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1.  Diarrhea Burden Due to Natural Infection with Enterotoxigenic Escherichia coli in a Birth Cohort in a Rural Egyptian Community 
Journal of Clinical Microbiology  2014;52(7):2595-2603.
Enterotoxigenic Escherichia coli (ETEC) is commonly associated with diarrhea in Egyptian children. Children less than 3 years old in Abu Homos, Egypt, had approximately five diarrheal episodes per child every year, and at least one of these episodes was due to ETEC. The epidemiology of ETEC diarrhea among children living in a rural Egyptian community was further evaluated in this study. Between January 2004 and April 2007, 348 neonates were enrolled and followed for 2 years. Children were visited twice weekly, and a stool sample was obtained every 2 weeks regardless of symptomatology. A stool sample was obtained whenever a child had diarrhea. From the routine stool culture, five E. coli-like colonies were selected and screened for heat-labile and heat-stable toxins by GM1 enzyme-linked immunosorbent assay (ELISA) and further typed for colonization factor antigens by dot blot assay. Incidence of ETEC infection was estimated among children with diarrhea (symptomatic) and without diarrhea (asymptomatic). Incidence of diarrhea and ETEC-associated diarrhea was 7.8 and 1.48 per child-year, respectively. High risk of repeated ETEC diarrhea was associated with being over 6 months of age, warm season, male gender, and crowded sleeping conditions. Exclusive breast-feeding was protective for repeated ETEC infection. ETEC-associated diarrhea remains common among children living in the Nile Delta. The protective role of breast-feeding demonstrates the importance of promoting exclusive breast-feeding during, at least, the first 6 months of life.
doi:10.1128/JCM.00215-14
PMCID: PMC4097688  PMID: 24829232
2.  TITLE Disposition and kinetics of Tetrabromobisphenol A in female Wistar Han rats 
Toxicology reports  2014;1:214-223.
Tetrabromobisphenol A (TBBPA) is the brominated flame retardant with the largest production volume worldwide. NTP 2-year bioassays found TBBPA dose-dependent increases in uterine tumors in female Wistar Han rats; evidence of reproductive tissues carcinogenicity was equivocal in male rats. To explain this apparent sex-dependence, the disposition and toxicokinetic profile of TBBPA were investigated using female Wistar Han rats, as no data were available for female rats. In these studies, the primary route of elimination following [14C]-TBBPA administration (25, 250 or 1,000 mg/kg) was in feces; recoveries in 72 h were 95.7±3.5%, 94.3±3.6% and 98.8±2.2%, respectively (urine: 0.2-2%; tissues: <0.1). TBBPA was conjugated to mono-glucuronide and —sulfate metabolites and eliminated in the bile. Plasma toxicokinetic parameters for a 250 mg/kg dose were estimated based on free TBBPA, as determined by UV/radiometric-HPLC analyses. Oral dosing by gavage (250 mg/kg) resulted in a rapid absorption of compound into the systemic circulation with an observed Cmax at 1.5 h post-dose followed by a prolonged terminal phase. TBBPA concentrations in plasma decreased rapidly after an IV dose (25 mg/kg) followed by a long elimination phase. These results indicate low systemic bioavailability (F<0.05), similar to previous reports using male rats. Elimination pathways appeared to become saturated leading to delayed excretion after a single oral administration of the highest dose (1,000 mg/kg); no such saturation or delay was detected at lower doses. Chronic high exposures to TBBPA may result in competition for metabolism with endogenous substrates in extrahepatic tissues (e.g., SULT1E1 estrogen sulfation) resulting in endocrine disruption.
doi:10.1016/j.toxrep.2014.03.005
PMCID: PMC4071299  PMID: 24977115
Disposition; Tetrabromobisphenol A; TBBPA; brominated flame retardant; persistent organic pollutants; toxicokinetics; disposition; female rat
3.  Proposed Mechanistic Description of Dose-Dependent BDE-47 Urinary Elimination in Mice Using a Physiologically Based Pharmacokinetic Model 
Toxicology and applied pharmacology  2013;273(2):335-344.
Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse health effects in humans, in experimental animals, and wildlife. This laboratory previously demonstrated that urinary elimination of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) is saturable at high doses in mice; however, this dose-dependent urinary elimination has not been observed in adult rats or immature mice. Thus, the primary objective of this study was to examine the mechanism of urinary elimination of BDE-47 in adult mice using a physiologically based pharmacokinetic (PBPK) model. To support this objective, additional laboratory data were collected to evaluate the predictions of the PBPK model using novel information from adult multi-drug resistance 1a/b knockout mice. Using the PBPK model, the roles of mouse major urinary protein (a blood protein carrier) and P-glycoprotein (an apical membrane transporter in proximal tubule cells in the kidneys, brain, intestines, and liver) were investigated in BDE-47 elimination. The resulting model and new data supported the major role of m-MUP in excretion of BDE-47 in the urine of adult mice, and a lesser role of P-gp as a transporter of BDE-47 in mice. This work expands the knowledge of BDE-47 kinetics between species and provides information for determining the relevancy of these data for human risk assessment purposes.
doi:10.1016/j.taap.2013.09.007
PMCID: PMC3913262  PMID: 24055880
PBPK; pharmacokinetics; PBDE; BDE-47; m-MUP; P-gp; mouse
4.  The Fate of β-Hexabromocyclododecane in Female C57BL/6 Mice 
Toxicological Sciences  2013;134(2):251-257.
1,2,5,6,9,10-Hexabromocyclododecane (HBCD) is a high production volume cycloaliphatic used as an additive flame retardant primarily in polystyrene foam building materials. HBCD mixtures contain three major stereoisomers, alpha (α), beta (β), and gamma (γ), at a typical ratio of 1.2:0.6:8.2. The toxicokinetic properties of the α and γ isomers differ. For instance, α-HBCD has greater bioavailability and potential for accumulation in mice than γ-HBCD. The present study reports comparative kinetics data for β-HBCD needed to support toxicological evaluations of HBCD mixtures. Results indicated that a single oral dose of 3mg/kg of [14C]-labeled β-HBCD was absorbed rapidly (≥ 85% total dose) in the female C57BL/6 mouse. The C max for β-HBCD-derived radioactivity in tissues, except adipose, was observed 3h following gavage. Approximately 90% of the administered dose was excreted in urine and feces within 24h, primarily as β-HBCD-derived metabolites. A portion of the dose (circa 9%) was excreted in feces as γ-HBCD. Oral administration of 30 or 100mg/kg of β-HBCD resulted initially in slower rates of [14C] elimination; however, cumulative excretion data were similar across the dosing range 4 days postdosing. Residual concentrations of [14C] in tissues were highest in adipose and liver. β-HBCD-derived radioactivity accumulated in most tissues following four consecutive daily oral doses of 3mg/kg. The extent of metabolism and excretion of β-HBCD in female C57BL/6 mice was similar to that for γ-HBCD. The potential for accumulation of β-HBCD-derived material in most tissues appeared to be less than for α-HBCD.
doi:10.1093/toxsci/kft121
PMCID: PMC3707439  PMID: 23733921
hexabromocyclododecane; toxicokinetics; mouse; brominated flame retardant; disposition; risk assessment; persistent organic pollutant.
5.  Toxicology and Carcinogenesis Study of Senna in the C3B6.129F1-Trp53tm1Brd N12 haploinsufficient mice 
Toxicologic pathology  2012;41(5):10.1177/0192623312464304.
Senna is a pod or leaf of Senna alexandrina P. Mill and is used as a stimulant laxative. In the large intestine, bacterial enzymes break sennosides and release rhein-9-anthrone, the active form for the laxative effect. To determine potential toxic effects of senna, a 5-week dose range finding study in the C57BL/6N mouse and a 40-week toxicology and carcinogenesis study in the C3B6.129F1-Trp53tm1Brd N12 haploinsufficient (p53+/−) mouse were conducted. In the 5-week study, C57BL/6N mice were exposed up to 10,000 ppm senna in feed. Increased incidences of epithelial hyperplasia of the cecum and colon were observed in males and females exposed to 5,000 or 10,000 ppm senna. These intestinal lesions were not considered to be of sufficient severity to cause mortality and, thus, in the p53+/− mouse 40-week study, the high dose of 10,000 ppm was selected. Significant increases in the incidences of epithelial hyperplasia of the colon and cecum were observed at 10,000 ppm in p53(+/−) males and females, and the incidence of hyperplasia of the colon was significantly increased at 3,000 ppm in females. In conclusion, the large intestine was the major target of senna-induced toxicity in both wild-type and the p53+/− mouse model. There was no neoplastic change, when senna was administered to p53 +/− mouse.
doi:10.1177/0192623312464304
PMCID: PMC3672319  PMID: 23125117
Senna; Trp53; carcinogenesis; toxicity; laxative; large intestine
6.  Malignant Dysembryoplastic Neuroepithelial Tumour in a Zebrafish (Danio rerio) 
Journal of comparative pathology  2012;148(0):220-224.
