Measuring intelligence in Autism and ADHD: Measurement invariance of the-Binet 5th edition and impact of subtest scatter on abbreviated IQ accuracy.

Scatter and heterogeneity in cognitive profiles is thought to be common in autism spectrum disorder (ASD), which may indicate differences in the construct of IQ. However, less research has investigated IQ scatter in attention-deficit/hyperactivity disorder (ADHD). Scatter is also thought to negatively impact the predictive validity of IQ summary scores, although there is research refuting this notion. Abbreviated IQ tests, such as the Stanford-Binet fifth edition (SB-5) abbreviated battery IQ (ABIQ), may be especially susceptible to the influence of scatter. We tested the measurement invariance of the SB-5 as well as the predictive validity of the ABIQ in predicting FSIQ in 1679 youth (21% female) ages 2-16 years with a clinical diagnosis of ASD or ADHD. Results indicated the SB-5 is measuring IQ the same way in ASD and ADHD. There were no differences between diagnostic groups in scatter between ABIQ (i.e., routing) subtests. Additionally, scatter was not related to dimensional autistic traits. Higher degree of scatter was associated with poorer predictive validity of the ABIQ and a higher likelihood of overestimating FSIQ, regardless of diagnosis. Overall, we found more similarities than differences between the ASD and ADHD groups. Our results show that the SB-5 ABIQ is generally a strong predictor of FSIQ in youth with neurodevelopmental disorders. However, the use of the SB-5 ABIQ in research and clinical applications, without consideration of scatter on routing subtests, is potentially problematic.

The Value of Telehealth and a Team-Based Approach in Improving Developmental and Behavioral Care During the COVID-19 Pandemic.

CASE: Billy is a 2.6-year-old boy who presented for evaluation in the developmental-behavioral pediatrics (DBP) clinic 2 weeks before the onset of pandemic-related clinic restrictions. Billy had received early intervention for the past year because of speech and fine motor delays. Billy's parents requested the evaluation in the DBP clinic because his delayed speech and disruptive behaviors had raised concern that he may have autism spectrum disorder. Owing to the onset of the pandemic, subsequent visits were completed through telehealth with a developmental-behavioral pediatrician, psychologist, behavioral clinician, and social workers who developed a collaborative plan of care. Billy was diagnosed with global developmental delay, significant tantrums, and impulsivity but did not meet the criteria for autism spectrum disorder.Billy lives with his parents and 2 sisters in a rural area, 3 hours from the DBP clinic. Both of his parents have been treated for depression in the past and reported that school was difficult for them. His sisters, ages 5 and 6 years, receive speech/language therapy but have not required additional special education services. His family has endured recent stressors including a flooding event that caused significant damage to their home, financial difficulties, and the recent unexpected death of a close family member. Billy's disruptive behaviors have resulted in difficulty finding and maintaining child care, further contributing to parental stress and dysfunction in the home.Despite assistance from the social worker, additional developmental and behavioral support services near the family's home were not identified. Therefore, services were offered to Billy and his parents through telehealth. Billy's parents began behavioral parent training with a clinician embedded within the DBP clinic and, with direct support from his parents, Billy began receiving supplemental speech/language and occupational therapies through telehealth. Through recurrent engagement with Billy's parents and frequent communication among the behavioral clinician, developmental-behavioral pediatrician, psychologist, and social worker, Billy was able to make significant developmental progress, and his parents reported improved ability to manage his difficult behaviors.How can telehealth be used to help families navigate complex systems and obtain optimal care and support?

Hospital Admissions Associated With Cancer Pain in Older Adults With and Without Dementia.

