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1.  Phase II trial of vatalanib in patients with advanced or metastatic pancreatic adenocarcinoma after first-line gemcitabine therapy (PCRT O4-001) 
Vatalanib (PTK 787/ZK22584) is an oral polytyrosine kinase inhibitor with strong affinity for platelet-derived growth factor and vascular endothelial growth factor (VEGF) receptors. We conducted an open-label, phase II multicenter therapeutic trial investigating the efficacy and tolerability of vatalanib in patients with metastatic or advanced pancreatic cancer who failed first-line gemcitabine-based therapy.
Vatalanib treatment consisted of a twice daily oral dosing using a “ramp-up schedule,” beginning with 250 mg bid during week 1,500 mg bid during week 2, and 750 mg bid on week three and thereafter. the primary objective of this study was to evaluate the 6-month survival rate.
Sixty-seven patients were enrolled. The median age was 64, and 66 %(N = 43) had only one prior regimen. Common grade 3/4 adverse events included hypertension (20 %; N = 13), fatigue (17 %; N = 11), abdominal pain (17 %; N = 11), and elevated alkaline phosphatase (15 %; N = 10). among the 65 evaluable patients, the 6-month survival rate was 29 % (95 % CI 18–41 %) and the median progression-free survival was 2 months. Fifteen patients survived 6 months or more. two patients had objective partial responses, and 28 % of patients had stable disease. Changes in biomarkers including soluble VEGF and vascular endothelial growth factor receptor did not correlate with response to drug.
Vatalanib was well tolerated as a second-line therapy and resulted in favorable 6-month survival rate in patients with metastatic pancreatic cancer, compared with historic controls.
PMCID: PMC4461053  PMID: 24939212
Vatalinib; Pancreatic adenocarcinoma; Tyrosine kinase inhibitor; Second-line treatment
2.  Prospective study of infantile hemangiomas: Incidence, clinical characteristics, and association with placental anomalies 
The British journal of dermatology  2014;170(4):907-913.
Background and Objective
The etiology and exact incidence of infantile hemangiomas (IH) are unknown. Prior studies have noted immunohistochemical and biologic characteristics shared by IH and placental tissue. We investigated the possible association between placental anomalies and the development of IH, as well as the demographic characteristics and other risk factors for IH.
578 pregnant women were prospectively enrolled and their offspring followed for 9 months. Placental evaluations were performed and demographic data collected on all mother-infant pairs.
594 infants were evaluated: 32 hemangiomas (either IH or congenital (CH)) were identified in 27 infants, yielding an incidence of 4.5% for IH and 0.3% for CH. Placental anomalies were noted in almost 35% of hemangioma-related pregnancies, approximately twice the incidence noted in pregnancies with unaffected infants. (p = 0.025). Other risk factors for IH included prematurity (p = 0.016) and low birth weight (p = 0.028). All IH were present by 3 months of age, and cessation of growth had occurred in all by 9 months of age. Most occurred on the trunk. Of note, 20% of identified IH were abortive/telangiectatic in nature, small focal lesions that did not proliferate beyond 3 months of age. Only one IH required intervention.
This is the first prospective American study to document the incidence of IH in infants followed from birth to early infancy. The association with placental anomalies was statistically significant. The overall incidence mirrors prior estimates, but the need for treatment was lower than previously reported.
PMCID: PMC4410180  PMID: 24641194
infantile hemangioma; congenital hemangioma; abortive/telangiectatic hemangioma; placental anomalies
3.  Childhood correlates of adult TV viewing time: a 32-year follow-up of the 1970 British Cohort Study 
To identify, using a longitudinal data set, parental and childhood correlates of adult television (TV) viewing time at 32-year follow-up.
Data were derived from the 1970 British Cohort Study, a longitudinal observational study of 17 248 British people born in a single week of 1970. The present analyses incorporated data from the age 10 and 42-year surveys. When participants were aged 10 years, their mothers provided information on how often participants watched TV and played sports (never/sometimes/often), and parents’ own occupation, as well as height and weight. A health visitor objectively assessed participants’ height and weight at age 10. Thirty-two years later, when participants were aged 42 years, they reported their daily TV viewing hours (none/0≤1/1<3/3<5/≥5), physical activity and health status. Associations between putative childhood and parental correlates and adult TV viewing time were investigated using logistic regression.
