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1.  Guidelines for the use of survivorship care plans: a systematic quality appraisal using the AGREE II instrument 
Survivorship care plans (SCPs) are written treatment summaries and follow-up care plans that are intended to facilitate communication and coordination of care among survivors, cancer care providers, and primary care providers. A growing number of guidelines for the use of SCPs exist, yet SCP use in the United States remains limited. Limited use of SCPs may be due to poor quality of these guidelines. The purpose of the study was to evaluate the quality of guidelines for SCP use, tools that are intended to promote evidence-based medicine.
We conducted a comprehensive search of the literature using MEDLINE/PubMed, EMBASE (Excerpta Medica Database), and CINAHL (Cumulative Index to Nursing and Allied Health Literature) published through April 2014, in addition to grey literature sources and bibliographic and expert reviews. Guideline quality was assessed using the AGREE II instrument (Appraisal of Guidelines for Research and Evaluation, 2nd edition), a tool developed by an international group of scientists to advance the quality of clinical practice guidelines. To promote consistency with extant studies using the AGREE II instrument and to clearly and unambiguously identify potentially useful guidelines for SCP use, we also summarized AGREE II scores by strongly recommending, recommending, or not recommending the guidelines that we evaluated.
Of 128 documents screened, we included 16 guidelines for evaluation. We did not strongly recommend any of the 16 guidelines that we evaluated; we recommended 5 and we did not recommend 11. Overall, guidelines scored highest on clarity of presentation (i.e., guideline language, structure, and format): Guidelines were generally unambiguous in their recommendations that SCPs should be used. Guidelines scored lowest on applicability (i.e., barriers and facilitators to implementation, implementation strategies, and resource implications of applying the guideline): Few guidelines discussed facilitators and barriers to guideline application; advice and tools for implementing guidelines were vague; and none explicitly discussed resource implications of implementing the guidelines.
Guidelines often advocated survivorship care plan use without justification or suggestions for implementation. Improved guideline quality may promote survivorship care plan use.
Electronic supplementary material
The online version of this article (doi:10.1186/s13012-015-0254-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4425878  PMID: 25935752
Survivorship care plan; Guidelines; Dissemination; Quality appraisal
2.  Distribution and mixing of old and new nonstructural carbon in two temperate trees 
The New Phytologist  2015;206(2):590-597.
We know surprisingly little about whole-tree nonstructural carbon (NSC; primarily sugars and starch) budgets. Even less well understood is the mixing between recent photosynthetic assimilates (new NSC) and previously stored reserves. And, NSC turnover times are poorly constrained. We characterized the distribution of NSC in the stemwood, branches, and roots of two temperate trees, and we used the continuous label offered by the radiocarbon (carbon-14, 14C) bomb spike to estimate the mean age of NSC in different tissues. NSC in branches and the outermost stemwood growth rings had the 14C signature of the current growing season. However, NSC in older aboveground and belowground tissues was enriched in 14C, indicating that it was produced from older assimilates. Radial patterns of 14C in stemwood NSC showed strong mixing of NSC across the youngest growth rings, with limited ‘mixing in’ of younger NSC to older rings. Sugars in the outermost five growth rings, accounting for two-thirds of the stemwood pool, had a mean age < 1 yr, whereas sugars in older growth rings had a mean age > 5 yr. Our results are thus consistent with a previously-hypothesized two-pool (‘fast’ and ‘slow’ cycling NSC) model structure. These pools appear to be physically distinct.
PMCID: PMC4405048  PMID: 25558814
carbohydrates; carbon allocation; Harvard Forest; radiocarbon (14C); storage; tree rings; wood
3.  Mutations in Tetratricopeptide Repeat Domain 7A Result in a Severe Form of Very Early Onset Inflammatory Bowel Disease 
Gastroenterology  2014;146(4):1028-1039.
Background & Aims
Very early onset inflammatory bowel diseases (VEOIBD), including infant disorders, are a diverse group of diseases found in children less than 6 years of age. They have been associated with several gene variants. We aimed to identify genes that cause VEOIBD.
We performed whole-exome sequencing of DNA from 1 infants with severe enterocolitis and her parents. Candidate gene mutations were validated in 40 pediatric patients and functional studies were carried out using intestinal samples and human intestinal cell lines.
