CD5 levels define functionally heterogeneous populations of naïve human CD4+ T cells.

Studies in murine models show that subthreshold TCR interactions with self-peptide are required for thymic development and peripheral survival of naïve T cells. Recently, differences in the strength of tonic TCR interactions with self-peptide, as read-out by cell surface levels of CD5, were associated with distinct effector potentials among sorted populations of T cells in mice. However, whether CD5 can also be used to parse functional heterogeneity among human T cells is less clear. Our study demonstrates that CD5 levels correlate with TCR signal strength in human naïve CD4+ T cells. Further, we describe a relationship between CD5 levels on naïve human CD4+ T cells and binding affinity to foreign peptide, in addition to a predominance of CD5hi T cells in the memory compartment. Differences in gene expression and biases in cytokine production potential between CD5lo and CD5hi naïve human CD4+ T cells are consistent with observations in mice. Together, these data validate the use of CD5 surface levels as a marker of heterogeneity among human naïve CD4+ T cells with important implications for the identification of functionally biased T- cell populations that can be exploited to improve the efficacy of adoptive cell therapies.

Percutaneous angioplasty used to manage native and recurrent coarctation of the aorta in infants younger than 1 year: immediate and midterm results.

Balloon angioplasty (BAP) used to manage native coarctation of the aorta (CoAo) in infants remains controversial. This study aimed to compare short- and midterm results of BAP between native CoAo (NaCo) and postsurgical recoarctations (ReCo) in infants younger than 1 year. This retrospective study compared the clinical, echocardiographic, hemodynamic, and angiographic data for infants who underwent BAP between July 2003 and September 2012. The 12 NaCo and 13 ReCo patients in this study underwent BAP at 4.61 ± 3.69 and 4.88 ± 3.07 months (p = 0.84) and weighed 5.49 ± 2.57 and 6.10 ± 2.11 kg (p = 0.52), respectively. Their respective heights were 60.58 ± 10.58 and 61.15 ± 6.74 cm (p = 0.87). All the ReCo patients had their initial surgery before the age of 3 months. The minimal CoAo diameter was 2.81 ± 0.96 mm in the NaCo group and 2.86 ± 1.0 mm in the ReCo group (p = 0.90). The relative gradient reduction was 62.79 ± 32.43 % in the NaCo group and 73.37 ± 20.78 % in the ReCo group (p = 0.33). The in situ complication rate (pseudoaneurysm) was 8.33 % in the NaCo group and 7.69 % in the ReCo group (p = 0.74). During the early follow-up evaluation, five NaCo patients (41.66 %) presented with recoarctation requiring BAP reintervention within 1.75 ± 1.41 months (all had their initial BAP before 3 months of age) compared with 1 ReCo patient (7.69 %) (p = 0.165). The mean follow-up period was 3.09 ± 2.69 years for the NaCo patients and 3.6 ± 3.18 years for the ReCo patients (p = 0.69), during which the blood pressure gradient was 12.33 ± 9.67 for the NaCo patients and 7.80 ± 8.78 for the ReCo patients (p = 0.17), with corresponding Doppler peak instantaneous gradients of 21.29 ± 11.19 and 16.20 ± 10.23 (p = 0.24). The resultant diameter ratio between the minimal isthmus diameter and the aortic diameter at the diaphragmatic level was 0.81 ± 0.15 in the NaCo group and 0.85 ± 0.12 in the ReCo group (p = 0.53). The immediate and midterm results of BAP for the NaCo and ReCo infants were comparable. Accordingly, BAP seems to be an acceptable alternative to surgery for infants older than 3 months.

Generation of functional human T cell development in NOD/SCID/IL2rγnull humanized mice without using fetal tissue: Application as a model of HIV infection and persistence.