Summary
Neuroectodermal tumours in man, including medulloblastoma, medulloepithelioma, neuroblastoma, esthesioneuroblastoma, primitive neuroectodermal tumour and dysembryoplastic neuroepithelial tumour, typically occur in children and young adults. These tumour types are occasionally observed in juvenile and adult zebrafish (Danio rerio), either as induced tumours in carcinogen-exposed zebrafish or as an incidental finding in zebrafish ≥ 2 years of age. An adult zebrafish submitted for routine histological examination was sent for a second opinion consultation after an uncharacteristic brain mass was identified. Microscopically, the expansile and infiltrative extracortical mass arising from the cerebellum had a diffuse microcystic pattern with solid hypercellular regions occupying 80% of the extrameningeal space and effacing the endomeninx and significantly displacing the metencephalon. The mass was composed of dense sheets of oligodendrocyte-like cells, random neurons and pseudocysts containing ‘floating neurons’ within a scant mucinous matrix. Neoplastic cells demonstrated positive perinuclear and intracytoplasmic expression of S-100. Malignant dysembryoplastic neuroepithelial tumour was diagnosed based upon the histologic features of the brain mass, which were indistinguishable from the human tumour. To our knowledge, this is the first report of a dysembryoplastic neuroepithelial tumour in a zebrafish.
doi:10.1016/j.jcpa.2012.05.015
PMCID: PMC4007653  PMID: 22819012
zebrafish; dysembryoplastic neuroepithelial tumor; brain; neoplasia
7.  Effect of CYP3A4*22, CYP3A5*3, and CYP3A Combined Genotypes on Cyclosporine, Everolimus, and Tacrolimus Pharmacokinetics in Renal Transplantation 
Cyclosporine, everolimus, and tacrolimus are the cornerstone of immunosuppressive therapy in renal transplantation. These drugs are characterized by narrow therapeutic windows, highly variable pharmacokinetics (PK), and metabolism by CYP3A enzymes. Recently, the decreased activity allele, CYP3A4*22, was described as a potential predictive marker for CYP3A4 activity. This study investigated the effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on cyclosporine, everolimus, and tacrolimus PK in renal transplant patients. CYP3A4*22 carriers showed a significant lower clearance for cyclosporine (−15%), and a trend was observed for everolimus (−7%) and tacrolimus (−16%). Patients carrying at least one CYP3A5*1 allele had 1.5-fold higher tacrolimus clearance compared with noncarriers; however, CYP3A5*3 appeared to be nonpredictive for everolimus and cyclosporine. CYP3A combined genotype did not significantly improve prediction of clearance compared with CYP3A5*3 or CYP3A4*22 alone. These data suggest that dose individualization of cyclosporine, everolimus, or tacrolimus therapy based on CYP3A4*22 is not indicated.
doi:10.1038/psp.2013.78
PMCID: PMC3944116  PMID: 24522145
8.  Metatranscriptomics reveal differences in in situ energy and nitrogen metabolism among hydrothermal vent snail symbionts 
The ISME Journal  2013;7(8):1556-1567.
Despite the ubiquity of chemoautotrophic symbioses at hydrothermal vents, our understanding of the influence of environmental chemistry on symbiont metabolism is limited. Transcriptomic analyses are useful for linking physiological poise to environmental conditions, but recovering samples from the deep sea is challenging, as the long recovery times can change expression profiles before preservation. Here, we present a novel, in situ RNA sampling and preservation device, which we used to compare the symbiont metatranscriptomes associated with Alviniconcha, a genus of vent snail, in which specific host–symbiont combinations are predictably distributed across a regional geochemical gradient. Metatranscriptomes of these symbionts reveal key differences in energy and nitrogen metabolism relating to both environmental chemistry (that is, the relative expression of genes) and symbiont phylogeny (that is, the specific pathways employed). Unexpectedly, dramatic differences in expression of transposases and flagellar genes suggest that different symbiont types may also have distinct life histories. These data further our understanding of these symbionts' metabolic capabilities and their expression in situ, and suggest an important role for symbionts in mediating their hosts' interaction with regional-scale differences in geochemistry.
doi:10.1038/ismej.2013.45
PMCID: PMC3721115  PMID: 23619306
symbiosis; hydrothermal vents; metatranscriptomics; chemoautotrophy; Alviniconcha
9.  Using whole exome sequencing to identify inherited causes of autism 
Neuron  2013;77(2):259-273.
