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Purpose Tissue engineering of esophagus is required for management of long-gap esophageal atresia (LGEA). Collagenous connective tissue membranes fabricated by in-body tissue architecture (iBTA), called biosheets, can repair esophageal defects and generate tissues similar to native esophagus. However, iBTA requires second-stage surgery because of heterotopic preparation of biosheets. Our aim was to develop orthotopic iBTA for primary engineering of the esophagus by interposing a tubular mold to the esophageal defect. Method The cervical esophagus of six rats was transected. An acrylic tube (internal diameter 2.6 mm, length 7.0 mm) was inserted and fixed between the ends of the upper and lower esophagus, and a 3 mm-long esophageal defect was created. Four weeks later, the rats were sacrificed for histological analysis. Results Postoperatively the rats could intake liquid food. After four weeks, the esophageal defects were filled with regenerated tissues. Histologically the new esophageal walls stained positive for collagen type I. The inner surfaces were covered with stratified squamous epithelium that expressed pan-cytokeratin. In only one of six rats, regeneration of muscular-like tissue was suggested by positive immunohistochemical staining for desmin. Conclusion Orthotopic iBTA can regenerate a substitute esophagus with esophageal epithelium and collagenous wall. This technique may be a novel treatment for esophageal atresia with gaps of various lengths including LGEA.

Secretory breast carcinoma constitutes the majority of breast cancers in children and young people less than 20 years of age. Noninvasive examination is particularly necessary for the diagnosis of breast carcinoma in children. Herein, we report a case of secretory breast carcinoma in a 6-year-old girl with psychomotor retardation. She was referred to our outpatient clinic for evaluation of a palpable mass in her left breast. A hard mass, rather than the increase in size typical of premature thelarche, was palpated. An excision biopsy was performed. Pathological findings revealed an invasive secretory breast carcinoma. We performed a retrospective review of the preoperative findings of this case, and compared it to the pathological diagnosis. Elastography, which can be performed without deep sedation or general anesthesia and without causing pain, resulted in a stiffness score of 4; however, the distinction between benign and malignant tumors on elastography, which is important to decide the intra-operative procedures, was not sufficient according to the Japanese breast cancer society clinical guidelines. This is the first report of secretory breast carcinoma in a child with a stiffness score determined by tissue elasticity imaging. A breast mass in a child with a high stiffness score of more than 4 on elastography should be referred for invasive diagnostic procedures, such as fine needle aspiration or excisional biopsy. According to our experience, an accurate preoperative diagnosis could be possible for malignant breast tumors in children. Such parameters as stiffness score on elastography are practical, noninvasive, and objective diagnostic tools for the accurate preoperative diagnosis of breast tumors in children.

The lack of appropriate pediatric formulations is a global issue and information on acceptability is urgently needed to develop standard pediatric formulations. This study aimed to assess perceptions of acceptability of several oral dosage forms among pediatric patients at a community and a pediatric hospital in Japan and collected information about age-appropriate pediatric formulations, aiming to contribute to drug development promotion worldwide.A cross-sectional observational study was performed. A convenience sample of caregivers was recruited from available chain-owned retail pharmacies and inpatient pediatric units. The questionnaire was composed of 3 parts: (1) acceptability of the 5 dosage forms (tablets, capsules, powders, liquids, and orally disintegrating tablet) by age; (2) acceptability of dosage size, amount, and volume by age; and (3) the actual method of administration. Face-to-face interviews were conducted at 3 independent community pharmacies (324 parents) and tertiary care pediatric hospital wards (112 nursing staff). Acceptability scores and acceptable dosages were then determined. The survey was conducted from October 1 to December 1, 2017, for the hospital setting and November 1 to 30, 2017, for the outpatient setting.The acceptability of oral dosage forms was roughly similar to the matrix drafted by the European Medical Agency. Differences in perception of the powder forms between communities and hospitals were also observed, with the nursing staff perceiving powder as being acceptable from the neonatal period.The difference in caregivers' perception of the acceptability of oral formulations between Japan and Europe was small. The powder form was found to be more acceptable in Japan. Further intervention studies are needed to assess the preferred pediatric formulation worldwide.

Introduction The need for pharmacist-led antimicrobial stewardship programs (ASP) is increasing. Objective We performed a retrospective study to assess whether pharmacist-led ASPs can decrease the duration of treatment for uncomplicated gram-negative bacteremia among patients admitted in a community hospital. Methods This research was conducted at a 325-bed regional general hospital in Japan, from January 2013 to June 2015. There are no infectious diseases specialists affiliated with the hospital. The outcomes of the pharmacist-led ASP group, who received pharmacist intervention, and the control group, who did not receive pharmacist intervention, were compared. The study included patients aged 18 years or older who were diagnosed with gram-negative bacteremia. The pharmacist performed an antimicrobial time-out at 72 hours after blood culture collection and optimized treatment based on the patient's clinical response and test results. The primary outcome was the duration of antibiotic treatment. Results In total, 34 patients in the pharmacist-led ASP group and 32 in the control group were included in the final analysis. The median number of days of antimicrobial treatment was 8 (interquartile range [IQR]: 7-14) days in the pharmacist-led ASP group and 14 (IQR: 10-15) days in the control group. The number of days of antimicrobial treatment significantly reduced in the pharmacist-led ASP group (p < 0.001). The de-escalation rates were 11 (32.4%) cases in the pharmacist-led ASP group and 4 (12.5%) cases in the control group. Hence, the trend was higher in the pharmacist-led ASP group than in the control group (p = 0.08). Conclusion The pharmacist-led ASP reduced the number of days of antimicrobial therapy for uncomplicated gram-negative bacteremia among patients admitted in a community hospital without an infectious diseases specialist.

