Sex steroid hormones and allergic diseases in children: a pilot birth cohort study in the Japan Environment and Children's Study cohort.

BACKGROUND: Numerous studies suggest that sex steroids might play a role in sex disparity observed in allergic diseases in adults. However, whether sex hormones influence allergic diseases in children remains unclear. The aim of the present study was to examine the association of sex steroid hormones with allergic disease in Japanese children. METHODS: The present cross-sectional study included 145 6-year-old children participating in a pilot birth cohort study in the Japan Environment and Children's Study. Data on allergic diseases were obtained from questionnaires, and serum levels of sex steroid hormones and allergen-specific IgE were measured. Logistic regression was performed to evaluate the association of sex hormones with allergic diseases. RESULTS: After adjusted sex, amount of body fat at 6 years, parental history of allergic disease, and exposure to tobacco smoke, serum dehydroepiandrosterone sulfate level was significantly associated with reduced odds of any allergic disease (adjusted odds ratio, 0.58; 95% confidence interval, 0.36-0.93; P = 0.024) and serum follicle-stimulating hormone level was significantly associated with increased odds of any allergic disease (adjusted odds ratio, 2.04; 95% confidence interval, 1.01-4.11, P = 0.046). Dehydroepiandrosterone sulfate level showed a significant association with number of allergic diseases. CONCLUSIONS: The current study findings suggest that sex hormones may play an important role in the development of allergic diseases in prepubertal children.

Changes in Internal Cerebral Vein Pulsation and Intraventricular Hemorrhage in Extremely Preterm Infants.

OBJECTIVES: This study aimed to investigate the relationship between internal cerebral vein (ICV) pulsation and intraventricular hemorrhage (IVH) and to identify the cut-off values that predict IVH. We hypothesized that the severity of ICV flow pulsations was related to IVH severity. STUDY DESIGN: In this prospective observational study, ICV flow was measured in 61 extremely preterm infants using ultrasonography at every 12 hours until 96 hours after birth and on days 7, 14, and 28. The ICV pulsation index (ICVPI = minimum/maximum ICV speed) was calculated and compared among the groups determined by Papile's IVH classification. The ICVPI cut-off values for IVH were determined by receiver operating characteristic curve analysis. RESULTS: Compared with those in the no IVH (NIVH) group (n = 51), the ICVPI median values in the severe IVH (SIVH; grades 3 and 4) group (n = 5) were lower at 25 to 96 hours and on day 7, whereas those in the mild IVH (MIVH; grades 1 and 2) group (n = 5) were lower at 37 to 60 hours. All SIVH events were initially detected within 60 hours after birth. The ICVPI cut-off values for SIVH were 0.92 at 13 to 24 hours, 0.42 at 25 to 36 hours, 0.58 at 37 to 48 hours, and 0.55 at 49 to 60 hours. Infants whose ICVPI values were below the cut-off value ≥3 times between 13 and 60 hours had a significantly higher SIVH incidence than those whose ICVPI values were below the cut-off value ≤2 times (57.1 vs. 1.9%, p < 0.001). CONCLUSION: Our results indicate that SIVH had sustained pronounced internal cerebral vein pulsations and that the ICVPI values may help predict SIVH. Further research on strategies to decrease venous pressure for IVH prevention is needed. KEY POINTS: · IVH preterm infants had sustained ICV pulsations.. · ICV flow in SIVH pulsated stronger.. · ICVPI fluctuation implies postnatal adaptation.. · We newly defined ICVPI to predict SIVH..

Fluctuations of aeroallergen-specific immunoglobulins and children's allergic profiles: Japan Environment & Children's Study of a pilot cohort.