Humanization of mice with functional T cells currently relies on co-implantation of hematopoietic stem cells from fetal liver and autologous fetal thymic tissue (so-called BLT mouse model). Here, we show that NOD/SCID/IL2rγnull mice humanized with cord blood- derived CD34+ cells and implanted with allogeneic pediatric thymic tissues excised during cardiac surgeries (CCST) represent an alternative to BLT mice. CCST mice displayed a strong immune reconstitution, with functional T cells originating from CD34+ progenitor cells. They were equally susceptible to mucosal or intraperitoneal HIV infection and had significantly higher HIV-specific T cell responses. Antiretroviral therapy (ART) robustly suppressed viremia and reduced the frequencies of cells carrying integrated HIV DNA. As in BLT mice, we observed a complete viral rebound following ART interruption, suggesting the presence of HIV reservoirs. In conclusion, CCST mice represent a practical alternative to BLT mice, broadening the use of humanized mice for research.

Right pulmonary artery torsion following surgical reimplantation.

We report the case of a 3-month-old boy with an anomalous origin of right pulmonary artery (AORPA) from the ascending aorta who presented postoperatively with torsion of the right pulmonary artery demonstrated on 3-D volume-rendered CT angiogram. To our knowledge, CT images of this entity have not been reported. This case illustrates a rare surgical complication that can be easily imaged by CT.

Atrial resynchronization following heart transplantation in childhood.

Despite preserved left ventricular function, exercise capacity is often impaired after cardiac transplantation due to autonomic denervation of the donor's sinus node. We present our experience with atrio-atrial resynchronization in 2 pediatric heart transplant recipients. Both were highly active, suffered from chronotropic incompetence, and underwent successful atrial resynchronization with an objective improvement in exercise capacity, restoration of a physiologic chronotropic response, and resolution of dyspnea. Long-term stable recipient sinus node function may, therefore, be maintained in some cardiac transplant recipients with standard atrio-atrial anastomes. Atrio-atrial pacing may be feasible and effective years after transplantation.

Experience in a single centre with percutaneous aortic valvoplasty in children, including those with associated cardiovascular lesions.

BACKGROUND: We report the experience in a single institution with balloon aortic valvoplasty for congenital aortic stenosis. Unlike most other reported series, we included patients with associated lesions involving the left side of the heart. METHODS: Between November, 1986, and November, 2006, we performed 161 interventions on 143 patients, of whom 33 were neonates, 33 infants, and 77 children, just over one-quarter (28.6%) having associated lesions. RESULTS: The overall reduction in peak-to-peak gradient of 60 ± 24% (p < 0.01), was more effective in primary versus secondary intervention (63 ± 24% versus 47 ± 23%; p < 0.03), and in those with fused bifoliate as opposed to truly bifoliate valves (66 ± 17% versus 53 ± 30%; p = 0.01). Patients with associated lesions were younger (40.89 ± 60.92 months versus 81.9 ± 72.9 months; p = 0.001), and were less likely to achieve a final pressure gradient of less than 20 mmHg (35.0% versus 61.2%; p < 0.01). Overall mortality was higher in cases with associated lesions (27.5% versus 1.9%; p < 0.0001) but not catheter-related death (2.5% versus 1.9%; p = 1.0). Reintervention was more frequently required in infants (p = 0.02) but not in cases with associated lesions (p = 0.35). CONCLUSIONS: Balloon valvoplasty is a safe and effective method for the treatment of congenital aortic stenosis. Prior surgery to the aortic valve, reintervention, associated cardiovascular lesions, and the anatomy of the valve predict a less effective reduction in the gradient. Major complications and catheterization-related death are mainly secondary to very young age, but not to associated cardiac lesions.

Fatal zygomycosis caused by Mucor indicus in a child with an implantable left ventricular assist device.

Mucor indicus is a rare, emerging cause of zygomycosis with 7 cases previously reported since 1975. We report the first case of endovascular M. indicus infection in a pediatric recipient of the Incor (Berlin Heart AG, Germany) implantable left ventricular assist device, and review the literature to describe the broadening clinical spectrum of zygomycosis caused by this emerging fungal pathogen.

Transcatheter ablation via a sternotomy approach as a hybrid procedure in a univentricular heart.