Objective:To determine whether carbapenem consumption andPseudomonas aeruginosaresistance rates can be used as benchmarks to compare and improve antimicrobial stewardship programs across multiple pediatric hospitals.Design:A prospective study.Setting and participants:Healthcare institutions in Japan with >100 pediatric beds.Methods:An annual survey of the total days of therapy (DOT) per 1,000 patient days for carbapenem antibiotics (meropenem, imipenem-cilastatin, panipenem-betamipron, doripenem) and susceptibility rates ofPseudomonas aeruginosato meropenem and imipenem-cilastatin from each institution was conducted over a 7-year period. Data were reported to the administration, as well as to the infection control team, of each institution annually.Results:Data were obtained from 32 facilities. The median total carbapenem DOT per 1,000 patient days was 16.6 and varied widely, with a range of 2.7 to 59.0. The median susceptibility to meropenem was 86.6%, ranging from 78.6% to 96.6%. We detected an inverse correlation between total carbapenem DOT versus susceptibility (r= – 0.36;P< .01). Over the 7-year period, the DOT per 1,000 patient days of carbapenem decreased by 27% from a median of 16.0 to 11.7 (P< .01). We also observed an improvement in susceptibility to meropenem from a median of 87% to 89.7% (P= .01) and to imipenem-cilastatin from 79% to 85% (P< .01). The decreases in the use of carbapenem were greater in institutions with antimicrobial stewardship programs led by pediatric infectious disease specialists.Conclusions:Antimicrobial use and resistance, targeting carbapenems andP. aeruginosa, respectively, can serve as benchmarks that can be utilized to promote antimicrobial stewardship across pediatric healthcare institutions.

Background Prosthetic patches can be used to repair large congenital diaphragmatic hernia defects but may be associated with infection, recurrence, and thoracic deformity. Biosheets (collagenous connective tissue membranes) have been used in regenerative medicine. We evaluated the efficacy of Biosheets in a rabbit model. Methods Biosheets were prepared by embedding silicone plates in dorsal subcutaneous pouches of rabbits for 4weeks. In group 1 (n=11), Gore-Tex® sheets (1.8×1.8cm) were implanted into a diaphragmatic defect. In group 2 (n=11), Seamdura®, a bioabsorbable artificial dural substitute, was implanted in the same manner. In group 3 (n=14), biosheets were autologously transplanted into the diaphragmatic defects. All rabbits were euthanized 3months after transplantation to evaluate their graft status. Results Herniation of liver was observed in 5 rabbits (45%) in group 1, 8 (73%) in group 2, and 3 (21%) in group 3. A significant difference was noted between groups 2 and 3 (P=0.017). Biosheets had equivalent burst strength and modulus of elasticity as native diaphragm. Muscular tissue regeneration in transplanted biosheets in group 3 was confirmed histologically. Conclusion Biosheets may be applied to diaphragmatic repair and replacement of diaphragmatic muscular tissue. Level of evidence Level III.

A 6-year-old boy developed left side scrotal pain. We diagnosed the patient as having left appendix testis torsion. We prescribed acetaminophen and the pain gradually improved. Four months after the initial episode of pain, the patient had scrotum pain again. Ultrasonography revealed a swollen appendage at the upper pole of the testis with calcification. We performed resection of the twisted appendix testis. Pathological examination revealed lymphocytic infiltration, fibrosis, edema, granulation tissue, and frequent foci of calcification. There was no necrosis. Some cases of appendix testis torsion whose initial symptoms are conservatively managed, require subsequent removal of the chronically inflamed appendage accompanied by acute inflammation for persistent or recurrent pain several months after appearance and resolution of the initial symptoms. Keywords: Acute scrotum, Torsion of appendix testis, Recurrence symptoms

A nine-year-old, otherwise healthy girl presented with abdominal pain. On exam, there was a palpable cystic tumor in the left abdomen. According to imaging examinations, we tentatively diagnosed the tumor as lymphangioma of mesentery with bleeding. We planned to perform laparoscopic surgery to remove the tumor. On laparoscopy, cyst aspiration was performed to reduce the volume of the cysts, and the aspirated fluid was found to contain red blood cells. Due to technical difficulties, laparoscopic surgery was converted to open surgery. RBCs were detected in the cyst fluid at the sigmoid colon and intestinal mesentery. Resection of the cystic tumor and sigmoidectomy were performed. On pathologic examination of the tumor, there were multiple cysts but there was no cavernous part. The largest cyst was 6 × 5 × 3 cm. Simple squamous epithelium cells were found along parts of the inner lining of enlarged luminal cysts. On immunohistochemical staining, the tumor was positive for CD31 and CD34, and negative on D2-40 antibody staining. Therefore, we diagnosed this specimen as hemangioma with giant cysts at the mesentery. We conclude that bleeding into cysts of a hemangioma of mesentery might lead to the development of giant cysts and, in turn, a cystic tumor in the abdomen.