BACKGROUND: Allergen-specific immunoglobulins have a crucial role in allergic diseases. Most wheeze episodes develop before school age, and allergic rhinitis later develops during early elementary school years. However, the clinical background and cytokine/chemokine profiles associated with changes in immunoglobulins during early school-age are poorly understood. METHODS: This study used blood samples from children participating in the JECS Pilot Study. We examined nineteen kinds of aeroallergen-specific immunoglobulins (IgE, IgG1, IgG4, and IgA) levels in patients at age 6 and age 8. Fluctuations of Der f 1- and Cry j 1-specific immunoglobulins levels during the two periods were compared to assess the frequency of allergic statuses and clusters of cytokine/chemokine profiles. RESULTS: The medians of aeroallergen-specific IgE levels did not fluctuate, and almost all IgG1 and IgG4 decreased. In IgA, four (e.g., Der f 1) increased, whereas the other four (e.g., Cry j 1) decreased. The ratio of the Der f 1-specific IgG1 level at age 8 to that at age 6 was higher in children with poor asthma control than in children with better asthma control. Moreover, the cytokine/chemokine cluster with relatively lower IL-33 and higher CXCL7/NAP2 was associated with lower Der f 1- and Cry j 1-specific IgG4 levels, but not IgE levels. CONCLUSIONS: The cluster of cytokine/chemokine profiles characterized by lower IL-33 and higher CXCL7/NAP2 was associated with the maintenance of aeroallergen-specific IgG4 levels. This result provides a basis for considering the control of aeroallergen-specific immunoglobulins.

A missense variant in NUF2, a component of the kinetochore NDC80 complex, causes impaired chromosome segregation and aneuploidy associated with microcephaly and short stature.

Mutations in proteins involved in cell division and chromosome segregation, such as microtubule-regulating, centrosomal and kinetochore proteins, are associated with microcephaly and/or short stature. In particular, the kinetochore plays an essential role in mitosis and cell division by mediating connections between chromosomal DNA and spindle microtubules. To date, only a few genes encoding proteins of the kinetochore complex have been identified as causes of syndromes that include microcephaly. We report a male patient with a rare de novo missense variant in NUF2, after trio whole-exome sequencing analysis. The patient presented with microcephaly and short stature, with additional features, such as bilateral vocal cord paralysis, micrognathia and atrial septal defect. NUF2 encodes a subunit of the NDC80 complex in the outer kinetochore, important for correct microtubule binding and spindle assembly checkpoint. The mutated residue is buried at the calponin homology (CH) domain at the N-terminus of NUF2, which interacts with the N-terminus of NDC80. The variant caused the loss of hydrophobic interactions in the core of the CH domain of NUF2, thereby impairing the stability of NDC80-NUF2. Analysis using a patient-derived lymphoblastoid cell line revealed markedly reduced protein levels of both NUF2 and NDC80, aneuploidy, increased micronuclei formation and spindle abnormality. Our findings suggest that NUF2 may be the first member of the NDC80 complex to be associated with a human disorder.

Exploratory analysis of plasma cytokine/chemokine levels in 6-year-old children from a birth cohort study.

This study aimed to reveal a new dimension of allergy profiles in the general population by using machine learning to explore complex relationships among various cytokines/chemokines and allergic diseases (asthma and atopic dermatitis; AD). We examined the symptoms related to asthma and AD and the plasma levels of 72 cytokines/chemokines obtained from a general population of 161 children at 6 years of age who participated in a pilot birth cohort study of the Japan Environment and Children's Study (JECS). The children whose signs and symptoms fulfilled the criteria of AD, which are mostly based on questionnaire including past symptoms, tended to have higher levels of the two chemokine ligands, CCL17 and CCL27, which are used for diagnosis of AD. On the other hand, another AD-related chemokine CCL22 level in plasma was higher only in children with visible flexural eczema, which is one of AD diagnostic criteria but was judged on the same day of blood examination unlike other criteria. Here, we also developed an innovative method of machine learning for elucidating the complex cytokine/chemokine milieu related to symptoms of allergic diseases by using clustering analysis based on the random forest dissimilarity measure that relies on artificial intelligence (AI) technique. To our surprise, the majority of children showing at least any asthma-related symptoms during the last month were divided by AI into the two clusters, either cluster-2 having elevated levels of IL-33 (related to eosinophil activation) or cluster-3 having elevated levels of CXCL7/NAP2 (related to neutrophil activation), among the total three clusters. Future studies will clarify better approach for allergic diseases by endotype classification.

Reversal of blood flow in deep cerebral vein in preterm intraventricular hemorrhage: two case reports.