We identified compound heterozygote mutations in the tetratricopeptide repeat domain 7 (TTC7A) gene in an infant from non-consanguineous parents with severe exfoliative apoptotic enterocolitis; we also detected the mutations in 2 unrelated families, each with 2 affected siblings. TTC7A interacts with EFR3 homolog B (EFR3B) to regulate phosphatidylinositol 4-kinase (PI4KA) at the plasma membrane. Functional studies demonstrated that TTC7A is expressed in human enterocytes. The mutations we identified in TTC7A result in either mislocalization or reduced expression of TTC7A. PI4KA was found to co-immunoprecipitate with TTC7A; the identified TTC7A mutations reduced this binding. Knockdown of TTC7A in human intestinal-like cell lines reduced their adhesion, increased apoptosis, and decreased production of phosphatidylinositol 4-phosphate.
In a genetic analysis, we identified loss of function mutations in TTC7A in 5 infants with VEOIBD. Functional studies demonstrated that the mutations cause defects in enterocytes and T cells that lead to severe apoptotic enterocolitis. Defects in the PI4KA–TTC7A–EFR3B pathway are involved in the pathogenesis of VEOIBD.
PMCID: PMC4002656  PMID: 24417819
IBD; intestinal atresia; autoimmunity; intestine
4.  Life Events, Chronic Stressors, and Depressive Symptoms in Low-Income Urban Mothers With Asthmatic Children 
The purpose of this secondary data analysis was to examine the relationship of individual sociodemographic variables, life events, chronic stressors including asthma control and management and environmental stressors to maternal depression.
Cross sectional descriptive design study consisting of baseline data from participants enrolled in a randomized clinical trial of an asthma communication educational intervention.
Two hundred and one mothers of children with asthma (ages 6-12) recruited from community pediatric practices and pediatric emergency departments of two urban university hospitals. Measurement: Subjects responded to a questionnaire that included sociodemographic characteristics, life events, and chronic stressors. Depressive symptoms were assessed with the CESD.
Close to 25% of the mothers had a score of 16 or greater on the CESD. Significant bivariate relationships between low education, unemployment, feeling unsafe, and the use of quick relief asthma drugs with high depressive symptoms were found. In the multiple logistic regression models, education or unemployment (in separate models) and the use of quick relief medications for asthma were positively associated with depressive symptoms.
Implications for practice include the need to assess for the presence of maternal depression particularly in mothers of children with a chronic illness such as asthma.
PMCID: PMC4334657  PMID: 19573208
asthma; depressive symptoms; mothers; chronic illness
5.  A comparison of the predictive accuracy of three screening models for pulmonary arterial hypertension in systemic sclerosis 
There is evidence that early screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) improves outcomes. We compared the predictive accuracy of two recently published screening algorithms (DETECT 2013 and Australian Scleroderma Interest Group (ASIG) 2012) for SSc-associated PAH (SSc-PAH) with the commonly used European Society of Cardiology/European Respiratory Society (ESC/ERS 2009) guidelines.
We included 73 consecutive SSc patients with suspected PAH undergoing right heart catheterization (RHC). The three screening models were applied to each patient. For each model, contingency table analysis was used to determine sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values for PAH. These properties were also evaluated in an ‘alternate scenario analysis’ in which the prevalence of PAH was set at 10%.
RHC revealed PAH in 27 (36.9%) patients. DETECT and ASIG algorithms performed equally in predicting PAH with sensitivity and NPV of 100%. The ESC/ERS guidelines had sensitivity of 96.3% and NPV of only 91%, missing one case of PAH; these guidelines could not be applied to three patients who had absent tricuspid regurgitant (TR) jet. The ASIG algorithm had the highest specificity (54.5%). With PAH prevalence set at 10%, the NPV of the models was unchanged, but the PPV dropped to less than 20%.
In this cohort, the DETECT and ASIG algorithms out-perform the ESC/ERS guidelines, detecting all patients with PAH. The ESC/ERS guidelines have limitations in the absence of a TR jet. Ultimately, the choice of SSc-PAH screening algorithm will also depend on cost and ease of application.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0517-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4332896  PMID: 25596924
6.  Challenges in Promoting Joint Use Agreements: Experiences From Community Transformation Grant Awardees in North Carolina, Illinois, and Wisconsin, 2011–2014 
Community Transformation Grant awardees in North Carolina, Illinois, and Wisconsin promoted joint use agreements (formal agreements between 2 parties for the shared use of land or facilities) as a strategy to increase access to physical activity in their states. However, awardees experienced significant barriers to establishing joint use agreements, including 1) confusion about terminology and an aversion to complex legal contracts, 2) lack of applicability to single organizations with open use policies, and 3) questionable value in nonurban areas where open lands for physical activity are often available and where the need is instead for physical activity programs and infrastructure. Furthermore, promotion of formal agreements may unintentionally reduce access by raising concerns regarding legal risks and costs associated with existing shared use of land. Thus, joint use agreements have practical limitations that should be considered when selecting among strategies to promote physical activity participation.
