Pulmonary artery wall thickness in children with Fontan physiology: an optical coherence tomography case control study.

INTRODUCTION: Failure of the Fontan circulation is not a well-understood clinical phenomena.For some patients, a gradual increase in pulmonary vascular resistance (PVR) and structural changes in the pulmonary artery may be an important causative factor. To further investigate this issue, we employed optical coherence tomography (OCT) to evaluate structural changes within the pulmonary arteries of Fontan patients and compared to those with a normal pulmonary circulation. MATERIALS AND METHODS: Pulmonary artery OCT was performed, without complications, in 12 Fontan and 11 control patients. Wall thickness and wall:vessel cross-sectional area (CSA) ratio were calculated after image acquisition, using digital planimetry. RESULTS: There was no difference in wall thickness between both groups. Median wall thickness for Fontan patients was 0.12 mm (IQR, 0.10-0.14) and for controls was 0.11 mm (IQR, 0.10-0.12; p = 0.62). Wall:vessel CSA ratio for Fontan patients was 0.13 (IQR, 0.12-0.16) and for controls was 0.13 (IQR, 0.11-0.15) (p = 0.73). There was no association between wall thickness and ventricle morphology, age at catheterisation, age at Fontan, years since Fontan completion, pulmonary artery pressure, and PVR. The vessel media was more readily visualised in control patients. DISCUSSION: OCT of the pulmonary arteries in Fontan patients is safe and feasible. Our OCT findings suggest that during childhood, pulmonary artery wall dimensions are normal in Fontan children with reassuring hemodynamics. Further evaluation of Fontan patients with abnormal hemodynamics and serial evaluation into adulthood are required to conclude on the utility of OCT for identifying early pulmonary artery structural changes.

Type I IFN Signaling Is Dispensable during Secondary Viral Infection.

Innate immune responses in general, and type I interferons (T1IFNs) in particular, play an important and often essential role during primary viral infections, by directly combatting the virus and by maximizing the primary adaptive immune response. Several studies have suggested that T1IFNs also contribute very substantially to the secondary (recall) response; they are thought (i) to be required to drive the early attrition of memory T cells, (ii) to support the subsequent expansion of surviving virus-specific memory cells, and (iii) to assist in the suppression and clearance of the infectious agent. However, many of these observations were predicated upon models in which T1IFN signaling was interrupted prior to a primary immune response, raising the possibility that the resulting memory cells might be intrinsically abnormal. We have directly addressed this by using an inducible-Cre model system in which the host remains genetically-intact during the primary response to infection, and in which T1IFN signaling can be effectively ablated prior to secondary viral challenge. We report that, in stark contrast to primary infection, T1IFN signaling is not required during the recall response. IFNαßR-deficient memory CD8+ and CD4+ memory T cells undergo attrition and expansion with kinetics that are indistinguishable from those of receptor-sufficient cells. Moreover, even in the absence of functional T1IFN signaling, the host's immune capacity to rapidly suppress, and then to eradicate, a secondary infection remains intact. Thus, this study shows that T1IFN signaling is dispensable during the recall response to a virus infection. Moreover, two broader implications may be drawn. First, a T cell's requirement for a cytokine is highly dependent on the cell's maturation / differentiation status. Consequently, second, these data underscore the importance of evaluating a gene's impact by modulating its expression or function in a temporally-controllable manner.

Intimal thickening at coronary bifurcations in pediatric heart transplant recipients.

Heart transplant recipients are at increased risk for atherosclerosis and cardiac allograft vasculopathy, both initially presenting as intimal thickening. We aimed to determine the presence, extent, and anatomical characteristics of intimal thickness at coronary bifurcations in children using OCT. We measured the intimal thickness of coronary arteries in pediatric transplant recipients using OCT during routine cardiac catheterization. Intimal thickening was defined as (i) a percent change in contralateral intimal thickness greater than 50% when comparing the thickness at the bifurcation to the baseline thickness, and (ii) greater than 0.1 mm. We evaluated 153 unique coronary bifurcations in 31 children (58% boys, median 12.7 years). Intimal thickening was almost exclusively observed in the left coronary system (22 of 67 bifurcations) and rare in the right coronary system (2 of 86 bifurcations; P < .001). There was a positive association between the relative size of the side branch and contralateral intimal thickening at coronary bifurcations (P = .009). Intimal thickening at coronary bifurcations is already present in the left coronary system in many pediatric transplant recipients. The correlation between intimal thickening and side branch size suggests that low shear stress and oscillating shear stress may have an important role in the development of intimal thickening at coronary bifurcations.