Valid data at both time points were available for 6188 participants. Logistic regression models showed that those who reported ‘often’ watching TV at baseline were significantly more likely to watch >3 h/days of TV at follow-up (OR 1.42, 95% CI 1.21 to 1.65), as were those whose father was from a lower socio-occupational class (intermediate, routine/manual) compared with managerial (OR 1.55, 95% CI 1.14 to 2.11; OR 2.05, 95% CI 1.47 to 2.87). Body mass index (BMI) at age 10 was inversely associated with high TV in adulthood (per unit increase; OR 0.93, 95% CI 0.90 to 0.96) although fathers BMI when the child was aged 10 was positively associated with high TV in adulthood (per unit increase; OR 1.04, 95% CI 1.02 to 1.06).
Findings suggest that childhood TV viewing time tracks into adulthood. Parents’ health behaviours and social position appear to be associated with their children's viewing habits, which may have important implications for the direction of future policy and practice. Specifically, findings support the case for early life interventions, particularly on socioeconomic inequalities, as a way of preventing sedentary behaviour in later life.
PMCID: PMC4392198  PMID: 25147213
4.  Establishing a clinic-based pancreatic cancer and periampullary tumour research registry in Quebec 
Current Oncology  2015;22(2):113-121.
Enrolling patients in studies of pancreatic ductal adenocarcinoma (pdac) is challenging because of the high fatality of the disease. We hypothesized that a prospective clinic-based study with rapid ascertainment would result in high participation rates. Using that strategy, we established the Quebec Pancreas Cancer Study (qpcs) to investigate the genetics and causes of pdac and other periampullary tumours (pats) that are also rare and underrepresented in research studies.
Patients diagnosed with pdac or pat were introduced to the study at their initial clinical encounter, with a strategy to enrol participants within 2 weeks of diagnosis. Patient self-referrals and referrals of unaffected individuals with an increased risk of pdac were also accepted. Family histories, epidemiologic and clinical data, and biospecimens were collected. Additional relatives were enrolled in families at increased genetic risk.
The first 346 completed referrals led to 306 probands being enrolled, including 190 probands affected with pdac, who represent the population focus of the qpcs. Participation rates were 88.4% for all referrals and 89.2% for pdac referrals. Family history, epidemiologic and clinical data, and biospecimens were ascertained from 91.9%, 54.6%, and 97.5% respectively of patients with pdac. Although demographics and trends in risk factors in our patients were consistent with published statistics for patients with pdac, the qpcs is enriched for families with French-Canadian ancestry (37.4%), a population with recurrent germ-line mutations in hereditary diseases.
Using rapid ascertainment, a pdac and pat research registry with high participation rates can be established. The qpcs is a valuable research resource and its enrichment with patients of French-Canadian ancestry provides a unique opportunity for studies of heredity in these diseases.
PMCID: PMC4399608  PMID: 25908910
Pancreatic cancer; periampullary tumours; research registry; cancer genetics; translational research
5.  Bacterial and fungal pattern recognition receptors in homologous innate signaling pathways of insects and mammals 
In response to bacterial and fungal infections in insects and mammals, distinct families of innate immune pattern recognition receptors (PRRs) initiate highly complex intracellular signaling cascades. Those cascades induce a variety of immune functions that restrain the spread of microbes in the host. Insect and mammalian innate immune receptors include molecules that recognize conserved microbial molecular patterns. Innate immune recognition leads to the recruitment of adaptor molecules forming multi-protein complexes that include kinases, transcription factors, and other regulatory molecules. Innate immune signaling cascades induce the expression of genes encoding antimicrobial peptides and other key factors that mount and regulate the immune response against microbial challenge. In this review, we summarize our current understanding of the bacterial and fungal PRRs for homologous innate signaling pathways of insects and mammals in an effort to provide a framework for future studies.