Antimicrobial stewardship programs (ASP) for oral antibiotics is still uncommon, despite the fact that oral antibiotics prescription accounts for 90% of total antibiotic consumption in developed countries. We introduced preauthorization and prospective audit and feedback (PAF) system on broad-spectrum oral antimicrobials as a part of ASP intervention from October 2015 in a tertiary children's hospital in Japan. Antimicrobial consumption and cost of targeted oral antimicrobials decreased from 11.1 days of therapy (DOT) per 1000 outpatient visits and 860,040 yen ($ 7167: 1 $ = 120 yen) to 1.9 DOT per 1000 outpatient visits and 142,200 yen ($ 1185) annually, respectively (p < 0.001). Interrupted time-series analysis showed that prescriptions for targeted antimicrobials decreased rapidly after initiation of preauthorization (p < 0.001). Prescriptions for non- targeted oral antimicrobial increased temporarily (p < 0.001), but a decreasing trend was found after the initiation (p < 0.001). In pre-intervention period, the main indications for using targeted antimicrobials were upper and lower respiratory infection, urinary tract infections, prophylaxis for medical procedures and otitis media, but only 21.4% of them were appropriate prescription. The appropriate prescription rate of post-intervention period increased to 58.5%. During the study period, the susceptibility pattern of major bacteria to these antimicrobials did not change. In conclusion, introduction of the preauthorization and PAF for selected oral antimicrobials decreased the antimicrobial use of both targeted and non-targeted antimicrobials. This intervention may be an effective method of ASP for other children's hospitals. (C) 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

This study aimed to investigate whether intra-tracheal administration of basic fibroblast growth factor (b-FGF) promotes the growth of tracheal cartilage. Trachea of 4-week old mice were intubated and 2.5 μg b-FGF administered (Group 4) for periods from 1 to 5 days. Cervical tracheal outer diameter and tracheal ring length were compared in Group 1 (no intervention), Group 2 (tracheal intubation), Group 3 (intra-tracheal administration of distilled water) and Group 4, at 8 weeks of age. Outer diameter and tracheal ring length in Group 4 were also compared with that in Group 1 at 12 and 16 weeks of age. At 8 weeks of age, tracheal ring length with b-FGF administration for more than 4 days in Group 4 was significantly increased over that following 1-day administration. At 8 weeks of age, mean outer diameter and the mean tracheal ring length in Group 4 were significantly greater than in the other groups. Mean outer diameter and mean tracheal ring length were significantly greater in Group 4 than in Group 1 at 12 and 16 weeks of age. This study has shown that intra-tracheal administration of b-FGF enlarges the tracheal lumen.

Background Intratracheal injection of basic fibroblast growth factor (b-FGF) has been shown to enlarge the tracheal lumen 4 weeks after treatment. The objective of this study was to investigate the long-term effect of tracheal cartilage growth promotion by intratracheal injection of b-FGF. Materials and methods New Zealand white rabbits were classified into four groups to receive either distilled water alone (Group 1; n = 16; control), 40 μg (Group 2; n = 10), 100 μg (Group 3; n = 13), or 200 μg (Group 4; n = 16) of b-FGF dissolved in water. The treatment was injected into the posterior wall of the cervical trachea using a tracheoscope. The animals were sacrificed 4 or 12 weeks later. Results Four weeks after treatment, the mean luminal areas of tracheas for Groups 1, 2, 3, and 4 were 27.2, 25.6, 32.2, and 36.2 mm2, respectively. At 12 weeks, these were 29.3, 37.9, 42.5, and 56.0 mm2, respectively. The levels of glycosaminoglycan at 12 weeks were 93.9, 152.5, 123.2, and 210.6 μg/mg, respectively. At 12 weeks, the levels of type II collagen were 77.2, 133.1, 99.2, and 148.9 μg/mg, respectively. Conclusion Twelve weeks after a single injection of b-FGF, the mean luminal area of the trachea continued to increase.

Tracheal cartilage reconstruction is an essential approach for the treatment of tracheal congenital abnormalities or injury. Here, we evaluated the use of allogeneic decellularized tracheas as novel support scaffolds. Six weaned pigs (4-week-old domestic males) were transplanted with allogeneic tracheal graft patches (three decellularized and three fresh tracheal scaffolds) onto artificial defects (approximately 15 × 15 mm). After 11 weeks, the tracheas were evaluated by bronchoscopy and histological studies. No pigs displayed airway symptoms during the observation period. Tracheal lumen restored by fresh graft patches showed more advanced narrowing than that treated with decellularized grafts by bronchoscopy. Histologically, fresh grafts induced typical cellular rejection; this was decreased with decellularized grafts. In addition, immunohistochemistry demonstrated regenerating foci of recipient cartilage along the adjacent surface of decellularized tracheal grafts. Decellularized allogeneic tracheal scaffolds could be effective materials for restoring impaired trachea.

Purpose Basic fibroblast growth factor (b-FGF) is a very effective growth factor that induces the proliferation of chondrocytes. This study aimed to investigate whether intra-tracheally-injected b-FGF solution promotes the growth of tracheal cartilage. Methods Group 1: 500μl of distilled water was injected at the posterior wall of the cervical trachea of New Zealand white rabbits by using a tracheoscope (n=5). Group 2: 100μg/500μl of b-FGF solution was injected at the posterior wall of the cervical trachea (n=5). Group 3: Biodegradable gelatin hydrogel microspheres incorporating 100μg/500μl of b-FGF solution were injected at the posterior wall of the cervical trachea (n=5). All animals were sacrificed 4weeks later, and the outer diameter and luminal area of the cervical trachea at the site of b-FGF injection were measured. Results The cervical tracheas in the two b-FGF injection groups were spindle-shaped and had a maximum diameter at the injection site. The median outer diameter of the cervical trachea in Groups 1, 2, and 3 was 7.3, 8.0, and 8.0mm, respectively, showing a significant difference among Groups 1, 2, and 3 (P=0.04). The median luminal area in Groups 1, 2, and 3 was 27.4, 29.4, and 32.1mm 2 , respectively. The ad hoc test showed a marginally significant difference only between groups 1 and 3 (p=0.056). Conclusion Intra-tracheal injection of slowly released b-FGF enlarged the tracheal lumen.