BACKGROUND: Neoplasm-related pain is often suboptimally treated, contributing to avoidable suffering and increased medical resource use and costs. We hypothesized that dementia may contribute to increased resource use and costs in patients hospitalized for neoplasm-related pain in the United States. AIMS: To examine how persons with cancer and dementia use medical resources and expenditures in US hospitals compared to ondividuals without dementia. DESIGN: This study examined a retrospective cohort. SETTING: Admissions to US hospitals for neoplasm-related pain from 2012-2016 PARTICIPANTS/SUBJECTS: METHODS: Data were obtained from the 2012-2016 National Inpatient Sample (NIS). The sample included hospital admissions of individuals aged 60 or older with a primary diagnosis of neoplasm-related pain. Dementia was defined using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), and ICD-10-CM diagnosis codes. Primary outcomes were number of admissions, costs, and length of stay (LOS). Descriptive statistics and multivariable regression models were used to examine the relationships among dementia, costs, and LOS. RESULTS: Of 12,034 admissions for neoplasm-related pain, 136 (1.1%) included a diagnosis of dementia and 11,898 (98.9%) did not. Constipation was present in 13.2% and 24.5% of dementia and nondementia admissions, respectively. The median LOS was 4 days in persons with dementia and three in those without. Mean costs per admission were higher in persons without dementia ($10,736 vs. $9,022, p = .0304). In adjusted regression results, increased costs were associated with nonelective admissions and longer LOS, and decreased costs with age above the mean. In contrast, decreased LOS was associated with age above the mean and nonelective admissions. Dementia was associated with neither endpoint. CONCLUSION: This study provides nurses and other health care professionals with data to further explore opportunities for improvement in cancer pain management in patients with and without dementia that may optimize use of medical resources.

Continuous Glucose Monitoring in the Intensive Care Unit During the COVID-19 Pandemic.

OBJECTIVE: Real-time continuous glucose monitoring (rtCGM) in critically ill hospitalized patients holds promise; however, real-world data are needed. RESEARCH DESIGN AND METHODS: We placed Dexcom G6 CGM on intensive care unit (ICU) patients at Montefiore Medical Center with confirmed coronavirus disease 2019 (COVID-19) infection and glycemic variability. We analyzed inpatient CGM accuracy using point-of-care (POC) glucose-CGM matched pairs and included patients for analysis regardless of clinical status. RESULTS: We included 11 patients with CGM: 8 on continuous insulin infusion (CII), 8 on vasopressors, 8 intubated, 4 on high-dose glucocorticoids, 6 on renal replacement therapy, and 2 with anasarca. Accuracy was 12.58% for mean and 6.3% for median absolute relative difference. CGM reduced POC testing by ∼60% for patients on CII. CONCLUSIONS: In this real-world preliminary analysis of rtCGM during critical illness, we demonstrate early feasibility, considerable accuracy, and meaningful reduction in the frequency of POC glucose testing.

Simultaneous Acquired Self-limited Hemophagocytic Lymphohistiocytosis and Kikuchi Necrotizing Lymphadenitis in a 16-Year-Old Teenage Girl: A Case Report and Review of the Literature.

OBJECTIVES: The aim of this study was to increase education and awareness among pediatric practitioners of possibility of simultaneous hemophagocytic lymphohistiocytosis and Kikuchi-Fujimoto disease/Kikuchi disease occurring in the pediatric population and the diagnostic dilemma it can present. We describe a case presentation of acquired and self-limited simultaneous hemophagocytic lymphohistiocytosis and Kikuchi-Fujimoto disease in a 16-year-old in the United States who presented with fevers, night sweats, and joint pain, along with tiredness and decreased appetite along with pancytopenia and elevated lactate dehydrogenase. To the best of our knowledge, simultaneous hemophagocytic lymphohistiocytosis and Kikuchi-Fujimoto in the pediatric population has not been described in North America but remains fairly common in Asia. The literature on both diseases and their simultaneous occurrence is comprehensively reviewed. METHODS: This was a case report and review of the literature. RESULTS: The patient was diagnosed with both hemophagocytic lymphohistiocytosis and Kikuchi-Fujimoto disease based on bone marrow aspiration/biopsy and axillary node biopsy, respectively. Both illnesses resolved completely. CONCLUSIONS: Benign causes of pancytopenia and elevated lactate dehydrogenase exist, but they may not be always straightforward diagnostically. Bone marrow aspiration and lymph node biopsy may be helpful in ascertaining the diagnosis. Hemophagocytic lymphohistiocytosis and Kikuchi-Fujimoto disease may represent a continuum of illness.

Surfactant protein A binds flagellin enhancing phagocytosis and IL-1ß production.