Outcomes of Radiofrequency Perforation for Pulmonary Atresia and Intact Ventricular Septum: A Single-Centre Experience.

Percutaneous radiofrequency perforation (RFP) of the pulmonary valve is used as a primary therapy in neonates with pulmonary atresia and intact ventricular septum (PAIVS). We sought to determine the safety and efficacy of RFP for PAIVS in a single center and assess the pre-intervention anatomical parameters associated with a biventricular outcome. We retrospectively reviewed all cases of PAIVS treated with RFP at a single center from 1999 through 2012. We collected baseline imaging data, technical aspects of the procedure, adverse events and outcomes. RFP was attempted in 18 patients with 17 successful procedures. There was no mortality; one patient had an acute complication requiring surgical intervention. All were alive at the most recent follow-up (median 4.9 years; IQR = 2.0-6.8 years), 12/17 (71%) had a biventricular circulation, 2/17 (12%) had a 1½ ventricle repair, 2/17 (12%) had a univentricular repair and 1/17 was lost to follow-up. A biventricular outcome in patients with PAIVS was associated with the pre-intervention tricuspid valve/mitral valve (TV/MV) ratio and tricuspid valve (TV) z-score. The median TV/MV ratio for patients who underwent a biventricular repair and a non-biventricular repair was 0.82 (IQR = 0.71-0.90) and 0.59 (IQR = 0.39-0.76), P = 0.036, respectively. The median TV z-scores were -3.2 [(-4.9 to -2.6), and -6.8 (-9.7 to -4.8] P = 0.036 for the biventricular and non-biventricular groups, respectively. RFP is a safe primary therapy for PAIVS. With appropriate patient selection, RFP will often result in a biventricular circulation. Both the TV/MV and TV z-score were found to be a predictor of a biventricular outcome in our cohort.

Antigen-specific naive CD8+ T cells produce a single pulse of IFN-γ in vivo within hours of infection, but without antiviral effect.

In vitro studies have shown that naive CD8(+) T cells are unable to express most of their effector proteins until after at least one round of cell division has taken place. We have reassessed this issue in vivo and find that naive CD8(+) T cells mount Ag-specific responses within hours of infection, before proliferation has commenced. Newly activated naive Ag-specific CD8(+) T cells produce a rapid pulse of IFN-γ in vivo and begin to accumulate granzyme B and perforin. Later, in vivo cytolytic activity is detectable, coincident with the initiation of cell division. Despite the rapid development of these functional attributes, no antiviral effect was observed early during infection, even when the cells are present in numbers similar to those of virus-specific memory cells. The evolutionary reason for the pulse of IFN-γ synthesis by naive T cells is uncertain, but the lack of antiviral impact suggests that it may be regulatory.

CD8+ memory T cells appear exhausted within hours of acute virus infection.

CD8(+) memory T cells are abundant and are activated in a near-synchronous manner by infection, thereby providing a unique opportunity to evaluate the coordinate functional and phenotypic changes that occur in vivo within hours of viral challenge. Using two disparate virus challenges of mice, we show that splenic CD8(+) memory T cells rapidly produced IFN-γ in vivo; however, within 18-24 h, IFN-γ synthesis was terminated and remained undetectable for ≥ 48 h. A similar on/off response was observed in CD8(+) memory T cells in the peritoneal cavity. Cessation of IFN-γ production in vivo occurred despite the continued presence of immunostimulatory viral Ag, indicating that the initial IFN-γ response had been actively downregulated and that the cells had been rendered refractory to subsequent in vivo Ag contact. Downregulation of IFN-γ synthesis was accompanied by the upregulation of inhibitory receptor expression on the T cells, and ex vivo analyses using synthetic peptides revealed a concurrent hierarchical loss of cytokine responsiveness (IL-2, then TNF, then IFN-γ) taking place during the first 24 h following Ag contact. Thus, within hours of virus challenge, CD8(+) memory T cells display the standard hallmarks of T cell exhaustion, a phenotype that previously was associated only with chronic diseases and that is generally viewed as a gradually developing and pathological change in T cell function. Our data suggest that, instead, the "exhaustion" phenotype is a rapid and normal physiological T cell response.

VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children.

BACKGROUND: Despite substantial evidence supporting a pharmacogenetic approach to warfarin therapy in adults, evidence on the importance of genetics in warfarin therapy in children is limited, particularly for clinical outcomes. We assessed the contribution of CYP2C9/VKORC1/CYP4F2 genotypes and variation in other genes involved in vitamin K and coagulation pathways to warfarin dose and related clinical outcomes in children. PROCEDURE: Clinical and genetic data for 93 children (age ≤ 18 years) who received warfarin therapy were obtained. DNA was genotyped for 93 selected single nucleotide polymorphisms using a custom assay. RESULTS: With a median age of 4.8 years, our cohort included more young children than most previous studies. Overall, 76.3% of dose variability was explained by weight, indication, VKORC1-1639G/A and CYP2C9 *2/*3, with genotypes accounting for 21.1% of variability. There was a strong correlation (R(2) = 0.68; P < 0.001) between actual and predicted warfarin dose using a pediatric genotype-based dosing model. VKORC1 genotype had a significant impact on time to therapeutic international normalized ratio (INR) (P = 0.047) and time to over-anticoagulation (INR > 4; P = 0.024) during the initiation of therapy. CYP2C9*3 carriers were also at increased risk of major bleeding while receiving warfarin (adjusted OR = 11.28). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose (P = 0.020) in a multivariate clinical and genetic model. CONCLUSIONS: This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in a young pediatric cohort and demonstrates an impact of genetic factors on clinical outcomes in children. Furthermore, we identified an additional variant in CYP2C9 of potential relevance for warfarin dosing in children.

Optical coherence tomography for the evaluation of asymmetric cardiac allograft vasculopathy in a child.

We present an unusual case of CAV in a child with isolated disease in the LAD coronary artery. Initial progression of the disease appeared to have been halted by the use of sirolimus, but the assessment of disease in other vessels (particularly the RCA) was of particular importance in deciding whether or not to relist this patient for transplantation. Due to the known limitations of coronary angiography, we used OCT to assess for angiographically silent CAV. The normal intravascular appearance of the RCA by OCT was reassuring, and the child was not relisted for transplantation. OCT offers multiple advantages for the assessment of CAV in children.

The impact of a care bundle with an emphasis on hemodynamic assessment on the short-term outcomes in neonates with congenital diaphragmatic hernia.

OBJECTIVE: To evaluate the short-term outcomes of implementing a care bundle emphasizing frequent hemodynamic assessments by echocardiography in neonates with congenital diaphragmatic hernia (CDH). STUDY DESIGN: This was a retrospective cohort study of infants with CDH admitted to a quaternary perinatal unit from January 2013 to March 2021. The primary composite outcome was defined as mortality or use of extracorporeal membrane oxygenation or need for respiratory support at discharge. RESULTS: We identified 37 and 20 CDH infants in Epoch I and II, respectively. More patch repairs (50% vs. 21.9%, p = 0.035) and echocardiograms (6[4-8] vs. 1[0-5], p = 0.003) were performed in Epoch II. While there were no differences in the primary outcome, there was a reduction in mortality in Epoch II (0% vs. 27%, p = 0.01). CONCLUSION: With the implementation of a CDH care bundle with an emphasis on hemodynamic assessment, we demonstrated a significant reduction in mortality.

G-CSF-mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands.

