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1.  Effect of Canagliflozin on Renal Threshold for Glucose, Glycemia, and Body Weight in Normal and Diabetic Animal Models 
PLoS ONE  2012;7(2):e30555.
Canagliflozin is a sodium glucose co-transporter (SGLT) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus (T2DM).
14C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human, rat, or mouse SGLT2 or SGLT1; 3H-2-deoxy-d-glucose uptake in L6 myoblasts; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed. Graded glucose infusions were performed to determine rate of urinary glucose excretion (UGE) at different blood glucose (BG) concentrations and the renal threshold for glucose excretion (RTG) in vehicle or canagliflozin-treated Zucker diabetic fatty (ZDF) rats. This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity.
Treatment with canagliflozin 1 mg/kg lowered RTG from 415±12 mg/dl to 94±10 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RTG. Canagliflozin dose-dependently decreased BG concentrations in db/db mice treated acutely. In ZDF rats treated for 4 weeks, canagliflozin decreased glycated hemoglobin (HbA1c) and improved measures of insulin secretion. In obese animal models, canagliflozin increased UGE and decreased BG, body weight gain, epididymal fat, liver weight, and the respiratory exchange ratio.
Canagliflozin lowered RTG and increased UGE, improved glycemic control and beta-cell function in rodent models of T2DM, and reduced body weight gain in rodent models of obesity.
PMCID: PMC3280264  PMID: 22355316
2.  Cutaneous angiosarcoma of the eyelids 
PMCID: PMC1771628  PMID: 12642333
angiosarcoma; eyelids
4.  Correlation of Ductal Lavage Cytology with Ductoscopy-Directed Duct Excision Histology in Women at High Risk for Developing Breast Cancer: A Prospective, Single-Institution Trial 
Annals of surgical oncology  2011;18(11):3192-3197.
The study was designed to determine which histological lesions produce cellular atypia in lavage specimens and whether ductoscopy adds useful information for the evaluation of high-risk patients with atypical lavage cytology.
We prospectively recruited women ≥35 years at high risk for developing breast cancer. All underwent ductal lavage. Women found to have atypia underwent ductoscopy-directed duct excision (group 1). Women without atypia were observed (group 2). Data included patient demographics, risk assessment, cytologic and histologic findings, and outcomes. Descriptive statistics were utilized for data summary and were compared using Fisher’s exact test.
We enrolled 102 women; 93 (91%) were Caucasian. Their median age was 49 (range 34–73) years with a median follow-up of 80 (range 5–90) months. Overall, 27 (26%) had atypical lavage cytology (group 1), and 75 (74%) had benign cytology (group 2). Subsequent duct excision in group 1 revealed benign histology in 11 (44%), papillomas in 9 (36%), atypical hyperplasia (AH) in 4 (16%), and ductal carcinoma in situ (DCIS) in 1 (4%). At follow-up, three patients developed breast cancer, including one group 1 patient and two group 2 patients. There were no differences between groups 1 and 2 according to patient demographics, Gail scores, or risk for subsequent breast cancer (P >0.05).
Although 20% of high-risk women with ductal lavage atypia have AH or malignancy on subsequent excision, the majority do not. Atypia identified by ductal lavage is not associated with a higher risk of developing subsequent breast cancer, even in this high-risk population.
PMCID: PMC3980449  PMID: 21847699
5.  Multi-Centre Evaluation of the Determine HIV Combo Assay when Used for Point of Care Testing in a High Risk Clinic-Based Population 
PLoS ONE  2014;9(4):e94062.
Determine HIV Combo (DHC) is the first point of care assay designed to increase sensitivity in early infection by detecting both HIV antibody and antigen. We conducted a large multi-centre evaluation of DHC performance in Sydney sexual health clinics.
We compared DHC performance (overall, by test component and in early infection) with conventional laboratory HIV serology (fourth generation screening immunoassay, supplementary HIV antibody, p24 antigen and Western blot tests) when testing gay and bisexual men attending four clinic sites. Early infection was defined as either acute or recent HIV infection acquired within the last six months.