Surfactant protein A (SP-A), a pulmonary collectin, plays a role in lung innate immune host defense. In this study the role of SP-A in regulating the inflammatory response to the flagella of Pseudomonas aeruginosa (PA) was examined. Intra-tracheal infection of SP-A deficient (SP-A-/-) C57BL/6 mice with wild type flagellated PA (PAK) resulted in an increase in inflammatory cell recruitment and increase in pro-inflammatory cytokines IL-6 and TNF-α, which was not observed with a mutant pseudomonas lacking flagella (fliC). SP-A directly bound flagellin, via the N-linked carbohydrate moieties and collagen-like domain, in a concentration dependent manner and enhanced macrophage phagocytosis of flagellin and wild type PAK. IL-1ß was reduced in the lungs of SP-A-/- mice following PAK infection. MH-s cells, a macrophage cell line, generated greater IL-1ß when stimulated with flagellin and SP-A. Historically flagella stimulate IL-1ß production through the toll-like receptor 5 (TLR-5) pathway and through a caspase-1 activating inflammasome pathway. IL-1ß expression became non-detectable in SP-A and flagellin stimulated MH-s cells in which caspase-1 was silenced, suggesting SP-A induction of IL-1ß appears to be occurring through the inflammasome pathway. SP-A plays an important role in the pathogenesis of PA infection in the lung by binding flagellin, enhancing its phagocytosis and modifying the macrophage inflammatory response.

Prostaglandin E2-induced changes in alveolar macrophage scavenger receptor profiles differentially alter phagocytosis of Pseudomonas aeruginosa and Staphylococcus aureus post-bone marrow transplant.

The effectiveness of hematopoietic stem cell transplantation as a therapy for malignant and nonmalignant conditions is complicated by pulmonary infections. Using our syngeneic bone marrow transplant (BMT) mouse model, BMT mice with a reconstituted hematopoietic system displayed increased susceptibility to Pseudomonas aeruginosa and Staphylococcus aureus. BMT alveolar macrophages (AMs) exhibited a defect in P. aeruginosa phagocytosis, whereas S. aureus uptake was surprisingly enhanced. We hypothesized that the difference in phagocytosis was due to an altered scavenger receptor (SR) profile. Interestingly, MARCO expression was decreased, whereas SR-AI/II was increased. To understand how these dysregulated SR profiles might affect macrophage function, CHO cells were transfected with SR-AI/II, and phagocytosis assays revealed that SR-AI/II was important for S. aureus uptake but not for P. aeruginosa. Conversely, AMs treated in vitro with soluble MARCO exhibited similar defects in P. aeruginosa internalization as did BMT AMs. The 3'-untranslated region of SR-AI contains a putative target region for microRNA-155 (miR-155), and miR-155 expression is decreased post-BMT. Anti-miR-155-transfected AMs exhibited an increase in SR-AI/II expression and S. aureus phagocytosis. Elevated PGE2 has been implicated in driving an impaired innate immune response post-BMT. In vitro treatment of AMs with PGE2 increased SR-AI/II and decreased MARCO and miR-155. Despite a difference in phagocytic ability, BMT AMs harbor a killing defect to both P. aeruginosa and S. aureus. Thus, our data suggest that PGE2-driven alterations in SR and miR-155 expression account for the differential phagocytosis of P. aeruginosa and S. aureus, but impaired killing ultimately confers increased susceptibility to pulmonary infection.

IL-36α exerts pro-inflammatory effects in the lungs of mice.

Interleukin (IL-) 36 cytokines (previously designated as novel IL-1 family member cytokines; IL-1F5- IL-1F10) constitute a novel cluster of cytokines structurally and functionally similar to members of the IL-1 cytokine cluster. The effects of IL-36 cytokines in inflammatory lung disorders remains poorly understood. The current study sought to investigate the effects of IL-36α (IL-1F6) and test the hypothesis that IL-36α acts as a pro-inflammatory cytokine in the lung in vivo. Intratracheal instillation of recombinant mouse IL-36α induced neutrophil influx in the lungs of wild-type C57BL/6 mice and IL-1αß(-/-) mice in vivo. IL-36α induced neutrophil influx was also associated with increased mRNA expression of neutrophil-specific chemokines CXCL1 and CXCL2 in the lungs of C57BL/6 and IL-1αß(-/-) mice in vivo. In addition, intratracheal instillation of IL-36α enhanced mRNA expression of its receptor IL-36R in the lungs of C57BL/6 as well as IL-1αß(-/-) mice in vivo. Furthermore, in vitro incubation of CD11c(+) cells with IL-36α resulted in the generation of neutrophil-specific chemokines CXCL1, CXCL2 as well as TNFα. IL-36α increased the expression of the co-stimulatory molecule CD40 and enhanced the ability of CD11c(+) cells to induce CD4(+) T cell proliferation in vitro. Furthermore, stimulation with IL-36α activated NF-κB in a mouse macrophage cell line. These results demonstrate that IL-36α acts as a pro-inflammatory cytokine in the lung without the contribution of IL-1α and IL-1ß. The current study describes the pro-inflammatory effects of IL-36α in the lung, demonstrates the functional redundancy of IL-36α with other agonist cytokines in the IL-1 and IL-36 cytokine cluster, and suggests that therapeutic targeting of IL-36 cytokines could be beneficial in inflammatory lung diseases.