Emergency mobilization of neutrophil granulocytes (neutrophils) from the bone marrow (BM) is a key event of early cellular immunity. The hematopoietic cytokine granulocyte-colony stimulating factor (G-CSF) stimulates this process, but it is unknown how individual neutrophils respond in situ. We show by intravital 2-photon microscopy that a systemic dose of human clinical-grade G-CSF rapidly induces the motility and entry of neutrophils into blood vessels within the tibial BM of mice. Simultaneously, the neutrophil-attracting chemokine KC (Cxcl1) spikes in the blood. In mice lacking the KC receptor Cxcr2, G-CSF fails to mobilize neutrophils and antibody blockade of Cxcr2 inhibits the mobilization and induction of neutrophil motility in the BM. KC is expressed by megakaryocytes and endothelial cells in situ and is released in vitro by megakaryocytes isolated directly from BM. This production of KC is strongly increased by thrombopoietin (TPO). Systemic G-CSF rapidly induces the increased production of TPO in BM. Accordingly, a single injection of TPO mobilizes neutrophils with kinetics similar to G-CSF, and mice lacking the TPO receptor show impaired neutrophil mobilization after short-term G-CSF administration. Thus, a network of signaling molecules, chemokines, and cells controls neutrophil release from the BM, and their mobilization involves rapidly induced Cxcr2-mediated motility controlled by TPO as a pacemaker.

A Canadian, retrospective, multicenter experience with selexipag for a heterogeneous group of pediatric pulmonary hypertension patients.

Introduction: Selexipag, an oral nonprostanoid prostaglandin receptor agonist, has led to reduced morbidity and mortality in adults with pulmonary arterial hypertension (PAH). While the adult literature has been extrapolated to suggest selexipag as an oral treatment for severe pediatric pulmonary hypertension (PH), longitudinal, multicenter data on the benefits of selexipag in this population are lacking. The purpose of this study is to present a longitudinal, multicentre experience with selexipag in a relatively large cohort of pediatric PH patients and add to the existing selexipag literature. Materials and methods: We performed a retrospective, multicenter review describing the clinical outcomes of pediatric PH patients receiving selexipag in addition to standard oral pulmonary vasodilator therapy across three Canadian centers between January 2005 and June 2021. Results: Twenty-four pediatric patients (fifteen female) with a mean age of 9.7 (range 2.0-15.5) years were included. Of this cohort, eighteen (75.0%) were in group 1, one (4.2%) was in group 2, four (16.7%) were in group 3, and one (4.2%) was in group 4. Twenty-two (91.7%) patients were on dual PH therapy after six months. Dosing was targeted to achieve 20-30 mcg/kg/dose orally every twelve hours. Median dose after twelve months was 30 mcg/kg/dose. Twelve months following selexipag initiation, median decreases of 0.2 cm in tricuspid annular plane systolic excursion, 3.5 mmHg in right-ventricular systolic pressure, and 6.1 mmHg in mean pulmonary arterial pressure were observed; none of these changes were statistically significant. Three patients died, one clinically deteriorated and required admission to a pediatric intensive care unit, ten had gastrointestinal symptoms, and three had flushing. Conclusion: Selexipag appears to be a safe and effective adjunctive therapy for pediatric PH patients and has a tolerable adverse effect profile aside from gastrointestinal disturbances. Additional prospective studies of changes in hemodynamics and functional classification over a longer period and with a larger sample are needed. Future research should aim to identify subgroups that stand to benefit from the addition of selexipag as well as optimal timing and dosing for the pediatric population.

Targeted neonatal echocardiography for patent ductus arteriosus in neonates reduces the surgical ligation rate without affecting healthcare outcomes.

Background: Surgical ligation of patent ductus arteriosus (PDA) can be associated with long-term morbidity and adverse outcomes in neonates. Targeted neonatal echocardiography (TNE) has been increasingly used to improve the hemodynamic management. We aimed to evaluate the preoperative assessment impacts of the hemodynamic significance of PDA using TNE on PDA ligation rates and neonatal outcomes. Methods: This observational study included preterm infants who underwent PDA ligation during two epochs (Epoch I: January 2013 to December 2014; Epoch II: January 2015 to June 2016). During Epoch II, a comprehensive TNE assessment was performed preoperatively to evaluate the hemodynamic significance of PDA. Primary outcome was the incidence of PDA ligation. Secondary outcomes included the incidence of postoperative cardiorespiratory instabilities, individual morbidities, and the composite outcome of death. Results: A total of 69 neonates underwent PDA ligation. No difference in baseline demographics was found between the epochs. The incidence of PDA ligation in very low birth weight (VLBW) infants was lower during Epoch II than Epoch I [7.5% vs. 14.6%, rate ratio =0.51 (95% confidence interval =0.30-0.88)]. No differences were observed between epochs in the proportion of VLBW infants who developed post-operative hypotension or oxygenation failure. The composite outcome of death or major morbidity did not significantly differ between Epoch I and Epoch II (91.1% vs. 94.1%, P=1.000). Conclusions: Incorporating TNE into a standardized hemodynamic assessment program, we demonstrated a 49% reduction in PDA ligation rate without any increase in postoperative cardiopulmonary instability or short-term neonatal morbidities in a cohort of VLBW infants.