BACKGROUND: Intraventricular hemorrhage during the early stage is a major complication in very low birth weight infants. Elevation of venous pressure is one of the contributing factors. The internal cerebral vein receives most of the venous flow from the subependymal germinal matrix, the most common site of origin of intraventricular hemorrhage. Recently, it has been reported that pulsatile or partially interrupted internal cerebral vein waveforms might also be risk factors for intraventricular hemorrhage in extremely low birth weight infants. Here, we report two cases of partially reversed internal cerebral vein flow with intraventricular hemorrhage. There are no published reports documenting this unique flow pattern. CASE PRESENTATION: Between 2013 and 2020, we had in our neonatal intensive care unit two cases of very low birth weight infants (27 and 25 weeks of gestational age) who showed a partially reversed internal cerebral vein waveform pattern, which was recognized as a new blood flow pattern. Their internal cerebral vein flow patterns were continuously flat early after birth. They showed an intraventricular hemorrhage on the unilateral side with partially interrupted internal cerebral vein flow at 31 and 41 hours after birth (27- and 25-week-old neonates, respectively). Consecutively, their internal cerebral vein flow changed to a partially reversed pattern with intraventricular hemorrhage on the contralateral side at 43 and 87 hours after birth (27- and 25-week-old neonates, respectively). Their flow patterns improved by day 7. These partially reversed patterns were equivalent to triphasic venous flow, and the reverse flow corresponded to A- and V-waves. CONCLUSION: In the two cases, the internal cerebral vein flow patterns were normal and flat before intraventricular hemorrhage and changed to a severe flow pattern (partially interrupted or reversed flow) at the same time as the detection of intraventricular hemorrhage. After the development of intraventricular hemorrhage, they improved. These cases indicate that a partially reversed or interrupted internal cerebral vein flow pattern may be derived from central venous pressure elevation and related to intraventricular hemorrhage in very low birth weight infants, however, it is difficult to determine when this flow pattern occurs in relation to intraventricular hemorrhage.

New reference ranges of procalcitonin excluding respiratory failure in neonates.

BACKGROUND: Existing reference data on serum procalcitonin (PCT) in neonates include the effects of respiratory disorders commonly occurring during birth. We aimed to determine new 95% reference intervals in neonates after excluding the influence of respiratory failure at birth, and to investigate the effects of gestational age (GA) and respiratory condition at birth on postnatal transient serum PCT elevation. METHODS: Samples were obtained from term and preterm neonates during the first 3 days of life. Neonates were classified into reference, respiratory failure, and bacterial infection groups. In the reference group, the correlation between PCT level and GA was investigated. RESULTS: The median PCT level within the 95% range 12-36 h after birth was 1.05 ng/mL (0.14-4.39) in term neonates (143 samples) and 1.01 ng/mL (0.15-4.44) in preterm neonates (95 samples). There was no correlation between GA and serum PCT level during 1-48 h after birth. There was a significant difference in median serum PCT level during 12-36 h after birth between the respiratory failure (9.56 ng/mL) and bacterial infection (49.82 ng/mL) groups in preterm neonates but no difference between term neonates (respiratory failure 6.83 ng/mL, and bacterial infection 7.43 ng/mL). CONCLUSIONS: Respiratory failure is the main effector for the transient elevation in serum PCT levels at 3 days of life. After excluding the influence of respiratory failure, the chronological pattern and range were very similar between term and preterm neonates. Procalcitonin can be useful for clinicians in distinguishing bacterial infection from respiratory failure, aiding decisions on appropriate antibiotic use.

Urea cycle disorders-update.

The urea cycle is a metabolic pathway for the disposal of excess nitrogen, which arises primarily as ammonia. Nitrogen is essential for growth and life-maintenance, but excessive ammonia leads to life-threatening conditions. The urea cycle disorders (UCDs) comprise diseases presenting with hyperammonemia that arise in either the neonatal period (about 50% of cases) or later. Congenital defects of the enzymes or transporters of the urea cycle cause the disease. This cycle utilizes five enzymes, two of which, carbamoylphosphate synthetase 1 and ornithine transcarbamylase are present in the mitochondrial matrix, whereas the others (argininosuccinate synthetase, argininosuccinate lyase and arginase 1) are present in the cytoplasm. In addition, N-acetylglutamate synthase and at least two transporter proteins are essential to urea cycle function. Severity and age of onset depend on residual enzyme or transporter function and are related to the respective gene mutations. The strategy for therapy is to prevent the irreversible toxicity of high-ammonia exposure to the brain. The pathogenesis and natural course are poorly understood because of the rarity of the disease, so an international registry system and novel clinical trials are much needed. We review here the current concepts of the pathogenesis, diagnostics, including genetics and treatment of UCDs.

Psychometric profile of the Ages and Stages Questionnaires, Japanese translation.