PMCID: PMC4309185  PMID: 25674081
recognition receptors; innate immunity; immune signaling; insects; mammals; pathogens
6.  Pharmacokinetics of a controlled-release liposome-encapsulated hydromorphone administered to healthy dogs 
The purpose of the study was to assess the pharmacokinetics of liposome-encapsulated (DPPC-C) hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs. A total of eight healthy Beagles aged 12.13 ± 1.2 months and weighing 11.72 ± 1.10 kg were used. Dogs randomly received liposome encapsulated hydromorphone, 0.5 mg/kg IV (n = 6), 1.0 mg/kg (n = 6), 2.0 mg/kg (n = 6), or 3.0 mg/kg (n = 7) SC with a 14–28 day washout between trials. Blood was sampled at serial intervals after drug administration. Serum hydromorphone concentrations were measured using liquid chromatography with mass spectrometry. Serum concentrations of hydromorphone decreased rapidly after IV administration of the DPPC-C formulation (half-life = 0.52 h, volume of distribution = 12.47 L/kg, serum clearance = 128.97 mL/min/kg). The half-life of hydromorphone after SC administration of DPPC-C formulation at 1.0, 2.0, and 3.0 mg/kg was 5.22, 31.48, and 24.05 h, respectively. The maximum serum concentration normalized for dose (CMAX/D) ranged between 19.41–24.96 ng/mL occurring at 0.18–0.27 h. Serum hydromorphone concentrations fluctuated around 4.0 ng/mL from 6–72 h after 2.0 mg/kg and mean concentrations remained above 4 ng/mL for 96 h after 3.0 mg/kg DPPC-C hydromorphone. Liposome-encapsulated hydromorphone (DPPC-C) administered SC to healthy dogs provided a sustained duration of serum hydromorphone concentrations.
PMCID: PMC4240744  PMID: 19000260
7.  A comparison of the effects of hydromorphone HCl and a novel extended release hydromorphone on arterial blood gas values in conscious healthy dogs 
Research in veterinary science  2009;88(1):154-158.
The purpose of this study was to evaluate arterial blood gases in dogs that were given hydromorphone or extended release liposome-encapsulated hydromorphone (LEH). Dogs were randomly administered LEH, n = 6, (2.0 mg kg−1), hydromorphone, n = 6, (0.2 mg kg−1) or a placebo of blank liposomes, n = 3, subcutaneously on separate occasions. Arterial blood samples were drawn at serial time points over a 6-h time period for blood gas analysis. There was no change from baseline values in PaCO2, PaO2, (HCO3−), pH, and SBEc in the dogs that received the placebo. Administration of hydromorphone resulted in significant increases in PaCO2 (maximum (mean + SD] 44.4 + 1.1 mm of Hg) and significant decreases in PaCO2 (minimum (mean + SD) 82.4 + 4.7 mm of Hg) and pH (minimum (mean + SD) 7.31 + 0.01) compared with baseline. Administration of LEH resulted in significant increases in PaCO2 (maximum (mean + SD) 44.6 + 0.9 mm of Hg) and significant decreases in PaO2 (minimum (mean + SD) 84.8 + 2.6 mm of Hg) and pH (minimum (mean + SD) 7.34 + 0.02) compared with baseline. There was no significant difference between these two groups at any time point. The changes observed in PaCO2, PaO2, and pH, however, were within clinically acceptable limits for healthy dogs. LEH was determined to cause moderate changes in arterial blood gas values similar to those caused by hydromorphone.
PMCID: PMC4235959  PMID: 19692102
Hydromorphone; Extended release; Liposome; Dog; Hypercapnia; Hypoxemia
8.  The association between objectively measured sitting and standing with body composition: a pilot study using MRI 
BMJ Open  2014;4(6):e005476.
To investigate the association between objectively measured sitting and standing, using a postural allocation technique, with MRI-assessed body composition.
The present study was a cross-sectional pilot study.
Participants were examined at one centre located in London, UK.
Normal weight Caucasian women (30.9±6.1 years; body mass index (BMI), 22.9±3.4 kg/m2) with desk-bound occupations were recruited to minimise variability in body composition outcomes. A convenience sample of 12 women was recruited in January 2014 from University College London.
Outcome measures
For each participant a number of body composition variables were attained from a single whole-body MRI session. Main outcome variables included: total and liver adiposity, visceral/subcutaneous fat ratio and BMI. Main exposure variables included: average sitting time, standing:sitting ratio and step count. Pearson correlations were carried out to examine associations between different activity categories and body composition variables.
There were significant correlations between average daily sitting and liver adiposity and visceral/subcutaneous abdominal fat ratio (r=0.66 and 0.64, respectively); standing:sitting ratio was moderately correlated with liver adiposity and visceral/subcutaneous abdominal fat ratio (r=−0.53 and −0.45); average daily step count was moderately correlated with liver adiposity, total adiposity and visceral/subcutaneous abdominal fat ratio (r=−0.45, −0.46 and −0.51, respectively).
This pilot study has provided preliminary evidence of relationships between objectively measured sitting and standing and precise measures of body composition.