Hybrid procedures that combine surgical and interventional techniques are increasingly utilized in patients with congenital heart disease. We performed a novel hybrid intervention involving transcatheter ablation via a sternotomy approach and atriotomy incision. A recalcitrant accessory pathway was successfully ablated in a patient with hemodynamically unstable supraventricular tachycardia and an extracadiac Fontan for hypoplastic left heart syndrome.

Neurally Adjusted Ventilatory Assist After Pediatric Cardiac Surgery: Clinical Experience and Impact on Ventilation Pressures.

BACKGROUND: After pediatric cardiac surgery, ventilation with high airway pressures can be detrimental to right ventricular function and pulmonary blood flow. Neurally adjusted ventilatory assist (NAVA) improves patient-ventilator interactions, helping maintain spontaneous ventilation. This study reports our experience with the use of NAVA in children after a cardiac surgery. We hypothesize that using NAVA in this population is feasible and allows for lower ventilation pressures. METHODS: We retrospectively studied all children ventilated with NAVA (invasively or noninvasively) after undergoing cardiac surgery between January 2013 and May 2015 in our pediatric intensive care unit. The number and duration of NAVA episodes were described. For the first period of invasive NAVA in each subject, detailed clinical and ventilator data in the 4 h before and after the start of NAVA were extracted. RESULTS: 33 postoperative courses were included in 28 subjects with a median age of 3 [interquartile range (IQR) 1-12] months. NAVA was used invasively in 27 courses for a total duration of 87 (IQR 15-334) h per course. Peak inspiratory pressures and mean airway pressures decreased significantly after the start of NAVA (mean differences of 5.8 cm H2O (95% CI 4.1-7.5) and 2.0 cm H2O (95% CI 1.2-2.8), respectively, P < .001 for both). There was no significant difference in vital signs or blood gas values. NAVA was used noninvasively in 14 subjects, over 79 (IQR 25-137) h. CONCLUSIONS: NAVA could be used in pediatric subjects after cardiac surgery. The significant decrease in airway pressures observed after transition to NAVA could have a beneficial impact in this specific population, which should be investigated in future interventional studies.

Noncoding regions are the main source of targetable tumor-specific antigens.

Tumor-specific antigens (TSAs) represent ideal targets for cancer immunotherapy, but few have been identified thus far. We therefore developed a proteogenomic approach to enable the high-throughput discovery of TSAs coded by potentially all genomic regions. In two murine cancer cell lines and seven human primary tumors, we identified a total of 40 TSAs, about 90% of which derived from allegedly noncoding regions and would have been missed by standard exome-based approaches. Moreover, most of these TSAs derived from nonmutated yet aberrantly expressed transcripts (such as endogenous retroelements) that could be shared by multiple tumor types. Last, we demonstrated that, in mice, the strength of antitumor responses after TSA vaccination was influenced by two parameters that can be estimated in humans and could serve for TSA prioritization in clinical studies: TSA expression and the frequency of TSA-responsive T cells in the preimmune repertoire. In conclusion, the strategy reported herein could considerably facilitate the identification and prioritization of actionable human TSAs.

Significant motor improvement in an infant with congenital heart disease and a rolandic stroke: The impact of early intervention.

OBJECTIVE: To report the impact of early motor intervention in an infant with congenital heart disease (CHD) and a stroke. METHODS AND RESULTS: A 35-week newborn with a complex CHD and a normal MRI presented with early motor developmental delay at 2 months. She began an intervention program, which included biweekly motor developmental therapy with a physiotherapist, parental education, and daily home exercises. At 4 months, she underwent cardiac surgery. Following surgery, she was diagnosed with a stroke involving the right sylvian artery territory. She continued her intensive intervention program. The 12-month assessment revealed an evident gain of motor function. Despite MRI evidence of a chronic infarct involving the primary motor cortex, the child had normal motor functions. CONCLUSION: This case report supports the positive impact of early intervention in infants with CHD and its potential effect on enhancing neuroplasticity, even in children with cerebro-vascular accidents involving areas of motor function.

Cardiac resynchronization therapy in congenital heart disease.