Objectives/Hypothesis Tracheoplasty using costal cartilage grafts to enlarge the tracheal lumen was performed to treat congenital tracheal stenosis. Fibrotic granulomatous tissue was observed at the edge of grafted costal cartilage. We investigated the junction between the native hyaline cartilage and the engineered cartilage plates that were generated by auricular chondrocytes for fabricating the airway. Study Design Controlled, prospecive study. Methods In group 1, costal cartilage from New Zealand white rabbits was collected and implanted into a space created in the cervical trachea. In group 2, chondrocytes from auricular cartilages were seeded on absorbable scaffolds. These constructs were implanted in the subcutaneous space. Engineered cartilage plates were then implanted into the trachea after 3 weeks of implantation of the constructs. The grafts in group 1 and 2 were retrieved after 4 weeks. Results In group 1, histological studies of the junction between the native hyaline cartilage and the implanted costal cartilage demonstrated chondrogenic tissue in four anastomoses sides out of the 10 examined. In group 2, the junction between the native trachea and the engineered cartilage showed neocartilage tissue in nine anastomoses sides out of 10. Conclusions Engineered cartilage may be beneficial for engineered airways, based on the findings of the junction between the native and engineered grafts. Level of Evidence 1a.

Tracheomalacia is a major cause of morbidity in conditions such as oesophageal atresia. However, symptoms usually improve with age. A more rapid growth of tracheal cartilage can be induced by basic-Fibroblast Growth Factor (b-FGF). This study aimed to investigate whether slow-release b-FGF could act as a novel treatment for tracheomalacia.Biodegradable gelatin hydrogel sheets incorporating 0.5, 5, or 50 μg/20 μl of b-FGF solution were inserted between the cervical trachea and esophagus of rats. No intervention was performed in rats in a control group. All animals were sacrificed 4 weeks later, and the luminal area of the cervical trachea and the thickness of the cartilage were measured.The mean luminal areas in the control group and in the b-FGF groups were 3.1, 3.2, 3.8, and 2.6mm(2), respectively, and showed a peak area at 5 μg of b-FGF. A significant difference was seen only between the control group and the b-FGF 5 μg group (p0.05). The mean thickness of the tracheal cartilage was 0.12, 0.13, 0.19, and 0.32 mm in the control and the b-FGF groups, respectively, and showed a dose-dependent increase, which was statistically significant between the b-FGF 5 μg or 50 μg groups and the control group (p0.01).This study showed that slow-release b-FGF enlarges the tracheal lumen and thickens the cartilage in a dose-dependent fashion.

Background/Purpose We have previously shown that intratracheal injection of slowly released (in gelatin) basic fibroblast growth factor (bFGF) significantly enlarged the tracheal lumen by a slight margin. This study aimed to investigate differences in tracheal cartilage growth by the intratracheal injection of bFGF doses in a rabbit model. Methods Water (group 1; n=7; control) or 100μg (group 2; n=8) or 200μg (group 3; n=8) of bFGF dissolved in water was injected into the posterior wall of the cervical trachea of New Zealand white rabbits using a tracheoscope. All animals were sacrificed four weeks later. Results The mean circumferences of cervical tracheas for groups 1, 2, and 3 were 18.8±0.83, 21.1±2.0, and 22.1±1.3mm, respectively. A significant difference was found between groups 1 and 2 (P=0.034) and groups 1 and 3 (P=0.004). The mean luminal areas of cervical tracheas for groups 1, 2, and 3 were 27.0±2.1, 32.2±4.8, and 36.3±4.6mm 2 , respectively. A significant difference was found between groups 1 and 3 (P=0.001). Conclusion Intratracheal injection of bFGF in the dose range used significantly promoted the growth of tracheal cartilage in a rabbit model. Levels of Evidence : Level II at treatment study (animal experiment).

Background Plasma citrulline has been reported to be a good indicator of intestinal functional volume in patients with intestinal dysfunction. We reconfirmed the facts and also investigated the dynamic changes of plasma citrulline in acute-phase patients with intestinal dysfunction. Methods We measured plasma citrulline in six patients with intestinal dysfunction who were in the acute and chronic phase for more than 6 months. Results Four patients out of six could be withdrawn from total parenteral nutrition, and their plasma citrulline level dynamically changed according to their intestinal states and finally increased up to 15 nmol/mL. Two patients, who could not be withdrawn from parenteral nutrition, showed very low levels of plasma citrulline throughout the treatment course (under 15 nmol/mL). Conclusion The cut-off level of plasma citrulline indicating permanent intestinal dysfunction may be 15 nmol/mL in our data. In the acute phase, plasma citrulline changed dynamically according to the intestinal state and may be a good indicator of fluctuating intestinal functions. Thus, although only a few patients were enrolled in this study, plasma citrulline may be a good indicator of stable-state as well as acute-unstable-state intestinal functions.

Background Antimicrobial stewardship programs (ASP) for oral antibiotics is limited, despite the fact that oral antibiotics account for 90% of total antibiotic consumption in developed countries. We aimed to analyze the effectiveness of ASP for oral antibiotics in a pediatric population. Methods We conducted a prospective study at a tertiary maternal and children fs hospital in Japan, consisting of 490 beds, with approximately 13,000 hospitalizations and 240,000 outpatient visits annually. Outpatient data on oral antimicrobial prescription, costs and proportions of resistant bacteria between 2013 and 2016 were analyzed. We conducted preauthorization and feedback as a means of intervention from October 2015 for targeted antimicrobials; vancomycin, linezolid, quinolones, faropenem, tebipenem pivoxil, polymyxin B. Antibiotic use density (AUD) was measured using days of therapy (DOT) /1000 visits. Interrupted time-series (ITS) analysis was performed to evaluate the effects of intervention. Results The main indications for use of targeted antimicrobials were urinary tract infections, pneumonia, and prophylactic administration in malignancy and were inappropriate in the majority prior to intervention. AUD and cost of targeted oral antimicrobials decreased from 11.0 DOT /1000 visits and 7,176 US dollars(USD) to 2.1 DOT/1000 visits and 1,665 USD, respectively (P < .001). ITS analysis showed that prescriptions for targeted antimicrobials decreased rapidly after initiation of preauthorization(-7.1 DOT /1000 visits; P < .001) (Figure 2-a). Prescriptions for non-targeted oral antimicrobial increased temporarily (+28 DOT/1000 visits; P < .001), but a decreasing trend was found after the initiation (P < .001) (Figure 2-b). During this study period, the susceptibility against quinolones did not change for E.coli, K.pneumoniae, and P.aeruginosa. Conclusion Introduction of the preauthorization system for selected oral antimicrobials decreased the AUD of both targeted and non-targeted antimicrobials. Disclosures N. Kinoshita, Standardization and dissemination of a community based network of infection control targeting children MHLW H29-SHINKOGYOSEI-IPPAN-002: Board Member, Salary; I. Miyairi, Standardization and dissemination of a community based network of infection control targeting children MHLW H29-SHINKOGYOSEI-IPPAN-002: Grant Investigator, Research grant