PMCID: PMC4067859  PMID: 24916091
Preventive Medicine; Public Health
9.  Non-contact ultra-widefield imaging of retinopathy of prematurity using the Optos dual wavelength scanning laser ophthalmoscope 
Eye  2013;27(5):589-596.
The purpose of this report is to demonstrate that a non-contact ultra-widefield dual wavelength laser camera (Optos) is able to capture high-quality images in retinopathy of prematurity (ROP).
Materials and methods
We conducted a retrospective review of patients attending the Oxford Eye Hospital with ROP between 1 August 2012 and 16 November 2012 that underwent standard clinical assessment. Anterior segment imaging, where relevant, was performed with Retcam. Retinal imaging was then performed with Optos, using a modified ‘flying baby position'.
The Optos scanning laser ophthalmoscope was able to acquire ultra-widefield fundal images in nine ROP subjects. The images obtained show clear views of the different stages of ROP features at the posterior pole and peripheral retina. Regression of ROP features were identified, following laser and intravitreal bevacizumab treatment. Additionally, ‘skip areas' missed by initial laser treatment could be identified in the peripheral retina.
The Optos ultra-widefield scanning laser ophthalmoscope is capable of acquiring clinically useful high-quality images of the fundus in ROP subjects. The imaging technique could potentially be used in monitoring ROP progression and documenting ROP regression following treatment.
PMCID: PMC3650286  PMID: 23519279
retinopathy of prematurity; ultra-widefield imaging; Optos
10.  Computer-aided quantification of retinal neovascularization 
Angiogenesis  2009;12(3):297-301.
Rodent models of retinal angiogenesis play a pivotal role in angiogenesis research. These models are a window to developmental angiogenesis, to pathological retinopathy, and are also in vivo tools for anti-angiogenic drug screening in cancer and ophthalmic research. The mouse model of oxygen-induced retinopathy (OIR) has emerged as one of the leading in vivo models for these purposes. Many of the animal studies that laid the foundation for the recent breakthrough of anti-angiogenic treatments into clinical practice were performed in the OIR model. However, readouts from the OIR model have been time-consuming and can vary depending on user experience. Here, we present a computer-aided quantification method that is characterized by (i) significantly improved efficiency, (ii) high correlation with the established hand-measurement protocols, and (iii) high intra-and inter-individual reproducibility of results. This method greatly facilitates quantification of retinal angiogenesis while at the same time increasing lab-to-lab reproducibility of one of the most widely used in vivo models in angiogenesis research.
PMCID: PMC4005267  PMID: 19757106
Oxygen-induced retinopathy; OIR; Retina; Neovascularization; Quantification; SWIFT_NV
11.  Efficacy of increased resistant starch consumption in human type 2 diabetes 
Endocrine Connections  2014;3(2):75-84.
Resistant starch (RS) has been shown to beneficially affect insulin sensitivity in healthy individuals and those with metabolic syndrome, but its effects on human type 2 diabetes (T2DM) are unknown. This study aimed to determine the effects of increased RS consumption on insulin sensitivity and glucose control and changes in postprandial metabolites and body fat in T2DM. Seventeen individuals with well-controlled T2DM (HbA1c 46.6±2 mmol/mol) consumed, in a random order, either 40 g of type 2 RS (HAM-RS2) or a placebo, daily for 12 weeks with a 12-week washout period in between. At the end of each intervention period, participants attended for three metabolic investigations: a two-step euglycemic–hyperinsulinemic clamp combined with an infusion of [6,6-2H2] glucose, a meal tolerance test (MTT) with arterio-venous sampling across the forearm, and whole-body imaging. HAM-RS2 resulted in significantly lower postprandial glucose concentrations (P=0.045) and a trend for greater glucose uptake across the forearm muscle (P=0.077); however, there was no effect of HAM-RS2 on hepatic or peripheral insulin sensitivity, or on HbA1c. Fasting non-esterified fatty acid (NEFA) concentrations were significantly lower (P=0.004) and NEFA suppression was greater during the clamp with HAM-RS2 (P=0.001). Fasting triglyceride (TG) concentrations and soleus intramuscular TG concentrations were significantly higher following the consumption of HAM-RS2 (P=0.039 and P=0.027 respectively). Although fasting GLP1 concentrations were significantly lower following HAM-RS2 consumption (P=0.049), postprandial GLP1 excursions during the MTT were significantly greater (P=0.009). HAM-RS2 did not improve tissue insulin sensitivity in well-controlled T2DM, but demonstrated beneficial effects on meal handling, possibly due to higher postprandial GLP1.