While cardiac resynchronization therapy (CRT) is of proven benefit in selected patients with severe ischemic or dilated cardiomyopathy, refractory symptoms, and conduction delay, extrapolation to congenital heart disease is not straightforward. This rapidly expanding patient population commonly suffers from heart failure, particularly in the presence of a single or systemic right ventricle. Surgical repair may also contribute to ventricular asynchrony. In this systematic review, the current state of knowledge regarding CRT in congenital heart disease is presented. Issues specific to congenital heart disease including right bundle branch block, right (pulmonary) ventricular dysfunction, systemic right ventricular dysfunction, and single ventricle dysfunction are explored. Evidence-based CRT applications for each of these particular conditions are reviewed. Initial experience with CRT in the acute postoperative setting and longer-term, including our own, is elaborated. Unlike standard indications based on multiple randomized clinical trials, supporting evidence for CRT in congenital heart disease is limited to case reports, case series, and small experimental crossover studies in the acute postoperative setting. The heterogeneous patient population, technical limitations from patient size, vascular access issues, and unique forms of ventricular asynchrony further obscure the selection of potential beneficiaries. Despite these limitations, experience thus far has been favorable. Quality of current data precludes definitive evidence-based recommendations, but optimistic initial results suggest that research endeavors in this field should be pursued. Multicenter prospective collaborative efforts are to be encouraged.

High renal regional oxygen saturation in femoral arteriovenous fistula after neonatal cardiac surgery.

The use of an indwelling arterial catheter is standard practice in the postoperative monitoring of paediatric cardiac surgery patients. Arteriovenous fistula related to this procedure can be difficult to diagnose. Regional haemoglobin oxygen saturation (rSO2) using near-infrared spectroscopy and central venous oxygen saturation (ScvO2) are monitored to follow the balance between oxygen consumption and delivery. Low values of these parameters are a sign of low cardiac output. High rSO2 and high ScvO2 are less frequently described. We report the discovery of an iatrogenic arteriovenous fistula in a neonate after cardiac surgery who had unexpectedly high values of renal rSO2 and femoral ScvO2. High renal rSO2 after femoral instrumentation should alert the physician to the possibility of arteriovenous fistula.

Left Atrial Inexcitability in Children With Congenital Lupus-Induced Complete Atrioventricular Block.

BACKGROUND: Congenital atrioventricular block is a well-established immunologic complication of maternal systemic lupus erythematosus. We sought to further characterize the electrophysiological manifestations of maternal systemic lupus erythematosus on neonatal atria. METHODS AND RESULTS: Cases of isolated congenital atrioventricular block treated at our center over the past 41 years were identified. Data were extracted from clinical charts, pacemaker interrogations, ECGs, echocardiograms, and histopathological reports, when available. Of 31 patients with isolated congenital atrioventricular block, 18 were negative for maternal antibodies and had normal epicardial atrial sensing and pacing thresholds. In contrast, 12 of 13 patients with positive maternal antibodies had epicardial pacemakers, 5 (42%) of whom had left atrial (LA) inexcitability and/or atrial conduction delay. In 3 patients, the LA could not be captured despite high-output pacing. The fourth patient had acutely successful LA appendage and left ventricular lead placement. At early follow-up, an increased delay between the surface P-wave and intracardiac atrial depolarization was observed, indicative of atrial conduction delay. The fifth patient exhibited LA lead dysfunction, with atrial under-sensing and an increased capture threshold, 2 weeks after implantation. Biopsies of LA appendages performed in 2 patients showed no evidence of atrial fibrosis or loss of atrial myocytes. CONCLUSIONS: Herein, we report previously undescribed yet prevalent electrophysiological ramifications of maternal systemic lupus erythematosus, which extend beyond congenital atrioventricular block to encompass alterations in LA conduction, including LA inexcitability. These manifestations can complicate epicardial pacemaker implantation in newborns. In the absence of histological evidence of extensive atrial fibrosis, immune-mediated functional impairment of electrical activity is suspected.

Draining Fluids through a Peritoneal Catheter in Newborns after Cardiac Surgery Helps to Control Fluid Balance.

