De novo disruptive heterozygous MMP21 variants are potential predisposing genetic risk factors in Chinese Han heterotaxy children.

BACKGROUND: Heterotaxy syndrome (HTX) is caused by aberrant left-right patterning early in embryonic development, which results in abnormal positioning and morphology of the thoracic and abdominal organs. Currently, genetic testing discerns the underlying genetic cause in less than 20% of sporadic HTX cases, indicating that genetic pathogenesis remains poorly understood. In this study, we aim to garner a deeper understanding of the genetic factors of this disease by documenting the effect of different matrix metalloproteinase 21 (MMP21) variants on disease occurrence and pathogenesis. METHODS: Eighty-one HTX patients with complex congenital heart defects and 89 healthy children were enrolled, and we investigated the pathogenetic variants related to patients with HTX by exome sequencing. Zebrafish splice-blocking Morpholino oligo-mediated transient suppression assays were performed to confirm the potential pathogenicity of missense variants found in these patients with HTX. RESULTS: Three MMP21 heterozygous non-synonymous variants (c.731G > A (p.G244E), c.829C > T (p.L277F), and c.1459A > G (p.K487E)) were identified in three unrelated Chinese Han patients with HTX and complex congenital heart defects. Sanger sequencing confirmed that all variants were de novo. Cell transfection assay showed that none of the variants affect mRNA and protein expression levels of MMP21. Knockdown expression of mmp21 by splice-blocking Morpholino oligo in zebrafish embryos revealed a heart looping disorder, and mutant human MMP21 mRNA (c.731G > A, c.1459A > G, heterozygous mRNA (wild-type&c.731G > A), as well as heterozygous mRNA (wild-type& c.1459A > G) could not effectively rescue the heart looping defects. A patient with the MMP21 p.G244E variant was identified with other potential HTX-causing missense mutations, whereas the patient with the MMP21 p.K487E variant had no genetic mutations in other causative genes related to HTX. CONCLUSION: Our study highlights the role of the disruptive heterozygous MMP21 variant (p.K487E) in the etiology of HTX with complex cardiac malformations and expands the current mutation spectrum of MMP21 in HTX.

Superfluid density and collective modes of fermion superfluid in dice lattice.

The superfluid properties of attractive Hubbard model in dice lattice are investigated. It is found that three superfluid order parameters increase as the interaction increases. When the filling factor falls into the flat band, due to the infinite large density of states, the resultant superfluid order parameters are proportional to interaction strength, which is in striking contrast with the exponentially small counterparts in usual superfluid (or superconductor). When the interaction is weak, and the filling factor is near the bottom of the lowest band (or the top of highest band), the superfluid density is determined by the effective mass of the lowest (or highest) single-particle band. When the interaction is strong and filling factor is small, the superfluid density is inversely proportional to interaction strength, which is related to effective mass of tightly bound pairs. In the strong interaction limit and finite filling, the asymptotic behaviors of superfluid density can be captured by a parabolic function of filling factor. Furthermore, when the filling is in flat band, the superfluid density shows a logarithmic singularity as the interaction approaches zero. In addition, there exist three undamped collective modes for strong interactions. The lowest excitation is gapless phonon, which is characterized by the total density oscillations. The two others are gapped Leggett modes, which correspond relative density fluctuations between sublattices. The collective modes are also reflected in the two-particle spectral functions by sharp peaks. Furthermore, it is found that the two-particle spectral functions satisfy an exact sum-rule, which is directly related to the filling factor (or density of particle). The sum-rule of the spectral functions may be useful to distinguish between the hole-doped and particle-doped superfluid (superconductor) in experiments.

Autophagy Is Deficient and May be Negatively Regulated by SERPINB3 in Middle Ear Cholesteatoma.

