Terminal syringomyelia associated with lumbar limited dorsal myeloschisis.

PURPOSE: Limited dorsal myeloschisis (LDM) is characterized by a fibroneural tethering stalk linking the skin lesion to the underlying spinal cord. Terminal syringomyelia, which is located at the lower third of the cord, is often associated with a tethered cord caused by various spinal dysraphisms; however, terminal syringomyelia has not been documented in LDM. The purpose of this study was to clarify the pathophysiological mechanisms of syringomyelia in LDM. METHODS: In our 16 patients with lumbar LDM, three patients had terminal syringomyelia. We retrospectively analyzed the clinical, neuroradiological, intraoperative, and histopathological findings for these patients, with particular attention to the clinical course of the syrinx. RESULTS: Patient 1 had a saccular skin lesion and patients 2 and 3 had flat lesions. In all patients, the syringomyelic cavity was located in the lower thoracolumbar cord, immediately rostral to the stalk-cord attachment at the lumbar level. The caudal pole of the syrinx extended to the thickened stalk at the attachment instead of at the caudal cord. Patient 3 had another syrinx in the stalk itself. The longitudinal axis of the syrinx and central canal coincided with the traveling angle of the LDM stalk at the stalk-cord attachment. In patient 1, histology revealed an ependyma-lined central canal in both the LDM stalk and meningocele sac. Patients 1 and 2 underwent syringostomy, but long-term effects were not obtained. Preoperative spontaneous resolution occurred in patient 3. CONCLUSIONS: The histological findings in patient 1 supported the idea that segmental myelocystocele is involved in the development of saccular LDM. The hydromyelic central canal herniates and distends the stalk, resulting in the formation of the myelocystocele. It is possible that the hydromyelic central canal also distends the stalk of flat LDM lesions. The syrinx in patient 3 differed from that in patients 1 and 2, in that the syrinx resolved spontaneously. Further studies are needed to clarify the outcomes of syrinxes associated with LDM stalks.

Congenital interdural arachnoid cyst of the tentorium cerebelli.

BACKGROUND: Intracranial interdural cyst is a rare lesion. The exact pathophysiology of these cysts remains unknown. CLINICAL PRESENTATION: We report an infant with interdural cyst of the tentorium cerebelli. Although the cyst mimicked an arachnoid cyst on pre- and postnatal magnetic resonance images, lateral suboccipital craniotomy revealed the cyst within the tentorium. Fenestration on the infratentorial side was performed with successful results. Histologically, the inner surface of the cyst was lined with arachnoid cells. CONCLUSION: We report detailed neuroradiological, intraoperative, and histological findings, and discuss the pathophysiology of the cyst in this case.

Chemokine levels predict progressive liver disease in Down syndrome patients with transient abnormal myelopoiesis.

BACKGROUND: Transient abnormal myelopoiesis (TAM) is a neonatal preleukemic syndrome that occurs exclusively in neonates with Down syndrome (DS). Most affected infants spontaneously resolve, although some patients culminate in hepatic failure despite the hematological remission. It is impossible to determine the patients who are at high risk of progressive liver disease and leukemic transformation. The objective is to search for biomarkers predicting the development of hepatic failure in DS infants with TAM. METHODS: Among 60 newborn infants with DS consecutively admitted to our institutions from 2003 to 2016, 41 infants with or without TAM were enrolled for the study. Twenty-two TAM-patients were classified into "progression group" (n = 7) that required any therapy and "spontaneous resolution group" (n = 15). Serum concentrations of chemokines (CXCL8, CXCL9, CXCL10, CCL2 and CCL5) and transforming growth factor (TGF)-ß1 were measured at diagnosis of TAM for assessing the outcome of progressive disease. RESULTS: Three patients developed leukemia during the study period (median, 1147 days; range, 33-3753). Three died of hepatic failure. All patients in the progression group were preterm birth <37 weeks of gestational age and were earlier than those in the spontaneous resolution group (median, 34.7 vs. 37.0 weeks, p < 0.01). The leukocyte counts and CXCL8 and CCL2 levels at diagnosis in the progression group were higher than those in the spontaneous resolution group (leukocyte: median, 81.60 vs. 27.30 × 109/L, p = 0.01; CXCL8: 173.8 vs. 34.3 pg/ml, p < 0.01; CCL2: 790.3 vs. 209.8 pg/mL, p < 0.01). Multivariate analyses indicated that an increased CCL2 value was independently associated with the progression and CXCL8 with the death of liver failure, respectively (CCL2: standardized coefficient [sc], 0.43, p < 0.01; CXCL8: sc = -0.46, p = 0.02). CONCLUSION: High levels of circulating CXCL8 and CCL2 at diagnosis of TAM may predict progressive hepatic failure in DS infants.