Dialysis can be used in severe cases, but may not be well tolerated. In such patients, peritoneal drainage could be an alternative option for fluid removal. We report the case of a newborn with a truncus arteriosus who developed postoperatively a complicated clinical course with right ventricular dysfunction, prerenal condition as well as fluid overload despite diuretic therapy. Dialysis was indicated for fluid removal. Peritoneal dialysis was started using a surgically placed Tenckhoff catheter and stopped due to inefficacy and leaks and no other modalities of dialysis were used. However, the catheter was left in place over a period of two months for fluid drainage and removed because of unexplained fever. In order to determine the effect of peritoneal drainage, we selected a period of one week before and one week after the removal of the drain to compare daily clinical data, urine electrolytes and renal function and found a positive effect on fluid balance control. We conclude that the fluid removal by continuous peritoneal drainage is a simple and safe alternative that can be used to control fluid balance in infants after cardiac surgery.

Treatment of isolated ventricular septal defects in children: Amplatzer versus surgical closure.

BACKGROUND: Isolated hemodynamically significant ventricular septal defects (VSD) were previously treated surgically. Since the introduction of percutaneous (PC) devices, the management of isolated VSD has evolved. In our center, Amplatzer devices have been implanted for selected isolated perimembranous VSD since 2002. METHODS: The charts of all isolated PC perimembranous VSD closures and all surgical closures performed since 2002 were reviewed retrospectively. Clinical, electrocardiographic, and echocardiographic data were analyzed. The preclosure, immediate postclosure, and 1-month, 6-month, and 12-month postclosure results were assessed. RESULTS: Thirty-seven patients underwent PC closure, and 34 had surgical treatment. Mean follow-up was 42.1 ± 26.0 months. The PC group was significantly older (p < 0.01) and larger in size (p < 0.001). Surgical patients had more severe congestive heart failure and a significantly lower VSD gradient (p < 0.004). At follow-up, there were no differences in the incidence of residual shunting between the two groups (p = 0.92). All valvular regurgitations improved over time, except for 3 aortic regurgitations (5.4%) in the PC group that got worse. Two permanent pacemakers were implanted for early complete heart block in the PC group, and one was implanted in the surgical group (p = 0.94). CONCLUSIONS: The surgical results in our population were excellent. The selection of patients with perimembranous VSD remains a challenge to avoid post-PC intervention complications such as heart block and aortic insufficiency. For isolated VSD, PC closure, which avoids the morbidity of open heart surgery, should be considered as part of the therapeutic armamentarium.

Thirty years of experience with epicardial pacing in children.

Due to underlying cardiovascular anatomy and size, epicardial pacing may be the preferred method of pacing in small children. To assess long-term safety, we reviewed all epicardial pacemakers implanted in children between 1971 and 2001. We found that 122 patients, with a median age of 5.4 years, had a total of 181 pacemakers and 260 electrodes implanted over a total follow-up of 789 patient-years. Of the total, 12 patients died after the first implantation, with one death attributable to dysfunction of the pacemaker. Reintervention was required in 75 patients after 5.0 +/- 3.2 years, due to depletion of the battery in 45 patients (60%), fracture or dysfunction of electrodes in 27 patients (36%), and infection in 3 patients (4%). In univariate analyses, risk factors for reintervention were an approach via a median sternotomy, with a relative risk of 2.3 (p = 0.0087), and an indication for pacing other than atrioventricular block, with a relative risk of 1.7 (p = 0.0314). In multivariate analyses, the approach via the median sternotomy independently predicted the need for reintervention, with a relative risk of 2.1, and 95% confidence intervals from 1.1 to 4.1 (p = 0.0256). The longevity of the second pacemaker and/or its electrode, assessed in 26 patients, was 3.7 +/- 2.6 years, not shorter than the first implantation (p = 0.4037). We conclude that epicardial pacing is a reliable means of achieving permanent pacing in children, with low morbidity and mortality. A substantial proportion, nonetheless, requires reintervention within five years, warranting meticulous follow-up.