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Introduction: Immune tolerance induction (ITI) was the primary therapeutic approach to eradicate inhibitors in haemophilia patients. Several large ITI registries had been reported, but successful predictors of ITI outcome are still debated. No reports are available on large ITI studies in non‐caucasian countries. Aim: We designed a retrospective cohort study of ITI in Japanese haemophilia patients with inhibitor. Methods: Retrospective data were collected from 155 haemophilia (H)A (140 severe‐type) and 7 HB (7 severe‐type) patients treated at 45 institutions. ITI outcome was centrally reviewed. We defined “success” as undetectable inhibitor after 2 consecutive measurements. Results: The ITI success rate was 71.2% for HA and 83.3% for HB. Cumulated success rates for HA achieving 50% and 75% were 0.7 and 2 years after treatment, respectively. Significant successful predictors in HA were low‐responding inhibitors compared to high‐responding inhibitors, shorter time to the start of ITI, and lower historical and treatment peak titres of inhibitor. Dose regimen (high dose; ≥90 IU/kg every day, low dose; ≤75 IU/kg, 3 d/wk) and the type of therapeutic product did not affect outcomes. The success rate of salvage ITI using von Willebrand factor‐containing factor VIII was 50% (n = 6/12), and patient age at the start of salvage ITI was a significant predictor. The inhibitor recurred in 6 HA cases (3.9%). Conclusion: The results provided potentially important information for improving future success rates for ITI in inhibitor patients. [ABSTRACT FROM AUTHOR]

Introduction MC710, a 1:10 protein weight ratio mixture of plasma-derived activated factor VII ( FVIIa) and factor X ( FX), is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. We evaluated the haemostatic efficacy and safety of one to two administrations of MC710 in 21 joint, muscle, and subcutaneous bleeding episodes in 14 male patients, in a multi-centre, open-label, non-randomized clinical trial. Methods Subjects were intravenously administered one or two doses of 60 or 120 μg kg−1 MC710 (as FVIIa) once or twice (to a maximum of 180 μg kg−1) over up to five bleeding episodes per subject. The haemostatic efficacy of MC710 was determined for each episode by investigator evaluation, using changes in visual analogue scale ( VAS) for pain relief, and/or knee joint or muscle circumference for swelling reduction, and range of motion ( ROM) for improvement of joint mobility. Results In 21 treatments for bleeding episodes, 19 were rated 'excellent' or 'effective' 8 h after the last treatment. VAS significantly decreased over time, and ROM significantly improved over time compared with the values before treatment. One mild adverse reaction, decreased blood potassium, and two serious adverse events, both knee joint bleeding, were observed within 1 week after first administration, with no significant effect on safety. Furthermore, diagnostic markers did not show any signs of disseminated intravascular coagulation ( DIC). Conclusion These results show that MC710 has sufficient haemostatic efficacy and safety, and can be used as a potential bypassing agent to control bleeding in haemophilia patients with inhibitors. [ABSTRACT FROM AUTHOR]

Aim: To obtain a better understanding of the changes in feeding behaviour from 1 to 6 months of age. By comparing breast- and bottle-feeding, we intended to clarify the difference in longitudinal sucking performance.Methods: Sucking variables were consecutively measured for 16 breast-fed and eight bottle-fed infants at 1, 3 and 6 months of age.Results: For breast-feeding, number of sucks per burst (17.8 +/- 8.8, 23.8 +/- 8.3 and 32.4 +/- 15.3 times), sucking burst duration (11.2 +/- 6.1, 14.7 +/- 8.0 and 17.9 +/- 8.8 sec) and number of sucking bursts per feed (33.9 +/- 13.9, 28.0 +/- 18.2 and 18.6 +/- 12.8 times) at 1, 3 and 6 months of age respectively showed significant differences between 1 and 6 months of age (p < 0.05). The sucking pressure and total number of sucks per feed did not differ among different ages. Bottle-feeding resulted in longer sucking bursts and more sucks per burst compared with breast-feeding in each month (p < 0.05).Conclusion: The increase in the amount of ingested milk with maturation resulted from an increase in bolus volume per minute as well as the higher number of sucks continuously for both breast- and bottle-fed infants. [ABSTRACT FROM AUTHOR]

Summary. Studies conducted in European and North American countries have demonstrated that various factors including races affect the frequency of inhibitor formation in haemophilia patients. The present study was undertaken to analyse factors affecting the incidence of inhibitor formation in Japanese haemophilia A and B patients. Analytical data were retrospectively collected from haemophilia A and B patients born after 1988, the year when monoclonal antibody-purified factor VIII products were first marketed in Japan. Various data were collected from 184 patients (153 cases of haemophilia A; 31 cases of haemophilia B). The sample size of haemophilia B cases was too small to reveal any significant differences between the inhibitor formation group and the inhibitor-free group in any of background variables. For patients with haemophilia A, on the other hand, univariate analysis identified the severity of haemophilia and a positive family history of inhibitor development as risk factors for the formation of inhibitors. In analyses of the clotting factor products used, the incidence of inhibitor formation did not differ significantly between the group treated with plasma-derived products (29.7%) and the group treated with recombinant products (25.0%). When background variables were compared, age was higher in the group treated with plasma-derived products but none of the other background variables differed between the two groups. These results suggest that in Japanese haemophilia patients, the type of clotting factor preparations used for therapy has not influenced the incidence of inhibitor formation. [ABSTRACT FROM AUTHOR]