Of 3,190 evaluation specimens, 39 were confirmed as HIV-positive (12 with early infection) and 3,133 were HIV-negative by reference testing. DHC sensitivity was 87.2% overall and 94.4% and 0% for the antibody and antigen components, respectively. Sensitivity in early infection was 66.7% (all DHC antibody reactive) and the DHC antigen component detected none of nine HIV p24 antigen positive specimens. Median HIV RNA was higher in false negative than true positive cases (238,025 vs. 37,591 copies/ml; p = 0.022). Specificity overall was 99.4% with the antigen component contributing to 33% of false positives.
The DHC antibody component detected two thirds of those with early infection, while the DHC antigen component did not enhance performance during point of care HIV testing in a high risk clinic-based population.
PMCID: PMC3979750  PMID: 24714441
6.  Post-parturient shedding of Listeria monocytogenes in breast milk of infected mice 
The objectives of this study were to develop an animal model to study Listeria monocytogenes infection during the peri-parturient period and identify sources of maternal shedding of the pathogen. Peri-parturient mice were infected intragastrically with L. monocytogenes that expressed bacterial luciferase. Mice were then imaged in vivo over time. Secreted breast milk samples from mice infected after parturition were enriched and plated for culture and imaging. Bioluminescence imaging technology was able to detect luciferase emitting L. monocytogenes in vaginal secretions and maternal and fetal organs at 72 and 96 h post infection in mice infected prior to, or just after, parturition. The results from this study clearly show that L. monocytogenes is shed in vaginal secretions and disseminates to the mammary chain, from which it can be shed in the milk of peri-parturient mice.
PMCID: PMC3974562  PMID: 24246517
Listeria monocytogenes; breast milk; bioluminescence
7.  Safety of an IV Formulation of Carbamazepine 
Epilepsy research  2009;84(0):242-244.
An intravenous formulation of carbamazepine (CBZ) was administered to 113 (60 male; 53 female) persons with epilepsy aged 19 to 87 years. Subjects received 100 mg of study drug as replacement for 100 mg of their usual morning dose of CBZ. There were no significant changes in blood pressure or heart rate suggesting that this formulation can be developed as replacement therapy for persons unable to take oral CBZ.
PMCID: PMC3973440  PMID: 19299110
Carbamazepine; intravenous; epilepsy; elderly; adults
8.  Impact of a cleaner-burning cookstove intervention on blood pressure in Nicaraguan women 
Indoor air  2012;23(2):105-114.
Few studies have evaluated the cardiovascular-related effects of indoor biomass burning or the role of characteristics such as age and obesity status, in this relationship. We examined the impact of a cleaner-burning cookstove intervention on blood pressure among Nicaraguan women using an open fire at baseline; we also evaluated heterogeneity of the impact by subgroups of the population. We evaluated changes in systolic and diastolic blood pressure from baseline to post-intervention (range: 273–383 days) among 74 female cooks. We measured indoor fine particulate matter (PM2.5; n=25), indoor carbon monoxide (CO; n=32), and personal CO (n=30) concentrations. Large mean reductions in pollutant concentrations were observed for all pollutants; for example, indoor PM2.5 was reduced 77% following the intervention. However, pollution distributions (baseline and post-intervention) were wide and overlapping. Although substantial reductions in blood pressure were not observed among the entire population, a 5.9 mmHg reduction (95% confidence interval [CI]: −11.3, −0.4) in systolic blood pressure was observed among women 40 or more years of age and a 4.6 mmHg reduction (95% CI: −10.0, 0.8) was observed among obese women. Results from this study provide an indication that certain subgroups may be more likely to experience improvements in blood pressure following a cookstove intervention.
