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1.  The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice 
Nature medicine  2014;20(5):524-530.
Acquisition of microbes by the neonate, which begins immediately during birth, is influenced by gestational age and mother’s microbiota and modified by exposure to antibiotics1. In neonates, prolonged duration of antibiotic therapy is associated with increased risk of sepsis after 4 days of life, known as late-onset sepsis (LOS)2, a disorder critically controlled by neutrophils3, but a role for the microbiota in regulating neutrophil behavior in the neonate has not been described. We exposed pregnant mouse dams to antibiotics in drinking water to limit transfer of maternal microbes to the neonates. Antibiotic exposure of dams decreased the total number of microbes in the intestine, altered the structure of intestinal microbiota and changed the pattern of microbial colonization. These changes were associated with decreased numbers of circulating and bone marrow neutrophils and granulocyte/macrophage restricted progenitor cells in the bone marrow. Antibiotic-exposure of dams attenuated the postnatal granulocytosis by reducing the number of interleukin (IL) 17-producing cells in intestine and consequent production of granulocyte colony stimulating factor (G-CSF). Relative granulocytopenia contributed to increased susceptibility of antibiotic-exposed neonatal mice to Escherichia coli K1 and Klebsiella pneumoniae sepsis, which could be partially reversed by administration of G-CSF. Restoration of normal microbiota, through TLR4- and MYD88-dependent mechanism, induced accumulation of IL17-producing type 3 innate lymphoid cells (ILC) in the intestine, promoted granulocytosis, and restored the IL17-dependent resistance to sepsis. Specific depletion of ILCs prevented the IL17- and G-CSF-dependent granulocytosis and resistance to sepsis. These data support a role for the intestinal microbiota in regulation of granulocytosis and host resistance to sepsis in the neonates.
doi:10.1038/nm.3542
PMCID: PMC4016187  PMID: 24747744
2.  Dusp3 and Psme3 Are Associated with Murine Susceptibility to Staphylococcus aureus Infection and Human Sepsis 
PLoS Pathogens  2014;10(6):e1004149.
Using A/J mice, which are susceptible to Staphylococcus aureus, we sought to identify genetic determinants of susceptibility to S. aureus, and evaluate their function with regard to S. aureus infection. One QTL region on chromosome 11 containing 422 genes was found to be significantly associated with susceptibility to S. aureus infection. Of these 422 genes, whole genome transcription profiling identified five genes (Dcaf7, Dusp3, Fam134c, Psme3, and Slc4a1) that were significantly differentially expressed in a) S. aureus –infected susceptible (A/J) vs. resistant (C57BL/6J) mice and b) humans with S. aureus blood stream infection vs. healthy subjects. Three of these genes (Dcaf7, Dusp3, and Psme3) were down-regulated in susceptible vs. resistant mice at both pre- and post-infection time points by qPCR. siRNA-mediated knockdown of Dusp3 and Psme3 induced significant increases of cytokine production in S. aureus-challenged RAW264.7 macrophages and bone marrow derived macrophages (BMDMs) through enhancing NF-κB signaling activity. Similar increases in cytokine production and NF-κB activity were also seen in BMDMs from CSS11 (C57BL/6J background with chromosome 11 from A/J), but not C57BL/6J. These findings suggest that Dusp3 and Psme3 contribute to S. aureus infection susceptibility in A/J mice and play a role in human S. aureus infection.
Author Summary
Staphylococcus aureus causes life-threatening infections in humans. Host genetic determinants influence the outcome of S. aureus infection, yet are poorly understood. Susceptible A/J and resistant C57BL/6J mice provide a unique platform to study the genetic difference responsible for variable host response to S. aureus infection. We showed that chromosome 11 in A/J was responsible for susceptibility to S. aureus. We further identified a QTL locus on Chromosome 11 significantly associated with S. aureus susceptibility. Five genes in the QTL (Dcaf7, Dusp3, Fam134c, Psme3, and Slc4a1) were significantly differently expressed in a) susceptible vs. resistant mice, and b) humans with S. aureus blood stream infection vs. healthy human subjects. Three genes (Dusp3, Psme3, and Dcaf7) were down-regulated in susceptible A/J mice. siRNA-mediated knockdown of Dusp3 and Psme3 in bone marrow derived macrophage (BMDMs) significantly enhanced cytokine responses through NF-κB activity upon S. aureus challenge in a pattern that was also present in S. aureus-challenged BMDMs from susceptible CSS11 (chr. 11 from A/J but otherwise C57BL/6J) mice, but not resistant C57BL/6J mice. These findings suggest that Dusp3 and Psme3 contribute to S. aureus infection susceptibility in A/J mice and play a role in human S. aureus infection.