We conducted a questionnaire survey of haemophilia treaters participating in the Fourth Seminar on Regular Replacement Therapy (sponsored by Baxter Bioscience, 4 March 2006) to clarify the current status (up to January 2006) of replacement therapy for haemophilia. The haemophilia treaters including medical doctor, nurse belonged to 48 institutions located in the 23 prefectures of Japan. Topics included age at the initiation of regular replacement therapy (prophylaxis), and expected future situation of patients who are currently receiving prophylaxis. Data were collected from 1267 patients with haemophilia A and 273 patients with haemophilia B who had been treated at the represented institutions. Of these haemophilia A and B patients, 23% and 16% had received a prophylactic treatment regimen respectively. A breakdown of each disease by severity demonstrated that of the patients with severe haemophilia A and B patients, 27% and 18% of patients received a prophylaxis treatment, compared to 17% and 19% of patients with moderate type, and 1% and 3% of patients with mild type respectively. Of those severe haemophilia A and B patients receiving prophylaxis, the percentage of primary prophylaxis, which means prophylaxis begins under 2 years of age, was still small for 24% and 29% respectively. However, approximately half of the patients received prophylaxis during the age of 2–14 years, which suggests that secondary prophylaxis is widely spread in the age group in Japan. Problems in introduction of prophylaxis include difficulty in peripheral venous access, a lack of understanding of the therapy by the caregiver. In addition, the fear of inhibitor development, as well as the psychological anxiety in paediatric patients, was also mentioned as barriers to initiating and continuing prophylaxis . [ABSTRACT FROM AUTHOR]

Background: Proton pump inhibitors (PPIs) are widely used to treat gastro-oesophageal reflux disease (GORD). However, the onset of action is considered slow and PPIs cannot completely block acid secretion at night. A new potassium-competitive acid blocker (P-CAB) can rapidly block acid secretion. However, whether this P-CAB can relieve GORD symptoms quickly and adequately soon after starting treatment is unknown., Aim: To determine how rapidly vonoprazan and lansoprazole provide heartburn relief., Methods: Patients (n = 32) with endoscopically confirmed erosive oesophagitis who experienced heartburn at least once a week were randomised in a double-blind manner to receive either daily vonoprazan (20 mg) or lansoprazole (30 mg) before breakfast for 14 days. Day time and night time heartburn were assessed daily throughout the study using a five-point Likert scale. The primary endpoint was the first day of complete day and night heartburn relief for at least seven consecutive days. The ethics committees of the participating institutions approved the study protocol., Results: Heartburn was relieved sooner with vonoprazan than with lansoprazole (P < 0.05, log-rank test). Heartburn was completely relieved in 31.3% and 12.5% of patients on day 1 with vonoprazan and lansoprazole, respectively. Significantly more patients achieved complete nocturnal heartburn relief with vonoprazan than lansoprazole (P < 0.01). Both regimens were well tolerated., Conclusions: Complete sustained heartburn relief was achieved sooner with vonoprazan than with lansoprazole during the first week of therapy. (UMIN000018776)., (© 2018 John Wiley & Sons Ltd.)

Quantitative PCR (qPCR) of human T-cell leukemia virus type 1 (HTLV-1) provirus is used for HTLV-1 testing and for assessment of risk of HTLV-1-related diseases. In this study, a reference material was developed for standardizing HTLV-1 qPCR. Freeze-dried TL-Om1 cells diluted with Jurkat cells were prepared and an assigned value for proviral load (PVL) of 2.71 copies/100 cells was determined by digital PCR. Nine Japanese laboratories using their own methods evaluated the PVLs of this reference material as 1.08-3.49 copies/100 cells. The maximum difference between laboratories was 3.2-fold. Correcting measured PVLs by using a formula incorporating the assigned value of this reference material should minimize such discrepancies., (© 2018 The Societies and John Wiley & Sons Australia, Ltd.)