PMCID: PMC3528797  PMID: 22913364
Biomass; Household air pollution; Cookstoves; Blood pressure; Intervention; Nicaragua
9.  Genes, environments, and developmental GEWIS: Methods for a multi-site study of early substance abuse 
The importance of including developmental and environmental measures in genetic studies of human pathology is widely acknowledged, but few empirical studies have been published. Barriers include the need for longitudinal studies that cover relevant developmental stages and for samples large enough to deal with the challenge of testing gene-environment-development interaction. A solution to some of these problems is to bring together existing data sets that have the necessary characteristics. As part of the NIDA-funded Gene-Environment-Development Initiative (GEDI) our goal is to identify exactly which genes, which environments, and which developmental transitions together predict the development of drug use and misuse. Four data sets were used whose common characteristics include (1) general population samples including males and females; (2) repeated measures across adolescence and young adulthood; (3) assessment of nicotine, alcohol and cannabis use and addiction; (4) measures of family and environmental risk; and (5) consent for genotyping DNA from blood or saliva. After quality controls, 2,962 individuals provided over 15,000 total observations. In the first gene-environment analyses, of alcohol misuse and stressful life events, some significant gene-environment and gene-development effects were identified. We conclude that in some circumstances, already-collected data sets can be combined for gene-environment and gene-development analyses. This greatly reduces the cost and time needed for this type of research. However, care must be taken to ensure careful matching across studies and variables.
PMCID: PMC3609892  PMID: 23461817
10.  ATG5 regulates plasma cell differentiation 
Autophagy  2013;9(4):528-537.
Autophagy is a conserved homeostatic process in which cytoplasmic contents are degraded and recycled. Two ubiquitin-like conjugation pathways are required for the generation of autophagosomes, and ATG5 is necessary for both of these processes. Studies of mice deficient in ATG5 reveal a key role for autophagy in T lymphocyte function, as well as in B cell development and B-1a B cell maintenance. However, the role of autophagy genes in B cell function and antibody production has not been described. Using mice in which Atg5 is conditionally deleted in B lymphocytes, we showed here that this autophagy gene is essential for plasma cell homeostasis. In the absence of B cell ATG5 expression, antibody responses were significantly diminished during antigen-specific immunization, parasitic infection and mucosal inflammation. Atg5-deficient B cells maintained the ability to produce immunoglobulin and undergo class-switch recombination, yet had impaired SDC1 expression, significantly decreased antibody secretion in response to toll-like receptor ligands, and an inability to upregulate plasma cell transcription factors. These results build upon previous data demonstrating a role for ATG5 in early B cell development, illustrating its importance in late B cell activation and subsequent plasma cell differentiation.
PMCID: PMC3627668  PMID: 23327930
B lymphocytes; ATG5; plasma cell differentiation; antibody secretion; immunity
11.  Cognition assessment using the NIH Toolbox 
Neurology  2013;80(11 Suppl 3):S54-S64.
Cognition is 1 of 4 domains measured by the NIH Toolbox for the Assessment of Neurological and Behavioral Function (NIH-TB), and complements modules testing motor function, sensation, and emotion. On the basis of expert panels, the cognition subdomains identified as most important for health, success in school and work, and independence in daily functioning were Executive Function, Episodic Memory, Language, Processing Speed, Working Memory, and Attention. Seven measures were designed to tap constructs within these subdomains. The instruments were validated in English, in a sample of 476 participants ranging in age from 3 to 85 years, with representation from both sexes, 3 racial/ethnic categories, and 3 levels of education. This report describes the development of the Cognition Battery and presents results on test-retest reliability, age effects on performance, and convergent and discriminant construct validity. The NIH-TB Cognition Battery is intended to serve as a brief, convenient set of measures to supplement other outcome measures in epidemiologic and longitudinal research and clinical trials. With a computerized format and national standardization, this battery will provide a “common currency” among researchers for comparisons across a wide range of studies and populations.
PMCID: PMC3662346  PMID: 23479546
12.  Use of Panitumumab-IRDye800 to Image Cutaneous Head and Neck Cancer in Mice 
To assess the feasibility of panitumumab in real-time fluorescent imaging and histologic processing of cutaneous squamous cell carcinoma (cSCC) in mice.
A near-infrared (NIR) fluorescent probe (IRDye800-CW) was covalently linked to a monoclonal antibody–targeting epidermal growth factor receptor (panitumumab) or nonspecific IgG and injected into mice bearing flank xenografts from a cSCC cell line (SCC-13 or SRB-12; n = 7), human split-thickness skin grafts (STSGs; n = 3), or a human tumor explant (n = 1). The tumor and lymph nodes were imaged and dissected using fluorescence guidance with the SPY imaging system and verified with a charge-coupled NIR system. An NIR scanning device (Odyssey) was used to measure fluorescence intensity in histological sections.