BACKGROUND: This study assessed the psychometric profile of 10 questionnaires (every 6 months, from 6 to 60 months) from the Japanese translation of the Ages and Stages Questionnaires, third edition (J-ASQ-3). METHODS: Data from 439 children in a birth cohort were used to identify the J-ASQ-3 score distribution, establish cut-off scores, and calculate the instrument's internal consistency. Data were also collected from 491 outpatients to examine J-ASQ-3 test-retest reliability and concurrent validity, which was examined using the Kyoto Scale of Psychological Development (KSPD) and the Japanese version of the Denver Developmental Screening Test II (J-Denver II). Both the original and the alternative screening criteria of the ASQ-3 were used (failure in at least one and at least two domains, respectively). RESULTS: Cronbach's alpha for each J-ASQ-3 subscale on each questionnaire ranged from 0.45 to 0.89. Test-retest reliability was >0.75 for the subscales on almost all questionnaires. Concurrent validity was also adequate. In comparison with the screening results of the KSPD, the overall sensitivity and specificity were 96.0% and 48.8%, respectively, when the ASQ-3 original criterion was used, and 92.1% and 74.9%, respectively, when the alternative criterion was used. In comparison with the screening results of the J-Denver II, the overall sensitivity and specificity were 75.6% and 74.7%, respectively, when the ASQ-3 original criterion was used, and 56.3% and 93.0%, respectively, when the alternative criterion was used. CONCLUSIONS: This study quantified the psychometric profiles of the Japanese translations of 10 ASQ-3 questionnaires. We demonstrated the validity of the J-ASQ-3 and determined new cut-off scores. Further studies with larger samples from a greater range of locations are required to clarify the suitability of this tool for all Japanese children.

Medium-chain triglycerides supplement therapy with a low-carbohydrate formula can supply energy and enhance ammonia detoxification in the hepatocytes of patients with adult-onset type II citrullinemia.

Citrin, encoded by SLC25A13, constitutes the malate-aspartate shuttle, the main NADH-shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Citrin deficiency is predicted to impair hepatic glycolysis and de novo lipogenesis, resulting in hepatic energy deficit. Secondary decrease in hepatic argininosuccinate synthetase (ASS1) expression has been considered a cause of hyperammonemia in CTLN2. We previously reported that medium-chain triglyceride (MCT) supplement therapy with a low-carbohydrate formula was effective in CTLN2 to prevent a relapse of hyperammonemic encephalopathy. We present the therapy for six CTLN2 patients. All the patients' general condition steadily improved and five patients with hyperammonemic encephalopathy recovered from unconsciousness in a few days. Before the treatment, plasma glutamine levels did not increase over the normal range and rather decreased to lower than the normal range in some patients. The treatment promptly decreased the blood ammonia level, which was accompanied by a decrease in plasma citrulline levels and an increase in plasma glutamine levels. These findings indicated that hyperammonemia was not only caused by the impairment of ureagenesis at ASS1 step, but was also associated with an impairment of glutamine synthetase (GS) ammonia-detoxification system in the hepatocytes. There was no decrease in the GS expressing hepatocytes. MCT supplement with a low-carbohydrate formula can supply the energy and/or substrates for ASS1 and GS, and enhance ammonia detoxification in hepatocytes. Histological improvement in the hepatic steatosis and ASS1-expression was also observed in a patient after long-term treatment.

Recovery of severe acute liver failure without transplantation in patients with Wilson disease.

Wilson disease (WD) is a disorder of copper metabolism that leads to liver cirrhosis. WD patients with a NWIS > 11 should receive LT; however, we encountered 2 WD patients with an NWIS > 11 who recovered from ALF without LT. The present report aimed to analyze cases of WD patients with a high NWIS who recovered from severe ALF and to discuss the clinical manifestations of the patients and the effects of treatments, including zinc (Zn) therapy, chelator therapy, PE, CHDF, and LT. We retrospectively evaluated the medical records of five patients (male, 2; female, 3) diagnosed with WD along with severe ALF. In cases 1, 2, and 3, complete recovery from ALF was noted without LT. In case 4, initial recovery from ALF was noted without LT; however, ALF worsened owing to bleeding from the esophageal varix. Thus, the patient eventually needed LT. In case 5, recovery from ALF was noted with LT. All cases, except case 2, showed ALF with maximum PELD/MELD scores ≥26 and NWISs ≥ 11, and had indications for LT. In cases of severe ALF with grade I or II encephalopathy, we recommend evaluations of the effects of Zn and chelator treatments while preparing for LT, as the condition may not improve without LT, and pediatricians or physicians can ask transplant surgeons to perform LT urgently if required.