Plasma concentration of N-terminal pro-atrial and N-terminal pro-brain natriuretic peptides and fluid balance in children with bronchiolitis.

The aim of this study was to evaluate the plasma levels of N-Terminal pro-brain natriuretic peptide (N-BNP), N-Terminal pro-atrial natriuretic peptide (N-ANP) and antidiuretic hormone (ADH) over time and their relationship to clinical indicators in hospitalized children with bronchiolitis. Prospective crossover clinical investigation. Hospitalized children in a university-affiliated hospital. Twenty-seven children (birth to 24 mo) with first episode of bronchiolitis and 34 age-matched healthy controls. Daily blood samples up to five consecutive days were obtained for N-BNP, N-ANP and ADH in the bronchiolitis group and on the initial blood draw in the control group. Daily total fluid intake, net fluid balance and clinical bronchiolitis severity levels were recorded. N-BNP and N-ANP levels were measured by enzyme-linked immunosorbent assay. ADH levels were measured by a double antibody technique. The mean age (months ± SD) in the bronchiolitis group was 4.2 ± 5.9 mo and 12.0 ± 6.1 mo in the control group; 51.9% of bronchiolitis patients were positive for respiratory syncytial virus (RSV). In patients with bronchiolitis on admission, plasma N-BNP measurements (mean ± SD) were elevated (996.0 ± 570.2 fmol/mL) compared to controls (552.7 ± 264.7 fmol/mL P < 0.005). Serum N-ANP levels were also initially elevated (3,889 ± 1,769.7 fmol/mL) compared to controls (2,173 ± 912 fmol/mL P < 0.005). The serum levels of N-BNP and N-ANP remained significantly elevated from day 2 through day 5. Similarly, ADH levels were significantly higher on admission in the bronchiolitis group (10 ± 7.49 pg/mL) vs. the control group (5.8 ± 5.5 pg/mL P < 0.05), but quickly decreased from day 2 through day 5. N-BNP, N-ANP and ADH concentrations were elevated in hospitalized children with bronchiolitis at admission. Based on our observation, judicious fluid management is indicated in children hospitalized with bronchiolitis.

Predictors of depressive symptoms in parents of chronically ill children admitted to the pediatric intensive care unit.

OBJECTIVE: To identify factors in the pediatric intensive care unit (PICU) patient population that may result in increased risk of depressive symptoms in their parents. DESIGN: Six-month, prospective, observational study in a tertiary-level PICU on parents of chronically ill children admitted to PICU. Parents were assessed by background questionnaire and standardized depression scale. RESULTS: Data was compared to various markers such as child's diagnosis, admission reason, palliative care diagnosis type (ACT code), and course/length of disease. Incidence of depressive symptoms in parents was inversely correlated with duration of child's chronic illness. Parents of children admitted for planned postoperative management were more likely to report depressive symptoms compared to parents of children admitted for acute changes in health. CONCLUSION: Parents of certain chronically ill children may benefit from routine screening for depression.

Interleukin-1 family member 9 stimulates chemokine production and neutrophil influx in mouse lungs.

Interleukin-1 (IL-1) is a proinflammatory cytokine that signals through the Type I IL-1 receptor (IL-1RI). Novel IL-1-like cytokines were recently identified. Their functions in lung disease remain unclear. Interleukin-1 family member-9 (IL-1F9) is one such IL-1-like cytokine, expressed in the lungs of humans and mice. IL-1F9 signals through IL-1 receptor-related protein 2 (IL-1Rrp2/IL-1RL2), which is distinct from IL-1RI. We sought to determine if IL-1F9 acts as a proinflammatory cytokine in lung disease. IL-1F9 protein was increased in lung homogenates of house dust mite-challenged A/J mice compared with controls, and expression was seen in airway epithelial cells. The intratracheal administration of recombinant mouse IL-1F9 increased airway hyperresponsiveness and induced neutrophil influx and mucus production, but not eosinophilic infiltration in the lungs of mice. In addition, IL-1α protein levels in bronchoalveolar lavage fluid, chemokines, and chemokine-receptor mRNA expression in the lungs were increased after the instillation of intratracheal IL-1F9. Consistent with these changes, NF-κB transcription factor activity was increased in the lungs of mice challenged with IL-1F9 and in a macrophage cell line treated with IL-1F9. These data suggest that IL-1F9 is upregulated during inflammation, and acts as a proinflammatory cytokine in the lungs.