HYPOTHESIS: Whereas autophagy has been linked to various human diseases, whether it also plays a role in cholesteatoma is virtually unknown. This study aimed to investigate the activity and regulation of autophagy in cholesteatoma. BACKGROUND: The treatment of middle ear cholesteatoma has been challenging due to an insufficient understanding of the underlying disease mechanism. METHODS: Expression of microtubule-associated protein 1A/1B-light chain 3 (LC3), the autophagy protein marker, and phosphorylated Akt (p-Akt), and mammalian target of rapamycin (p-mTOR), the known autophagy regulators, in fresh retroauricular skin and cholesteatoma tissue samples was analyzed by immunoblotting. The results were further confirmed by immunohistochemistry and statistical analyses. Cell proliferation of primary retroauricular skin- and cholesteatoma-derived fibroblasts was evaluated by methyl thiazol tetrazolium (MTT) assay. Ectopic expression of serine proteinase inhibitor, clade B, member 3 (SERPINB3) in the fibroblasts was achieved by electroporation and the expression was detected by immunoblotting. RESULTS: LC3 expression was significantly decreased in cholesteatoma in most of the 15 paired retroauricular skin/cholesteatoma tissue samples. However, p-Akt and p-mTOR expression in the cholesteatoma samples was not significantly different from that in the control subjects. Immunohistochemical studies further demonstrated an inverse correlation between LC3 expression and cholesteatoma. The cholesteatoma fibroblasts proliferated faster than the retroauricular skin fibroblasts, and had higher SERPINB3 but lower LC3 expression. Furthermore, overexpression of SERPINB3 in the retroauricular skin fibroblasts enhanced cell proliferation and downregulated LC3 expression. CONCLUSION: Autophagy is significantly suppressed in cholesteatoma tissues, which may not involve the Akt/mTOR signaling pathway. More importantly, SERPINB3 may promote cell proliferation and negatively regulate autophagy in cholesteatoma fibroblasts. Together, these findings warrant further investigation into the pathogenic mechanism of cholesteatoma.

Fetal pulmonary valve stenosis or atresia with intact ventricular septum: Predictors of need for neonatal intervention.

OBJECTIVES: To compare the fetal echocardiographic measurements and neonatal outcome of fetuses with diagnosis of critical pulmonary stenosis (CPS/IVS) and pulmonary atresia with intact ventricular septum (PA/IVS) to identify the predictors of neonatal ductus dependence and the need for neonatal intervention. METHODS: Forty-four fetuses with a diagnosis of membranous PA/IVS or CPS/IVS referred to Shanghai Xinhua Hospital Affiliated to Shanghai Jiaotong University between June 2009 and November 2014 were respectively analyzed. We analyzed their fetal and pediatric echocardiographic features and clinical features after birth. RESULTS: Among the 29 infants in the final analysis, 19 were ductal dependent and were diagnosed as CPS/IVS or PA/IVS after birth. Ten patients with fetal CSP/IVS were ductal independent and were diagnosed as pulmonary stenosis after birth. In midtrimester, significance was only detected in pulmonary valve (PV) regurgitation between 2 groups (P = .009). The fetuses with PV regurgitation in midtrimester were more likely to be ductal independent (odds ratio = 6.67; P = .010) than those with absence of PV regurgitation in the midtrimester scan. In late trimester, the infants in ductus-independent group had better fetal right ventricular development than those in ductus dependent group. The right ventricle over left ventricle length ratio in last scan over 0.86 had the best capability in predicting ductus independence during neonatal period with help of receiver-operating characteristic curve and the logistic regression analysis. CONCLUSION: Among fetuses with pulmonary valve stenosis and right ventricle dysplasia at the time of first fetal echo in midtrimester, use of pulmonary valve regurgitation can identify who will be ductal dependent at births. In late trimester, right ventricle over left ventricle length ratio less than 0.86 had the best capability of predicting neonatal ductal dependence. Fetuses with reversed ductus arteriosus flow direction in late trimester were more likely to be ductus dependent after birth.

Evaluating the risk factors of reintervention of neonates with PA/IVS and CPS/IVS after PBPV as initial intervention method.

OBJECTIVES: To analyze the clinical features, immediate and short-term outcome of percutaneous balloon pulmonary valvuloplasty (PBPV) of neonates with pulmonary atresia with intact ventricular septum (PA/IVS) or critical pulmonary stenosis with intact ventricular septum (CPS/IVS) who underwent PBPV as initial intervention methods to evaluate the risk factors of reintervention. METHOD: Thirty-eight neonates with PA/IVS or CPS/IVS admitted to Shanghai Xinhua Hospital between June 2009 and November 2014 who underwent PBPV as initial procedures were respectively studied. We analyzed their clinical features, the immediate and short-term outcome of PBPV, and evaluated the risk factors for reintervention. RESULTS: Thirty-eight neonates with PA/IVS and CPS/IVS who underwent PBPV as initial procedures were included in our study with a mean age of 13±8 days. Among the 12 patients who underwent reintervention, 7 patients had PA/IVS (64%) and 5 had CPS/IVS (36%). Patients with PA/IVS (p=0.005), small pulmonary valve diameter (p=0.035), and bad pulmonary valve development were important risk factors. The immediate and short-term outcome of PBPV was better in patients who did not need reintervention, and the peak-to-peak pulmonary transvalvular gradient in the 1st month after PBPV had the best capability in predicting reintervention with help of receiver operating characteristic curve and the logistic regression analysis. Days of prostaglandin E1 (PGE1) infusion after PBPV >5 days was also found to be a risk factor for reintervention. CONCLUSION: The short- and mid-term outcome of pulmonary valve perforation and PBPV in neonates with PA/IVS and CPS/IVS was favorable. Risk factors include PA/IVS, small pulmonary valve, bad short-term pulmonary valve development, the peak-to-peak pulmonary transvalvular gradient in the 1st month after procedure >42mmHg, and PGE1 infusion >5 days.