doi:10.1371/journal.ppat.1004149
PMCID: PMC4047107  PMID: 24901344
3.  Novel FOXF1 mutations in sporadic and familial cases of Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins imply a role for its DNA binding domain 
Sen, Partha | Yang, Yaping | Navarro, Colby | Silva, Iris | Szafranski, Przemyslaw | Kolodziejska, Katarzyna E. | Dharmadhikari, Avinash V. | Mostafa, Hasnaa | Kozakewich, Harry | Kearney, Debra | Cahill, John B. | Whitt, Merrissa | Bilic, Masha | Margraf, Linda | Charles, Adrian | Goldblatt, Jack | Gibson, Kathleen | Lantz, Patrick | Garvin, Julian | Petty, John | Kiblawi, Zeina | Zuppan, Craig | McConkie-Rosell, Allyn | McDonald, Marie T. | Peterson-Carmichael, Stacey L. | Gaede, Jane T. | Shivanna, Binoy | Schady, Deborah | Friedlich, Philippe S. | Hays, Stephen R. | Palafoll, Irene Valenzuela | Siebers-Renelt, Ulrike | Bohring, Axel | Finn, Laura S. | Siebert, Joseph R. | Galambos, Csaba | Nguyen, Lananh | Riley, Melissa | Chassaing, Nicolas | Vigouroux, Adeline | Rocha, Gustavo | Fernandes, Susana | Brumbaugh, Jane | Roberts, Kari | Ho-ming, Luk | Lo, Ivan | Lam, Stephen | Gerychova, Romana | Jezova, Marta | Valaskova, Iveta | Fellmann, Florence | Afshar, Katayoun | Giannoni, Eric | Muhlethaler, Vincent | Liang, Jinlong | Beckmann, Jacques S. | Lioy, Janet | Deshmukh, Hitesh | Srinivasan, Lakshmi | Swarr, Daniel T. | Sloman, Melissa | Shaw-Smith, Charles | van Loon, Rosa Laura | Hagman, Cecilia | Sznajer, Yves | Barrea, Catherine | Galant, Christine | Detaille, Thierry | Wambach, Jennifer A. | Cole, F. Sessions | Hamvas, Aaron | Prince, Lawrence S. | Diderich, Karin E.M. | Brooks, Alice S. | Verdijk, Rob M. | Ravindranathan, Hari | Sugo, Ella | Mowat, David | Baker, Michael L. | Langston, Claire | Welty, Stephen | Stankiewicz, Pawel
Human mutation  2013;34(6):801-811.
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Non-pulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and ten deletions, we have identified an additional thirty eight novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, twenty missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic whereas four familial cases with three showing maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA binding domain, indicating its plausible role in gene regulation. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.
doi:10.1002/humu.22313
PMCID: PMC3663886  PMID: 23505205
Lung; Development; Angiogenesis; ACD/MPV; FOXF1; Imprinting
4.  Haplotype Association Mapping Identifies a Candidate Gene Region in Mice Infected With Staphylococcus aureus 
G3: Genes|Genomes|Genetics  2012;2(6):693-700.
Exposure to Staphylococcus aureus has a variety of outcomes, from asymptomatic colonization to fatal infection. Strong evidence suggests that host genetics play an important role in susceptibility, but the specific host genetic factors involved are not known. The availability of genome-wide single nucleotide polymorphism (SNP) data for inbred Mus musculus strains means that haplotype association mapping can be used to identify candidate susceptibility genes. We applied haplotype association mapping to Perlegen SNP data and kidney bacterial counts from Staphylococcus aureus-infected mice from 13 inbred strains and detected an associated block on chromosome 7. Strong experimental evidence supports the result: a separate study demonstrated the presence of a susceptibility locus on chromosome 7 using consomic mice. The associated block contains no genes, but lies within the gene cluster of the 26-member extended kallikrein gene family, whose members have well-recognized roles in the generation of antimicrobial peptides and the regulation of inflammation. Efficient mixed-model association (EMMA) testing of all SNPs with two alleles and located within the gene cluster boundaries finds two significant associations: one of the three polymorphisms defining the associated block and one in the gene closest to the block, Klk1b11. In addition, we find that 7 of the 26 kallikrein genes are differentially expressed between susceptible and resistant mice, including the Klk1b11 gene. These genes represent a promising set of candidate genes influencing susceptibility to Staphylococcus aureus.
doi:10.1534/g3.112.002501
PMCID: PMC3362298  PMID: 22690378
host genetic susceptibility; infectious disease; kallikrein gene family
5.  Matrix Metalloproteinase-14 Mediates a Phenotypic Shift in the Airways to Increase Mucin Production 
Rationale: Induced mainly by cigarette smoking, chronic obstructive pulmonary disease (COPD) is a global public health problem characterized by progressive difficulty in breathing and increased mucin production. Previously, we reported that acrolein levels found in COPD sputum could activate matrix metalloproteinase-9 (MMP9).