Summary
Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, POMGNT1), some implicated for the first time in ASD. At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.
doi:10.1016/j.neuron.2012.11.002
PMCID: PMC3694430  PMID: 23352163
10.  Modulation of Gene Expression using Electrospun Scaffolds with Templated Architecture 
The fabrication of biomimetic scaffolds is a critical component to fulfill the promise of functional tissue engineered materials. We describe herein a simple technique, based on printed circuit board manufacturing, to produce novel templates for electrospinning scaffolds for tissue engineering applications. This technique facilitates fabrication of electrospun scaffolds with templated architecture, which we defined as a scaffold's bulk mechanical properties being driven by its fiber architecture. Electrospun scaffolds with templated architectures were characterized with regard to fiber alignment and mechanical properties. Fast Fourier transform analysis revealed a high degree of fiber alignment along the conducting traces of the templates. Mechanical testing showed that scaffolds demonstrated tunable mechanical properties as a function of templated architecture. Fibroblast seeded scaffolds were subjected to a peak strain of 3% or 10% at 0.5 Hz for 1 hour. Exposing seeded scaffolds to the low strain magnitude (3%) significantly increased collagen I gene expression compared to the high strain magnitude (10%) in a scaffold architecture dependent manner. These experiments indicate that scaffolds with templated architectures can be produced and modulation of gene expression is possible with templated architectures. This technology holds promise for the long term goal of creating tissue engineered replacements with the biomechanical and biochemical make-up of native tissues.
doi:10.1002/jbm.a.34102
PMCID: PMC3324655  PMID: 22447576
electrospinning; tissue engineering; anisotropic scaffold; collagen I; cyclic strain
11.  Hypoparathyroidism in the Adult: Epidemiology, Diagnosis, Pathophysiology, Target Organ Involvement, Treatment, and Challenges for Future Research 
Journal of Bone and Mineral Research  2011;26(10):2317-2337.
doi:10.1002/jbmr.483
PMCID: PMC3405491  PMID: 21812031
hypoparathyroidism; calcium; epidemiology; genetics; parathyroid hormone; hypocalcemia
12.  The role of p21-activated kinase in the initiation of atherosclerosis 
Background
p21-activated kinase (PAK) has been implicated in the inflammatory activation of endothelial cells by disturbed fluid shear stress, which is the initiating stimulus in atherosclerosis. The study addresses whether PAK1 contributes to inflammatory marker expression in endothelial cells at atherosclerosis-susceptible regions of arteries in vivo.
Method
Aortas from WT and PAK1-/- C57BL/6J mice on a normal chow diet were fixed, dissected and processed for immunohistochemistry using a panel of inflammatory markers. We visualized and quantified staining in the endothelium at the greater and lesser curvatures of the arch of aorta, as atherosclerosis-resistant and susceptible regions, respectively.
Results
Fibronectin, VCAM-1 and the activated RelA NF-κB subunit were localized to the lesser curvature and decreased in PAK1-/- mice. The activated RelB NF-κB subunit was also localized to the lesser curvature but was increased in PAK1-/- mice. Low levels of staining for ICAM-1 and the monocyte/macrophage marker Mac2 indicated that overall inflammation in this tissue was minimal.
Conclusion
These data show that PAK1 has a significant pro-inflammatory function at atherosclerosis-prone sites in vivo. These effects are seen in young mice with very low levels of inflammation, suggesting that inflammatory activation of the endothelium is primarily biomechanical. Activation involves NF-κB, expression of leukocyte recruitment receptors and fibronectin deposition. These results support and extend in vitro studies demonstrating that PAK contributes to activation of inflammatory pathways in endothelial cells by fluid shear stress.