iPSC-derived natural killer cells expressing the FcγR fusion CD64/16A can be armed with antibodies for multitumor antigen targeting.

BACKGROUND: Antibody therapies can direct natural killer (NK) cells to tumor cells, tumor-associated cells, and suppressive immune cells to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). This antigen-specific effector function of human NK cells is mediated by the IgG Fc receptor CD16A (FcγRIIIA). Preclinical and clinical studies indicate that increasing the binding affinity and avidity of CD16A for antibodies improves the therapeutic potential of ADCC. CD64 (FcγRI), expressed by myeloid cells but not NK cells, is the only high affinity IgG Fc receptor and is uniquely capable of stably binding to free monomeric IgG as a physiological function. We have reported on the generation of the FcγR fusion CD64/16A, consisting of the extracellular region of CD64 and the transmembrane and cytoplasmic regions from CD16A, retaining its signaling and cellular activity. Here, we generated induced pluripotent stem cell (iPSC)-derived NK (iNK) cells expressing CD64/16A as a potential adoptive NK cell therapy for increased ADCC potency. METHODS: iPSCs were engineered to express CD64/16A as well as an interleukin (IL)-15/IL-15Rα fusion (IL-15RF) protein and differentiated into iNK cells. iNK cells and peripheral blood NK cells were expanded using irradiated K562-mbIL21-41BBL feeder cells and examined. NK cells, ovarian tumor cell lines, and therapeutic monoclonal antibodies were used to assess ADCC in vitro, performed by a DELFIA EuTDA assay or in real-time by IncuCyte assays, and in vivo. For the latter, we developed a xenograft mouse model with high circulating levels of human IgG for more physiological relevance. RESULTS: We demonstrate that (1) iNK-CD64/16A cells after expansion or thaw from cryopreservation can be coupled to therapeutic antibodies, creating armed iNK cells; (2) antibody-armed iNK-CD64/16A cells can be redirected by added antibodies to target new tumor antigens, highlighting additional potential of these cells; (3) cytokine-autonomous activity by iNK-CD64/16A cells engineered to express IL-15RF; and that (4) antibody-armed iNK-CD64/16A cells thawed from cryopreservation are capable of sustained and robust ADCC in vitro and in vivo, as determined by using a modified tumor xenograft model with high levels of competing human IgG. CONCLUSIONS: iNK cells expressing CD64/16A provide an off-the-shelf multiantigen targeting platform to address tumor heterogeneity and mitigate antigen escape.

Left ventricle pseudoaneurysm after aortic valvuloplasty.

Acquired left ventricular aneurysm is extremely rare in children. This report describes an infant with acquired left ventricular aneurysm after percutaneous aortic balloon valvuloplasty for critical aortic stenosis. The potential risk factors for myocardial injury during cardiac catheterization and potential complications are discussed.

Celiac disease and cardiomyopathy in an adolescent with occult cirrhosis.

Patients with celiac disease commonly present with gastrointestinal symptoms including abdominal pain, bloating, constipation or diarrhea. Extraintestinal manifestations of this small bowel disease are increasingly recognized, and greater numbers of patients are being diagnosed after presenting solely with nongastrointestinal symptoms. The present report describes a case involving a 16-year-old girl with oligomenorrhea who was found to have celiac disease and liver cirrhosis of unknown etiology. Subsequent evaluation revealed cardiac dysfunction consistent with cirrhotic cardiomyopathy, a rare finding in the paediatric population. This patient's unusual presentation permits an exploration of several conditions uncommonly reported in conjunction with celiac disease.