PMCID: PMC4415413  PMID: 25880770
7.  Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis 
Immunity  2013;39(2):357-371.
Liver fibrosis is a consequence of chronic liver diseases and thus a major cause of mortality and morbidity. Clinical evidence and animal studies suggest that local tissue homeostasis is disturbed due to immunological responses to chronic hepatocellular stress. Poorly defined stress-associated inflammatory networks are thought to mediate gradual accumulation of extracellular-matrix-components, ultimately leading to fibrosis and liver-failure. Here we have reported that hepatic expression of interleukin-33 (IL-33) was both required and sufficient for severe hepatic fibrosis in vivo. We have demonstrated that IL-33’s pro-fibrotic effects related to activation and expansion of liver resident innate lymphoid cells (ILC2). We identified ILC2-derived IL-13, acting through type-II IL-4 receptor-dependent signaling via the transcription factor STAT6 and hepatic stellate-cell activation, as a critical downstream cytokine of IL-33-dependent pathologic tissue remodeling and fibrosis. Our data reveal key immunological networks implicated in hepatic fibrosis and support the concept of modulation of IL-33 bioactivity for therapeutic purposes.
PMCID: PMC4172965  PMID: 23954132
8.  MHCII-Mediated Dialog between Group 2 Innate Lymphoid Cells and CD4+ T Cells Potentiates Type 2 Immunity and Promotes Parasitic Helminth Expulsion 
Immunity  2014;41(2):283-295.
Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity.
Graphical Abstract
•Genetic ablation of ILC2s impairs type-2 immunity•MHCII-expressing ILC2s potentiate Th2 responses•IL-2 from T cells promotes ILC2 proliferation and expression of type-2 cytokines•MHCII and IL-13 expression by ILC2s is important for N. brasiliensis expulsion
Type-2 innate lymphoid cells proliferate and release interleukin-13 during protective immunity to helminth infection and detrimentally during allergy and asthma. McKenzie and colleagues establish that these activities are potentiated through an MHC class II-mediated dialogue with T cells.
PMCID: PMC4148706  PMID: 25088770
9.  T-bet is essential for NKp46+ innate lymphocyte development through the Notch pathway 
Nature immunology  2013;14(4):389-395.
Innate lymphoid cells (ILCs) including lymphoid tissue-inducer (LTi) cells, IL-22-producing NKp46+ innate cells and IL-13-producing nuocytes play important roles in regulating intestinal microbiota, defence against pathogens and formation of lymphoid tissue1-4. Their development is dependent on Id2 and Rorγt or Rorα5-7. Lineage tracing experiments have shown that the common lymphoid precursor gives rise to nuocytes, LTi cells and NKp46+ ILCs6,8,9, but these studies have not deciphered the discrete steps and transcription factors that specify ILC subset development, activation and maintenance. Whether NKp46+ ILCs arise directly from LTi cells, or rather represent a separate lineage that diverges earlier in development, remains controversial10-12. We investigated the requirement for the transcriptional master regulator T-bet (encoded by Tbx21) which is critical for the development of both T cells and NK cells13,14, in driving differentiation of ILC populations. Here we report that T-bet played an essential role for the development of NKp46+ ILCs, but was dispensable for LTi cells or nuocytes. Tbx21+/+ LTi cells adopted an NKp46+ phenotype in vitro and in vivo but not in the absence of Tbx21. Decrease of T-bet expression coordinately reduced Notch1 and Notch2 and we show Notch signaling is necessary for the transition of LTi cells into NKp46+ ILCs. In addition, Tbx21−/− mice have an accumulation in CD4− LTi cells and differentiation into NKp46+ ILCs came solely from this population. Our results pinpoint T-bet as the critical regulator of NKp46+ ILC differentiation by regulation of Notch2 signaling. NKp46+ cells are an important element of the protective intestinal mucosal cellular arsenal, and here, we uncover the distinct molecular pathways that guide the development of NKp46+ ILCs.
PMCID: PMC4076532  PMID: 23455676
Lymphoid tissue inducer cells; innate lymphoid cells; nuocytes; NKp46; GFP reporter mouse
10.  Mcl-1 is essential for the survival of plasma cells 
Nature immunology  2013;14(3):290-297.
The long-term survival of plasma cells is entirely dependent on signals derived from their environment. These extrinsic factors presumably induce and sustain the expression of antiapoptotic proteins of the Bcl-2 family. It is uncertain whether there is specificity among Bcl-2 family members in the survival of plasma cells and whether their expression is linked to specific extrinsic factors. We found here that deletion of the gene encoding the antiapoptotic protein Mcl-1 in plasma cells resulted in rapid depletion of this population in vivo. Furthermore, we found that the receptor BCMA was needed to establish high expression of Mcl-1 in bone marrow but not spleen plasma cells and that establishing this survival pathway preceded the component of plasma cell differentiation that depends on the transcriptional repressor Blimp-1. Our results identify a critical role for Mcl-1 in the maintenance of plasma cells.