Immunodeficient mice.
In vivo and in vitro imaging lab.
Tumor tissue could be delineated from the human STSG with tumor-to-background ratios of 4.5 (Pearl) and 3.4 (SPY). Tumor detection was substantially improved with panitumumab-IRDye800 compared with IgG-IRDye800. Biopsies positive for fluorescence were assessed by histology and immunohistochemistry (n = 18/18) to confirm the presence of tumor, yielding a 100% sensitivity. Biopsies of non-fluorescent tissue negative for malignancy (n = 18/18) yielded a specificity of 100%. Furthermore, the SPY system was able to detect residual disease as small as 200 μm in diameter. In addition, the Odyssey confirmed fluorescence of microscopic disease (in tumor samples of frozen and paraffin-embedded histologic specimens) but not in adjacent noncancerous tissue.
These data suggest panitumumab-IRDye800 may have clinical utility in detection and removal of subclinical cSCC using Food and Drug Administration–approved imaging hardware.
PMCID: PMC3951339  PMID: 23525846
optical imaging; cutaneous cancer; head and neck carcinoma; panitumumab
13.  A Laboratory-Based Evaluation of Four Rapid Point-of-Care Tests for Syphilis 
PLoS ONE  2014;9(3):e91504.
Syphilis point-of-care tests may reduce morbidity and ongoing transmission by increasing the proportion of people rapidly treated. Syphilis stage and co-infection with HIV may influence test performance. We evaluated four commercially available syphilis point-of-care devices in a head-to-head comparison using sera from laboratories in Australia.
Point-of-care tests were evaluated using sera stored at Sydney and Melbourne laboratories. Sensitivity and specificity were calculated by standard methods, comparing point-of-care results to treponemal immunoassay (IA) reference test results. Additional analyses by clinical syphilis stage, HIV status, and non-treponemal antibody titre were performed. Non-overlapping 95% confidence intervals (CI) were considered statistically significant differences in estimates.
In total 1203 specimens were tested (736 IA-reactive, 467 IA-nonreactive). Point-of-care test sensitivities were: Determine 97.3%(95%CI:95.8–98.3), Onsite 92.5%(90.3–94.3), DPP 89.8%(87.3–91.9) and Bioline 87.8%(85.1–90.0). Specificities were: Determine 96.4%(94.1–97.8), Onsite 92.5%(90.3–94.3), DPP 98.3%(96.5–99.2), and Bioline 98.5%(96.8–99.3). Sensitivity of the Determine test was 100% for primary and 100% for secondary syphilis. The three other tests had reduced sensitivity among primary (80.4–90.2%) compared to secondary syphilis (94.3–98.6%). No significant differences in sensitivity were observed by HIV status. Test sensitivities were significantly higher among high-RPR titre (RPR≥8) (range: 94.6–99.5%) than RPR non-reactive infections (range: 76.3–92.9%).
The Determine test had the highest sensitivity overall. All tests were most sensitive among high-RPR titre infections. Point-of-care tests have a role in syphilis control programs however in developed countries with established laboratory infrastructures, the lower sensitivities of some tests observed in primary syphilis suggest these would need to be supplemented with additional tests among populations where syphilis incidence is high to avoid missing early syphilis cases.
PMCID: PMC3950184  PMID: 24618681
14.  Effect of Bifidobacterium breve M-16V Supplementation on Fecal Bifidobacteria in Preterm Neonates - A Randomised Double Blind Placebo Controlled Trial 
PLoS ONE  2014;9(3):e89511.
Probiotic supplementation significantly reduces the risk of necrotising enterocolitis (NEC) and all cause mortality in preterm neonates. Independent quality assessment is important before introducing routine probiotic supplementation in this cohort.
To assess product quality, and confirm that Bifidobacterium breve (B. breve) M-16V supplementation will increase fecal B. breve counts without adverse effects.