PMCID: PMC3987287  PMID: 24671124
euglycemic–hyperinsulinemic clamp; GLP1; flux; stable isotopes
12.  Breast cancer subtypes: response to radiotherapy and potential radiosensitisation 
The British Journal of Radiology  2013;86(1023):20120601.
Radiotherapy (RT) is of critical importance in the locoregional management of early breast cancer. Over 50% of patients receive RT at some time during the treatment of their disease, equating to over 500 000 patients worldwide receiving RT each year. Unfortunately, not all patients derive therapeutic benefit and some breast cancers are resistant to treatment, as evidenced by distant metastatic spread and local recurrence. Prediction of individual responses to RT may allow a stratified approach to this treatment permitting those patients with radioresistant tumours to receive higher doses of RT (total and/or tumour cavity boost doses) and/or radiosensitising agents to optimise treatment. Also, for those patients unlikely to respond at all, it would prevent harmful side effects occurring for no therapeutic gain. More selective targeting would better direct National Health Service resources, ease the burden on heavily used treatment RT machines and reduce the economic cost of cancer treatment. Unfortunately, there are no robust and validated biomarkers for predicting RT outcome. We review the available literature to determine whether classification of breast cancers according to their molecular profile may be used to predict successful response to, or increased morbidity from, RT. Class-specific biomarkers for targeting by radiosensitising agents are also discussed.
PMCID: PMC3608055  PMID: 23392193
13.  Review of Brucellosis Cases from Laboratory Exposures in the United States in 2008 to 2011 and Improved Strategies for Disease Prevention 
Journal of Clinical Microbiology  2013;51(9):3132-3136.
Five laboratory-acquired brucellosis (LAB) cases that occurred in the United States between 2008 and 2011 are presented. The Centers for Disease Control and Prevention (CDC) reviewed the recommendations published in 2008 and the published literature to identify strategies to further prevent LAB. The improved prevention strategies are described.
PMCID: PMC3754678  PMID: 23824776
14.  Oral Cavity Squamous Cell Carcinoma - Characteristics and Survival in Aboriginal and Non-Aboriginal Western Australians 
The Open Dentistry Journal  2014;8:168-174.
Squamous cell carcinoma (SCC) is the most common type of malignancy affecting the oral cavity. While exposures to main risk factors for oral SCC such as smoking and alcohol use are higher amongst the Aboriginal people, little is known about oral cancer in this population. This study aimed to describe characteristics and survival of oral SCC in Aboriginal and non-Aboriginal Western Australians.
All primary oral SCC cases reported to the Western Australian Cancer Registry (WACR) between 1990 and 1999 were analysed with respect to person characteristics including: date of birth, sex and indigenous status; and disease characteristics including: date of biopsy, disease stage and site as well as date of recurrence and date of death. Exclusion criteria included diagnosis not based on incisional or excisional biopsy, diagnosis other than oral SCC or a history of another malignant neoplasm.
Aboriginal individuals were more likely to reside in rural areas. No statistically significant differences in oral SCC characteristics and survival were noted between Aboriginal and non-Aboriginal Western Australians.
This study provides new information on person and disease characteristics of Aboriginal Western Australians diagnosed with oral SCC.
PMCID: PMC4200744  PMID: 25328552
Aboriginality; epidemiology; oral cancer; survival analysis.
15.  A mechanism of benefit of soy genistein in asthma: inhibition of eosinophil p38-dependent leukotriene synthesis 
Dietary intake of the soy isoflavone genistein is associated with reduced severity of asthma, but the mechanisms responsible for this effect are unknown.
To determine whether genistein blocks eosinophil leukotriene C4 (LTC4) synthesis and to evaluate the mechanism of this effect, and to assess the impact of a 4-week period of soy isoflavone dietary supplementation on indices of eosinophilic inflammation in asthma patients.
Human peripheral blood eosinophils were stimulated in the absence and presence of genistein, and LTC4 synthesis was measured. 5-lipoxygenase (5-LO) nuclear membrane translocation was assessed by confocal immunofluorescence microscopy. Mitogen-activated protein (MAP) kinase activation was determined by immunoblot. Human subjects with mild-to-moderate persistent asthma and minimal or no soy intake were given a soy isoflavone supplement (100 mg/day) for 4 weeks. The fraction of exhaled nitric oxide (FENO) and ex vivo eosinophil LTC4 production were assessed before and after the soy isoflavone treatment period.