Aim: The aim of this study was to predict the neurological prognosis of very low birthweight (VLBW) infants. We examined the relationship between nutritional status, brain volume measured by magnetic resonance imaging (MRI) and anthropometric measurements of VLBW infants at term-equivalent age (TEA)., Methods: We evaluated 27 VLBW infants, born at Showa University Hospital in Japan between April 2012 and August 2013, who underwent brain MRI at TEA. Based on their clinical data, we analysed their protein and energy intake., Results: Median values for the 27 VLBW infants were as follows: gestational age, 29.7 weeks; birthweight 1117 g; protein intake 2.7 g/kg/day and energy intake 97.9 kcal/kg/day. At TEA, the standard deviation scores (SDSs) of body weight, body length and the occipitofrontal circumference (OFC) were -0.8, -1.4 and 0.7, respectively. Multiple regression analysis revealed that the SDSs of body length and the OFC at TEA were significant determinants of white matter volume, but that the SDS of body weight at TEA was not., Conclusion: Our findings suggest that the SDSs of body length and the OFC at TEA may be better indicators than body weight for predicting the development of the central nervous system in VLBW infants receiving nutritional management., (©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Aim: Mother's milk is optimum for preterm infants, but human milk fortifier is required at times, because some nutrients are sometimes insufficient for infant growth. It is important to measure the nutrients in breast milk at bedside so that the amount of nutrients that need to be supplemented can be determined. A human milk analyser (HMA, Miris) is currently available. We examined if the macronutrient values measured by human milk analyser are comparable with those measured by conventional methods. We also sought to discover whether we could dilute the milk sample used for the human milk analyser measurement if the amount of milk available for testing was insufficient., Subjects and Methods: First, the results of protein, fat and lactose content in breast milk samples obtained using the human milk analyser and conventional methods were compared. Second, we measured diluted samples and compared the values with nondiluted samples., Results: When comparing the human milk analyser and conventional methods, all three nutrients exhibited a significantly positive correlation (p < 0.001); lactose content was reliable on the condition that it is 6-7 g/dL. The lactose content measured by the HPLC method was obtained by 3.05 x human milk analyser value - 13.4. When comparing diluted and nondiluted samples, fat and protein had expected values after dilution whereas lactose did not., Conclusion: The human milk analyser can inform us about the amount of major nutrients in breast milk: fat, protein and lactose. However, when human milk is diluted, the lactose content measured by the human milk analyser is overestimated.

Aim: To determine if the degree of attachment affects uniformity in the drainage of breast milk from mammary lobe during breastfeeding., Methods: Thirty-seven pairs of healthy breast-fed infants and mothers were the subjects. A total of 48 measurements were obtained. Foremilk was obtained from three nipple openings. After the breastfeeding session, hindmilk was sampled from the same three nipple openings and creamatocrit (CrCt) was measured. The difference in CrCt values of hindmilk, which corresponds to the degree of emptying of the lobe, and the difference in CrCt values between fore- and hindmilk samples (delta CrCt), which corresponds to the change in the degree of emptying among the lobe were calculated., Results: The maximum difference in the CrCt value of hindmilk samples among nipple ducts was 7.0 +/- 4.1% in the shallow attachment (S) group (n = 23) and 2.9 +/- 1.2% in the deep attachment (D) group (n = 25) in the left breast and 5.4 +/- 2.2% in the S group (n = 21) and 3.6 +/- 1.9% in the D group (n = 27) in the right breast. The mean maximum difference in delta CrCt values among nipple ducts was 7.6 +/- 2.9% and 2.6 +/- 1.3% in the left and 5.8 +/- 2.3% and 3.4 +/- 1.4% in the right breast, in the S group and D group, respectively. These differences were significantly smaller in the D group than the S group (p < 0.01)., Conclusion: The results revealed that deep attachment is helpful in draining milk from all mammary lobe uniformly, which may contribute to successful breastfeeding.

Background: Human telomerase reverse transcriptase (hTERT) is catalytic subunit of human telomerase., Methods: We studied the immortalization of a series of human dental and periodontal cells by ectopic expression of hTERT and co-expression of hTERT with human papilloma virus 16 (HPV16) or simian virus 40 (SV40). Differentiation abilities of the established cell lines were studied in terms of the mineralized matrix formation and gene expression., Results: We established immortalized gingival fibroblasts by hTERT, dental papilla and periodontal ligament cells by hTERT and HPV16, and pulp cells by hTERT and SV40. The papilla and pulp cells showed mineralization and dentin sialophosphoprotein (DSPP) expression when cultured in the presence of beta-glycerophosphate. The immortalized periodontal ligament cells did not show mineralization or DSPP expression, although expressions of alkaline phosphatase, osteopontin and osteocalcin were detected., Conclusions: These cell lines will be useful tools for studying the repair and regeneration of dental and periodontal tissues and various diseases including odontogenic tumors.

To clarify the clinical implication of a newly discovered 'TT virus (TTV)', we assayed TTV DNA in sera from 50 haemophiliacs by a seminested-PCR. TTV DNA was detected in 75% (35/50), which was a much higher prevalence than for HBV (HBc-Ab), HCV RNA, or HGV RNA. In particular, TTV DNA was found in 44.4% (4/8) of patients who had been treated only with virally inactivated factor VIII concentrates. Elevated ALT levels were observed in patients with HCV RNA and TTV DNA; however, the elevation in TTV DNA was obtained from patients co-infected with HCV RNA (62.9%, 22/35). There was no significant difference in ALT levels between TTV DNA-positive and DNA-negative in patients without HCV RNA. 85.3% (35/41) of TTV DNA-positive sera in 1990 were again positive for TTV DNA in 1995. These findings suggest that many haemophiliacs have been infected with TTV. Although TTV infection was not associated with serum ALT elevation, persistent TTV infection may contribute to cryptogenic hepatic failure in haemophiliacs.