Methods and Participants
Strain identity (16S rRNA gene sequencing), viability over 2 year shelf-life were confirmed, and microbial contamination of the product was ruled out. In a controlled trial preterm neonates (Gestation <33 weeks) ready to commence or on feeds for <12 hours were randomly allocated to either B. breve M-16V (3×109 cfu/day) or placebo (dextrin) supplementation until the corrected age 37 weeks. Stool samples were collected before (S1) and after 3 weeks of supplementation (S2) for studying fecal B. breve levels using quantitative PCR (Primary outcome). Secondary outcomes included total fecal bifidobacteria and NEC≥Stage II. Categorical and continuous outcomes were analysed using Chi-square and Mann-Whitney tests, and McNemar and Wilcoxon signed-rank tests for paired comparisons.
A total of 159 neonates (Probiotic: 79, Placebo: 80) were enrolled. Maternal and neonatal demographic characteristics were comparable between the groups. The proportion of neonates with detectable B. breve increased significantly post intervention: Placebo: [S1:2/66 (3%), S2: 25/66 (38%), p<0.001] Probiotic: [S1: 29/74 (40%), S2: 67/74 (91%), p<0.001].
Median S1 B. breve counts in both groups were below detection (<4.7 log cells.g−1), increasing significantly in S2 for the probiotic group (log 8.6) while remaining <4.7 log in the control group (p<0.001). There were no adverse effects including probiotic sepsis and no deaths. NEC≥Stage II occurred in only 1 neonate (placebo group).
B. breve M-16V is a suitable probiotic strain for routine use in preterm neonates.
Trial Registration
Australia New Zealand Clinical Trial Registry ACTRN 12609000374268
PMCID: PMC3940439  PMID: 24594833
15.  Heterozygous inactivation of the Nf1 gene in myeloid cells enhances neointima formation via a rosuvastatin-sensitive cellular pathway 
Human Molecular Genetics  2012;22(5):977-988.
Mutations in the NF1 tumor suppressor gene cause Neurofibromatosis type 1 (NF1). Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity. Some NF1 patients develop cardiovascular disease, which represents an underrecognized disease complication and contributes to excess morbidity and mortality. Specifically, NF1 patients develop arterial occlusion resulting in tissue ischemia and sudden death. Murine studies demonstrate that heterozygous inactivation of Nf1 (Nf1+/−) in bone marrow cells enhances neointima formation following arterial injury. Macrophages infiltrate Nf1+/− neointimas, and NF1 patients have increased circulating inflammatory monocytes in their peripheral blood. Therefore, we tested the hypothesis that heterozygous inactivation of Nf1 in myeloid cells is sufficient for neointima formation. Specific ablation of a single copy of the Nf1 gene in myeloid cells alone mobilizes a discrete pro-inflammatory murine monocyte population via a cell autonomous and gene-dosage dependent mechanism. Furthermore, lineage-restricted heterozygous inactivation of Nf1 in myeloid cells is sufficient to reproduce the enhanced neointima formation observed in Nf1+/− mice when compared with wild-type controls, and homozygous inactivation of Nf1 in myeloid cells amplified the degree of arterial stenosis after arterial injury. Treatment of Nf1+/− mice with rosuvastatin, a stain with anti-inflammatory properties, significantly reduced neointima formation when compared with control. These studies identify neurofibromin-deficient myeloid cells as critical cellular effectors of Nf1+/− neointima formation and propose a potential therapeutic for NF1 cardiovascular disease.
PMCID: PMC3561913  PMID: 23197650
16.  Adult Soft Tissue Sarcoma Local Recurrence After Adjuvant Treatment Without Resection of Core Needle Biopsy Tract 
Core needle biopsies of sarcomas allow a diagnosis in a high percentage of patients with few complications. However, it is unclear whether the tract needs to be excised to prevent recurrences.
We therefore determined the rates of recurrence and metastases in patients with Stage III extremity sarcomas, who underwent wide local resection without excision of the needle tract and also received adjuvant treatment.
We retrospectively reviewed 59 adult patients with deep, larger than 5 cm, high-grade soft tissue sarcomas of the upper or lower extremity treated between January 1999 and April 2009. All the patients underwent a core needle biopsy. Resection was performed with wide margins. The biopsy tract was not resected during the definitive surgery. Fifty-seven patients (97%) received preoperative and/or postoperative radiation, whereas 49 patients (83%) received chemotherapy. Local recurrence and distant recurrence rates were determined. The minimum followup was 24 months (median, 56 months; range, 24–122 months).