New concepts of IL-10-induced lung fibrosis: fibrocyte recruitment and M2 activation in a CCL2/CCR2 axis.

IL-10 is most commonly recognized as an anti-inflammatory cytokine possessing immunosuppressive effects necessary for regulated resolution of proinflammation. However, its role in the development of fibrosis during inflammatory resolution has not been clear. Few prior studies have linked IL-10 with the inhibition of fibrosis principally on the basis of regulating inflammation thought to be driving fibroproliferation. In contrast, in a model of long-term overexpression of IL-10, we observed marked induction of lung fibrosis in mice. The total cell number retrieved by bronchoalveolar lavage (BAL) increased 10-fold in the IL-10 overexpression (IL-10 OE) mice, with significant infiltration of T and B lymphocytes and collagen-producing cells. The presence of increased fibrocytes, isolated from collagenase-digested lungs, was identified by flow cytometry using dual staining of CD45 and collagen 1. Quantitative PCR analysis on an array of chemokine/chemokine receptor genes showed that receptor CCR2 and its ligand, CCL2, were highly upregulated in IL-10 OE mice, suggesting that IL-10-induced fibrocyte recruitment was CCL2/CCR2 specific. Given the prior association of alternatively activated (M(2)) macrophages with development of fibrosis in other disease states, we also examined the effect of IL-10 OE on the M(2) macrophage axis. We observed significantly increased numbers of M(2) macrophages in both BAL and whole lung tissue from the IL-10 OE mice. Administration of rabbit anti-CCL2 antiserum to IL-10 OE mice for three consecutive weeks significantly decreased fibrosis as evidenced by lung hydroxyproline content, compared with mice that received preimmune rabbit serum. These results indicate that overexpression of IL-10 induces fibrosis, in part, by fibrocyte recruitment and M(2) macrophage activation, and likely in a CCL2/CCR2 axis.

Bactericidal effects of silver plus titanium dioxide-coated endotracheal tubes on Pseudomonas aeruginosa and Staphylococcus aureus.

PURPOSE: Ventilator-associated pneumonia (VAP) is a nosocomial infection resulting in significant morbidity and mortality. Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) are pathogens associated with VAP. Silver (Ag) coating of endotracheal tubes (ETTs) reduces bacterial colonization, however titanium dioxide (TiO(2)) coating has not been studied. METHODS: Five types of ETT coatings were applied over silica layer: Ag, solgel TiO(2), solgel TiO(2) with Ag, Degussa P25 TiO(2) (Degussa TiO(2)), and Degussa TiO(2) with Ag. After ETTs were incubated with P. aeruginosa or S. aureus; colonization was determined quantitatively. RESULTS: Pseudomonas aeruginosa and S. aureus grew for 5 days on standard ETTs. Compared to standard ETTs, P. aeruginosa growth was significantly inhibited by solgel TiO(2) with Ag at 24 hours, and by Degussa TiO(2) with Ag at 24 and 48 hours after inoculation. No significant difference in S. aureus growth was observed between the control and any of the five coatings for 5 days. CONCLUSION: In vitro, solgel TiO(2) with Ag and Degussa TiO(2) with Ag both attenuated P. aeruginosa growth, but demonstrated no effect on S. aureus colonization. Further studies using alternative coating and incorporating UV light exposure are needed to identify their potential utility in reducing VAP.

Surfactant protein A modulates cell surface expression of CR3 on alveolar macrophages and enhances CR3-mediated phagocytosis.