A Significant Difference in the Blood Carnitine Values Obtained by the Enzymatic Cycling and Tandem Mass Spectrometry Methods.

BACKGROUND: There are no reports in the literature of blood samples obtained from the same individual being subjected to analysis at the same time using the enzymatic cycling (EC) method along with electrospray tandem mass spectrometry (ESI/MS/MS) before and after carnitine treatment. METHODS: Blood samples from 29 patients (median age: 73 years old, age range: 41 - 89 years) receiving regular hemodialysis for chronic renal failure before and after carnitine treatment for 3 months were measured by the EC method, and using a dried blood spot (DBS) and ESI/MS/MS. RESULTS: Before the carnitine treatment, the rate of increase or decrease in the free and acyl-carnitine levels of the DBS using the ESI/MS/MS method to those measured by the EC methods was a median of -28.6% (-36.0 to -14.1%) and -20.8% (-30.0 to 1.5%), respectively. After carnitine treatment, the rate of increase or decrease in the free and acyl-carnitine levels of the DBS with the ESI/MS/MS method compared to the EC method was a median of 52.0% (28.4 to 66.7%) and -31.9% (-47.2 to -21.1%), respectively. CONCLUSIONS: There were significant differences in the blood carnitine values using the ESI/MS/MS and EC methods. Caution should be exercised when evaluating DBS values measured by the ESI/MS/MS method.

Factors associated with occupation changes after pregnancy/delivery: result from Japan Environment & Children's pilot study.

BACKGROUND: In Japan, although the number of females who continue to work after marriage has recently increased, the proportion of those working while parenting their infants is still not clearly increasing, indicating that it is still difficult for them to continue working after delivery. The present study aimed to clarify factors influencing females' continuation of work, using data obtained by continuously following up the same subjects and focusing on occupation changes, family environments, and the type of employment after pregnancy or delivery. METHODS: Based on the results of the questionnaire survey, which was conducted involving 164 participants at 4 universities, as part of the Japan Environment and Children's Pilot Study (JECS Pilot Study) led by the Ministry of Environment and the National Institute for Environmental Studies, the occupational status was compared between the detection of pregnancy (weeks 0 to 7) and 1 year after delivery. RESULTS: compared with changed their occupations significantly more frequently (OR = 5.07, 95% CI = 2.57-10.01, P < 0.001). Furthermore, on examining in detail, occupation changes were particularly marked among (OR = 12.48, 95% CI = 4.43-35.15, P < 0.001). This tendency was especially shown among < > (OR = 10.36, 95% CI = 1.59-67.38, P = 0.014) and < > (OR = 15.15, 95% CI = 2.55-90.17, P = 0.003). CONCLUSIONS: Analysis revealed that the type of employment, rather than the category of occupation, was associated with the continuation of work after pregnancy or delivery more closely, as compared with continued to work less frequently. Furthermore, on comparison of the category of occupation among , < > and < > were shown to be more likely to continue to be engaged in the same occupation after pregnancy or delivery. These differences may be related to availability of the child-care leave program and other support resources, therefore, it may be important to establish social systems that enable all females, to use these support resources if they wish, and actively work, while delivering and parenting their children.

Early liver transplantation in neonatal-onset and moderate urea cycle disorders may lead to normal neurodevelopment.

Urea cycle disorders (UCDs) are inherited metabolic diseases that lead to hyperammonemia. Neurodevelopmental outcomes of patients with UCDs depend on the maximum ammonia concentration (MAC) in the blood during onset. MAC ≥360 µM is a marker of poor neurodevelopmental outcomes. We investigated the neurodevelopmental outcomes and MAC at onset for 177 patients with UCDs in Japan (median age, 8 years and 2 months; range, 10 days-72 years), including 57 patients with male ornithine transcarbamylase (OTCD), 59 patients with female OTCD, 23 patients with carbamoyl-phosphate synthetase 1 deficiency (CPSD), 28 patients with arginosuccinate synthetase deficiency, 9 patients with arginosuccinate lyase deficiency (ALD), and 1 patient with arginase 1 deficiency. Neurodevelopmental outcomes of patients with CPSD and ALD were poor because most had neonatal onset with blood MAC ≥300 µM at onset. Although OTCD, particularly female late-onset OTCD, has good neurodevelopmental outcomes among those with UCDs, it is not necessarily a mild disease with good long-term outcomes. Patients with severe UCDs and MAC ≥300 µM at onset should undergo liver transplantation (LT). Moreover, this study suggested that if the onset of UCD began during the neonatal period, then even UCD patients with MAC <300 µM at onset should undergo LT to protect the brain.