Objectives: To determine whether acrolein increases expression and activity of MMP14, a critical membrane-bound endopeptidase that can initial a MMP-activation cascade.
Methods: MMP14 activity and adduct formation were measured following direct acrolein treatment. MMP14 expression and activity was measured in human airway epithelial cells. MMP14 immunohistochemistry was performed with COPD tissue, and in acrolein- or tobacco-exposed mice.
Measurements and Main Results: In a cell-free system, acrolein, in concentrations equal to those found in COPD sputum, directly adducted cysteine 319 in the MMP14 hemopexin-like domain and activated MMP14. In cells, acrolein increased MMP14 activity, which was inhibited by a proprotein convertase inhibitor, hexa-d-arginine. In the airway epithelium of COPD subjects, immunoreactive MMP14 protein increased. In mouse lung, acrolein or tobacco smoke increased lung MMP14 activity and protein. In cells, acrolein-induced MMP14 transcripts were inhibited by an epidermal growth factor receptor (EGFR) neutralizing antibody, EGFR kinase inhibitor, metalloproteinase inhibitor, or mitogen-activated protein kinase (MAPK) 3/2 or MAPK8 inhibitors, but not a MAPK14 inhibitor. Decreasing the MMP14 protein and activity in vitro by small interfering (si)RNA to MMP14 diminished the acrolein-induced MUC5AC transcripts. In acrolein-exposed mice or transgenic mice with lung-specific transforming growth factor-α (an EGFR ligand) expression, lung MMP14 and MUC5AC levels increased and these effects were inhibited by a EGFR inhibitor, erlotinib.
Conclusions: Taken together, these findings implicate acrolein-induced MMP14 expression and activity in mucin production in COPD.
doi:10.1164/rccm.200903-0328OC
PMCID: PMC2773913  PMID: 19661247
cigarette smoke; acrolein; erlotinib; mucous cell metaplasia; chronic obstructive pulmonary disease
6.  Two Genes on A/J Chromosome 18 Are Associated with Susceptibility to Staphylococcus aureus Infection by Combined Microarray and QTL Analyses 
PLoS Pathogens  2010;6(9):e1001088.
Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N2 backcross mice (F1 [C18A]×C57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus–challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 β and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies.
Author Summary
Staphylococcus aureus has a wide spectrum of human infection, ranging from asymptomatic nasal carriage to overwhelming sepsis and death. Mouse models offer an attractive strategy for investigating complex diseases such as S. aureus infections. A/J mice are highly susceptible to S. aureus infection compared with C57BL/6J mice. We showed that genes on chromosomes 8, 11, and 18 in A/J are responsible for susceptibility to S. aureus by using chromosome substitution strains (CSS). From the ∼4200 genes on these three chromosomes, we identified 191 which were differentially expressed between A/J and C57BL/6J when challenged with S. aureus. Next, we identified two significant QTLs on chromosome 18 that are associated with susceptibility to S. aureus infection in N2 backcross mice. Ten genes (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTLs and were differentially expressed between A/J and C57BL/6J. One gene on each QTL, Tnfaip8 and Seh1l, affected expression of cytokines in mouse macrophages exposed to S. aureus. These cytokine response patterns were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18, but not C57BL/6J. Tnfaip8 and Seh1l are strong candidates for genes influencing susceptibility to S. aureus of A/J mice.
doi:10.1371/journal.ppat.1001088
PMCID: PMC2932726  PMID: 20824097
7.  Critical Role of NOD2 in Regulating the Immune Response to Staphylococcus aureus▿  
Infection and Immunity  2009;77(4):1376-1382.