PMCID: PMC4041127  PMID: 23377201
11.  Stress and Quality of Life in Caregivers of Inner-city Minority Children with Poorly Controlled Asthma 
Caregiver quality of life (QOL) is known to influence asthma management behaviors. Risk factors for low caregiver QOL in families of inner-city children with asthma remain unclear. This study evaluated the interrelationships of asthma control, stress, and caregiver QOL.
Data were analyzed from a home-based behavioral intervention for children with persistent asthma post asthma emergency department treatment. Caregivers reported on baseline demographics, asthma control, asthma management stress, life stress, and QOL. Hierarchical regression analysis examined the contributions of socio-demographic factors, asthma control, asthma management stress, and life stress in explaining caregiver QOL.
Children (N=300) were primarily African-American (96%) and young (Mean age of 5.5 years). Caregivers were predominantly the biological mother (92%), single (70%), and unemployed (54%). Poor QOL was associated with higher caregiver education and number of children in the home, low asthma control, and increased asthma management stress and life stress. The model accounted for 28% of variance in caregiver QOL.
Findings underscore the need for multi-faceted interventions to provide caregivers of children with asthma tools to cope with asthma management demands and contemporary life stressors.
PMCID: PMC3575578  PMID: 23414978
asthma; caregiver; stress; quality of life
12.  The Staphylococcus aureus ArlRS Two-Component System Is a Novel Regulator of Agglutination and Pathogenesis 
PLoS Pathogens  2013;9(12):e1003819.
Staphylococcus aureus is a prominent bacterial pathogen that is known to agglutinate in the presence of human plasma to form stable clumps. There is increasing evidence that agglutination aids S. aureus pathogenesis, but the mechanisms of this process remain to be fully elucidated. To better define this process, we developed both tube based and flow cytometry methods to monitor clumping in the presence of extracellular matrix proteins. We discovered that the ArlRS two-component system regulates the agglutination mechanism during exposure to human plasma or fibrinogen. Using divergent S. aureus strains, we demonstrated that arlRS mutants are unable to agglutinate, and this phenotype can be complemented. We found that the ebh gene, encoding the Giant Staphylococcal Surface Protein (GSSP), was up-regulated in an arlRS mutant. By introducing an ebh complete deletion into an arlRS mutant, agglutination was restored. To assess whether GSSP is the primary effector, a constitutive promoter was inserted upstream of the ebh gene on the chromosome in a wildtype strain, which prevented clump formation and demonstrated that GSSP has a negative impact on the agglutination mechanism. Due to the parallels of agglutination with infective endocarditis development, we assessed the phenotype of an arlRS mutant in a rabbit combined model of sepsis and endocarditis. In this model the arlRS mutant displayed a large defect in vegetation formation and pathogenesis, and this phenotype was partially restored by removing GSSP. Altogether, we have discovered that the ArlRS system controls a novel mechanism through which S. aureus regulates agglutination and pathogenesis.
Author Summary
Staphylococcus aureus is a bacterial pathogen that is responsible for causing significant disease in humans. The development of antibiotic resistant strains has made these infections more difficult to treat, and an improved understanding of how this pathogen causes infections will facilitate the development of new tools for treatment. It has long been recognized that S. aureus can bind human matrix proteins to form stable clumps in a process called agglutination, but the importance of agglutination during infection is only just becoming understood. In this work, we developed several techniques to investigate the S. aureus agglutination mechanism. We discovered that the ArlRS two-component regulatory system controls agglutination by regulating the expression of the ebh gene, which encodes the Giant Staphylococcal Surface Protein (GSSP). When ArlRS is non-functional, S. aureus agglutination is prevented through the action of GSSP. These phenotypes were confirmed in a rabbit model of sepsis and infective endocarditis, demonstrating that ArlRS is an important regulator of virulence. Taken together, the identification of ArlRS as a regulator of S. aureus agglutination and pathogenesis may lead to innovative directions for therapeutic development.
PMCID: PMC3868527  PMID: 24367264
13.  The inclusion of N-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study 
Arthritis Research & Therapy  2013;15(6):R193.
Pulmonary arterial hypertension (PAH) is a major cause of mortality in systemic sclerosis (SSc). Screening guidelines for PAH recommend multiple investigations, including annual echocardiography, which together have low specificity and may not be cost-effective. We sought to evaluate the predictive accuracy of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in combination with pulmonary function tests (PFT) (‘proposed’ algorithm) in a screening algorithm for SSc-PAH.