Genistein inhibited eosinophil LTC4 synthesis (IC50 80 nm), blocked phosphorylation of p38 MAP kinase and its downstream target MAPKAP-2, and reduced translocation of 5-LO to the nuclear membrane. In patients with asthma, following 4 weeks of dietary soy isoflavone supplementation, ex vivo eosinophil LTC4 synthesis decreased by 33% (N = 11, P = 0.02) and FENO decreased by 18% (N = 13, P = 0.03).
At physiologically relevant concentrations, genistein inhibits eosinophil LTC4 synthesis in vitro, probably by blocking p38- and MAPKAP-2-dependent activation of 5-LO. In asthma patients, dietary soy isoflavone supplementation reduces eosinophil LTC4 synthesis and eosinophilic airway inflammation. These results support a potential role for soy isoflavones in the treatment of asthma.
PMCID: PMC3873088  PMID: 17979994
asthma; eosinophils; genistein; 5-lipoxygenase; soy isoflavones
16.  Physiological effects of housing density on C57BL/6J mice over a 9-month period1 
Journal of animal science  2012;90(13):5182-5192.
The National Research Council has consistently recommended housing densities for animals used in science and agriculture. For mice, the recommended density is 77.4 cm2 (12 in2) for a 15–25 gm mouse. The Council noted that its recommendations were based on “best professional judgment” and encouraged alternatives that were data driven. As part of a continual effort of The Jackson Laboratory to ensure the health and well-being of production and research mice while promoting cost-effective, state-of-the-art research, several density-driven studies have been conducted by lab researchers. The objectives of this study were to determine the effect of housing density on parameters related to mouse physiology and air quality in the cages and to assess the value of specific measured parameters in such studies. The study discussed in this report monitored C57BL/6J mice in individually ventilated cages from weaning until 9 months of age. Housing densities were equivalent to 66.4 and 36.8 cm2/mouse (10.3 and 5.7 in2), representing increases in density of 17% and 110%, respectively, over the National Research Council recommendation. Clinical physiological parameters representing general health and well-being were measured. Hematological traits, plasma lipids and glucose, growth, bone mineral density and percent body fat did not differ between densities. In the more densely housed mice, however, adrenal glands were significantly smaller, heart rates were significantly lower, and food consumption was less. Cage air microenvironment was evaluated for ammonia, carbon dioxide, temperature and humidity in cages changed weekly or every 2 weeks. The cage microenvironment remained within acceptable limits at the higher density of mice at both cage-changing frequencies. The results suggest that mice housed in individually ventilated cages for up to 9 months at up to twice the density currently recommended by the National Research Council show no measurable adverse effects. Continued re-evaluation of the recommendation by measuring additional relevant parameters of health and general well-being and studying additional strains is warranted.
PMCID: PMC3561486  PMID: 22952366
adrenal weight; animal husbandry; cage air microenvironment; heart rate; mouse housing density; animal well-being
17.  Effects of Valproic Acid on Organic Acid Metabolism in Children: A Metabolic Profiling Study 
Clinical pharmacology and therapeutics  2011;89(6):10.1038/clpt.2011.47.
Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a measure of mitochondrial function, were obtained in children 3.5 to 17.3 years old treated for seizure disorders with valproic acid (VPA; n=52). Age-matched patients treated with carbamazepine (CBZ; n=50) and untreated healthy children (n=22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although untreated and CBZ control subjects were not distinguished by the principal component analysis (PCA) scores plot, a distinct boundary was apparent between the VPA and control/CBZ groups. Inter-individual variability in VPA-induced alterations in endogenous pathways reflecting branched chain amino acid metabolism and oxidative stress was observed. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity.
PMCID: PMC3822904  PMID: 21544075
18.  Genomic Insights into the Immune System of the Sea Urchin 
Science (New York, N.Y.)  2006;314(5801):952-956.
Comparative analysis of the sea urchin genome has broad implications for the primitive state of deuterostome host defense and the genetic underpinnings of immunity in vertebrates. The sea urchin has an unprecedented complexity of innate immune recognition receptors relative to other animal species yet characterized. These receptor genes include a vast repertoire of 222 Toll-like receptors, a superfamily of more than 200 NACHT domain–leucine-rich repeat proteins (similar to nucleotide-binding and oligomerization domain (NOD) and NALP proteins of vertebrates), and a large family of scavenger receptor cysteine-rich proteins. More typical numbers of genes encode other immune recognition factors. Homologs of important immune and hematopoietic regulators, many of which have previously been identified only from chordates, as well as genes that are critical in adaptive immunity of jawed vertebrates, also are present. The findings serve to underscore the dynamic utilization of receptors and the complexity of immune recognition that may be basal for deuterostomes and predicts features of the ancestral bilaterian form.