Les patients ayant une maladie cœliaque ont souvent des symptômes gastro-intestinaux, y compris des maux de ventre, des ballonnements, de la constipation ou de la diarrhée. On relève de plus en plus les manifestations extra-intestinales de cette maladie de l'intestin grêle, et plus de patients sont diagnostiqués après avoir présenté seulement des symptômes non gastro-intestinaux. Dans le présent rapport, les auteurs décrivent le cas d'une adolescente de 16 ans ayant une oligoménorrhée chez qui on a découvert une maladie cœliaque et une cirrhose hépatique d'étiologie inconnue. L'évaluation subséquente a révélé une dysfonction cardiaque évocatrice d'une myocardiopathie cirrhotique, une observation rare au sein de la population pédiatrique. La présentation inhabituelle de cette patiente ouvre la voie à l'exploration de plusieurs pathologies dont on rend rarement compte en présence d'une maladie cœliaque.

Patterns of Early Coronary Artery Changes in Pediatric Heart Transplant Recipients Detected Using Optical Coherence Tomography.

BACKGROUND: Cardiac allograft vasculopathy, the leading cause of graft failure in pediatric heart transplant recipients, is characterized by diffuse and concentric coronary intimal thickening. Early treatment yields better outcomes. While coronary angiography is the standard for cardiac allograft vasculopathy screening and diagnosis, it only identifies luminal narrowing, which occurs in more severe disease. Coronary optical coherence tomography (OCT) is a high-definition intravascular imaging modality that may offer earlier diagnosis. We used OCT to investigate coronary intimal thickening in pediatric transplant recipients and examined its (1) location (ie, vessel type and location) and (2) nature (ie, characteristics of cross-sectional and longitudinal thickening). METHODS: Sites collected coronary angiography and OCT data from participants (N=258 vessel segments from 73 individuals; median age: 11.5 years [8.4-15.3]; 55% male). Images were collected from the left anterior descending, left circumflex, and right coronary arteries, and location (ie, proximal, middle, and distal) were classified using coronary angiography. RESULTS: OCT identified 32 vessel segments meeting criteria for significant thickening, 88% of which were angiographically silent. Longitudinal thickening was segmental rather than global in 88%, and cross-sectional thickening was 48% eccentric and 52% concentric. Intimal thickening prevalence and severity measures did not consistently differ between coronary artery type (P=1.000) or location (P=0.248) but increased with time since transplant and age at transplant and OCT procedure. CONCLUSIONS: In pediatric transplant recipients, we observed a surprisingly high prevalence of segmental and eccentric intimal thickening. Insights from intravascular imaging suggest these patterns of coronary vascular changes may precede overt cardiac allograft vasculopathy. Identifying early changes may offer opportunity for enhanced surveillance and earlier intervention.

Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation.

Primary atopic disorders are a group of inborn errors of immunity that skew the immune system toward severe allergic disease. Defining the biology underlying these extreme monogenic phenotypes reveals shared mechanisms underlying common polygenic allergic disease and identifies potential drug targets. Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia. Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis. RNA-Seq of JAK1GOF human whole blood, iPSCs, and transgenic zebrafish revealed a shared core set of dysregulated genes involved in IL-4, IL-13, and IFN signaling. Immunophenotypic and transcriptomic analysis of patients carrying a JAK1GOF variant revealed marked Th cell skewing. Moreover, long-term ruxolitinib treatment of 2 children carrying the JAK1GOF (p.A634D) variant remarkably improved their growth, eosinophilia, and clinical features of allergic inflammation. This work highlights the role of JAK1 signaling in atopic immune dysregulation and the clinical impact of JAK1/2 inhibition in treating eosinophilic and allergic disease.

A protective role for ELR+ chemokines during acute viral encephalomyelitis.