NOD2 (the nucleotide-binding oligomerization domain containing protein 2) is known to be involved in host recognition of bacteria, although its role in the host response to Staphylococcus aureus infection is unknown. NOD2-deficient (Nod2−/−) mice and wild-type (WT) littermate controls were injected intraperitoneally with S. aureus suspension (107 bacteria/g of body weight), and their survival was monitored. Cultured bone marrow-derived neutrophils were harvested from Nod2−/− and WT mice and tested for cytokine production and phagocytosis. Compared to WT mice, Nod2−/− mice were significantly more susceptible to S. aureus infection (median survival of 1.5 days versus >5 days; P = 0.003) and had a significantly higher bacterial tissue burden. Cultured bone marrow-derived neutrophils from Nod2−/− and WT mice had similar levels of peritoneal neutrophil recruitment and intracellular killing, but bone marrow-derived neutrophils from Nod2−/− mice had significantly reduced ability to internalize fluorescein-labeled S. aureus. Nod2−/− mice had significantly higher levels of Th1-derived cytokines in serum (tumor necrosis factor alpha, gamma interferon, and interleukin-2 [IL-2]) compared to WT mice, whereas the levels of Th2-derived cytokines (IL-1β, IL-4, IL-6, and IL-10) were similar in Nod2−/− and WT mice. Thus, mice deficient in NOD2 are more susceptible to S. aureus. Increased susceptibility is due in part to defective neutrophil phagocytosis, elevated serum levels of Th1 cytokines, and a higher bacterial tissue burden.
doi:10.1128/IAI.00940-08
PMCID: PMC2663139  PMID: 19139201
8.  Acrolein-Activated Matrix Metalloproteinase 9 Contributes to Persistent Mucin Production 
Chronic obstructive pulmonary disease (COPD), a global public health problem, is characterized by progressive difficulty in breathing, with increased mucin production, especially in the small airways. Acrolein, a constituent of cigarette smoke and an endogenous mediator of oxidative stress, increases airway mucin 5, subtypes A and C (MUC5AC) production; however, the mechanism remains unclear. In this study, increased mMUC5AC transcripts and protein were associated with increased lung matrix metalloproteinase 9 (mMMP9) transcripts, protein, and activity in acrolein-exposed mice. Increased mMUC5AC transcripts and mucin protein were diminished in gene-targeted Mmp9 mice [Mmp9(-/-)] or in mice treated with an epidermal growth factor receptor (EGFR) inhibitor, erlotinib. Acrolein also decreased mTissue inhibitor of metalloproteinase protein 3 (an MMP9 inhibitor) transcript levels. In a cell-free system, acrolein increased pro-hMMP9 cleavage and activity in concentrations (100–300 nM) found in sputum from subjects with COPD. Acrolein increased hMMP9 transcripts in human airway cells, which was inhibited by an MMP inhibitor, EGFR-neutralizing antibody, or a mitogen-activated protein kinase (MAPK) 3/2 inhibitor. Together these findings indicate that acrolein can initiate cleavage of pro-hMMP9 and EGFR/MAPK signaling that leads to additional MMP9 formation. Augmentation of hMMP9 activity, in turn, could contribute to persistent excessive mucin production.
doi:10.1165/rcmb.2006-0339OC
PMCID: PMC2274947  PMID: 18006877
mucus; COPD; matrix metalloproteinase; cigarette smoke; oxidative stress
9.  CD8+ T Cells Contribute to Macrophage Accumulation and Airspace Enlargement Following Repeated Irritant Exposure 
BACKGROUND
Persistent macrophage accumulation and alveolar enlargement are hallmark features of chronic obstructive pulmonary disease (COPD). A role for CD8+ lymphocytes in the development of COPD is suggested based on observations that this T cell subset is increased in the airways and parenchyma of smokers that develop COPD with airflow limitation. In this study, we utilize a mouse model of COPD to examine the contributions of CD8+ T cells in the persistent macrophage accumulation and airspace enlargement resulting from chronic irritant exposure.
METHODS
We analyzed pulmonary inflammation and alveolar destruction in wild-type and Cd8-deficient mice chronically exposed to acrolein, a potent respiratory tract irritant. We further examined cytokine mRNA expression levels by RNase protection assay, matrix metalloproteinase (MMP) activity by gelatin zymography, and epithelial cell apoptosis by active caspase3 immunohistochemistry in wild-type and Cd8-deficient mice exposed chronically to acrolein.
RESULTS
These studies demonstrate that CD8+ T cells, are important mediators of macrophage accumulation in the lung and the progressive airspace enlargement in response to chronic acrolein exposures. The expression of several inflammatory cytokines (IP-10, IFN-γ, IL-12, RANTES, and MCP-1), MMP2 and MMP9 gelatinase activity, and caspase3 immunoreactivity in pulmonary epithelial cells were attenuated in the Cd8-deficient mice compared to wild-type.