doi:10.1186/1471-2261-12-55
PMCID: PMC3489605  PMID: 22824149
Fluid shear stress; Endothelial cells; Vascular inflammation; Fibronectin
13.  Recent Decrease in Acute GVHD in Children with Leukemia Receiving Unrelated Donor Bone Marrow Transplants 
Unrelated donor (URD) BMT is an effective treatment for leukemia in children, but success is limited by graft versus host disease (GVHD) and relapse. In this study we describe the incidence and risk factors for GVHD over time in children receiving URD BMT. We analyzed outcomes of 638 myeloablative URD BMT performed between 1990 and 2003 for treatment of AML, ALL, CML or MDS, using the Center for International Blood & Marrow Transplant Research (CIBMTR) database. Recipients were <18 years of age, and had available high resolution HLA typing for HLA A, B, C and DRB1. Overall, 27% of recipients developed aGVHD grades III-IV and risk was significantly higher in recipients of T-replete compared with T-depleted grafts (OR 3.12, 95%CI 2.02-4.83; p< 0.0001). Acute GVHD significantly reduced risk of relapse in children with ALL (OR 0.34 95% CI 0.13-0.86, p=0.0052) but not AML (OR 0.58, 95% CI 0.22-2.98; p=0.26). Risk of aGVHD was higher in children transplanted in earlier years (1990-1998, n=365) compared to 1999-2003 (OR 1.93 95%CI 1.27-2.91; p=0.002). We conclude that outcomes have changed significantly over time, with reduced risk of aGVHD in more recent transplants.
doi:10.1016/j.bbmt.2008.12.495
PMCID: PMC3365559  PMID: 19203727
14.  Concurrent Change in Dehydroepiandrosterone Sulfate and Functional Performance in the Oldest Old: Results From the Cardiovascular Health Study All Stars Study 
Introduction.
The correlation between dehydroepiandrosterone sulfate (DHEAS) decline and age led to the hypothesis that DHEAS might be a marker of primary aging, though conflicting data from observational studies of mortality do not support this. We evaluated concurrent DHEAS and functional decline in a very old cohort to test if DHEAS change tracks with functional change during aging.
Methods.
DHEAS and functional performance (gait speed, grip strength, Modified Mini-Mental State Examination [3MSE] score, and digit symbol substitution test [DSST] score) were measured in 1996–1997 and 2005–2006 in 989 participants in the Cardiovascular Health Study All Stars study (mean age 85.2 years in 2005–2006, 63.5% women and 16.5% African American). We used multivariable linear regression to test the association of DHEAS decline with functional decline.
Results.
After adjustment, each standard deviation decrease in DHEAS was associated with greater declines in gait speed (0.12 m/s, p = .01), grip strength (0.09 kg, p = .03), 3MSE score (0.13 points, p < .001), and DSST score (0.14 points, p = .001) in women only. Additional adjustment for baseline DHEAS attenuated the association with grip strength but did not alter other estimates appreciably, and baseline DHEAS was unassociated with functional decline.
Conclusions.
In this cohort of very old individuals, DHEAS decline tracked with declines in gait speed, 3MSE score, and DSST score, but not grip strength, in women independent of baseline DHEAS level. DHEAS decline might be a marker for age-associated performance decline, but its relevance is specific to women.
doi:10.1093/gerona/glq072
PMCID: PMC2920580  PMID: 20466773
Aging; Biomarker; Dehydroepiandrosterone sulfate; Function
15.  Carcinogenesis Studies of Cresols in Rats and Mice 
Toxicology  2008;257(1-2):33-39.
Cresols, monomethyl derivatives of phenol, are high production chemicals with potential for human exposure. The three isomeric forms of cresol are used individually or in mixtures as disinfectants, preservatives, and solvents or as intermediates in the production of antioxidants, fragrances, herbicides, insecticides, dyes, and explosives. Carcinogenesis studies were conducted in groups of 50 male F344/N rats and 50 female B6C3F1 mice exposed to a 60:40 mixture of m and p cresols (m-/p-cresol) in feed. Rats and mice were fed diets containing 0, 1500, 5000, or 15,000 ppm and 0, 1000, 3000, or 10,000 ppm, respectively. Survival of each exposed group was similar to that of their respective control group. Mean body weight gains were depressed in rats exposed to 15,000 ppm and in mice exposed to 3000 ppm and higher. A decrease of 25% over that of controls for the final mean body weight in mice exposed to 10,000 ppm appeared to be associated with lack of palatability of the feed. A marginally increased incidence of renal tubule adenoma was observed in the 15,000 ppm-exposed rats. The increased incidence was not statistically significant, but did exceed the range of historical controls. No increased incidence of hyperplasia of the renal tubules was observed; however, a significantly increased incidence of hyperplasia of the transitional epithelium associated with an increased incidence of nephropathy was observed at the high exposure concentration. The only significantly increased incidence of a neoplastic lesion related to cresol exposure observed in these studies was that of squamous cell papilloma in the forestomach of 10,000 ppm-exposed mice. A definitive association with irritation at the site-of-contact could not be made because of limited evidence of injury to the gastric mucosa at the time of necropsy. However, given the minimal chemical-related neoplastic response in these studies, it was concluded that there was no clear evidence of carcinogenicity in male rats or female mice exposed to the cresol mixture.
