Measures for the Prevention of Mother-to-Child Human T-Cell Leukemia Virus Type 1 Transmission in Japan: The Burdens of HTLV-1-Infected Mothers.

The main mode of mother-to-child transmission of the human T-cell leukemia virus (HTLV)-1 is through breastfeeding. Although the most reliable nutritional regimen to prevent HTLV-1 transmission is exclusive formula feeding, a recent meta-analysis revealed that short-term breastfeeding within 90 days does not increase the risk of infection. The protocol of the Japanese Health, Labor, and Welfare Science Research Group primarily recommended exclusive formula feeding for mothers who are positive for HTLV-1. However, there has been no quantitative research on the difficulties experienced by HTLV-1-positive mothers in carrying out these nutritional regimens, including the psychological burden. Therefore, this review was performed to clarify the burdens and difficulties encountered by mothers who are positive for HTLV-1; to this end, we analyzed the data registrants on the HTLV-1 career registration website "Carri-net" website. The data strongly suggest that it is not sufficient to simply recommend exclusive formula feeding or short-term breastfeeding as a means of preventing mother-to-child transmission; it is important for health care providers to understand that these nutritional regimens represent a major burden for pregnant women who are positive for HTLV-1 and to provide close support to ensure these women's health.

How Can We Prevent Mother-to-Child Transmission of HTLV-1?

The perception of human T-cell leukemia virus type 1 (HTlV-1) infection as a "silent disease" has recently given way to concern that its presence may be having a variety of effects. HTLV-1 is known to cause adult T-cell leukemia (ATL), an aggressive cancer of peripheral CD4 T cells; however, it is also responsible for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Most patients develop ATL as a result of HTLV-1 mother-to-child transmission. The primary route of mother-to-child transmission is through the mother's milk. In the absence of effective drug therapy, total artificial nutrition such as exclusive formula feeding is a reliable means of preventing mother-to-child transmission after birth, except for a small percentage of prenatal infections. A recent study found that the rate of mother-to-child transmission with short-term breastfeeding (within 90 days) did not exceed that of total artificial nutrition. Because these preventive measures are in exchange for the benefits of breastfeeding, clinical applications of antiretroviral drugs and immunotherapy with vaccines and neutralizing antibodies are urgently needed.

Mother-to-Child Transmission of Human T-Cell Leukemia Virus Type 1: Mechanisms and Nutritional Strategies for Prevention.

Approximately 95% of mother-to-child transmission (MTCT) of human T-cell leukemia virus type-1 (HTLV-1) is derived from prolonged breastfeeding, which is a major cause of adult T-cell leukemia (ATL). Exclusive formula feeding (ExFF) is therefore generally used to prevent MTCT. A recent cohort study revealed that 55% of pregnant carriers chose short-term breastfeeding for ≤3 months in Japan. Our meta-analysis showed that there was no significant increase in the risk of MTCT when breastfeeding was carried out for ≤3 months compared with ExFF (pooled relative risk (RR), 0.72; 95% confidence interval (CI), 0.30-1.77), but there was an almost threefold increase in risk when breastfeeding was carried out for up to 6 months (pooled RR, 2.91; 95% CI, 1.69-5.03). Thus, short-term breastfeeding for ≤3 months may be useful in preventing MTCT. Breastmilk is the best nutritional source for infants, and any approach to minimizing MTCT by avoiding or limiting breastfeeding must be balanced against the impact on the child's health and mother-child bonding. To minimize the need for nutritional interventions, it is necessary to identify factors that predispose children born to carrier mothers to MTCT and thereby predict MTCT development with a high degree of accuracy.

The Effect of Early Postnatal Nutrition on Human T Cell Leukemia Virus Type 1 Mother-to-Child Transmission: A Systematic Review and Meta-Analysis.