Pulmonary surfactant protein A (SP-A), a member of the collectin family, plays an important role in innate immune defense of the lung. In this study, we examined the role of SP-A in modulating complement receptor-mediated phagocytosis. Complement receptors (CR), CR3 (CD11b), and CR4 (CD11c) were expressed at reduced levels on the surface of alveolar macrophages from Sp-a(-/-) compared with Sp-a(+/+) mice. Administration of intratracheal SP-A to Sp-a(-/-) mice induced the translocation of CR3 from alveolar macrophage intracellular pools to the cell surface. Intratracheal challenge with Haemophilus influenza enhanced CR3 expression on the surface of alveolar macrophages from Sp-a(-/-) and Sp-a(+/+) mice, but relative expression remained lower in the Sp-a(-/-) mice at all time points post-inoculation. The effects of SP-A on macrophage and neutrophil CR3 redistribution between intracellular and cell surface pools were restricted to cells isolated from the lung. SP-A augmented CR3-mediated phagocytosis in a manner that was attenuated by N-glycanase or collagenase treatment of SP-A, implicating the N-linked sugar and collagen-like domains in that function. The binding of CR3 to SP-A was calcium dependent and mediated by the I-domain of CR3 and to a lesser extent by the CR3 lectin domain. Mapping of the domains of SP-A that were required for optimal binding to CR3 revealed that the N-linked sugars were more critical than the collagen-like domain or the extent of oligomeric assembly. We conclude that SP-A modulates the cell surface expression of CR3 on alveolar macrophages, binds to CR3, and enhances CR3-mediated phagocytosis.

Surfactant protein A enhances production of secretory leukoprotease inhibitor and protects it from cleavage by matrix metalloproteinases.

Mice lacking surfactant protein A (SP-A) are susceptible to bacterial infection associated with an excessive inflammatory response in the lung. To determine mechanisms by which SP-A is antiinflammatory in the lung during bacterial infection, SP-A regulation of secretory leukoprotease inhibitor (SLPI), an inhibitor of serine proteases, was assessed. SLPI protein expression and antineutrophil elastase activity were reduced in bronchoalveolar fluid of SP-A(-/-) compared with SP-A(+/+) mice. Intratracheal administration of SP-A to SP-A(-/-) mice enhanced SLPI protein expression and antineutrophil elastase activity in the lung. SLPI mRNA was similar in whole lung and alveolar type II cells; however, it was significantly reduced in alveolar macrophages from SP-A(-/-) compared with SP-A(+/+) mice. In vitro, SP-A enhanced SLPI production by macrophage THP-1 cells but not respiratory epithelial A549 cells. SP-A inhibited LPS induced IkappaB-alpha degradation in THP-1 cells, which was partially reversed with knockdown of SLPI. Matrix metalloproteinase (MMP)-12 cleaved SLPI and incubation with SP-A reduced MMP-12-mediated SLPI cleavage. The collagen-like region of SP-A conferred protection of SLPI against MMP mediated cleavage. SP-A plays an important role in the lung during bacterial infection regulating protease and antiprotease activity.

Surfactant protein D regulates the cell surface expression of alveolar macrophage beta(2)-integrins.

The beta(2)-integrin receptors (CD11a/CD18, CD11b/CD18, and CD11c/CD18) are expressed on the surface of alveolar macrophages and are important for the phagocytic clearance of pathogens. In the present study, we demonstrate that surfactant protein D (SP-D) modulates surface expression of CD11b and CD11c, but not CD11a or CD18, on alveolar macrophages. While cell surface receptors were reduced, CD11b and CD11c mRNAs were increased by SP-D deficiency. CCSP-rtTA(+)/(tetO)(7)-rSPD(+)/SP-D(-/-) mice, which conditionally express SP-D in the lung, were used to study the kinetics and reversibility of beta(2)-integrin receptors in response to changes in alveolar SP-D. Surface CD11b and CD11c were reduced on the alveolar macrophages within 3 days of SP-D deficiency and were restored with 3 days for CD11b and 7 days for CD11c of repletion of SP-D. SP-D deficiency caused a loss of cellular CD11b and CD11c content, indicating that the decrease in total cell content of the receptors was related to degradation rather than to redistribution of the receptor within the macrophage. CD11b and CD11c staining colocalized with Lamp-1 during SP-D deficiency, supporting the concept that reduced macrophage receptor levels resulted from increased lysosomal trafficking. Hydroxychloroquine, a lysomotropic agent, prevented the reduction of cellular and surface CD11b and CD11c. SP-D regulates surface CD11b and CD11c levels on the alveolar macrophage by modulating receptor trafficking, providing a mechanism by which SP-D mediates phagocytic activity in the alveolar macrophage.