The functional role of ELR-positive CXC chemokines in host defense during acute viral-induced encephalomyelitis was determined. Inoculation of the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of mice resulted in the rapid mobilization of PMNs expressing the chemokine receptor CXCR2 into the blood. Migration of PMNs to the CNS coincided with increased expression of transcripts specific for the CXCR2 ELR-positive chemokine ligands CXCL1, CXCL2, and CXCL5 within the brain. Treatment of JHMV-infected mice with anti-CXCR2 blocking antibody reduced PMN trafficking into the CNS by >95%, dampened MMP-9 activity, and abrogated blood-brain-barrier (BBB) breakdown. Correspondingly, CXCR2 neutralization resulted in diminished infiltration of virus-specific T cells, an inability to control viral replication within the brain, and 100% mortality. Blocking CXCR2 signaling did not impair the generation of virus-specific T cells, indicating that CXCR2 is not required to tailor anti-JHMV T cell responses. Evaluation of mice in which CXCR2 is genetically silenced (CXCR2-/- mice) confirmed that PMNs neither expressed CXCR2 nor migrated in response to ligands CXCL1, CXCL2, or CXCL5 in an in vitro chemotaxis assay. Moreover, JHMV infection of CXCR2-/- mice resulted in an approximate 60% reduction of PMN migration into the CNS, yet these mice survived infection and controlled viral replication within the brain. Treatment of JHMV-infected CXCR2-/- mice with anti-CXCR2 antibody did not modulate PMN migration nor alter viral clearance or mortality, indicating the existence of compensatory mechanisms that facilitate sufficient migration of PMNs into the CNS in the absence of CXCR2. Collectively, these findings highlight a previously unappreciated role for ELR-positive chemokines in enhancing host defense during acute viral infections of the CNS.

The pathogenesis of murine coronavirus infection of the central nervous system.

Mouse hepatitis virus (MHV) is a positive-strand RNA virus that causes an acute encephalomyelitis that later resolves into a chronic fulminating demyelinating disease. Cytokine production, chemokine secretion, and immune cell infiltration into the central nervous system are critical to control viral replication during acute infection. Despite potent antiviral T-lymphocyte activity, sterile immunity is not achieved, and MHV chronically persists within oligodendrocytes. Continued infiltration and activation of the immune system, a result of the lingering viral antigen and RNA within oligodendrocytes, lead directly to the development of an immune-mediated demyelination that bears remarkable similarities, both clinically and histologically, to the human demyelinating disease multiple sclerosis. MHV offers a unique model system for studying host defense during acute viral infection and immune-mediated demyelination during chronic infection.

Early life events, sex, and arterial blood pressure in critically ill infants.

OBJECTIVE: To determine whether photo-protecting total parenteral nutrition in preterm infants influences arterial blood pressure differently according to gender. Blood pressure is influenced by complex mechanisms of vasomodulation. Oxidants are mediators and effectors in such reactions. Shielding total parenteral nutrition from light contributes to decrease the generation of peroxides. Girls may be better protected against an oxidant load than boys. We questioned whether shielding total parenteral nutrition may have cardiovascular effects that are influenced by gender. DESIGN: A post hoc subgroup analysis of the effect of shielding parenteral nutrition from light. SETTING: Neonatal intensive care unit. SUBJECTS: Preterm infants <1000 g with indwelling arterial catheters who received light exposed (n = 20) or light protected (n = 20) parenteral nutrition. INTERVENTIONS: Invasive monitoring, total parenteral nutrition. MEASUREMENTS AND MAIN RESULTS: Arterial blood pressure was recorded hourly and compared between light exposed and light protected over the first week of life; timed average maximum velocity (m/s) was measured in the superior mesenteric artery by Doppler; presence of ductus arteriosus was documented by cardiac ultrasound. Data were analyzed by analysis of variance. No differences were noted between light exposed and light protected in clinical determinants that may influence blood pressure. There was an interaction (p < .01) between gender and total parenteral nutrition on blood pressure. In girls (n = 17), systolic and diastolic blood pressures were higher (p < .01) and heart rate lower (p < .01) during light exposed. There was no effect on BP observed in boys (n = 23). The linear correlation between timed average maximum velocity and systolic blood pressure was positive (p < .05). There was no echocardographic difference in hemodynamic variables between boys (n = 21) and girls (n = 9) who had a patent ductus. CONCLUSION: Failure to shield total parenteral nutrition from light results in higher blood pressure in a selected population of critically ill female infants. This information adds to our understanding of the multiple determinants involved in optimizing arterial blood pressure in a critical care environment.