The main route of mother-to-child transmission (MTCT) of human T cell leukemia virus type 1 is vertical transmission via breastfeeding. Although the most reliable method for preventing MCTC is exclusive formula feeding (ExFF), short-term breastfeeding (STBF) or frozen-thawed breast milk feeding (FTBMF) has been offered as an alternative method if breastfeeding is strongly desired. The aim of this review was to clarify the pooled risk ratio of MCTC of STBF and FTBMF compared with ExFF. This study was registered with PROSPERO (number 42018087317). A literature search of PubMed, CINAHL, the Cochrane Database, EMBASE, and Japanese databases through September 2018 identified 1979 articles, 10 of which met the inclusion criteria. Finally, 11 articles, including these 10 studies and the report of a recent Japanese national cohort study, were included in the meta-analysis. The pooled relative risks of STBF ≤3 months, STBF ≤6 months, and FTBMF compared with ExFF were 0.72 (95% confidence interval (CI): 0.30-1.77; p = 0.48), 2.91 (95% CI: 1.69-5.03; p = 0.0001), and 1.14 (95% CI: 0.20-6.50; p = 0.88), respectively. This meta-analysis showed no statistical difference in the risk of MTCT between STBF ≤3 months and ExFF, but the risk of MTCT significantly increased in STBF ≤6 months.

Issues of infant feeding for postnatal prevention of human T-cell leukemia/lymphoma virus type-1 mother-to-child transmission.

BACKGROUND: Nationwide antenatal human T-cell leukemia/lymphoma virus type-1 (HTLV-1) antibody screening has been conducted in Japan. The purpose of our study was to clarify the issues related to feeding options to prevent postnatal mother-to-child transmission. METHODS: Of the pregnant carriers at 92 facilities in Japan between 2012 and 2015, 735 were followed prospectively. Among the children born to them, 313 (42.6%) children were followed up to the age of 3 and tested for HTLV-1 antibodies. The mother-to-child transmission rate was calculated for each feeding option selected before birth. RESULTS: Among the 313 pregnant carriers, 55.0, 35.1, 6.1, and 3.8% selected short-term breast-feeding (≤3 months), exclusive formula feeding, frozen-thawed breast-milk feeding, and longer-term breast-feeding, respectively. Despite short-term breast-feeding, 8-18% of the mothers continued breast-feeding for 4-6 months. The mother-to-child transmission rate with short-term breast-feeding was 2.3% (4/172), and its risk ratio compared with that of exclusive formula feeding was not significantly different (0.365; 95% CI: 0.116-1.145). Because of the small number of children who were fed by frozen-thawed breast-milk, their mother-to-child transmission rate was not statistically reliable. CONCLUSIONS: Pregnant HTLV-1 carriers tended to select short-term breast-feeding in Japan. While short-term breast-feeding was not always easy to wean within 3 months, it may be a viable option for preventing postnatal mother-to-child transmission because the vertical transmission rate with short-term breast-feeding was not significantly higher than that with exclusive formula feeding. Increasing the follow-up rates for children born to pregnant carriers may provide clearer evidence of preventative effects by short-term breast-feeding and frozen-thawed breast-milk feeding.

Establishment of a novel diagnostic test algorithm for human T-cell leukemia virus type 1 infection with line immunoassay replacement of western blotting: a collaborative study for performance evaluation of diagnostic assays in Japan.