Early-onset neonatal hyperkalemia associated with maternal hypermagnesemia: a case report.

BACKGROUND: Neonatal nonoliguric hyperkalemia (NOHK) is a metabolic abnormality that occurs in extremely premature neonates at approximately 24 h after birth and is mainly due to the immature functioning of the sodium (Na+)/potassium (K+) pump. Magnesium sulfate is frequently used in obstetrical practice to prevent preterm labor and to treat preeclampsia; this medication can also cause hypermagnesemia and hyperkalemia by a mechanism that is different from that of NOHK. Herein, we report the first case of very early-onset neonatal hyperkalemia induced by maternal hypermagnesemia. CASE PRESENTATION: A neonate born at 32 weeks of gestation developed hyperkalemia (K+ 6.4 mmol/L) 2 h after birth. The neonate's blood potassium concentration reached 7.0 mmol/L 4 h after birth, despite good urine output. The neonate and his mother had severe hypermagnesemia caused by intravenous infusion of magnesium sulfate given for tocolysis due to pre-term labor. CONCLUSION: The early-onset hyperkalemia may have been caused by the accumulation of potassium ions transported through the placenta, the shift of potassium ions from the intracellular to the extracellular space in the infant due to the malfunctioning of the Na+/K+ pump and the inhibition of renal distal tube potassium ion secretion, there is a possibility that these mechanisms were induced by maternal and fetal hypermagnesemia after maternal magnesium sulfate administration. Because neonatal hyperkalemia poses a significant risk for the development of life-threatening cardiac arrhythmia, this case highlights the necessity of maternal blood magnesium monitoring during magnesium sulfate administration and neonatal blood potassium monitoring when there is severe maternal hypermagnesemia at delivery.

Regional differences in infant 25-Hydroxyvitamin D: Pilot study of the Japan Environment and Children's Study.

BACKGROUND: In recent years, a resurgence in the number of infants with vitamin D deficiency has been noted. In addition to seasonal differences in exposure to ultraviolet (UV) rays, regional differences in dietary habits and lifestyles may affect susceptibility to vitamin D deficiency. No studies have been conducted, however, on infants in multiple regions of Japan to determine the extent of differences in vitamin D status. METHODS: 25-Hydroxyvitamin D (25OHD) was measured on radioimmunoassay in 126 infants aged 2-4 years, who participated in the Pilot Study of the Japan Environment and Children's Study (JECS) by the Ministry of Environment of Japan. A multiple regression model with 25OHD level as the outcome variable, and season and region as explanatory variables, was generated. RESULTS: Both region and season during which infants participated in this study significantly affected 25OHD level (P = 0.0087 and <0.0001, respectively; Wald test). Reflecting decreased exposure to UV rays, infants who were examined in winter had lower 25OHD than those examined in summer. Infants from both Fukuoka Prefecture (33°N) and Kumamoto Prefecture (32°N), however, had lower 25OHD than those from Tochigi Prefecture (36°N), contrary to expectations given the extent of UV exposure. CONCLUSIONS: Regional differences in daily habits and/or environmental factors affect 25OHD level in Japanese infants. The JECS is expected to identify those factors to provide guidance on preventing infantile vitamin D deficiency.

Plasma exchange and chelator therapy rescues acute liver failure in Wilson disease without liver transplantation.

AIM: Wilson disease (WD) in patients with a New Wilson Index (NWI) score ≥ 11 is fatal, and these patients are good candidates for liver transplantation (LT). However, plasma exchange and chelator therapy are indispensable and effective even for WD with a score ≥ 11. Moreover, continuous hemodiafiltration (CHDF) with these treatments is essential for acute liver failure (ALF) in WD with hepatic encephalopathy because CHDF can exclude toxic metabolites that may cause damage to the brain. Here, we describe four rescued patients presenting with ALF in WD and discuss the available treatment options. METHODS: We have experienced 11 male and 8 female patients presenting with WD at the Department of Pediatrics, Kumamoto University Hospital between 1999 and 2014. A male and 4 female patients were diagnosed as WD with ALF using a combination of clinical findings and biochemical tests. RESULTS: The NWI score was ≥ 11 in cases 1 to 3. Cases 1 and 2 with hepatic encephalopathy received plasma exchange, CHDF, coagulation factor replacement treatment (CFRT) and LT. Cases 3 and 4 without encephalopathy obtained stable status without LT by plasma exchange, blood infusion, and CFRT. CONCLUSIONS: It is better to undergo LT for WD patients with a NWI score ≥ 11, however, there is a possibility of remission by plasma exchange and medical therapy even without LT. WD patients with a NWI score ≥ 11can be rescued by conservative therapy when the ALF of WD does not present with ALF and hepatic encephalopathy. Therefore, ALF with hepatic encephalopathy itself is an indication for LT in WD.