Prolonged PR Interval at Birth Predicting the High Occurrence of Fatal Atrioventricular Block in Hypoplastic Left Heart Syndrome.

Infants with hypoplastic left heart syndrome (HLHS) are at high mortality especially when they are associated with bradyarrhythmias. However, the risk factor of developing high-grade atrioventricular block (HAVB) is still unclear. Seventy-three patients with HLHS in our institutions from 2002 to 2011 were enrolled. The survival rate was assessed by the anatomical types, treatments, occurrence of HAVB, severe tricuspid regurgitation (TR), and restrictive atrial septal defect (ASD) along with electrocardiogram findings at birth. There were 23 (32%) cardiogenic and 7 (10%) non-cardiogenic deaths. The occurrence rate of HAVB but not severe TR or restrictive ASD was higher in 30 deceased patients than in 43 survived patients [7 (23%) vs. 1 (2.3%), p = 0.0038]. The overall mortality rate was higher in patients with HAVB than in those without it (p = 0.0002). Of 7 deceased patients with HAVB, 6 HAVB occurred within 10 days post-surgery, and 3 HAVB led to the early death. The mortality rate of patients with prolonged PR (≥ 0.15 s) but not wide QRS (> 0.08 s) or prolonged QTc (> 0.43 s) at birth was higher than each without it (p = 0.0106). Multivariate analysis indicated that prolonged PR but no other variables was independently associated with the mortality (hazard ratio: 2.948, p = 0.0104). Prolonged PR at birth in HLHS infants predicts the development of fatal HAVB.

Serum neutrophil gelatinase-associated lipocalin as a predictor of the development of bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease mostly occurring in preterm infants. The pathogenesis of BPD involves early inflammation and remodeling of the premature lung. AIM: To search for the novel predictive marker of BPD development, we studied serum levels of neutrophil gelatinase-associated lipocalin (NGAL), an innate immune mediator, in preterm infants. METHODS: Serum NGAL concentrations at birth were measured by enzyme-linked immunosorbent assay. The reference levels were determined in 52 infants having no anomalies or inherited diseases. The levels and clinical variables were assessed in association with BPD. RESULTS: Geometric means (95%CI) of serum NGAL levels at birth of infants having no underlying diseases were 32.4 (22.1-47.5), 58.6 (47.9-71.8), and 126.2 (99.0-168.7) ng/mL for <31, 31-36 and >36 gestational weeks (GW), respectively (p<0.001). These levels positively correlated with neutrophil (p<0.0001) or monocyte counts (p<0.0001). The median NGAL levels (307.8 ng/mL) and neutrophil counts (4141/µL) at birth of 16 preterm infants (<31 GW) who developed BPD were higher than those (42.9 ng/mL and 1357/µL) of 20 infants (<31 GW) who did not (p<0.0001 and p=0.012), respectively. In multivariable analysis for 36 infants born less than 31 GW, higher NGAL levels (≥ 82 ng/mL) but not neutrophil counts at birth had a significant association with developing BPD (gestational-age adjusted odds ratio [OR]=37.45 [3.08-455.49], p<0.01). CONCLUSIONS: High serum levels of NGAL at birth could be an early sensitive marker for BPD in preterm infants, because their levels were physiologically low.

Serum prohepcidin concentrations at birth and 1 month after birth in premature infants.