BACKGROUND: The reliable diagnosis of human T-cell leukemia virus type 1 (HTLV-1) infection is important, particularly as it can be vertically transmitted by breast feeding mothers to their infants. However, current diagnosis in Japan requires a confirmatory western blot (WB) test after screening/primary testing for HTLV-1 antibodies, but this test often gives indeterminate results. Thus, this collaborative study evaluated the reliability of diagnostic assays for HTLV-1 infection, including a WB-based one, along with line immunoassay (LIA) as an alternative to WB for confirmatory testing. RESULTS: Using peripheral blood samples from blood donors and pregnant women previously serologically screened and subjected to WB analysis, we analyzed the performances of 10 HTLV-1 antibody assay kits commercially available in Japan. No marked differences in the performances of eight of the screening kits were apparent. However, LIA determined most of the WB-indeterminate samples to be conclusively positive or negative (an 88.0% detection rate). When we also compared the sensitivity to HTLV-1 envelope gp21 with that of other antigens by LIA, the sensitivity to gp21 was the strongest. When we also compared the sensitivity to envelope gp46 by LIA with that of WB, LIA showed stronger sensitivity to gp46 than WB did. These findings indicate that LIA is an alternative confirmatory test to WB analysis without gp21. Therefore, we established a novel diagnostic test algorithm for HTLV-1 infection in Japan, including both the performance of a confirmatory test where LIA replaced WB on primary test-reactive samples and an additional decision based on a standardized nucleic acid detection step (polymerase chain reaction, PCR) on the confirmatory test-indeterminate samples. The final assessment of the clinical usefulness of this algorithm involved performing WB analysis, LIA, and/or PCR in parallel for confirmatory testing of known reactive samples serologically screened at clinical laboratories. Consequently, LIA followed by PCR (LIA/PCR), but neither WB/PCR nor PCR/LIA, was found to be the most reliable diagnostic algorithm. CONCLUSIONS: Because the above results show that our novel algorithm is clinically useful, we propose that it is recommended for solving the aforementioned WB-associated reliability issues and for providing a more rapid and precise diagnosis of HTLV-1 infection.

Implementation of nationwide screening of pregnant women for HTLV-1 infection in Japan: analysis of a repeated cross-sectional study.

BACKGROUND: Screening of pregnant women carrying human T-lymphotropic virus type 1 (HTLV-1) has a crucial role in reducing the number of HTLV-1 carriers. A national HTLV-1 screening program for pregnant women was started in 2011 in Japan. The purpose of this study is to report on the implementation of this nationwide screening program. METHODS: This was a retrospective repeated cross-sectional study. We used datasets from surveys of HTLV-1-antibody-positive pregnant women performed by the Japan Association of Obstetricians and Gynecologists in 2011, 2013, and 2016. Outcomes for evaluation included the number of persons (pregnant women) who conducted the screening test, the number of positive persons (women) identified by these tests, and the proportion of positive persons to the number of persons (women) who conducted the tests. RESULTS: Numbers of target facilities changed yearly: 1857 in 2011, 2544 in 2013, and 2376 in 2016. The mean number of screening-test participants increased per facility, but the median increased or decreased. The mean number of positive individuals identified decreased. Multivariate analysis results revealed the number of screenings was slightly reduced yearly, although areas (Kanto and Kinki) and high volume in facility types increased. Regarding the positive rates, some areas (Hokkaido/Tohoku, Kanto, and Chugoku/Shikoku) exhibited decreases or increases by facility type. The number of western blotting (WB) implementations decreased in 2016, positive rates identified by WB decreased in 2016 in all areas, and the number of facility types increased. The number of PCR participants increased in 2016 in Kanto and Kinki, but a decrease in facility type was observed. Positive rates were decreased in all areas (except the central region) but facility types were increased. CONCLUSIONS: The nationwide screening program for HTLV-1 in Japan was almost fully implemented. However, regional variations in screening tests were observed during this implementation. Thus, some incentives are needed to encourage proper implementation across all regions.

A Nationwide Antenatal Human T-Cell Leukemia Virus Type-1 Antibody Screening in Japan.