Liver transplantation may prevent neurodevelopmental deterioration in high-risk patients with urea cycle disorders.

UCDs are among the most common inherited metabolic diseases in Japan. We investigated the clinical manifestations, treatment, and prognoses of 177 patients with UCDs who were evaluated and treated from January 1999 to March 2009 in Japan, using a questionnaire survey. Among these 177 patients, 42 (seven with carbamoyl phosphate synthetase 1 deficiency, 27 with ornithine transcarbamylase deficiency, seven with argininosuccinate synthetase deficiency, and one with arginase 1 deficiency) underwent living-donor LT. Although this study was retrospective and included limited neurodevelopmental information before and after LT, we evaluated whether LT could improve neurodevelopmental outcomes in patients with UCDs. The neurodevelopmental outcomes of patients with a MAC of <300 µmol/L at the time of onset were not significantly different between the LT and non-LT groups (P=.222). LT may have prevented further neurodevelopmental complications in children with MAC ≥300 µmol/L (P=.008) compared with non-transplant management. Therefore, Liver transplant should be considered in patients with UCD with a MAC of ≥300 µmol/L at the time of disease onset.

Medically dependent severe motor and intellectual disabilities: Time study of medical care.

BACKGROUND: Improvements in neonatal medicine and pediatric emergency medicine have led to an increasing number of children with severe disabilities requiring medical care, such as tracheal suction, on a daily basis. Most of these children, discharged directly from hospitals to their parents' homes, need home medical support. To provide data for the establishment of appropriate support systems, we analyzed the care for such children in a time study conducted at an institution. METHODS: A minute-by-minute time study of the work of 33 staff members in a ward for patients (medically dependent severe motor and intellectual disabilities [SMID]) requiring frequent medical care was carried out over 48 h. Data were compared with those from a ward for ordinary non-medically dependent SMID patients. RESULTS: Time of life care for medically dependent SMID and ordinary SMID was almost identical, but the time for medical care for the former was 10-fold longer than that of the latter. Also, tasks involving information exchange and recording of the time of care were performed fourfold more frequently in the medically dependent SMID than in the ordinary SMID ward. CONCLUSIONS: Medically dependent SMID children and adults, predominantly with tracheostomies, needed much more medical care and more concentrated involvement of the staff compared with ordinary SMID. This study provides valuable data for the development of support systems for medically dependent SMID children being cared for at home. In addition, it sheds light on the situation faced by non-SMID children requiring frequent medical care.

Citrulline for urea cycle disorders in Japan.

BACKGROUND: The amino acid l-citrulline is used as a therapeutic agent for urea cycle disorders (UCD) including ornithine transcarbamylase deficiency (OTCD), carbamoyl phosphate synthetase I deficiency (CPSD), and N-acetylglutamate synthase deficiency. There are few reports, however, on the use of l-citrulline in Japan and little consensus regarding the effects of l-citrulline. METHODS: We conducted a questionnaire survey of patients undergoing l-citrulline treatment for a UCD to evaluate the current status of this therapy. The survey included patient background, details of l-citrulline treatment, clinical examination data, treatment, frequency of vomiting, and liver transplantation. RESULTS: We retrospectively investigated 43 questionnaire respondents (OTCD, n = 33; CPSD, n = 10). The weight of male OTCD patients improved by +0.79 SD, and the ammonia level decreased by a mean of 44.3 µmol/L in all patients. The protein intake of all patients and of male OTCD patients increased by 0.14 g/kg/day and 0.17 g/kg/day, respectively. CONCLUSIONS: l-Citrulline effectively reduced ammonia level, increased protein intake, and improved weight gain in UCD patients. l-Citrulline should be considered a standard therapy in OTCD and CPSD patients.