We evaluated our proposed algorithm (PFT with NT-proBNP) on 49 consecutive SSc patients with suspected pulmonary hypertension undergoing right heart catherisation (RHC). The predictive accuracy of the proposed algorithm was compared with existing screening recommendations, and is presented as sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV).
Overall, 27 patients were found to have pulmonary hypertension (PH) at RHC, while 22 had no PH. The sensitivity, specificity, PPV and NPV of the proposed algorithm for PAH was 94.1%, 54.5%, 61.5% and 92.3%, respectively; current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines achieved a sensitivity, specificity, PPV and NPV of 94.1%, 31.8%, 51.6% and 87.5%, respectively. In an alternate case scenario analysis, estimating a PAH prevalence of 10%, the proposed algorithm achieved a sensitivity, specificity, PPV and NPV for PAH of 94.1%, 54.5%, 18.7% and 98.8%, respectively.
The combination of NT-proBNP with PFT is a sensitive, yet simple and non-invasive, screening strategy for SSc-PAH. Patients with a positive screening result can be referred for echocardiography, and further confirmatory testing for PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. The findings of this study should be confirmed in larger studies.
PMCID: PMC3978999  PMID: 24246100
14.  Selective Inhibition of Matrix Metalloproteinase-9 Attenuates Secondary Damage Resulting from Severe Traumatic Brain Injury 
PLoS ONE  2013;8(10):e76904.
Traumatic brain injury (TBI) is a leading cause of death and long-term disability. Following the initial insult, severe TBI progresses to a secondary injury phase associated with biochemical and cellular changes. The secondary injury is thought to be responsible for the development of many of the neurological deficits observed after TBI and also provides a window of opportunity for therapeutic intervention. Matrix metalloproteinase-9 (MMP-9 or gelatinase B) expression is elevated in neurological diseases and its activation is an important factor in detrimental outcomes including excitotoxicity, mitochondrial dysfunction and apoptosis, and increases in inflammatory responses and astrogliosis. In this study, we used an experimental mouse model of TBI to examine the role of MMP-9 and the therapeutic potential of SB-3CT, a mechanism-based gelatinase selective inhibitor, in ameliorating the secondary injury. We observed that activation of MMP-9 occurred within one day following TBI, and remained elevated for 7 days after the initial insult. SB-3CT effectively attenuated MMP-9 activity, reduced brain lesion volumes and prevented neuronal loss and dendritic degeneration. Pharmacokinetic studies revealed that SB-3CT and its active metabolite, p-OH SB-3CT, were rapidly absorbed and distributed to the brain. Moreover, SB-3CT treatment mitigated microglial activation and astrogliosis after TBI. Importantly, SB-3CT treatment improved long-term neurobehavioral outcomes, including sensorimotor function, and hippocampus-associated spatial learning and memory. These results demonstrate that MMP-9 is a key target for therapy to attenuate secondary injury cascades and that this class of mechanism-based gelatinase inhibitor–with such desirable pharmacokinetic properties–holds considerable promise as a potential pharmacological treatment of TBI.
PMCID: PMC3806745  PMID: 24194849
15.  Factors Associated with Completion of a Behavioral Intervention for Caregivers of Urban Children with Asthma 
Rates of preventive follow-up asthma care after an acute emergency department (ED) visit are low among inner-city children. We implemented a novel behavioral asthma intervention, Pediatric Asthma Alert (PAAL) intervention, to improve outpatient follow-up and preventive care for urban children with a recent ED visit for asthma.
The objective of this article is to describe the PAAL intervention and examine factors associated with intervention completers and noncompleters.
Children with persistent asthma and recurrent ED visits (N = 300) were enrolled in a randomized controlled trial of the PAAL intervention that included two home visits and a facilitated follow-up visit with the child’s primary care provider (PCP). Children were categorized as intervention completers, that is, completed home and PCP visits compared with noncompleters, who completed at least one home visit but did not complete the PCP visit. Using chi-square test of independence, analysis of variance, and multiple logistic regression, the intervention completion status was examined by several sociodemographic, health, and caregiver psychological variables.
Children were African-American (95%), Medicaid insured (91%), and young (aged 3–5 years, 56%). Overall, 71% of children randomized to the intervention successfully completed all home and PCP visits (completers). Factors significantly associated with completing the intervention included younger age (age 3–5 years: completers, 65.4%; noncompleters, 34.1%; p < .001) and having an asthma action plan in the home at baseline (completers: 40%; noncompleters: 21%; p = .02). In a logistic regression model, younger child age, having an asthma action plan, and lower caregiver daily asthma stress were significantly associated with successful completion of the intervention.