Japan has been running a nationwide antenatal human T-cell leukemia virus type-1 (HTLV-1) antibody screening program since 2010 for the prevention of HTLV-1 mother-to-child transmission. As part of the program, pregnant women are invited to take an HTLV-1 antibody screening test, usually within the first 30 weeks of gestation, during regular pregnancy checkups. Pregnant women tested positive on the antibody screening test undergo a confirmatory test, either western blotting or line immunoassay. In indeterminate case, polymerase chain reaction (PCR) is used as a final test to diagnose infection. Pregnant women tested positive on a confirmatory or PCR test are identified as HTLV-1 carriers. As breastfeeding is a predominant route of postnatal HTLV-1 mother-to-child transmission, exclusive formula feeding is widely used as a postnatal preventive measure. Although there is insufficient evidence that short-term breastfeeding during ≤3 months does not increase the risk of mother-to-child transmission compared to exclusive formula feeding, this feeding method is considered if the mother is eager to breastfeed her child. However, it is important that mothers and family members fully understand that there is an increase in the risk of mother-to-child transmission when breastfeeding would be prolonged. As there are only a few clinical studies on the protective effect of frozen-thawed breastmilk feeding on mother-to-child transmission of HTLV-1, there is little evidence to recommend this feeding method. Further study on the protective effects of these feeding methods are needed. It is assumed that the risk of anxiety or depression may increase in the mothers who selected exclusive formula feeding or short-term breastfeeding. Thus, an adequate support and counseling for these mothers should be provided. In addition to raising public awareness of HTLV-1 infection, epidemiological data from the nationwide program needs to be collected and analyzed. In most cases, infected children are asymptomatic, and it is necessary to clarify how these children should be followed medically.

Bacteriuria With CTX-M-8 Extended-Spectrum ß-Lactamase-Producing Escherichia coli in a Patient With Incomplete Kawasaki Disease.

We report the case of a 2-month-old infant with incomplete Kawasaki disease that presented as an apparent urinary tract infection. The patient's fever persisted despite antibiotic treatment. Intravenous immunoglobulin and aspirin therapy cured both the incomplete Kawasaki disease and bacterial pyuria. Renal sonography, voiding cystourethrography, and renal parenchyma radionuclide scanning did not detect any abnormalities. Temporary dilation of the coronary artery was noted. In a urine specimen obtained through transurethral catheterization, the growth of 105 colony-forming units/mL of extended-spectrum ß-lactamase-producing Escherichia coli was detected. Polymerase chain reaction analysis revealed that the enzyme genotype was CTX-M-8, which is a rare type in Japan. In conclusion, attention should be paid to a misleading initial presentation of fever and pyuria, which might be interpreted as urinary tract infection in patients with Kawasaki disease. Furthermore, pediatricians should consider incomplete Kawasaki disease when patients present with fever and pyuria, which are consistent with urinary tract infection, but do not respond to antibiotic treatment.

Proviral Features of Human T Cell Leukemia Virus Type 1 in Carriers with Indeterminate Western Blot Analysis Results.

Western blotting (WB) for human T cell leukemia virus type 1 (HTLV-1) is performed to confirm anti-HTLV-1 antibodies detected at the initial screening of blood donors and in pregnant women. However, the frequent occurrence of indeterminate results is a problem with this test. We therefore assessed the cause of indeterminate WB results by analyzing HTLV-1 provirus genomic sequences. A quantitative PCR assay measuring HTLV-1 provirus in WB-indeterminate samples revealed that the median proviral load was approximately 100-fold lower than that of WB-positive samples (0.01 versus 0.71 copy/100 cells). Phylogenic analysis of the complete HTLV-1 genomes of WB-indeterminate samples did not identify any specific phylogenetic groups. When we analyzed the nucleotide changes in 19 HTLV-1 isolates from WB-indeterminate samples, we identified 135 single nucleotide substitutions, composed of four types, G to A (29%), C to T (19%), T to C (19%), and A to G (16%). In the most frequent G-to-A substitution, 64% occurred at GG dinucleotides, indicating that APOBEC3G is responsible for mutagenesis in WB-indeterminate samples. Moreover, interestingly, five WB-indeterminate isolates had nonsense mutations in Pol and/or Tax, Env, p12, and p30. These findings suggest that WB-indeterminate carriers have low production of viral antigens because of a combination of a low proviral load and mutations in the provirus, which may interfere with host recognition of HTLV-1 antigens.

AICAR Attenuates TNFα-Induced Inappropriate Secretion of Monocyte Chemoattractant Protein-1 and Adiponectin in 3T3-L1 Adipocytes.