Assessment of longitudinal systolic ventricular dysfunction and asynchrony using velocity vector imaging in children with a single right ventricle.

Assessment of ventricular dysfunction and asynchrony is very important in predicting the outcome for children with a single right ventricle. However, the assessment is inaccurate and subjective because of the unusual ventricular shape. This study aimed to evaluate the feasibility and clinical value of velocity vector imaging for assessing longitudinal systolic ventricular dysfunction and intraventricular asynchrony in children with a single right ventricle. The study enrolled 36 children with a single right ventricle and 36 age-matched children with a normal heart. Peak systolic velocity, peak displacement, strain, strain rate, time to peak systolic velocity, and time to peak systolic strain were measured via velocity vector imaging using the Siemens Sequoia C512 echocardiography instrument. The maximum positive rate of ventricular pressure change (Max [dp/dt]) was obtained by cardiac catheterization for all the children with a single right ventricle. In the children with a single right ventricle, the maximal temporal differences and the standard deviations of the times to peak systolic velocity and peak systolic strain were higher (P < 0.01) than in the children with a normal heart. Moreover, the strain and strain rate values were significantly lower in all six segments (P < 0.05). The strain rate of the basal segment adjacent to the rudimentary chamber correlated best with Max (dp/dt) (r = 0.86; P < 0.01). Longitudinal systolic dysfunction and intraventricular asynchrony could be assessed accurately using velocity vector imaging in children with a single right ventricle.

From random coil polymers to helical structures induced by carbon nanotubes and supramolecular interactions.

A simple method is reported for the preparation of double-helical structures through a series of achiral random and block copolymers poly(styrene-co-4-vinylbenzyl triazolylmethyl methylthymine) (PS-co-PVBT) with various T units on the side chains through click reactions of poly(styrene-co-4-vinylbenzyl azide) (PS-co-PVBN(3)) with propargyl thymine (PT) and also the synthesis of the A-appended pyrene derivative (A-Py) through click chemistry. This double-helical structure is observed from achiral random-coil polystyrene (PS) main chains, stabilized through the combination of multiple A-T hydrogen bonds, and π-π stacking between pyrene units and single-walled carbon nanotubes (SWCNTs).

[Evaluation of early monitoring of cardiotoxicity induced by anthracyclines].

OBJECTIVE: Anthracyclines (ANT) are effective for leukemia and solid tumors. However the long-term life quality of patients is seriously affected by ANT-related cardiotoxicity. The aim of this study was to evaluate the value of two dimension echocardiography (2DE) and serum biochemical indicators in monitoring ANT-related cardiotoxicity. METHODS: Seventy children who received ANT chemotherapy (ANT dose: 124 ± 73 mg/m2) and were followed up for 22 ± 13 months were enrolled. 2DE with aspects of conventional indexes (left ventricular diameter and wall thickness, ejection fraction, E/A), myocardial performance index (MPI) and tissue Doppler imaging (TDI) were performed. Serum levels of troponin (CTnI) and brain natriuretic peptide (BNP) were measured. Thirty-seven healthy children served as the control group. RESULTS: There were no significant differences in conventional indexes of 2DE between the ANT and the control groups. The MPI of left and right ventricular in the ANT group increased significantly compared with that in the control group (0.237 ± 0.06 vs 0.203 ± 0.06, 0.171 ± 0.05 vs 0.140 ± 0.04 respectively; P<0.01). TDI showed the late diastolic peak velocity in the basal and middle sections of left ventricular, interventricular septum and right ventricular in the ANT group were significantly higher than the controls. There were significant differences in the ratio of early to late diastolic peak velocity of the middle section of left ventricular and the basal and middle sections of the interventricular septum between the two groups (P<0.05). The changes of MPI and TDI became more obvious with the increased dose of ANT. There were no significant differences in serum CtnI and BNP levels between the two groups. CONCLUSIONS: The heart function of patients who received ANT chemotherapy needs to be monitored for a long term. MPI and TDI can be used as early indexes for monitoring the heart function.

