. Seventy-one % of the total body weight reduction (-2.49 kg) was estimated by a decrease in fat mass (-1.77 kg), and the remaining reduction (22%) by water volume (-0.55 kg). A minor but significant reduction in the skeletal muscle index was also observed. Correlation analyses were performed to identify variables associated with changes in visceral adipose tissue and the only significant variable identified was diet therapy (Spearman's r = -0.416, p = 0.043). Ipragliflozin significantly decreased visceral adipose tissue, and improved parametres for metabolic dysfunction. Adequate diet therapy would be necessary to induce and enhance the therapeutic merit.

To investigate the differences in glycemic variability between the long-acting insulins glargine and degludec using continuous glucose monitoring, we conducted an open-label, multicenter, prospective, observational study that enrolled 21 participants with type 1 diabetes mellitus currently receiving basal-bolus insulin therapy with glargine. To avoid the potential influence of diet and exercise on glycemic control, all participants were housed and monitored within the hospital for the duration of the study. Once glycemic control was achieved with glargine, glycemic variability was evaluated using continuous glucose monitoring for 3 days. Glargine was then replaced by degludec and glycemic variability again assessed via continuous glucose monitoring. The primary outcome measure of mean amplitude of glycemic excursions was significantly reduced with degludec (p = 0.028), as was area under the curve for daily blood glucose level <70 mg/dL (p = 0.046). The required insulin dose was reduced up to 25% in the degludec group, although 24-h mean glucose concentrations were not different between groups. In conclusion, once or twice daily glargine was successfully replaced by a daily injection of degludec. When replacing glargine with degludec, a lower dose should be utilized to avoid hypoglycemia. Degludec is an effective and promising long-acting insulin that reduced hypoglycemia and daily blood glucose variability in participants with type 1 diabetes.

Background: The early diagnosis of inherited thrombophilia in children is challenging because of the rarity and hemostatic maturation., Methods: We explored protein C (PC), protein S (PS), and antithrombin (AT) deficiencies in 306 thromboembolic patients aged ≤20 y using the screening of plasma activity and genetic analysis., Results: Reduced activities were determined in 122 patients (40%). Low PC patients were most frequently found in the lowest age group (0-2 y, 45%), while low PS or low AT patients were found in the highest age group (16-20 y; PS: 30% and AT: 20%). Genetic study was completed in 62 patients having no other causes of thromboembolism. Mutations were determined in 18 patients (8 PC, 8 PS, and 2 AT genes). Six of eight patients with PC gene mutation were found in age 0-2 y (75%), while six of eight patients with PS gene mutation were in 7-20 y. Two AT gene-mutated patients were older than 4 y. Four PC-deficient and two PS-deficient patients carried compound heterozygous mutations. All but one PC gene-mutated patient suffered from intracranial thromboembolism, while PS/AT gene-mutated patients mostly developed extracranial venous thromboembolism., Conclusion: Stroke in low PC infants and deep vein thrombosis in low PS/AT school age children could be targeted for genetic screening of pediatric thrombophilias.

For the purpose of establishing a new adoptive immunotherapy for bile duct carcinoma (BDC), we have directed our attention to superantigens (SAgs), the most potent known activators of T lymphocytes. In our previous study, staphylococcal enterotoxin A (SEA) was conjugated chemically with MUSE11 mAb, which recognizes the MUC1 cancer-associated antigen, and shown to enhance the specific cytotoxic activity of T-LAK cells against MUC1-expressing BDC cells (TFK-1) in vitro and in vivo. However, it is probable that SEA might cause side-effects because of nonspecific binding to class II positive cells. In order to overcome these, we generated mutated SEA (mSEA) by changing Asp at position 227 of native SEA to Ala, which has reduced affinity to MHC class II molecules, but retains the potential for T cell activation. When mSEA-D227A was administered to rabbits to examine effects on blood pressure, 500 times more mSEA-D227A was tolerated than native SEA. This prompted us to construct a mSEA-D227A-conjugated mAb, reactive with MUC1. It augmented the antitumor activity of T-LAK cells significantly, and furthermore, mSEA-D227A could be conjugated to two bispecific antibodies, BsAb (anti-MUC1 x anti-CD3) and BsAb (anti-MUC1 x anti-CD28), which in combination had greater enhancing effects than mSEA-D227A-conjugated anti-MUC1 mAb, and combination of unconjugated BsAbs. These findings indicate a utility of mSEA-D227A-conjugated antibodies for targeted cancer immunotherapy.