AIM: The increase in monocyte chemoattractant protein-1 (MCP-1) and the decrease in adiponectin production from hypertrophic adipocytes are associated with adipose tissue inflammation and its metabolic complications. The aim of this study was to determine whether 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR), an adenosine monophosphate-activated protein kinase (AMPK) activator, modulates these adipocytokine productions in tumor necrosis factor-α (TNFα)-treated adipocytes. METHODS: AICAR and/or other reagents were added to the culture medium, and then, TNFα was added to fully differentiated 3T3-L1 adipocytes. The MCP-1 and adiponectin production in the culture supernatant was measured by ELISA. AMPK, phosphatidylinositol 3-kinase (PI3K), and nuclear factor-κB (NF-κB) activities were also assayed. RESULTS: Treatment with TNFα increased MCP-1 and decreased adiponectin secretion dose-dependently in the 3T3-L1 adipocytes, and AICAR significantly inhibited these TNFα-mediated changes. Interestingly, metformin, another AMPK activator, did not have such effects on these adipocytokines. Both the AMPK and PI3K systems in the cells were significantly activated by the AICAR treatment, but the effects of AICAR on adipocytokines were not weakened by the addition of dorsomorphin, an AMPK inhibitor, or LY294002, a PI3K inhibitor. Pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, showed protective effects similar to those as AICAR. AICAR, but not metformin, significantly inhibited the TNFα-stimulated activation of NF-κB, and dorsomorphin did not change AICAR's effect. CONCLUSION: AICAR attenuates the TNFα-induced secretion of MCP-1 and adiponectin in 3T3-L1 adipocytes. The observed effects of AICAR seem to be mainly due to the inhibition of NF-κB activation rather than the activation of the AMPK pathway, at least in TNFα-treated adipocytes.

Standardization of Quantitative PCR for Human T-Cell Leukemia Virus Type 1 in Japan: a Collaborative Study.

Quantitative PCR (qPCR) analysis of human T-cell leukemia virus type 1 (HTLV-1) was used to assess the amount of HTLV-1 provirus DNA integrated into the genomic DNA of host blood cells. Accumulating evidence indicates that a high proviral load is one of the risk factors for the development of adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis. However, interlaboratory variability in qPCR results makes it difficult to assess the differences in reported proviral loads between laboratories. To remedy this situation, we attempted to minimize discrepancies between laboratories through standardization of HTLV-1 qPCR in a collaborative study. TL-Om1 cells that harbor the HTLV-1 provirus were serially diluted with peripheral blood mononuclear cells to prepare a candidate standard. By statistically evaluating the proviral loads of the standard and those determined using in-house qPCR methods at each laboratory, we determined the relative ratios of the measured values in the laboratories to the theoretical values of the TL-Om1 standard. The relative ratios of the laboratories ranged from 0.84 to 4.45. Next, we corrected the proviral loads of the clinical samples from HTLV-1 carriers using the relative ratio. As expected, the overall differences between the laboratories were reduced by half, from 7.4-fold to 3.8-fold on average, after applying the correction. HTLV-1 qPCR can be standardized using TL-Om1 cells as a standard and by determining the relative ratio of the measured to the theoretical standard values in each laboratory.

Proteinuria caused by glomerular hypertension during adolescence associated with extremely premature birth: a report of two cases.