A 1-year-old boy was admitted to our department with undescended testis on the left side of the body. Upon surgical exploration, a diagnosis of polyorchidism was made. The accessory proximal testis was removed and the distal testis underwent orchidopexy. Pathological findings revealed duplication of the vas deferens and epididymis but without an accessory testis. We then performed further intra-abdominal exploration in order to identify intra-abdominal testis arising from complete urogenital nonunion. We concluded that this represents the first documented case exhibiting duplication of the vas deferens and epididymis.

The number and types of minimally invasive surgical procedures being performed in children have increased exponentially in the last 15 years. Laparoscopic fundoplication is commonly performed for gastroesophageal reflux disease (GERD), although the population of patients who undergo this procedure is different in adults and children. In Japan, laparoscopic fundoplication has become a standard procedure, even for children with neurological impairment; however, its indications remain controversial. In this article we review the status of laparoscopic antireflux surgery for infants and children, looking at its indications, the procedures available, the complications, and the training required to perform the procedure safely and effectively.

Background: Infants with severe congenital anomaly often need to undergo operation followed by antibiotic therapy. As a result they inevitably acquire abnormal intestinal microbiota, which cause severe infections such as necrotizing enterocolitis. Also, intestinal function deteriorates and their nutritional state is very poor. In order to prevent these situations probiotic therapy is proposed as an effective supporting treatment. Probiotic therapy were therefore applied to infants with severe congenital anomaly as early as possible to ascertain its efficacy. Methods: As probiotics, two bacteria were used: Bifidobacterium breve Yakult and Lactobacillus casei Shirota. Probiotic therapy was used in four infants with severe congenital anomaly as early as possible after surgery. Their intestinal microbiota and physical growth were followed through the treatment course. Results: Two patients suffered from meconium peritonitis with ileal atresia. One patient was born with complex anomalies (omphalocele, bladder exstrophy, myelomeningocele). The fourth patient suffered from complete urorectal septum malformation. The intestinal microbiota of these four patients was first induced to be probiotic dominant and finally changed to commensal anaerobe dominant that was similar to normal intestinal microbiota. Pathogenic bacteria were seldom detected. The patients' physical growth was excellent despite short bowel and pulmonary hypoplasia. Conclusion: Probiotic therapy was effective in inducing probiotic dominant intestinal microbiota and normal intestinal microbiota in infants with severe congenital anomalies. As a result their intestinal absorptive functions were activated and severe infections were completely prevented. All of the infants grew well despite their physical disadvantages.

The performance of a Stirling engine depends significantly on performance of heat exchanger. The heat exchanger of a Stirling engine comprises a heater, a cooler, and a regenerator. The heater and cooler perform heat transferring from high and low external heat sources to working gas, while the regenerator absorbs heat from the working gas when the gas flows from heater to cooler, and releases heat during the reverse process. These auxiliary devices increase the weight of the engine and reduce its specific power. In this study, in order to improve the performance of the compact Stirling engine, a new heat exchanger(hereafter called the prototype heat exchanger) with a heater that reduces the energy loss from combustion gas, and a cooling system that uses fuel gas were developed. The performances of these systems were then compared with that of a conventional multi-tube heat exchanger. The prototype heat exchanger capable of reducing the heat loss in a heat exchanger via conbusting in a tube. Additionally, the weight of the prototype heat exchanger is lighter than that of a conventional multi-tube heat exchanger. The prototype heat exchanger is advantageous for reducing the engine weight and improving the specific power. Experiments conducted on the prototype heat exchanger installed on the engine showed excellent results and its superior performance.

Complete urorectal septum malformation sequence (URSMS) is usually a lethal anomaly that is characterized by urethral obstruction, imperforate anus, ambiguous genitalia, renal agenesis or dysplasia, and mullerian duct maldevelopment. This anomaly is thought to be caused by the cessation of urorectal septum migration toward the caudal cloacal membrane. Teratogenic factors or a genetic abnormality is postulated as the etiology. To date, only 4 patients with URSMS have survived the neonatal period; however, 2 of these infants died before the age of 1 year. We report the survival in a case with complete URSMS who had moderate pulmonary hypoplasia and preserved left renal function. The cloacal remnant wasdilated more than expected because the wall of the muscle layer was torn, perhaps in early fetal life, and timely placement of vesico-amniotic shunts prevented severe pulmonary hypoplasia caused by oligohydramnios.