In order to enhance cell mediated cytotoxicity, bispecific antibodies (BsAbs), molecules combining two or more antibodies with different antigenic specificities, have been developed as new agents for immunotherapy. Our recent studies revealed that simultaneous administration of two kinds of BsAbs (anti-tumor x anti-CD3 plus anti-tumor x anti-CD28) together with lymphokine activated killer cells with a T cell phenotype (T-LAK cells) inhibited growth of human xenotransplanted tumors in severe combined immunodeficient (SCID) mice, while single BsAb was without effect. Three kinds of BsAbs (anti-tumor x anti-CD3, anti-tumor x anti-CD28, anti-tumor x anti-CD2) showed the highest cytotoxicity against tumor cells when given simultaneously with T-LAK cells or peripheral blood mononuclear cells in vitro and in vivo. BsAbs can be preserved for immediate application, while cytotoxic T lymphocytes (CTLs) must be made-to-order, and are time-consuming to prepare. Tumor associated antigens, such as MAGE antigens, SART antigens, MUC1 antigen, c-erbB 2 antigen or cancer/testis antigens can be served to target antigens for BsAb production. By conjugation with antibodies to effector cells (anti-CD3, anti-CD28, anti-CD16, anti-CD64, anti-CD89 or anti-CD2), many kinds of BsAbs can be produced to cover most types of cancers from different organs. Therefore this strategy might be ubiquitously applicable to most malignancies.

Wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) injection into the facial nerve of the cat resulted in retrograde labeling in the geniculate and jugular ganglia ipsilaterally. Labeled fibers were found to enter into the brain stem through the intermediate and vagal nerves. These fibers ascended or descended into the dorsal portion of the spinal trigeminal tract and were distributed to the principal sensory nucleus of the trigeminal nerve, marginal layer of the interpolar part of the spinal trigeminal nucleus, nucleus of the solitary tract and ventrolateral portion of the cuneate nucleus. It was of particular interest in the present study that the intensive labeling was present in the medial portion of laminae I-IV of the upper cervical spinal cord. The immunohistochemical study revealed a lot of substance P-immunoreactive neurons in the geniculate and jugular ganglia, and heavy accumulation of immunoreactive fibers in laminae I-II of the upper cervical spinal cord.

Serial 30 microns-thick sections through the midbrain tegmentum were stained with cresyl violet. The PL was found to be situated along the medial edge of the lateral lemniscus. The PL consisted of small- (10-15 microns) and medium-sized neurons (25-35 microns), and was the most prominent at the caudal level of the superior colliculus. In order to confirm the existence of the inhibitory paralemniscal-facial pathway, a combined HRP and immunohistochemical technique was use in the rat. This experiment revealed that 10.9% of the total number of GABA immunoreactive PL neurons also labeled with HRP after HRP injection was made in the medial part of the facial nucleus (FN). Electron microscopic observations were carried out on the medial part of the facial nucleus (FN) after kainic acid injection was made into the contralateral PL in the cat. The majority of degenerating PL fibers were ranged from 0.5 to 3.1 microns in diameter and made synaptic contacts with somata, proximal dendrites and dendritic profiles. These fibers, containing either round or pleomorphic vesicles, formed asymmetrical or symmetrical synapses. It was of particular interest in the present study that 40.7% of the total number of degenerating fibers make synaptic contacts with large dendrites more than 3.0 microns in diameter.

Exercise tests with sublingual nitroglycerin were performed on 7 patients with true positive and 8 patients with false positive exercise test results. Four of 7 patients with true positive changes and 8 patients with false positive changes underwent exercise cardiac scintigraphy. Scintigrams showed perfusion defects in 4 patients with true positive outcomes, and no perfusion defect in 8 patients with false positive outcomes. Exercise tests with sublingual nitroglycerin were performed with the same load as that without nitroglycerin. In all 7 patients with true positive exercise test results, ST segment depression observed in the control exercise test was not observed in the nitroglycerin exercise test. In the false positive patients, ST segment depression observed in the control exercise test remained unchanged in 7 of 8 patients receiving nitroglycerin. Exercise tests with sublingual nitroglycerin as well as exercise cardiac scintigraphy are valuable tods in differentiating false positive from true positive patients. Furthermore, these data suggest that ST segment depression in the false positive patients may not be related to myocardial ischemia.