BACKGROUND: Prematurity and low birth weight are risk factors for the future development of chronic kidney disease (CKD) and hypertension caused by fewer nephrons with limited filtration surface area. Few reports to date have evaluated their clinical backgrounds and pathological findings, including glomerular hypertension and focal segmental glomerulosclerosis. CASE-DIAGNOSIS/TREATMENT: This report describes two patients, a 15-year-old girl (patient 1), with a birth weight of 618 g and a gestational age of 24 weeks, and a 14-year-old boy (patient 2), with a birth weight of 842 g and a gestational age at 25 weeks. Both had a birth weight appropriate for gestational age. Both were first diagnosed with proteinuria during adolescence, and patient 2 also had hypertension. Pathological findings included glomerulomegaly in both and hypertrophy of the juxtaglomerular apparatus and perihilar glomerulosclerosis in patient 1, suggesting glomerular hypertension. Treatment with lisinopril resulted in the immediate disappearance of proteinuria. Renal dysfunction was observed in both patients, but neither showed evidence of severe aggravation after a follow-up of 5 or 6 years. CONCLUSIONS: Proteinuria in both patients was caused by glomerular hypertension with hyperfiltration. Extremely preterm birth itself may be a risk factor for future CKD. Long-term follow-up of patients born prematurely and at low birth weight, including urinalysis and blood pressure measurements, is necessary to diagnose and treat late renal complications.

Perinatal dioxin exposure and psychosocial and behavioral development in school-aged children.

OBJECTIVE: The aim of this study was to elucidate the association between psychosocial and behavioral problems in children at school age and dioxin level in breast milk or estimated dioxin exposure (EDE) through breastfeeding in the general Japanese population. METHODS: Dioxin level of breast milk at 1month of age and breastfeeding ratio through the first year of life were used to calculate the EDE of infants born in 1998-2005 in Japan. The Japanese Social Difficulties Questionnaire (SDQ) for the assessment of children's behavior was sent by mail to mothers whose breast milk underwent the dioxin survey, at the time when their infants were aged 6-13 years. RESULTS: The study subjects were 175 pairs of mothers and their first infants (79 boys, 96 girls). The mean total dioxin levels of breast milk were 18.3 and 19.8 (pgTEQ/g fat) and EDEs were 16.4 and 19.6 (ngTEQ/kg/year) in boys and girls, respectively. In linear multiple regression analyses after adjusting for age at SDQ, maternal age, birth weight and maternal smoking habit, dioxin level in breast milk was not significantly related to the total difficulties score (TDS) of SDQ in boys, B=2.29 (95% CI -7.60-12.18), or in girls, B=-1.04 (95% CI -9.24-7.15). EDE correlated to the TDS in neither boys, B=-0.99 (95% CI -4.14-2.15), nor girls, B=1.08 (95% CI -2.69-4.85). CONCLUSION: No evidence was found of a correlation between perinatal dioxin exposure and behavioral and psychosocial problems of children measured by SDQ. These results support the benefits of recommending breastfeeding.

Renal function in angiotensinogen gene-mutated renal tubular dysgenesis with glomerular cysts.

BACKGROUND: Inherited renal tubular dysgenesis (RTD) is caused by mutations in the genes encoding the components of the renin-angiotensin system (RAS). RTD is characterized by oligohydramnios, renal failure, neonatal hypocalvaria, and severe hypotension. The histological characteristics, underlying mechanism, and long-term prognosis remain poorly known. CASE-DIAGNOSIS/TREATMENT: We describe here a 4-year-old female with RTD. Endocrinologic analysis showed a discrepancy between low plasma renin activity and high active renin concentration, suggesting a loss of the renin substrate, angiotensinogen (AGT). Direct sequencing revealed a frameshift deletion at nucleotide 1,355 in exon 5 in the AGT gene. Although a histological hallmark is regarded to be the absence or poor development of the proximal tubule, the patient does have minimally impaired function of the proximal tubule. Glomerular cysts without glomerular tufts were noted in approximately half of the glomeruli. The urinary concentrating ability and sodium reabsorption and potassium excretion in the distal nephron were severely affected. CONCLUSIONS: The patient has an impaired function of the distal nephron despite minimally affected function of the proximal tubule, probably attributed to renal tubular dysgenesis and fetal hypoperfusion. The renal tubular maturity and the severity of ischemic injury may be key determinants of the clinical symptoms and pathological findings in RTD, in which the RAS plays an important role.