Introduction We have designed an engineered graft fabricated from a biodegradable scaffold using chondrocytes and applied this construct to augment repair of tracheal stenosis. This study investigated the feasibility of using such tissue-engineered airways with autologous chondrocytes in a rabbit model. Material and Methods Chondrocytes were isolated and expanded from the auricular cartilage of New Zealand white rabbits, then seeded onto composite 3-layer scaffolds consisting of a collagen sheet, a polyglycolic acid mesh, and a copolymer (l-lactide/ ɛ -caprolactone) coarse mesh. The engineered grafts were implanted into a 0.5 × 0.8-cm defect created in the midventral portion of the cervical trachea. Gelatin sponges that slowly released basic fibroblast growth factor (b-FGF) were then placed on the constructs, which were retrieved 1 or 3 months after implantation. Results The biodegradable scaffold seeded with chondrocytes could maintain airway structure up to 3 months after implantation. Tracheal epithelial regeneration occurred in the internal lumen of this composite scaffold. Three months after implantation, staining of the sections showed cartilage accumulation in the engineered tracheal wall. Conclusion This composite biodegradable scaffold may be useful for developing engineered trachea. A gelatin sponge slowly releasing b-FGF might enhance chondrogenesis.

Background Collagenous connective tissue membranes (biosheets) are useful for engineering cardiovascular tissue in tissue engineering. The aim was to evaluate the use of biosheets as a potential tracheal substitute material in vivo in a rabbit model. Methods Group 1: Rectangular-shaped Gore-Tex (4×7mm) was implanted into a 3×6mm defect created in the midventral portion of the cervical trachea. Group 2: Rectangular-shaped dermis was implanted into a tracheotomy of similar size. Group 3: Biosheets were prepared by embedding silicone moulds in dorsal subcutaneous pouches in rabbits for 1month. Rectangular-shaped biosheets were implanted into a tracheotomy of similar size in an autologous fashion. All groups (each containing 10 animals) were sacrificed 4weeks after implantation. Main Results All materials maintained airway structure for up to 4weeks after implantation. Regenerative cartilage in implanted Biosheets in group 3 was confirmed by histological analysis. Tracheal epithelial regeneration occurred in the internal lumen of group 3. There were significant differences in the amounts of collagen type II and glycosaminoglycan between group 3 and group 1 or 2. Conclusion We confirm that cartilage can self-regenerate onto an airway patch using Biosheets.

Hidenori Nakagawa, M.D. 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535 Japan E-mail : nakagawa-h@ncchd.go.jp Tel : +81-3-3416-0181 FAX : +81-3-3416-2222 Study design: Retrospective study Study period: Between January 2010 and December 2014 Study setting: National Center for Child Health and Development, Tokyo, Japan Antimicrobials: Ampicillin/Sulbactam, Piperacillin/Tazobactam, Cefmetazole (cephamycin antibiotic), Cefotaxime, Ceftazidime, Cefepime, Meropenem, Gentamicin, and Amikacin, which are frequently used in our hospital.. Antimicrobial consumption: Annual DOT (Days of Therapy) per 1000 patient-days of each antimicrobials was calculated from the database in pharmaceutical department. Gram-negative bacteria: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa, which are frequently isolated in our hospital. Susceptibility test: Standard microdilution method according to the CLSI (Clinical and Laboratory Standards Institute) M100-S19 criteria.

In this study, the mutual fusion of chondrocyte pellets was promoted in order to produce large-sized tissue-engineered cartilage with a three-dimensional (3D) shape. Five pellets of human auricular chondrocytes were first prepared, which were then incubated in an agarose mold. After 3 weeks of culture in matrix production-promoting medium under 5.78g/cm(2) compression, the tissue-engineered cartilage showed a sufficient mechanical strength. To confirm the usefulness of these methods, a transplantation experiment was performed using beagles. Tissue-engineered cartilage prepared with 50 pellets of beagle chondrocytes was transplanted subcutaneously into the cell-donor dog for 2 months. The tissue-engineered cartilage of the beagles maintained a rod-like shape, even after harvest. Histology showed fair cartilage regeneration. Furthermore, 20 pellets were made and placed on a beta-tricalcium phosphate prism, and this was then incubated within the agarose mold for 3 weeks. The construct was transplanted into a bone/cartilage defect in the cell-donor beagle. After 2 months, bone and cartilage regeneration was identified on micro-computed tomography and magnetic resonance imaging. This approach involving the fusion of small pellets into a large structure enabled the production of 3D tissue-engineered cartilage that was close to physiological cartilage tissue in property, without conventional polyper scaffolds.

Aim Severe tracheomalacia is a life-threatening disease, but symptoms usually improve with growth. The aims of this study were to investigate how slow release basic-Fibroblast Growth Factor (b-FGF) acts on tracheal cartilage, and whether growth-promoted trachea is more resistant against an increase in externally-applied pressure. Methods Biodegradable gelatin hydrogel sheets soaked in 10μl of distilled water (sham) or 0.5 or 5μg/10μl of b-FGF solution were inserted behind the cervical trachea of three-week-old male Wistar rats. The cervical trachea was harvested 4weeks later. Extratracheal pressure was increased from 0 to 40 cmH 2 O in a chamber, while video-recording the internal lumen. The luminal area at each pressure was expressed as a proportion to that at 0 cmH 2 O. The amounts of collagen type II and glycosaminoglycan were measured by ELISA. Results The luminal areas at 40 cmH 2 O in the control (no intervention), sham, and each of the b-FGF groups were 0.65, 0.62, 0.72, and 0.73, respectively. The amounts of collagen type II and glycosaminoglycan in each group were 127, 136, 193, 249μg/mg, respectively, and 15, 16, 19, 33μg/mg, respectively. There were significant differences between the control group and the FGF 5 group ( P =0.02, 0.01, 0.01, for luminal area, collagen, and glycosaminoglycan, respectively). Conclusion 5μg of slow-release b-FGF promotes matrix production (collagen type II and glycosaminoglycan). The growth-enhanced trachea was more resistant to collapse, suggesting that slowly released b-FGF might be useful in patients with severe tracheomalacia.