doi:10.1016/j.tox.2008.12.005
PMCID: PMC2826171  PMID: 19114085
carcinogenicity; cresols; m-cresol; p-cresol; forestomach papilloma; renal tubule adenoma
16.  Disposition of 2,2′,4,4′,5,5′-hexabromodiphenyl ether (BDE153) nd its interaction with other PBDEs in rodents 
The disposition of the 14C-labeled polybrominated diphenyl ether (PBDE), 2,2′,4,4′,5,5′-hexaBDE (BDE153) was investigated in rodents following single and multiple doses and in a mixture with radiolabeled 2,2′,4,4′-tetraBDE (BDE47) and 2,2′,4,4′,5-pentaBDE (BDE99).In single exposure studies, there was little or no effect of dose on BDE153 disposition in male rats in the range of 1–100 µmol/kg. No major sex or species differences in the in vivo fate of BDE153 were detected. BDE153 was: 1) approximately 70% absorbed in rats or mice following gavage. 2) retained in tissues. 3) poorly metabolized and slowly excreted.Mixture studies indicated that, relative to each other, more BDE47 was distributed to adipose tissue, more BDE153 accumulated in liver, and BDE99 was metabolized to the greatest extent. BDE153 was probably retained in liver due to minimal metabolism and elimination after "first pass" distribution to the tissue following gavage.
doi:10.1080/00498250600815906
PMCID: PMC2826160  PMID: 16971346
Polybrominated diphenyl ethers; PBDE; metabolism and disposition; persistent organic pollutants
17.  Plasma levels of soluble interleukin 2 receptor, soluble CD30, interleukin 10 and B cell activator of the tumour necrosis factor family during follow‐up in vasculitis associated with proteinase 3‐antineutrophil cytoplasmic antibodies: associations with disease activity and relapse  
Annals of the Rheumatic Diseases  2006;65(11):1484-1489.
Objectives
To evaluate whether T cell activation, as reflected by levels of soluble interleukin 2 receptor (sIL2R), soluble CD30 (sCD30), IL‐10 and B cell activator of the tumour necrosis factor family (BAFF) at diagnosis and during initial follow‐up, is predictive for persistent or renewed antineutrophil cytoplasmic antibody (ANCA) positivity and clinical relapse in patients with vasculitis associated with proteinase 3‐antineutrophil cytoplasmic antibodies (PR3‐ANCA).
Methods
87 Patients with PR3‐ANCA‐associated vasculitis and at least 2 years of follow‐up were included in the study. At diagnosis, and at 3, 6, 12, 18 and 24 months after diagnosis, cytoplasmic ANCA titres were detected by indirect immunofluorescence (IIF), and PR3‐ANCA, sIL2R, sCD30, IL‐10 and BAFF levels were assessed by ELISA. 31 healthy volunteers provided plasma samples for comparison. Levels of immune markers were related to ANCA positivity and relapse during follow‐up.
Results
Plasma levels of sIL2R, sCD30 and BAFF were higher in patients than in controls at all time points. Plasma levels of sIL2R, sCD30 and IL‐10 were higher at diagnosis and relapse than during remission. At 18 months, sCD30 (p<0.001) and sIL2R levels (p = 0.01) were significantly higher in PR3‐ANCA‐positive patients (detected by ELISA) than in PR3‐ANCA‐negative patients. ANCA‐positive patients detected by ELISA or IIF at 24 months had significantly higher plasma sCD30 levels (p = 0.02 and p = 0.03, respectively) than ANCA‐negative patients.
Conclusion
Increased T cell activation in patients with ANCA‐associated vasculitis in remission during and after immunosuppressive treatment is associated with persistent or renewed ANCA positivity.
doi:10.1136/ard.2005.046219
PMCID: PMC1798350  PMID: 16504995
18.  Heat stroke and 10K “fun runs”: new safety measures are called for 
doi:10.1136/bjsm.2006.030338
PMCID: PMC2465058  PMID: 17021011
19.  Phenotypic and Genotypic Analysis of Enterotoxigenic Escherichia coli in Samples Obtained from Egyptian Children Presenting to Referral Hospitals▿  
Journal of Clinical Microbiology  2008;47(1):189-197.