The local recurrence rate was 9%. Fifteen patients (25%) developed metastasis after diagnosis. Seven of the 59 patients (12%) had microscopic positive margins at resection.
Our data demonstrate no increase in local recurrence rates or rates of metastatic disease compared with previously published studies when resection of the core biopsy tract was not performed.
Level of Evidence
Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3563812  PMID: 22968531
Accurate assignment of gestational age at time of fetal death is important for research and clinical practice. An algorithm to estimate gestational age (GA) at fetal death was developed and evaluated.
The algorithm developed by the Stillbirth Collaborative Research Network (SCRN) incorporated clinical and postmortem data. The SCRN conducted a population-based case-control study of women with stillbirths and live births from 2006 to 2008 in five geographic catchment areas. Rules were developed to estimate a due date, identify an interval during which death likely occurred, and estimate GA at the time of fetal death. Reliability of using fetal foot length to estimate GA at death was assessed.
The due date estimated for 620 singleton stillbirths studied was considered clinically reliable for 87%. Only 25.2% of stillbirths were documented alive within two days before diagnosis and 47.6% within one week of diagnosis. The algorithm-derived estimate of GA at time of fetal death was 1 or more weeks earlier than the GA at delivery for 43.5% of stillbirths. GA estimated from fetal foot length agreed with GA by algorithm within two weeks for 75% within a subset of well-dated stillbirths.
Precise assignment of GA at death, defined as reliable dating criteria and a short interval (≤1 week) during which fetal death was known to have occurred, was possible in 46.6% of cases. Fetal foot length is a relatively accurate measure of GA at death and should be collected in all stillbirth cases.
PMCID: PMC3564237  PMID: 23374059
19.  Ascending aorta thrombus adjacent to a cholesterol-rich plaque as the source of multiple emboli 
Ascending aortic thrombus causing thromboembolism in the absence of hyper-coagulable states is a rare occurrence. We present a case of a 40-year old healthy female smoker who presented with a 6-month history of three transient ischaemic attacks, hand pain and numbness despite being on dual anti-platelet therapy. Computed tomography revealed a mid-ascending aorta thrombus. She underwent ascending aorta replacement on cardiopulmonary bypass, but without the use of circulatory arrest. She recovered uneventfully. We identified a fresh thrombus adjacent to a soft, cholesterol-rich plaque as the culprit lesion. We advocate surgical excision of such lesions as the only way of removing the underlying cause of thromboembolism. In addition, rupture-prone aortic plaques may lead to a penetrating aortic ulcer or an intramural haematoma and ultimately aortic dissection.
PMCID: PMC3568809  PMID: 23243036
Thrombus; Ascending aorta; Plaque
20.  Microbiology and Risk Factors for Central Line-Associated Bloodstream Infections among Pediatric Oncology Outpatients – a Single Institution Experience of 41 Cases 
Risk factors for central line-associated bloodstream infections (CLABSI) among children with cancer in the outpatient setting remain poorly defined, and the microbiology may differ from hospital-onset CLABSI.
Materials and Methods
We conducted a matched case-control study of oncology patients followed at the Dana Farber/Children’s Hospital Cancer Center. Cases (N=41) were patients with CLABSI as per National Healthcare Safety Network criteria who had not been hospitalized in the preceding 48 hours. For each case we randomly selected two oncology outpatients with a central venous catheter and a clinic visit within 30 days of the case subject’s CLABSI. Multivariate conditional logistic regression models were used to identify independent risk factors for CLABSI. We compared the microbiology to that of 54 hospital-onset CLABSI occurring at our institution during the study period.
Independent predictors of community-onset CLABSI included neutropenia in the prior week (odds ratio [OR] 17.46, 95% confidence interval [CI] 4.71-64.67) and tunneled externalized catheter (vs. implantable port; OR 10.30, 95% CI 2.42-43.95). Non-enteric Gram-negative bacteria were more frequently isolated from CLABSI occurring among outpatients.
Pediatric oncology outpatients with recent neutropenia or tunneled externalized catheters are at increased risk of CLABSI. The microbiology of community-onset CLABSI differs from hospital-onset CLABSI.