Purpose Our objective was to investigate the feasibility of engineering cartilage on the esophagus layer and outside the esophagus. Moreover, we investigated the feasibility of tracheoplasty with cartilage engineered on the esophagus in rabbits. Methods Chondrocytes were isolated from auricular cartilages. 1. Engineered cartilage formation by histological findings on/into the esophageal layer was compared with that of injectable scaffold and preformed scaffold with chondrocytes. 2. Chondrocytes adhered to gelatin+vicryl mesh™ and b-FGF, were implanted on the outer esophageal surface. Four weeks after seeding, we found that cartilage was implanted in the midposterior portion of the cervical trachea (n=5), and it was retrieved 8weeks after seeding. Results 1. A gelatin sponge incorporating β-TCP with vicryl mesh™ showed the best performance for fabricating engineered cartilage on the outer side of the esophagus. 2. Two of 5 rabbits died due to obstructed esophagus. Cartilage engineered outside the esophagus by a composite scaffold as the main material in the gelatin sponge, maintained the airway structure for up to 1month after implantation. Tracheal epithelial regeneration occurred in the internal lumen of this engineered cartilage. Conclusion Tracheoplasty with cartilage engineered outside the esophagus may be useful for reconstructing airways.

Most patients with thymic cysts complain of a slowly enlarging, asymptomatic cervical mass. Only 6-10% suffer dysphagia, dyspnoea, stridor, cervical pain or vocal paralysis. In some rare cases sudden onset of severe dyspnoea or asphyxia is the first symptom, especially in neonates and small infants. We report a unique case of a 20-month-old child, who required emergency tracheal intubation due to asphyxia. Cervicomediastinal thymic cyst might need to be included in causes of life-threatening airway obstruction in young children.

At 24 weeks of gestation, a fetus was suspected of having a huge intraabdominal cyst by fetal ultrasound. Multicystic dysplastic kidney (MCDK) was the most probable diagnosis; however, because a solid area was visualized in the large cystic lesion, a neoplasm of the kidney could not be ruled out. A 3529-g boy was born at 35 weeks of gestation by cesarean delivery. Eight days after birth, the tumor was resected. Histopathologic examination confirmed MCDK. The cause of MCDK in this patient was assumed to be ureteral obstruction in early fetal life. These findings suggested that the affected kidney had experienced mesenchyme-to-epithelium transition followed by interaction between the metanephric blastema and ureteral bud.

This chapter reviews principles of reconstructing complex composite tissues, provides an overview of earlier and recent developments in tissue engineering design for phalanges and small joints in the digit, and discusses the current technologies for reconstruction. Stem cells are proposed as an alternative cell source for the engineering of the digit tissues. Autologous somatic cells are preferable as they have a limited expansion capability and require multiple tissue biopsies in order to obtain all cell types needed for digit engineering. Scaffolds provide three-dimensional (3D) architecture for regenerating tissues by supplying cell anchorage sites, mechanical stability, and structural guidance. In vivo , they provide an interface that allows a construct to respond to physiological and biological changes and guide the remodeling of the extracellular matrix to allow integration with the surrounding native tissue. A tissue engineering approach aimed at mimicking the physiological properties and structure of two different tissues (cartilage and bone) using a cell-scaffold construct would be ideal for repair and regeneration of limbs and digits. When single (monophasic) scaffolds are used, the natural environment is not adequately replicated and new tissue formation is incomplete. Therefore, several attempts are made to develop biphasic composite constructs for bone-cartilage engineering by combining two distinct scaffold materials. Biphasic composite scaffolds manufactured by image-based design and solid free-form fabrication are used to simultaneously generate bone and cartilage in discrete regions and provide for the development of a stable interface between cartilage and subchondral bone.

Construction of engineered respiratory tract using tissue-engineered cartilage has not yet been reported. In order to generate artificial trachea using human chondrocytes obtained from tracheal cartilage, we investigated whether human tracheal chondrocytes can act as a cell source to fabricate engineered airway patches to augment stenotic parts of the trachea. After informed consent, chondrocytes were obtained from five patients who needed tracheal surgery. A small piece of resected tracheal cartilage was digested by collagenase type 2 for 3–4 h. This yielded chondrocytes, which were expanded in vitro and seeded onto biodegradable scaffolds; these were then implanted subcutaneously in athymic mice. The implanted constructs were retrieved 8 weeks later for histologic and biochemical analysis. In monolayer cultures, chondrocytes proliferated well, showing a 100- to 1,000-fold increase in 1 month. Once expanded, the cells lost their original morphological and biologic characteristics, but the engrafted scaffold showed histologic and biochemical characteristics of cartilage. Viable chondrocytes and extracellular matrix were detected, and glycosaminoglycan (GAG) in vivo was present. Here we show that a small piece of human tracheal cartilage can generate sufficient chondrocytes in vitro and form tracheal cartilage architecture in an in vivo environment.

A 41-day-old female infant with VACTERL association was transferred to the pediatric intensive care unit of our hospital. She had been delivered at 36 weeks gestation by spontaneous vaginal delivery and weighed 2340 g. Esophageal atresia type A with long gap, anal atresia, cardiac anomaly (atrial septal defect and patent ductus arteriosus), thoracic vertebral dysplasia, left renal agenesis, and minor anomalies (left-side facial nerve palsy, left-side difficulty in hearing, and the absence of the right thenar) had been diagnosed by various examinations. She was transferred to our hospital to receive treatment for heart failure due to a cardiac anomaly. We recognized vaginal atresia during a radical operation for anal atresia (rectovestibular fistula) at 8 months of age. Furthermore, magnetic resonance imaging (MRI) revealed agenesis of the uterus. MURCS association includes Mullerian duct aplasia or hypoplasia, renal aplasia, and cervicothoracic somite dysplasia. This is the first case of complete VACTERL association combined with MURCS association.