[Study of scintillating luminescence spectra of lead tungstate scintillation crystal doped with ions].

The light yield of the as-grown PbWO4, annealed PbWO4 and BaF2:PbWO4 crystals were raised by utilizing our improved crystal growth instrument and technique. Their scintillating properties including transmittance, decay time and light yield were studied. Results reveal that the scintillating performances of the crystals were improved evidently by using the crystal annealing technique and the ions doping technique, especially the negative ions doping technique. The influence results of the two techniques are different. The ions doping technique raises their transmittance intensity in the whole measuring wavelength range. But the influence of annealing PbWO4 crystal on their transmittance is complicated. It improves its transmittance intensity at the wavelength above 360 nm, but weakens the transmittance intensity of the annealed PbWO4 crystal in the wavelength range from 320 to 360 nm. These phenomena should be related to the crystal defects which have absorption peaks in this wavelength range, especially for V(Pb)3+ defect which has characterized absorption peaks in this wavelength range. Also, the absorption of the defects influences the character of the decay time of these crystals. The big defect concentration relates to the short decay time. It should be mentioned that the ions doping technique reduces the defect content in the crystal, which is beneficial to the high transmittance intensity but induces slightly longer decay time than that of as-grown crystal and well annealed PbWO4 crystal. Also, the ions doping technique of the F- ion doped crystal leads to high light yield. The annealing technique and ions doping technique improve the light yield of crystals. The light yield of BaF2:PbWO4 reaches 65 p.e./MeV, which is near to the requirement of PET. The good result is related to the degeneration of the [WO4]2- tetrahedron induced by the F- occupying the O2- site in the crystal cell.

[The spectrum characterization of non-stoichiometry potassium lithium niobate crystals].

A batch of potassium lithium niobate (KLN) crystals with different compositions were grown by using TSSG technique. Samples with three different compositions were well polished. By using near infrared cw:Ti-sapphire laser, their Second Harmonic Generation (SHG) properties were investigated. The results showed that the SHG effect is related to the composition of the samples, and their frequency-doubling efficiency enhanced with the raise of Li ions content in the crystal. By using infrared Raman technique, the properties of nonlinear lattice vibration of thee samples were investigated, and the character of Raman spectrum were analyzed, as well the effect of composition on the SHG properties were discussed. The analysis results showed the striking effects of Li content for these Raman peaks. For KLN sample with small Li content, the three character peaks belonged to [NbO6]7- octahedron show simple peak. With the raise of Li content in crystal, the peaks belonged to v2 mode were partly split, and the peak belongs to v5 mode was broadened. When the Li content approach to the chemical composition KLN crystal, and the structure of [NbO6]7- octahedron is almost to be disorganized, the peaks belonged to v5 mode were split, and the peaks belonged to v1 mode and v2 mode were partly split also, with more distinct weak peaks in the wavelength range of 100-400 cm(-1). These effects were caused by the raise of Li content, which leads to the severer aberrance of [NbO6]7- octahedron in KLN crystal, and disturbing the lattice vibration of the octahedron. This phenomenon is agreed with the nonlinear properties of potassium lithium niobate crystal.

[Diagnostic value of the currently used criteria and brain natriuretic peptide for diagnosing congestive heart failure in children with congenital heart disease].