PMCID: PMC3574641  PMID: 23412591
catheter infections; pediatric oncology; community-onset CLABSI; neutropenia
21.  Identification of the optimal therapeutic antibody for fluorescent imaging of cutaneous squamous cell carcinoma 
Cancer Biology & Therapy  2013;14(3):271-277.
Intraoperative, real-time fluorescence imaging may significantly improve tumor visualization and resection and postoperatively, in pathological assessment. To this end, we sought to determine the optimal FDA approved therapeutic monoclonal antibody for optical imaging of human cutaneous squamous cell carcinoma (cSCC). A near-infrared (NIR) fluorescent probe (IRDye800) was covalently linked to bevacizumab, panitumumab or tocilizumab and injected systemically into immunodeficient mice bearing either cutaneous tumor cell lines (SCC13) or cutaneous human tumor explants. Tumors were then imaged and resected under fluorescent guidance with the SPY, an FDA-approved intraoperative imaging system, and the Pearl Impulse small animal imaging system. All fluorescently labeled antibodies delineated normal tissue from tumor in SCC13 xenografts based on tumor-to-background (TBR) ratios. The conjugated antibodies produced TBRs of 1.2–2 using SPY and 1.6–3.6 using Pearl; in comparison, isotype control antibody IgG-IRDye produced TBRs of 1.0 (SPY) and 0.98 (Pearl). Comparison between antibodies revealed them to be roughly equivalent for imaging purposes with both the SPY and Pearl (p = 0.89 SPY, p = 0.99 Pearl; one way ANOVA). Human tumor explants were also imaged and tumor detection was highest with panitumumab-IRDye800 when using the SPY (TBR 3.0) and Pearl (TBR 4.0). These data suggest that FDA approved antibodies may be clinically used for intraoperative detection of cSCC.
PMCID: PMC3595310  PMID: 23298904
optical imaging; cancer; surgery; cutaneous squamous cell carcinoma; antibody; animal model; fluorescence
22.  Pilot- and bench-scale testing of faecal indicator bacteria survival in marine beach sand near point sources 
Journal of applied microbiology  2009;107(1):72-84.
Factors affecting faecal indicator bacteria (FIB) and pathogen survival/persistence in sand remain largely unstudied. This work elucidates how biological and physical factors affect die-off in beach sand following sewage spills.
Methods and Results
Solar disinfection with mechanical mixing was pilot-tested as a disinfection procedure after a large sewage spill in Los Angeles. Effects of solar exposure, mechanical mixing, predation and/or competition, season, and moisture were tested at bench scale. First-order decay constants for Escherichia coli ranged between −0·23 and −·102 per day, and for enterococci between −0·5 and −1·0 per day. Desiccation was a dominant factor for E. coli but not enterococci inactivation. Effects of season were investigated through a comparison of experimental results from winter, spring, and fall.
Moisture was the dominant factor controlling E. coli inactivation kinetics. Initial microbial community and sand temperature were also important factors. Mechanical mixing, common in beach grooming, did not consistently reduce bacterial levels.
Significance and Impact of the Study
Inactivation rates are mainly dependent on moisture and high sand temperature. Chlorination was an effective disinfection treatment in sand microcosms inoculated with raw influent.
PMCID: PMC3938294  PMID: 19302327
degradation; detection; disinfection; indicators; soil; water quality
23.  Association between Socioeconomic Factors and Cancer Risk: A Population Cohort Study in Scotland (1991-2006) 
PLoS ONE  2014;9(2):e89513.
Lung and upper aero-digestive tract (UADT) cancer risk are associated with low socioeconomic circumstances and routinely measured using area socioeconomic indices. We investigated effect of country of birth, marital status, one area deprivation measure and individual socioeconomic variables (economic activity, education, occupational social class, car ownership, household tenure) on risk associated with lung, UADT and all cancer combined (excluding non melanoma skin cancer).
We linked Scottish Longitudinal Study and Scottish Cancer Registry to follow 203,658 cohort members aged 15+ years from 1991–2006. Relative risks (RR) were calculated using Poisson regression models by sex offset for person-years of follow-up.