Hospital surveillance was established in the Nile River Delta to increase the understanding of the epidemiology of diarrheal disease among Egyptian children. Between September 2000 and August 2003, samples obtained from children less than 5 years of age who had diarrhea and who were seeking hospital care were cultured for enteric bacteria. Colonies from each culture with a morphology typical of that of Escherichia coli were tested for the heat-labile (LT) and heat-stable (ST) toxins by a GM-1-specific enzyme-linked immunosorbent assay and colonization factor (CF) antigens by an immunodot blot assay. Enterotoxigenic E. coli (ETEC) isolates were recovered from 320/1,540 (20.7%) children, and ETEC isolates expressing a known CF were identified in 151/320 (47%) samples. ST CFA/I, ST CS6, ST CS14, and LT and ST CS5 plus CS6 represented 75% of the CFs expressed by ETEC isolates expressing a detectable CF. Year-to-year variability in the proportion of ETEC isolates that expressed a detectable CF was observed (e.g., the proportion that expressed CFA/I ranged from 10% in year 1 to 21% in year 3); however, the relative proportions of ETEC isolates expressing a CF were similar over the reporting period. The proportion of CF-positive ETEC isolates was higher among isolates that expressed ST. ETEC isolates expressing CS6 were isolated significantly less often (P < 0.001) than isolates expressing CFA/I in children less than 1 year of age. Macrorestriction profiling of CFA/I-expressing ETEC isolates by using the restriction enzyme XbaI and pulsed-field gel electrophoresis demonstrated a wide genetic diversity among the isolates that did not directly correlate with the virulence of the pathogen. The genome plasticity demonstrated in the ETEC isolates collected in this work suggests an additional challenge to the development of a globally effective vaccine for ETEC.
doi:10.1128/JCM.01282-08
PMCID: PMC2620865  PMID: 18971368
20.  Case Series Study of Traveler's Diarrhea in U.S. Military Personnel at Incirlik Air Base, Turkey▿  
Clinical and Vaccine Immunology : CVI  2008;15(12):1884-1887.
Military personnel with traveler's diarrhea (n = 202) while deployed to Incirlik Air Base, Turkey, from June to September 2002 were evaluated for pathogen-specific immune responses. Serologic and fecal immunoglobulin A (IgA) titers to enterotoxigenic Escherichia coli antigens (CS6, CS3, and LT) were quite low. In contrast, subjects with Campylobacter infections had high serologic and fecal IgA responses.
doi:10.1128/CVI.00163-08
PMCID: PMC2593170  PMID: 18845833
21.  Accelerated atherosclerosis in patients with Wegener's granulomatosis 
Annals of the Rheumatic Diseases  2004;64(5):753-759.
Background: Several autoimmune disorders are complicated by excess cardiovascular disease. In addition to traditional risk factors, non-traditional risk factors such as endothelial activation and excessive vascular remodelling might be determinants of the progression of atherosclerosis in patients with an autoimmune disease.
Objective: To evaluate whether patients with Wegener's granulomatosis (WG) have an increased prevalence of atherosclerosis and to determine predisposing factors.
Methods: 29 WG patients (19 men; mean (SD) age, 53 (14) years) with inactive disease and 26 controls (16 men; age 53 (15) years) were studied. Common carotid intima–media thickness (IMT) was measured by ultrasound. In all individuals traditional risk factors for cardiovascular disease were determined. High sensitivity C reactive protein (hsCRP) was measured. Endothelial activation was assessed by measuring thrombomodulin, vascular cell adhesion molecule-1, and von Willebrand factor. As a marker of vascular remodelling matrix metalloproteinases (MMP-3 and MMP-9) and TIMP-1 were measured.
Results: IMT was increased in WG patients compared with controls (p<0.05). No differences in traditional risk factors and endothelial activation markers between patients and controls were found. Levels of hsCRP, MMPs, and TIMP-1 were increased in WG patients (p<0.05).
Conclusions: Increased IMT found in WG patients cannot be explained by an increased prevalence of traditional risk factors. Although endothelial activation markers in WG patients with inactive disease were not increased, the raised levels of hsCRP, MMPs, and TIMP-1 suggest that enhanced inflammation and excessive vascular remodelling are contributing factors in the development of accelerated atherosclerosis in WG.
doi:10.1136/ard.2004.029033
PMCID: PMC1755479  PMID: 15374854
23.  Impact of angiotensin converting enzyme inhibition on post-coronary artery bypass interleukin 6 release 
Heart  2002;87(3):252-255.
Background: Angiotensin 1 converting enzyme (ACE) inhibitors reduce morbidity and mortality after coronary artery bypass graft surgery (CABG). This benefit may result from an anti-inflammatory action.