CONCLUSIONS
These results indicate that CD8+ T cells actively contribute to macrophage accumulation and the development of irritant-induced airspace enlargement.
doi:10.1016/j.yexmp.2007.08.020
PMCID: PMC2140237  PMID: 17950725
10.  Genotypic Characteristics of Staphylococcus aureus Isolates from a Multinational Trial of Complicated Skin and Skin Structure Infections▿ † 
Journal of Clinical Microbiology  2007;46(2):678-684.
The impact of bacterial genetic characteristics on the outcome of patients with Staphylococcus aureus infections is uncertain. This investigation evaluated potential associations between bacterial genotype and clinical outcome using isolates collected as part of an international phase 2 clinical trial (FAST II) evaluating telavancin for the treatment of complicated skin and skin structure infections (cSSSI). Ninety S. aureus isolates from microbiologically evaluable patients with cSSSI enrolled in the FAST II trial from 11 sites in the United States (56 isolates, or 62%) and 7 sites in South Africa (34 isolates, or 38%) were examined for staphylococcal cassette chromosome mec, agr, and the presence of 31 virulence genes and subjected to pulsed-field gel electrophoresis (PFGE). South African methicillin-susceptible S. aureus (MSSA) isolates were more likely to carry certain virulence genes, including sdrD (P = 0.01), sea (P < 0.01), and pvl (P = 0.01). All 44 (49%) methicillin-resistant S. aureus (MRSA) isolates were from the United States; 37 (84%) were strain USA 300 by PFGE. In the United States, MRSA isolates were more likely than MSSA isolates to carry genes for sdrC (P = 0.03), map/eap (P = 0.05), fnbB (P = 0.11), tst (P = 0.02), sea (P = 0.04), sed (P = 0.04), seg (P = 0.11), sej (P = 0.11), agr (P = 0.09), V8 (P = 0.06), sdrD, sdrE, eta, etb, and see (P < 0.01 for all). MRSA isolates were more often clonal than MSSA isolates by PFGE. Isolates from patients who were cured were significantly more likely to contain the pvl gene than isolates from patients that failed or had indeterminate outcomes (79/84 [94%] versus 3/6 [50%]; P = 0.01). S. aureus strains from different geographic regions have different distributions of virulence genes.
doi:10.1128/JCM.01822-07
PMCID: PMC2238106  PMID: 18077636
11.  The Role of Metallothionein in the Pathogenesis of Acute Lung Injury 
Often fatal, acute lung injury has a complicated etiology. Previous studies from our laboratory in mice have demonstrated that survival during acute lung injury is a complex trait governed by multiple loci. We also found that the increase in metallothionein (MT) is one of the greatest noted in transcriptome-wide analyses of gene expression. To assess the role of MT in nickel-induced acute lung injury, the survival of Mt-transgenic, Mt1/2(+/+), and Mt1/2(+/+) mice was compared. Pulmonary inflammation and global gene expression were compared in Mt1/2(+/+) and Mt1/2(+/+) mice. Gene-targeted Mt1/2(+/+) mice were more susceptible than Mt1/2(+/+) mice to nickel-induced inflammation, surfactant-associated protein B transcript loss, and lethality. Similarly, Mt-transgenic mice exhibited increased survival. MAPPFinder analyses also noted significant decreases in genes involved in protein processing (e.g., ubiquitination, folding), which were greater in Mt1/2(+/+) mice as compared with Mt1/2(+/+) mice early in the progression of acute lung injury, possibly due to a zinc-mediated transcript destabilization. In contrast, transcript levels of genes associated with the inflammatory response, extracellular matrix regulation, and coagulation/fibrinolysis were increased more in Mt1/2(+/+) mice as compared with Mt1/2(+/+) mice late in the development of acute lung injury. Thus, MT ultimately improves survival in the progression of acute lung injury in mice. Transcriptome-wide analysis suggests that this survival may be mediated through changes in the destabilization of transcripts associated with protein processing, the subsequent augmentation of transcripts controlling inflammation, extracellular matrix regulation, coagulation/fibrinolysis, and disruption of surfactant homeostasis.
doi:10.1165/rcmb.2005-0248OC
PMCID: PMC2644192  PMID: 16166738
microarray; surfactant; inflammation; fibrinolysis; extracellular matrix

Results 1-11 (11)