Effect of lung surfactant collectins on bronchoalveolar macrophage interaction with Blastomyces dermatitidis: inhibition of tumor necrosis factor alpha production by surfactant protein D.

Alveolar surfactant modulates the antimicrobial function of bronchoalveolar macrophages (BAM). Little is known about the effect of surfactant-associated proteins in bronchoalveolar lavage fluid (BALF) on the interaction of BAM and Blastomyces dermatitidis. We investigated BALF enhancement or inhibition of TNF-alpha production by BAM stimulated by B. dermatitidis. BAM from CD-1 mice were stimulated with B. dermatitidis without or with normal BALF, surfactant protein A-deficient (SP-A-/-) or surfactant protein D-deficient (SP-D-/-) BALF, or a mixture of SP-A-/- and SP-D-/- BALF. An enzyme-linked immunosorbent assay was used to measure tumor necrosis factor alpha (TNF-alpha) in culture supernatants. BALFs were standardized in protein concentration. BAM plus B. dermatitidis (BAM-B. dermatitidis) TNF-alpha production was inhibited > or = 47% by BALF or SP-A-/- BALF (at 290 or 580 microg of protein/ml, P < 0.05 to 0.01); in contrast, SP-D-/- BALF did not significantly inhibit TNF-alpha production. If SP-A-/- BALF was mixed in equal amounts with SP-D-/- BALF, TNF-alpha production by BAM-B. dermatitidis was inhibited (P < 0.01). Finally, pure SP-D added to SP-D-/- BALF inhibited TNF-alpha production by BAM-B. dermatitidis (P < 0.01). B. dermatitidis incubated with BALF and washed, plus BAM, stimulated 63% less production of TNF-alpha than did unwashed B. dermatitidis (P < 0.05). SP-D was detected by anti-SP-D antibody on BALF-treated unwashed B. dermatitidis in an immunofluorescence assay (IFA). The BALF depleted by a coating of B. dermatitidis lost the ability to inhibit TNF-alpha production (P < 0.05). 1,3-beta-Glucan was a good stimulator of BAM for TNF-alpha production and was detected on B. dermatitidis by IFA. beta-Glucan incubated with BALF inhibited the binding of SP-D in BALF to B. dermatitidis as demonstrated by IFA. Our data suggest that SP-D in BALF binds beta-glucan on B. dermatitidis, blocking BAM access to beta-glucan, thereby inhibiting TNF-alpha production. Thus, whereas BALF constituents commonly mediate antimicrobial activity, B. dermatitidis may utilize BALF constituents, such as SP-D, to blunt the host defensive reaction; this effect could reduce inflammation and tissue destruction but could also promote disease.

Decreased bacterial clearance from the lungs of mice following primary respiratory syncytial virus infection.

Virus respiratory infections often precede bacterial pneumonia in healthy individuals. In order to determine the potential role of respiratory syncytial virus (RSV) in bacterial secondary infections, a mouse sequential pulmonary infection model was developed. Mice were exposed to RSV then challenged with Streptococcus pneumoniae (StPn). Exposure of BALB/c mice to 10(6)-10(7) plaque forming units (pfu) of virus of RSV significantly decreased StPn clearance 1-7 days following RSV exposure. This finding was not restricted to StPn alone: exposure to RSV followed by Staphylococcus aureus (SA) or Pseudomonas aeruginosa(PA) resulted in similar decreases in bacterial clearance. Both bronchoalveolar lavage (BAL) cell counts and pulmonary histopathology demonstrated that RSV-StPn exposed mice had increased lung cellular inflammation compared to mice receiving StPn or RSV alone. The effect of RSV infection on bacterial clearance was dependent on the mouse genetic background: C57BL/6J mice (relatively resistant to RSV infection) demonstrated a modest change in StPn clearance following RSV exposure, whereas FVBN/J mice (similar to the BALB/cJ mice in RSV susceptibility) demonstrated a similar degree of RSV-associated decrease in StPn clearance 7 days following RSV exposure. Neutrophils from the RSV-StPn sequentially exposed BALB/cJ mice were functionally altered-produced greater levels of peroxide production but less myeloperoxidase (MPO) compared to mice receiving StPn alone. These data demonstrate that RSV infection decreases bacterial clearance, potentially predisposing to secondary bacterial pneumonia despite increased lung cellular inflammation, and suggest that functional changes occur in the recruited neutrophils that may contribute to the decreased bacterial clearance.