BACKGROUND: Premature newborns are vulnerable to iron imbalance, although the iron homeostasis during the perinatal period remains unclear. To clarify the iron metabolism of premature infants, we measured serum prohepcidin concentrations of preterm infants, and analyzed the association with iron parameters. METHODS: Seventy-one (61 preterm and 10 term) infants were enrolled for the study, that had no underlying diseases including asphyxia, bleedings, infection, and anomalies. Serum concentrations of prohepcidin at birth and 1 month after birth were determined by enzyme-linked immunosorbent assay. RESULTS: Prohepcidin levels at birth but not 1 month postnatal age positively correlated with gestational age (correlation coefficient [CC]:0.334, P = 0.005) and birth weight (CC: 0.367, P = 0.002). The levels at birth of preterm infants (median: 29.93 ng/ml, range: 4.0-110.6) were lower than those of full-term infants, and increased thereafter. On the other hand, the levels in small-for-gestational age infants were not associated with gestational age or birth weight. Prohepcidin levels at birth correlated positively with red cell counts (CC = 0.487, P = 0.025), unsaturated iron binding capacity (CC = 0.755, P = 0.001), total protein (CC = 0.624, P = 0.005), and serum albumin levels (CC = 0.500, P = 0.025), and negatively with serum iron levels (CC = -0.688, P = 0.003), but not ferritin levels. Multivariate analyses indicated that prohepcidin levels at birth were lower in infants with pregnancy-induced hypertension (P = 0.03) or premature rupture of membrane (P = 0.01). CONCLUSIONS: Prohepcidin production was physiologically low at birth of preterm infants according to the gestational age, and the levels might be susceptible to the in utero stress. The postnatal increase might reflect the maturation and/or adaptation of iron homeostasis.

Successful cord blood transplantation for a CHARGE syndrome with CHD7 mutation showing DiGeorge sequence including hypoparathyroidism.

It is rare that coloboma, heart anomalies, choanal atresia, retarded growth and development, and genital and ear anomalies (CHARGE) syndrome patients have DiGeorge sequence showing severe immunodeficiency due to the defect of the thymus. Although the only treatment to achieve immunological recovery for these patients in countries where thymic transplantation is not ethically approved would be hematopoietic cell transplantation, long-term survival has not been obtained in most patients. On the other hand, it is still not clarified whether hypoparathyroidism is one of the manifestations of CHARGE syndrome. We observed a CHARGE syndrome patient with chromodomain helicase DNA-binding protein 7 mutation showing DiGeorge sequence including the defect of T cells accompanied with the aplasia of the thymus, severe hypoparathyroidism, and conotruncal cardiac anomaly. He received unrelated cord blood transplantation without conditioning at 4 months of age. Recovery of T cell number and of proliferative response against mitogens was achieved by peripheral expansion of mature T cells in cord blood without thymic output. Although he is still suffering from severe hypoparathyroidism, he is alive without serious infections for 10 months.

Improvement in the outcome of patients with antenatally diagnosed congenital diaphragmatic hernia using gentle ventilation and circulatory stabilization.

BACKGROUND/OBJECTIVES: No definitive treatment strategy has been established for patients with an antenatal diagnosed congenital diaphragmatic hernia (AD-CDH). From 1997 to 2003 in this department fetal stabilization (FS) was administered using both morphine and diazepam via the placenta just before delivery of the fetus by cesarean section. In contrast, from 2004 to the present, a combination of gentle ventilation (GV) and a delayed operation was selected, which was performed when the patient's circulatory stabilization (CS) was achieved. PATIENTS AND METHODS: This study included 22 patients in the FS group and 16 patients in the GV + CS group, respectively. The outcomes in both groups were compared and the outcome in AD-CDH patients with a patch repaired operation, liver-up or lower lung-to-thorax transverse area ratio (L/T, <0.10) was further investigated in both groups. RESULTS: The overall survival rate (SR) was 93.8% in the GV + CS group and 59.1% in the FS group, respectively (P = 0.04). For the patients with the lower L/T, the SR was 85.7% in GV + CS group and 53.8% in the FS group (P = 0.33). Regarding the patients using a patch and liver-up, the SR in GV + CS group was better than that in the FS group (patch: FS 44.4%, GV +/- CS 87.5%, P = 0.18; liver-up: FS 57.8 and 87.5%, P = 0.30). CONCLUSION: Our strategy of using GV +/- CS might thus be considered to be more effective than that using FS in the treatment of AD-CDH patients.