The majority of caregivers of high-risk children with asthma were successfully engaged in this home and PCP-based intervention. Caregivers of older children with asthma and those with high stress may need additional support for program completion. Further, the lack of an asthma action plan may be a marker of preexisting barriers to preventive care.
PMCID: PMC3773483  PMID: 22991952
asthma; children; controller medications; inner city; preventive care
16.  LeuX tRNA-dependent and -independent mechanisms of Escherichia coli pathogenesis in acute cystitis 
Molecular microbiology  2007;67(1):116-128.
Uropathogenic Escherichia coli (UPEC) contain multiple horizontally acquired pathogenicity-associated islands (PAI) implicated in the pathogenesis of urinary tract infection. In a murine model of cystitis, type 1 pili-mediated bladder epithelial invasion and intracellular proliferation are key events associated with UPEC virulence. In this study, we examined the mechanisms by which a conserved PAI contributes to UPEC pathogenesis in acute cystitis. In the human UPEC strain UTI89, spontaneous excision of PAI IIUTI89 disrupts the adjacent leuX tRNA locus. Loss of wild-type leuX-encoded tRNA5Leu significantly delayed, but did not eliminate, FimB recombinase-mediated phase variation of type 1 pili. FimX, an additional FimB-like, leuX-independent recombinase, was also found to mediate type 1 pili phase variation. However, whereas FimX activity is relatively slow in vitro, it is rapid in vivo as a non-piliated strain lacking the other fim recombinases rapidly expressed type 1 pili upon experimental infection. Finally, we found that disruption of leuX, but not loss of PAI IIUTI89 genes, reduced bladder epithelial invasion and intracellular proliferation, independent of type 1 piliation. These findings indicate that the predominant mechanism for preservation of PAI IIUTI89 during the establishment of acute cystitis is maintenance of wild-type leuX, and not PAI IIUTI89 gene content.
PMCID: PMC3675907  PMID: 18036139
17.  The Effect Seizure Focus on Regional Language Processing Areas 
Epilepsia  2012;53(6):1044-1050.
To determine the effect of seizure focus location within the left hemisphere on the expression of regional language dominance.
In this cross sectional study we investigated 90 patients (mean age 23.3±12.9 years) with left hemisphere focal epilepsy (mean age onset 11.7 ±8.3 years). 18 patients had a frontal lobe focus, 72 temporal lobe focus (43 mesial; 29 neocortical). Subjects performed an auditory word definition language paradigm using 3T BOLD EPI fMRI. Data was analyzed in SPM2. Regional laterality indices (LI) for inferior frontal gyrus (IFG), and Wernicke’s area (WA), were calculated using a bootstrap method. Categorical language dominance and mean LI were analyzed.
Key Findings
Mean WA LI was lower for subjects with a mesial temporal focus compared to a frontal focus (p=0.04). There was a greater proportion of atypical language in WA for subjects with a mesial temporal focus compared to a frontal focus (χ2=4.37, p=0.04). WA LI did not differ for subjects with a neocortical focus compared to a mesial focus or a frontal focus. Mean IFG LI and proportion of atypical language in IFG were similar across seizure focus groups. Age and age of onset were not correlated with mean laterality in WA or IFG. Epilepsy duration tended to be negatively correlated with WA LI (r=−0.18, p=0.10), but not IFG LI.
Temporal lobe foci have wide-ranging effects on the distributed language system. In contrast, the effects of a frontal lobe focus appear restricted to anterior rather than posterior language processing areas.
PMCID: PMC3370082  PMID: 22554135
Reorganization; Language dominance; Childhood epilepsy
18.  Development and function of group 2 innate lymphoid cells 
Current Opinion in Immunology  2013;25(2):148-155.
► ILC2 provide an innate source of type-2 cytokines (IL-5, IL-9 and IL-13). ► IL-13 production by ILC2 is critical to anti-helminthic immunity. ► ILC2 regulate allergic airways inflammation and lung tissue homeostasis. ► ILC2 development is instructed by the transcriptional regulators, RORα and Gata3. ► Bone marrow ILC2 precursors give rise to mature ILC2 upon adoptive transfer.
The innate lymphoid cell (ILC) family has recently expanded with the discovery of type-2 innate lymphoid cells (ILC2). These cells arise from lymphoid progenitors in the bone marrow and, under the control of the transcriptional regulators RORα and Gata3, they mature to give rise to IL-5, IL-9 and IL-13 producing ILC2. These cells are critical components of the innate immune response to parasitic worm infections and have also been implicated in the pathogenesis of asthma and allergy. Recent advances in our understanding of the molecular regulation of ILC2 development and function now present the opportunity to develop new genetic models to assess ILC2 immune function and to investigate possible therapeutic interventions.