PMCID: PMC3707132  PMID: 17095692
19.  A Review of the Elements of Human Well-Being with an Emphasis on the Contribution of Ecosystem Services 
Ambio  2012;41(4):327-340.
Natural ecosystems perform fundamental life-support services upon which human civilization depends. However, many people believe that nature provides these services for free and therefore, they are of little or no value. While we do not pay for them, we pay significantly for their loss in terms of wastewater treatment facilities, moratoriums on greenhouse gases, increased illnesses, reduced soil fertility and losses in those images of nature that contribute to our basic happiness. Little is understood about the well-being benefits of the natural environment and its ecosystem services. The interwoven relationship of ecosystems and human well-being is insufficiently acknowledged in the wider philosophical, social, and economic well-being literature. In this article, we discuss an approach to examine human well-being and the interactions of its four primary elements—basic human needs, economic needs, environmental needs, and subjective well-being—and ecosystem services.
PMCID: PMC3393065  PMID: 22581385
Ecosystem services; Human well-being; Sustainability; Ecological economics; Subjective happiness
20.  Aggregation of Sea Urchin Phagocytes Is Augmented In Vitro by Lipopolysaccharide 
PLoS ONE  2013;8(4):e61419.
Development of protocols and media for culturing immune cells from marine invertebrates has not kept pace with advancements in mammalian immune cell culture, the latter having been driven by the need to understand the causes of and develop therapies for human and animal diseases. However, expansion of the aquaculture industry and the diseases that threaten these systems creates the need to develop cell and tissue culture methods for marine invertebrates. Such methods will enable us to better understand the causes of disease outbreaks and to develop means to avoid and remedy epidemics. We report a method for the short-term culture of phagocytes from the purple sea urchin, Strongylocentrotus purpuratus, by modifying an approach previously used to culture cells from another sea urchin species. The viability of cultured phagocytes from the purple sea urchin decreases from 91.6% to 57% over six days and phagocyte morphology changes from single cells to aggregates leading to the formation of syncytia-like structures. This process is accelerated in the presence of lipopolysaccharide suggesting that phagocytes are capable of detecting this molecular pattern in culture conditions. Sea urchin immune response proteins, called Sp185/333, are expressed on the surface of a subset of phagocytes and have been associated with syncytia-like structures. We evaluated their expression in cultured phagocytes to determine their possible role in cell aggregation and in the formation of syncytia-like structures. Between 0 and 3 hr, syncytia-like structures were observed in cultures when only ∼10% of the cells were positive for Sp185/333 proteins. At 24 hr, ∼90% of the nuclei were Sp185/333-positive when all of the phagocytes had aggregated into syncytia-like structures. Consequently, we conclude that the Sp185/333 proteins do not have a major role in initiating the aggregation of cultured phagocytes, however the Sp185/333 proteins are associated with the clustered nuclei within the syncytia-like structures.
PMCID: PMC3629189  PMID: 23613847
21.  Cenozoic climate change and diversification on the continental shelf and slope: evolution of gastropod diversity in the family Solariellidae (Trochoidea) 
Ecology and Evolution  2013;3(4):887-917.
Recent expeditions have revealed high levels of biodiversity in the tropical deep-sea, yet little is known about the age or origin of this biodiversity, and large-scale molecular studies are still few in number. In this study, we had access to the largest number of solariellid gastropods ever collected for molecular studies, including many rare and unusual taxa. We used a Bayesian chronogram of these deep-sea gastropods (1) to test the hypothesis that deep-water communities arose onshore, (2) to determine whether Antarctica acted as a source of diversity for deep-water communities elsewhere and (3) to determine how factors like global climate change have affected evolution on the continental slope. We show that although fossil data suggest that solariellid gastropods likely arose in a shallow, tropical environment, interpretation of the molecular data is equivocal with respect to the origin of the group. On the other hand, the molecular data clearly show that Antarctic species sampled represent a recent invasion, rather than a relictual ancestral lineage. We also show that an abrupt period of global warming during the Palaeocene Eocene Thermal Maximum (PETM) leaves no molecular record of change in diversification rate in solariellids and that the group radiated before the PETM. Conversely, there is a substantial, although not significant increase in the rate of diversification of a major clade approximately 33.7 Mya, coinciding with a period of global cooling at the Eocene–Oligocene transition. Increased nutrients made available by contemporaneous changes to erosion, ocean circulation, tectonic events and upwelling may explain increased diversification, suggesting that food availability may have been a factor limiting exploitation of deep-sea habitats. Tectonic events that shaped diversification in reef-associated taxa and deep-water squat lobsters in central Indo-West Pacific were also probably important in the evolution of solariellids during the Oligo-Miocene.