OBJECTIVE: To improve the accuracy of diagnosis of heart failure (HF) has been the focus of research for a long time. The diagnosis for HF with congenital heart disease, however, is more difficult. The aim of the study was to evaluate the diagnostic criteria for HF in children and examine the value of plasma brain natriuretic peptide (BNP) and NT-proBNP for diagnosing HF in pediatric patients with congenital heart disease, and to look for the most valuable index for the diagnosis according to the multifactor analysis. METHODS: Totally 118 children with congenital heart disease were enrolled. They were diagnosed using modified Ross score, Qingdao criteria, NYU PHFI, and plasma BNP and NT-proBNP. According to modified Ross score as the referent criteria, other diagnostic criteria and plasma BNP and NT-proBNP were studied. The sensitivity, specificity and area of the ROC curve were examined. Logistic regression analysis was used to select the valuable index for diagnosing HF. RESULTS: (1) The value of each clinical criteria: 1 The sensitivity of Qingdao criteria for diagnosing HF was 47.9%. The specificity was 100% and the accuracy was 57.6%. 2 There were 52 patients younger than six months in whom 27 (51.9%) were breast fed. Only 25 children were measured with Ross score. The Ross score was positively correlated with the modified Ross score (r = 0.948). The area under the ROC curve of Ross score diagnosing HF was 0.985, and the sensitivity was 88%, while the specificity was 100%. 3 NYU PHFI score was positively correlated with the modified Ross score. The area under the ROC curve of the NYU PHFI diagnosing HF was 0.964, and the sum of sensitivity and specificity was favorite when > or = 8 was set as the cut-off point. If > 2 was set as cut-off point, it had a high sensitivity but a low specificity. The sensitivity of NYU PHFI was 100% > was set 2 as cut-point for diagnosing HF, but the specificity was 4.5%. (2) Plasma BNP and NT-proBNP were positively correlated with the modified Ross score, and increased with the severity of congestive HF. The area under the ROC curve of BNP was 0.880, and the cut-off line was > or = 349 pg/ml. The area under the ROC curve of NT-proBNP was 0.981, and the cut-off line was > or = 499 fmol/ml. (3) Logistic regression analysis showed that in multifactor analysis, only plasma concentration of NT-proBNP, dyspnea, tachycardia, tachypnea, failure to thrive were the independent predictors for diagnosing HF. (4) Plasma concentration of NT-proBNP incorporated with clinical criteria would improve its accuracy. CONCLUSION: All the clinical criteria commonly used were valuable for diagnosing HF in children with congenital heart disease, but each has its own limits, such as the low sensitivity of Qingdao, the low adaptation of Ross score because of the high breast-feeding rate in our country and the low specificity of NYU PHFI when > 2 was set as the cut-off point. Plasma concentrations of BNP and NT-proBNP were valuable for diagnosing HF in children with congenital heart disease, and NT-proBNP was the independent predictor for HF.

[Diagnostic value of plasma concentration of pro-brain natriuretic peptide in congestive heart failure in pediatric patients with ventricular septal defects].

OBJECTIVE: The value of plasma brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) can reflect cardiac function and therefore can be used for diagnosing congestive heart failure (CHF) and evaluating cardiac function. There are few reports, however, on the value of BNP and NT-proBNP in pediatric cases of congenital heart defect. The aim of this study was to assess the value of plasma NT-proBNP in the diagnosis of CHF and evaluation of cardiac function in pediatric patients with ventricular septal defect (VSD). METHODS: Fifty-one patients with VSD aged from 2 months to 2 years old (mean 7.9 months) were enrolled. According to the modified Ross Score, the patients were divided into three groups, no CHF group (20 patients), mild CHF group (18 patients) and moderate to severe CHF group (13 patients). Fifteen age-matched normal children were used as controls. Plasma NT-proBNP was measured using enzyme immunoassay. All patients had complete echocardiographic study, including measurement of left ventricular end diastolic volume index (LVEDVI), left ventricular end systolic wall stress (LVSEWS), heart rate corrected mean velocity of circumferential fiber shortening (mVcFc), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and contractility index (Con). The correlation between plasma NT-proBNP level and modified Ross Score and echocardiographic cardiac functional indexes was determined. The sensitivity, specificity and ROC curve of plasma NT-proBNP for diagnosing CHF was studied. RESULTS: Plasma NT-proBNP was positively correlated with modified Ross Score (r = 0.75, P < 0.01). Plasma NT-proBNP concentration in moderate to severe CHF group (2061 +/- 908) fmol/ml was significantly higher than that of mild CHF group (810 +/- 335) fmol/ml, and Plasma NT-proBNP concentration in mild CHF group was higher than that in no CHF group (309 +/- 68) fmol/ml. 97.14% of normal controls and subjects in no CHF group had their plasma NT-proBNP below 400 fmol/ml. 83.3% of children in mild CHF group had their plasma NT-proBNP between (400-1400) fmol/ml while in moderate and severe CHF group 84.6% of children had their plasma NT-proBNP beyond 1400 fmol/ml. Plasma NT-proBNP was also positively correlated with LVEDVI and LVSEWS. There was no correlation among mVcFc, LVEF, LVFS, Con and plasma NT-proBNP concentration. Using plasma NT-proBNP concentration > or = 400 fmol/ml as cut-point for diagnosing CHF, the sensitivity was 89.3%, the specificity was 91.2%, and the area under the ROC curve was 0.944. CONCLUSIONS: Plasma NT-proBNP level could be used to assess cardiac function and diagnose CHF in pediatric patients with VSD.