Prenatal findings in a case of massive fetomaternal hemorrhage associated with intraplacental choriocarcinoma.

We describe biochemical assessment of maternal circulation in a case of massive fetomaternal hemorrhage at term associated with intraplacental choriocarcinoma. Markedly elevated maternal serum hCG level at 37 weeks of gestation suggested choriocarcinoma as a cause of fetomaternal hemorrhage in this case. Measurement of maternal hCG may be a useful parameter when intraplacental choriocarcinoma is in the differential diagnosis. In addition, the placenta should be examined in all cases of fetomaternal hemorrhage.

Spontaneous resolution of cystic hygroma and hydrops in a fetus with Noonan's syndrome.

Many studies have shown that the prognosis of cystic hygroma associated with hydrops fetalis is poor. We report a rare case of fetal cystic hygroma and hydrops fetalis that spontaneously resolved with subsequent delivery at 37 weeks of a living female infant with Noonan's syndrome. The prognostic significance of prenatal resolution of cystic hygroma and hydrops is uncertain. Serial evaluation of affected fetuses with ultrasound imaging may help clarify pathogenesis of cystic hygroma with associated hydrops, as well as mechanisms underlying spontaneous resolution.

Dominant expression of interleukin-10 and transforming growth factor-beta genes in activated T-cells of chronic active Epstein-Barr virus infection.

Chronic active Epstein-Barr virus (EBV) infection is a chronic mononucleosis syndrome associated with clonal proliferation of EBV-carrying T-/natural killer (NK)-cells. High levels of circulating EBV and activated T-cells are sustained during the prolonged disease course, whereas it is not clear how ectopic EBV infection in T-/NK-cells has been established and maintained. To assess the biological role of activated T-cells in chronic active EBV infection (CAEBV), EBV DNA and cellular gene expressions in peripheral T-cells were quantified in CAEBV and infectious mononucleosis (IM) patients. In CAEBV, HLA-DR(+) T-cells had higher viral load and larger amounts of IFN gamma, IL-10, transforming growth factor-beta (TGF beta), and cytotoxic T lymphocyte antigen-4 (CTLA4) mRNA than HLA-DR(-)T-cells. HLA-DR(+) T cells of IM patients transcribed more IFN gamma and IL-10 than their HLA-DR(-)T cells. Expression levels of IFN gamma and forkhead box p3 (Foxp3) in CAEBV HLA-DR(+) T-cells were higher than in IM HLA-DR(+) T-cells. The effective variables to discriminate the positivity of HLA-DR were IL-10, IFN gamma, CTLA4, TGF beta, and IL-2 in the order of statistical weight. EBV load in CAEBV T-cells correlated with the expression levels of only IL-10 and TGF beta. These results suggest that CAEBV T-cells are activated to transcribe IFN gamma, IL-10, and TGF beta excessively, and the latter two genes are expressed preferentially in the EBV-infected subsets. The dominant expression of regulatory cytokines in T-cells may imply a viral evasion mechanism in the disease.

Cytokine imbalance in hyper-IgE syndrome: reduced expression of transforming growth factor beta and interferon gamma genes in circulating activated T cells.