PMCID: PMC3776222  PMID: 23562755
19.  Synthetic polymer nanoparticles conjugated with FimHA from E. coli pili to emulate the bacterial mode of epithelial internalization 
Amphiphilic block copolymer nanoparticles are conjugated with uropathogenic Escherichia coli type 1 pilus adhesin FimHA through amidation chemistry to enable bladder epithelial cell binding and internalization of the nanoparticles in vitro.
PMCID: PMC3325780  PMID: 22360307
20.  Prevalent and Incident Bacterial Vaginosis Are Associated with Sexual and Contraceptive Behaviours in Young Australian Women 
PLoS ONE  2013;8(3):e57688.
To determine prevalence and incidence of bacterial vaginosis (BV) and risk factors in young sexually-active Australian women.
1093 women aged 16–25 years were recruited from primary-care clinics. Participants completed 3-monthly questionnaires and self-collected vaginal smears 6-monthly for 12-months. The primary endpoint was a Nugent Score = 7–10 (BV) and the secondary endpoint was a NS = 4–10 (abnormal flora [AF]). BV and AF prevalence estimates and 95% confidence intervals (95%CI) were derived, and adjusted odds ratios (AOR) calculated to explore epidemiological associations with prevalent BV and AF. Proportional-hazards regression models were used to examine factors associated with incident BV and AF.
At baseline 129 women had BV [11.8% (95%CI: 9.4–14.2)] and 188 AF (17.2%; 15.1–19.5). Prevalent BV was associated with having a recent female partner [AOR = 2.1; 1.0–4.4] and lack of tertiary-education [AOR = 1.9; 1.2–3.0]; use of an oestrogen-containing contraceptive (OCC) was associated with reduced risk [AOR = 0.6; 0.4–0.9]. Prevalent AF was associated with the same factors, and additionally with >5 male partners (MSP) in 12-months [AOR = 1.8; 1.2–2.5)], and detection of C.trachomatis or M.genitalium [AOR = 2.1; 1.0–4.5]. There were 82 cases of incident BV (9.4%;7.7–11.7/100 person-years) and 129 with incident AF (14.8%; 12.5–17.6/100 person-years). Incident BV and AF were associated with a new MSP [adjusted rate ratio (ARR) = 1.5; 1.1–2.2 and ARR = 1.5; 1.1–2.0], respectively. OCC-use was associated with reduced risk of incident AF [ARR = 0.7; 0.5–1.0].
This paper presents BV and AF prevalence and incidence estimates from a large prospective cohort of young Australian women predominantly recruited from primary-care clinics. These data support the concept that sexual activity is strongly associated with the development of BV and AF and that use of an OCC is associated with reduced risk.
PMCID: PMC3589386  PMID: 23472099
21.  Home-based chlamydia and gonorrhoea screening: a systematic review of strategies and outcomes 
BMC Public Health  2013;13:189.
In many countries, low Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) screening rates among young people in primary-care have encouraged screening programs outside of clinics. Nucleic acid amplification tests (NAATs) make it possible to screen people in homes with self-collected specimens. We systematically reviewed the strategies and outcomes of home-based CT/NG screening programs.
Electronic databases were searched for home-based CT and/or NG screening studies published since January 2005. Screening information (e.g. target group, recruitment and specimen-collection method) and quantitative outcomes (e.g. number of participants, tests and positivity) were extracted. The screening programs were classified into seven groups on the basis of strategies used.
We found 29 eligible papers describing 32 home-based screening programs. In seven outreach programs, people were approached in their homes: a median of 97% participants provided specimens and 76% were tested overall (13717 tests). In seven programs, people were invited to receive postal test-kits (PTKs) at their homes: a median of 37% accepted PTKs, 79% returned specimens and 19% were tested (46225 tests). PTKs were sent along with invitation letters in five programs: a median of 33% returned specimens and 29% of those invited were tested (15126 tests). PTKs were requested through the internet or phone without invitations in four programs and a median of 32% returned specimens (2666 tests). Four programs involved study personnel directly inviting people to receive PTKs: a median of 46% accepted PTKs, 21% returned specimens and 9.1% were tested (341 tests). PTKs were picked-up from designated locations in three programs: a total of 6765 kits were picked-up and 1167 (17%) specimens were returned for screening. Two programs used a combination of above strategies (2395 tests) but the outcomes were not reported separately. The overall median CT positivity was 3.6% (inter-quartile range: 1.7-7.3%).