PMCID: PMC3631403  PMID: 23610633
Biogeography; deep sea; Eocene–Oligocene transition; phylogeny
22.  Decreased dopamine activity predicts relapse in methamphetamine abusers 
Molecular psychiatry  2011;17(9):918-925.
Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with PET and [11C]raclopride in sixteen METH abusers both after placebo and after challenge with 60 mg oral methylphenidate (to measure DA release) to assess if it predicted clinical outcomes. For this purpose METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The 6 METH abusers who relapsed during the follow up period had lower D2R availability in dorsal striatum than controls and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal dopamine changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.
PMCID: PMC3261322  PMID: 21747399
methamphetamine; dopamine release; positron emission tomography; relapse; early withdrawal
24.  Primary cervical cancer screening with HPV testing compared with liquid-based cytology: results of round 1 of a randomised controlled trial – the HPV FOCAL Study 
British Journal of Cancer  2012;107(12):1917-1924.
Round 1 data of human papillomavirus (HPV) FOCAL, a three-arm, randomised trial, which aims to establish the efficacy of HPV DNA testing as a primary screen for cervical cancer, are presented.
The three arms are: Control arm – liquid based cytology with atypical squamous cells of unknown significance (ASC-US) triage with hrHPV testing; Intervention Arm – hrHPV at entry with liquid-based cytology (LBC) triage of hrHPV positives, with exit screen at 4 years; Safety check arm – hrHPV at entry with LBC triage of hrHPV positives with exit screen at 2 years.
A total of 6154 women were randomised to the control arm and 12 494 to the HPV arms (intervention and safety check). In the HPV arm, the baseline cervical intraepithelial neoplasia (CIN)2+ and CIN3+ rate was 9.2/1000 (95%CI; 7.4, 10.9) and 4.8/1000 (95%CI; 3.6, 6.1), which increased to 16.1/1000 (95%CI 13.2, 18.9) for CIN2+ and to 8.0/1000 (95%CI; 5.9, 10.0) for CIN3+ after subsequent screening of HPV-DNA-positive/cytology-negative women. Detection rate in the control arm remained unchanged after subsequent screening of ASC-US-positive/hrHPV DNA-negative women at 11.0/1000 for CIN2+ and 5.0/1000 for CIN3+.
After subsequent screening of women who were either hrHPV positive/cytology negative or ASC-US positive/HPV negative, women randomised to the HPV arms had increased CIN2+ detection compared with women randomised to the cytology arm.
PMCID: PMC3516684  PMID: 23169286
HPV; cervical cancer; screening; randomised trial; North America
25.  Clinical severity and quality of life in children and adolescents with Rett syndrome 
Neurology  2011;77(20):1812-1818.
The clinical features and genetics of Rett syndrome (RTT) have been well studied, but examination of quality of life (QOL) is limited. This study describes the impact of clinical severity on QOL among female children and adolescents with classic RTT.
Cross-sectional and longitudinal analyses were conducted on data collected from an NIH-sponsored RTT natural history study. More than 200 participants from 5 to 18 years of age with classic RTT finished their 2-year follow-up at the time of analysis. Regression models after adjustment for their MECP2 mutation type and age at enrollment were used to examine the association between clinical status and QOL.
Severe clinical impairment was highly associated with poor physical QOL, but worse motor function and earlier age at onset of RTT stereotypies were associated with better psychosocial QOL; conversely, better motor function was associated with poorer psychosocial QOL.
Standard psychosocial QOL assessment for children and adolescents with RTT differs significantly with regard to their motor function severity. As clinical trials in RTT emerge, the Child Health Questionnaire 50 may represent one of the important outcome measures.
PMCID: PMC3233210  PMID: 22013176

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