Hyper-IgE syndrome (HIES) is a primary immunodeficiency disease characterized by recurrent infections and marked immunoglobulin (Ig)E elevation. To assess the proper T-cell defects of HIES, the cytokine profile of naturally activated T cells was compared between HIES, atopic dermatitis and chronic granulomatous disease (CGD). Intracellular flow cytometric analysis after in vitro stimulation showed no difference in the proportion of interferon (IFN)gamma- or interleukin 4 (IL-4)-producing T cells among these diseases. Quantitative polymerase chain reaction (PCR) for the cytokine genes was performed using circulating highly fractionated HLA-DR+ and HLA-DR- T cells. The IFNgamma/IL-4 or IFNgamma/IL-10 ratios were lower in HLA-DR+ T cells of HIES than in CGD (P = 0.0106, 0.0445), but did not differ between HIES and atopy. The transforming growth factor-beta (TGFbeta)/IL-4 ratio in HLA-DR+ T cells of HIES was lower than that of atopy (0.0106) or CGD (0.0062). The TGFbeta/IL-4 ratio in HLA-DR- T cells of HIES was also lower than that of atopy (0.0285). Stepwise logistic regression analysis identified TGFbeta/IL-4 ratios in HLA-DR+ (0.0001) or HLA-DR- (0.0086) T cells as the most powerful parameters to distinguish HIES from atopy and/or CGD. Serum IgE levels negatively correlated with IFNgamma/IL-4 (0.0108), IFNgamma/IL-10 (0.0254), or TGFbeta/IL-4 (0.0163) ratios in HLA-DR+, but not HLA-DR-, T cells. These results suggested that the in vivo activated T cells of HIES did not sufficiently express the IFNgamma and TGFbeta genes, which could affect IL-4-dependent IgE production. The reduced TGFbeta expression may involve the indigenous T-cell defects of HIES.

Dominant expression of interleukin 10 but not interferon gamma in CD4(-)CD8(-)alphabetaT cells of autoimmune lymphoproliferative syndrome.

Cytokine expression in CD4-CD8- double-negative (DN) T cells of autoimmune lymphoproliferative syndrome (ALPS) was analysed. Two patients with DN alphabetaT-cell expansion showed higher serum interleukin 10 (IL-10) levels than one patient without it. Intracellular flow-cytometric analysis indicated the IL-10-expressing CD3+CD4-CD8- cells in patients with lymphoproliferation. Quantitative real-time polymerase chain reaction revealed approximately 100 times higher IL-10, but not interferon-gamma or transforming growth factor-beta in DN than in single-positive T cells. IL-10 was exclusively expressed in DN alphabeta but not (gamma)(delta)T cells. Circulating DN alphabetaT cells may constitutively express IL-10 and contribute to the ALPS phenotype.

Interferon-gamma, interleukin-18, monokine induced by interferon-gamma and interferon-gamma-inducible protein-10 in histiocytic necrotizing lymphadenitis.

Apoptosis of histiocytes is a characteristic feature of necrotizing lymphadenitis (HNL). Recent studies have indicated that Fas and perforin-based pathways are involved in the apoptotic process of HNL. Elevated levels of serum interferon (IFN)-gamma are reported in HNL. The CXC chemokine interferon-gamma-inducible protein-10 (IP-10) and monokine induced by interferon-gamma (MIG) cause tissue necrosis, and interleukin (IL)-18 induces the expression of IFN-gamma and Fas ligand (FasL) by T and natural killer (NK) cells. This study was designed to determine the expression of IFN-gamma, IL-18, MIG and IP-10 in HNL. Ten cases of HNL were analyzed by using immunohistochemical staining and/or reverse transcriptase-polymerase chain reaction (RT-PCR). As a control, we included four cases of non-specific lymphadenitis. MIG and IP-10 proteins, which enhance the release of granzyme, showed a similar distribution pattern in viable tissues surrounding dead tissue, mostly within histiocytes, and lymphocytes in HNL. IL-18 was located within histiocytes, especially phagocytic histiocytes, but not within lymphocytes. In addition, IFN-gamma-positive lymphocytes were frequently detected in the surrounding dead tissue, and the lymphocytes in the same area were frequently positive for CXCR3, a specific receptor of MIG and IP-10. In non-specific lymphadenitis, MIG, IP-10 and IL-18 positive cells were detected, but their numbers were relatively small compared with HNL, while IFN-gamma positive cells were rarely encountered. Our findings suggest that the cytokine and chemokine pathways of IFN-gamma, IL-18, MIG and IP-10 play an important role in the pathogenesis of apoptosis associated with HNL.