[A case of lupus anticoagulant hypoprothrombinemia syndrome following adenovirus gastroenteritis and mycoplasma pneumonia].

We describe a previously healthy 9-year-old girl who had multiple purpura several days after acute adenovirus gastroenteritis and mycoplasma pneumonia. Initial laboratory evaluation revealed a prolonged prothrombin time (PT) and APTT, low complement levels (C4, CH50), and positive immune complex (C1q) in her serum. Platelet count, fibrinogen, and other routine blood chemistry tests were normal. The prolonged APTT was not corrected by mixture of the patient's plus normal plasma. Clotting activities of factors II, V, VIII, IX, X, XI, and XII reduced. Further examinations revealed the presence of lupus anticoagulant (LA), phosphatidylserine-dependent anti-prothrombin antibodies (aPS/PT), and anticardiolipin antibodies. Mycoplasma pneumonia was treated by minocycline and the patient's skin lesions disappeared spontaneously within a week. During follow-up, she showed no other bleeding symptoms, and no signs of SLE or other autoimmune diseases. Four weeks after admission to our hospital, blood coagulation tests and serum complements normalized. Clotting activities of factors and antiphospholipid antibodies were not detected, half year later. The bleeding in this case was associated with acquired hypoprothrombinemia caused by antiphospholipid antibodies following acute adenovirus gastroenteritis and mycoplasma pneumonia.

Restored left ventricular function following transcatheter closure of a persistent ductus arteriosus in an adult.

Recently, transcatheter device occlusion has become the first choice treatment for adult persistent ductus arteriosus (PDA). However, various complications such as atrial fibrillation requiring anticoagulation, pulmonary hypertension, and ventricular dysfunction may challenge the interventionist. We report a 61-year-old patient with a large PDA complicated by left ventricular dysfunction, atrial fibrillation, and left atrial thrombus. Computed tomography documented the PDA of Krichenko type A with the narrowest diameter of 8 mm. We successfully closed the PDA using an Amplatzer duct occluder under anticoagulation with wafarin. His post-operative course was complicated by ventricular tachycardia and deteriorating left ventricular pump function. Although endomyocardial biopsy from the left ventricle showed myocardial hypertrophy and interstitial fibrosis, possibly caused by chronic volume overload, left ventricular pump function improved dramatically with restoration of sinus rhythm during follow-up. Left ventricular dysfunction, even when associated with histological changes, may be nearly normalized by volume unloading in an adult with a large PDA. .

Retrospective multicenter survey on food-related symptoms suggestive of cow's milk allergy in NICU neonates.

BACKGROUND: Cow's milk allergy (CMA) is one of the causes of gastrointestinal symptoms in neonates. A relationship between non-immunoglobulin (Ig) E mediated allergic reactions and CMA in early infancy has been proposed, but the clinical features and pathogenesis have not been established. The objective of this study is to determine the clinical characteristics of the neonates found in the earlier study to have food-related symptoms that suggested CMA. METHODS: A second questionnaire was sent to 53 NICUs, as a follow-up to the earlier study, to collect information on the background, onset age, clinical features, and results of clinical examinations. RESULTS: The median birth weight was 2614g and the median gestational age was 36.9 weeks. Symptoms developed within 6 days after birth in 40% of cases. Gastrointestinal symptoms were seen in 90% of cases and were mainly vomiting, bloody stool and abdominal distention. A specific IgE test, a lymphocyte stimulation test, and a fecal eosinophil test were conducted in 88%, 23% and 55% of cases, respectively, and the positive rates were 30%, 84%, and 75%, respectively. An oral food challenge (OFC) test was performed in 26% for confirmation of the diagnosis. CONCLUSIONS: We confirmed that the clinical manifestations of food-related symptoms suggestive of CMA in neonates were distinctly different from those of common immediate type food allergy and were largely affected by underlying factors such as prematurity and gastroenterological surgery. Further OFC-based prospective accumulation of cases of CMA in neonates will be particularly important to reveal the full clinical features of this disease.