21,832 first primary tumours (including 3,505 lung, 1,206 UADT) were diagnosed. Regardless of cancer, economically inactivity (versus activity) was associated with increased risk (male: RR 1.14, 95% CI 1.10–1.18; female: RR 1.06, 95% CI 1.02–1.11). For lung cancer, area deprivation remained significant after full adjustment suggesting the area deprivation cannot be fully explained by individual variables. No or non degree qualification (versus degree) was associated with increased lung risk; likewise for UADT risk (females only). Occupational social class associations were most pronounced and elevated for UADT risk. No car access (versus ownership) was associated with increased risk (excluding all cancer risk, males). Renting (versus home ownership) was associated with increased lung cancer risk, UADT cancer risk (males only) and all cancer risk (females only). Regardless of cancer group, elevated risk was associated with no education and living in deprived areas.
Different and independent socioeconomic variables are inversely associated with different cancer risks in both sexes; no one socioeconomic variable captures all aspects of socioeconomic circumstances or life course. Association of multiple socioeconomic variables is likely to reflect the complexity and multifaceted nature of deprivation as well as the various roles of these dimensions over the life course.
PMCID: PMC3937337  PMID: 24586838
24.  Is the relationship between the built environment and physical activity moderated by perceptions of crime and safety? 
Direct relationships between safety concerns and physical activity have been inconsistently patterned in the literature. To tease out these relationships, crime, pedestrian, and traffic safety were examined as moderators of built environment associations with physical activity.
Exploratory analyses used two cross-sectional studies of 2068 adults ages 20–65 and 718 seniors ages 66+ with similar designs and measures. The studies were conducted in the Baltimore, Maryland-Washington, DC and Seattle-King County, Washington regions during 2001–2005 (adults) and 2005–2008 (seniors). Participants were recruited from areas selected to sample high- and low- income and walkability. Independent variables perceived crime, traffic, and pedestrian safety were measured using scales from validated instruments. A GIS-based walkability index was calculated for a street-network buffer around each participant’s home address. Outcomes were total physical activity measured using accelerometers and transportation and leisure walking measured with validated self-reports (IPAQ-long). Mixed effects regression models were conducted separately for each sample.
Of 36 interactions evaluated across both studies, only 5 were significant (p < .05). Significant interactions did not consistently support a pattern of highest physical activity when safety was rated high and environments were favorable. There was not consistent evidence that safety concerns reduced the beneficial effects of favorable environments on physical activity. Only pedestrian safety showed evidence of a consistent main effect with physical activity outcomes, possibly because pedestrian safety items (e.g., crosswalks, sidewalks) were not as subjective as those on the crime and traffic safety scales.
Clear relationships between crime, pedestrian, and traffic safety with physical activity levels remain elusive. The development of more precise safety variables and the use of neighborhood-specific physical activity outcomes may help to elucidate these relationships.
PMCID: PMC3942774  PMID: 24564971
Ecological models; Older adults; Parks; Social environment; Walkability; Traffic; Transportation
25.  Pharmacokinetics of Natural and Engineered Secreted Factors Delivered by Mesenchymal Stromal Cells 
PLoS ONE  2014;9(2):e89882.
Transient cell therapy is an emerging drug class that requires new approaches for pharmacological monitoring during use. Human mesenchymal stem cells (MSCs) are a clinically-tested transient cell therapeutic that naturally secrete anti-inflammatory factors to attenuate immune-mediated diseases. MSCs were used as a proof-of-concept with the hypothesis that measuring the release of secreted factors after cell transplantation, rather than the biodistribution of the cells alone, would be an alternative monitoring tool to understand the exposure of a subject to MSCs. By comparing cellular engraftment and the associated serum concentration of secreted factors released from the graft, we observed clear differences between the pharmacokinetics of MSCs and their secreted factors. Exploration of the effects of natural or engineered secreted proteins, active cellular secretion pathways, and clearance mechanisms revealed novel aspects that affect the systemic exposure of the host to secreted factors from a cellular therapeutic. We assert that a combined consideration of cell delivery strategies and molecular pharmacokinetics can provide a more predictive model for outcomes of MSC transplantation and potentially other transient cell therapeutics.
PMCID: PMC3931832  PMID: 24587097

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