A variety of strategies have been used in home-based CT/NG screening programs. The screening strategies and their feasibility in the local context need to be carefully considered to maximize the effectiveness of home-based screening programs.
PMCID: PMC3599833  PMID: 23496833
Sexually transmitted infections; Chlamydia trachomatis; Screening; Home
23.  Rorα is essential for nuocyte development 
Nature immunology  2012;13(3):229-236.
Nuocytes are essential in innate type-2 immunity and contribute to the exacerbation of asthma responses. Here we show that nuocytes arise in the bone marrow and differentiate from common lymphoid progenitors, which makes them distinct new members of the lymphoid lineage. Nuocytes required interleukin 7 (IL-7), IL-33 and Notch signalling for development in vitro. Double negative 1 (DN1) and DN2 pro-T-cell progenitors maintained nuocyte potential in vitro, although the thymus was not essential for nuocyte development. Notably, the transcription factor Rorα was critical for nuocyte development and their role in parasitic worm expulsion.
PMCID: PMC3343633  PMID: 22267218
24.  The PICALM Protein Plays a Key Role in Iron Homeostasis and Cell Proliferation 
PLoS ONE  2012;7(8):e44252.
The ubiquitously expressed phosphatidylinositol binding clathrin assembly (PICALM) protein associates with the plasma membrane, binds clathrin, and plays a role in clathrin-mediated endocytosis. Alterations of the human PICALM gene are present in aggressive hematopoietic malignancies, and genome-wide association studies have recently linked the PICALM locus to late-onset Alzheimer's disease. Inactivating and hypomorphic Picalm mutations in mice cause different degrees of severity of anemia, abnormal iron metabolism, growth retardation and shortened lifespan. To understand PICALM’s function, we studied the consequences of PICALM overexpression and characterized PICALM-deficient cells derived from mutant fit1 mice. Our results identify a role for PICALM in transferrin receptor (TfR) internalization and demonstrate that the C-terminal PICALM residues are critical for its association with clathrin and for the inhibitory effect of PICALM overexpression on TfR internalization. Murine embryonic fibroblasts (MEFs) that are deficient in PICALM display several characteristics of iron deficiency (increased surface TfR expression, decreased intracellular iron levels, and reduced cellular proliferation), all of which are rescued by retroviral PICALM expression. The proliferation defect of cells that lack PICALM results, at least in part, from insufficient iron uptake, since it can be corrected by iron supplementation. Moreover, PICALM-deficient cells are particularly sensitive to iron chelation. Taken together, these data reveal that PICALM plays a critical role in iron homeostasis, and offer new perspectives into the pathogenesis of PICALM-associated diseases.
PMCID: PMC3431333  PMID: 22952941
25.  Factors Associated with Second Hand Smoke Exposure In Young Inner City Children with Asthma 
To examine the association of social and environmental factors with levels of second hand smoke (SHS) exposure, as measured by salivary cotinine, in young inner city children with asthma.
We used data drawn from a home-based behavioral intervention for young high risk children with persistent asthma post emergency department (ED) treatment (N=198). SHS exposure was measured by salivary cotinine and caregiver report. Caregiver demographic and psychological functioning, household smoking behavior and asthma morbidity were compared with child cotinine concentrations. Chi-square and ANOVA tests and multivariate regression models were used to determine the association between cotinine concentrations with household smoking behavior and asthma morbidity.
Over half (53%) of the children had cotinine levels compatible with SHS exposure and mean cotinine concentrations were high at 2.42 ng/ml (SD 3.2). The caregiver was the predominant smoker in the home (57%) and (63%) reported a total home smoking ban. Preschool age children, and those with caregivers reporting depressive symptoms and high stress had higher cotinine concentrations than their counterparts. Among children living in a home with a total home smoking ban, younger children had significantly higher mean cotinine concentration than older children (Cotinine: 3–5 year olds, 2.24 ng/ml (SD 3.5); 6–10 year olds, 0.63 ng/ml (SD 1.0); p <0.05). In multivariate models, the factors most strongly associated with high child cotinine concentrations were increased number of household smokers (β = 0.24) and younger child age (3–5 years) (β = 0.23; P <0.001, R2 = 0.35).
Over half of young inner-city children with asthma were exposed to second hand smoke and caregivers are the predominant household smoker. Younger children and children with depressed and stressed caregivers are at significant risk of smoke exposures, even when a household smoking ban is reported. Further advocacy for these high-risk children is needed to help caregivers quit and to mitigate smoke exposure.
PMCID: PMC3113681  PMID: 21545248
asthma; children; cotinine; second hand smoke

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