Objective: To examine the effect of ACE inhibition on interleukin 6 (IL-6) concentrations after CABG.
Patients and methods: 161 patients undergoing elective first time CABG were recruited, of whom 41 (25%) were receiving ACE inhibitor treatment; 21 patients with confounding postoperative complications were excluded. After these exclusions there were 33 patients (24%) on ACE inhibitor treatment. Plasma IL-6 was measured preoperatively and again six hours after CABG.
Results: Baseline IL-6 concentrations (geometric mean (SEM)) were non-significantly lower among the patients receiving ACE inhibitors (3.7 (0.1) v 4.3 (0.1) pg/ml, p = 0.12). Overall, post-CABG IL-6 concentrations increased significantly (mean rise 177 (12) pg/ml, p < 0.0005). This response was blunted among ACE inhibitor treated patients. Median increases in IL-6 concentrations were 117 v 193 pg/ml, for treated v non-treated patients, respectively (Kruskal–Wallis, p = 0.02), with peak postoperative IL-6 concentrations lower among the subjects receiving ACE inhibitors than in untreated subjects (142 (19) v 196 (13) pg/ml, p = 0.02). The effect of ACE inhibitors remained significant after multivariate analysis (p = 0.018).
Conclusions: ACE inhibitor treatment is associated with a reduction in IL-6 response to CABG. The data suggest that this class of drug may have a direct anti-inflammatory effect, which could explain some of its clinical benefit.
PMCID: PMC1767034  PMID: 11847165
angiotensin converting enzyme; inflammation; interleukin 6; coronary artery bypass graft
24.  A chloride-inducible gene expression cassette and its use in induced lysis of Lactococcus lactis. 
Applied and Environmental Microbiology  1997;63(12):4877-4882.
A chloride-inducible promoter previously isolated from the chromosome of Lactococcus lactis (J. W. Sanders, G. Venema, J. Kok, and K. Leenhouts, Mol. Gen. Genet., in press) was exploited for the inducible expression of homologous and heterologous genes. An expression cassette consisting of the positive-regulator gene gadR, the chloride-inducible promoter Pgad, and the translation initiation signals of gadC was amplified by PCR. The cassette was cloned upstream of Escherichia coli lacZ, the holin-lysin cassette (lytPR) of the lactococcal bacteriophage r1t, and the autolysin gene of L. lactis, acmA. Basal activity of Pgad resulted in a low level of expression of all three proteins. Growth in the presence of 0.5 M NaCl of a strain containing the gadC::lacZ fusion resulted in a 1,500-fold increase of beta-galactosidase activity. The background activity levels of LytPR and AcmA had no deleterious effects on cell growth, but induction of lysin expression by addition of 0.5 M NaCl resulted in inhibition of growth. Lysis was monitored by following the release of the cytoplasmic marker enzyme PepX. Released PepX activity was maximal at 1 day after induction of lytPR expression with 0.1 M NaCl. Induction of acmA expression resulted in slower release of PepX from the cells. The presence of the inducing agent NaCl resulted in the stabilization of osmotically fragile cells.
PMCID: PMC168815  PMID: 9406408
25.  Stress response in Lactococcus lactis: cloning, expression analysis, and mutation of the lactococcal superoxide dismutase gene. 
Journal of Bacteriology  1995;177(18):5254-5260.
In an analysis of the stress response of Lactococcus lactis, three proteins that were induced under low pH culture conditions were detected. One of these was identified as the lactococcal superoxide dismutase (SodA) by N-terminal amino acid sequence analysis. The gene encoding this protein, designated sodA, was cloned by the complementation of a sodA sodB Escherichia coli strain. The deduced amino acid sequence of L. lactis SodA showed the highest degree of similarity to the manganese-containing Sod (MnSod) of Bacillus stearothermophilus. A promoter upstream of the sodA gene was identified by primer extension analysis, and an inverted repeat surrounding the -35 hexanucleotide of this promoter is possibly involved in the regulation of the expression of sodA. The expression of sodA was analyzed by transcriptional fusions with a promoterless lacZ gene. The induction of beta-galactosidase activity occurred in aerated cultures. Deletion experiments revealed that a DNA fragment of more than 130 bp surrounding the promoter was needed for the induction of lacZ expression by aeration. The growth rate of an insertion mutant of sodA did not differ from that of the wild type in standing cultures but was decreased in aerated cultures.
PMCID: PMC177316  PMID: 7665513

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