Background/purpose This study examined whether an injectable hydrogel could buttress the balloon used in fetal tracheal occlusion, thus preventing its displacement. Methods Fetal lambs (n = 11) underwent tracheal occlusion through local delivery of a detachable silicone balloon and were divided in 2 groups: group I had no further manipulations, and group II received an intratracheal injection of a rapidly polymerizing hydrogel, cranially to the balloon. Near term, balloon placement was examined, the lung volume—to—body weight ratio (LV:BW) was determined, and tracheal histology was performed. Statistical analysis was by the Fisher's Exact test, with significance set at P Results Complete tracheal occlusion was achieved in all fetuses intraoperatively. The rate of balloon dislodgement was significantly higher in group I (4 of 7, or 57.1%) than in group II (0 of 4). In group II, balloons were recovered in situ with a column of residual hydrogel reinforcing their cephalad position. Animals in which balloon occlusion was maintained had significantly higher LV:BW, with no evidence of tracheal damage. Conclusions Intratracheal delivery of a rapidly polymerizing hydrogel cephalad to detachable silicone balloons results in improved fetal tracheal occlusion, with no harmful effects to the trachea. This adjuvant principle may enhance minimally invasive balloon tracheal occlusion for treatment of severe fetal pulmonary hypoplasia.

Background/purpose This study was aimed at comparing albumin and dextran as intrapulmonary hyperoncotic enhancers of fetal lung growth after tracheal occlusion. Methods Fetal lambs (n = 27) were divided proportionally into 5 groups: group I consisted of sham-operated controls; group II underwent tracheal occlusion (TO); groups III, IV, and V underwent TO and intratracheal infusion of 60 mL of either saline, 6% dextran-70, or 25% albumin, respectively. Multiple fetal lung analyses were performed near term. Statistical analysis was by 1-way analysis of variance (ANOVA) and post-hoc analyses by the Bonferroni correction for multiple comparisons ( P Results The lung volume-to-body weight ratio was significantly higher in groups IV and V than in all other groups with no differences between groups II and III, nor between groups IV and V. Airspace fraction was not significantly different among the groups, nor was there any evidence of alveolar cellular damage. Type-II pneumocyte density was higher in group I than in groups II, IV, and V, with no differences among the latter 3 groups. Lung liquid biochemical profile was normal in all groups. Conclusions Albumin is as effective as dextran as an intrapulmonary hyperoncotic booster of lung growth acceleration after fetal tracheal occlusion, with no lasting effects on its fetal lung liquid levels. As a naturally occurring oncotic agent, albumin may be a safer option in the clinical application of this therapeutic concept.

Background/Purpose: To develop practical and less invasive techniques for fetal endoscopic surgery, new methods of lifting the uterine wall to allow fetal surgery without maternal laparotomy were developed and assessed. Methods: Fetal endoscopic surgical procedures, including tracheostomy and umbilical vascular cannulation, were performed using one of the three methods to enter the uterus without maternal laparotomy in pregnant goats (n = 6; 105 to 115 days' gestation): (1) direct uterine lifting with an air-cushion device; (2) indirect uterine lifting, in which the uterine wall was fixed to the maternal abdominal wall using balloon tip ports inserted percutaneously by Seldinger's method, then the maternal abdomen was lifted mechanically; and (3) combined method, in which low pressure CO 2 (5 mm Hg for initial inflation and 2 mm Hg for maintenance) was insufflated into the uterus in addition to the indirect uterine lifting cited above. Results: The direct uterine lifting caused massive injury of myometrium and uterine membranes. The creation of intrauterine space and the protection of the membranes were not accomplished effectively by the indirect uterine lifting only. The combined method provided the adequate intrauterine space and excellent endoscopic visibility for completion of the endoscopic procedures with minimal uterine injury. Conclusion: The fetal endoscopic surgery may be accomplished simply and safely by the combined method, a novel technique of uterine lifting to allow fetal surgery without maternal laparotomy.

A case showing many of the typical visceral features of cloacal exstrophy is reported. The patient had fn imperforate anus, a cecal-cloacal fistula, dehiscence of the pubiic symphysis, and lumbosacral spina bifida with synsingomyelia, but the lower abdominal wall was intact without any visceral extroversion. The pertinent literature was reviewed, and it was found that this case corresponded to t typical case of “completely covered cloacal exstrophy.” Only six cases, including the present one, have so far been reported in the literature. From a clinical viewpoint, it apparently occupies an intermediate position in the wide spectrum of cloacal anomalies between “classical cloacal exstrophy” and “imperforate anus with recto-cloacal fistula,” but anatomatically and embryologically it is definitely a variant of cloacal exstrophy. In other words, it looks like an imperforate anus with recto-cloacal exstrophy, but should be treated as a variant of loacal exstrophy. The anatomy, classification, embryology, diagnosis, and management of this peculiar surgical condition are discussed, and recognition of this entity is urged.

Open surgery is the standard therapeutic approach for renal malignant tumor in children; while in adults, laparoscopic radical nephrectomy (LRN) is used. Only few reports on LRN in children have been published because the most common form of pediatric renal malignancy, Wilms tumor, is well known for presenting with large palpable masses. Here, we report the case of a 13-year-old girl with small chromophobe renal cell carcinoma (RCC) who was managed by LRN. RCC is a rare condition, with an incidence rate of only 2–6% of all renal tumors in children. We found LRN for small RCC to be feasible and safe.