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1.  Impact of Fitness Versus Obesity on Routinely Measured Cardiometabolic Risk in Young, Healthy Adults 
The American journal of cardiology  2013;111(7):991-995.
Obesity demonstrates a direct relation with cardiovascular risk and all-cause mortality, while cardiorespiratory fitness demonstrates an inverse relation. In clinical practice, several cardiometabolic (“CM”) risk factors are commonly measured to gauge cardiovascular risk yet the interaction between fitness and obesity with regard CM risk has not been fully explored. We studied 2,634 Brazilian adults referred for an employer-sponsored heath exam. Obesity was defined as BMI >30 kg/m2 or waist circumference > 102cm (men) or >88cm (women) when BMI 25–30kg/m2. Fitness was quantified by stage achieved on an Ellestad treadmill stress test, with those completing stage 4 considered fit. Hepatic steatosis was determined by ultrasound. We compared CM risk factors after stratifying patients into 4 groups: fit/normal weight, fit/obese, unfit/normal weight & unfit/obese. Approximately 22% of patients were obese; 12% were unfit. Fitness and obesity were moderately correlated (ρ=0.38–50). 6.5% of the sample was unfit/normal weight, and 16% fit/obese. In overweight and obese patients, fitness was negatively associated with CM risk (p<0.01 for all values). In fit patients, increasing BMI was positively associated with CM risk (p<0.01 for all values). In instances of discordance between fitness and obesity, obesity was the stronger determinant of CM risk. Fitness and obesity are independently associated with CM risk. The effects of fitness and obesity are additive but obesity is more strongly associated with CM risk when fitness and obesity are discordant. These findings underscore the need for weight loss in obese individuals and suggest an unmeasured benefit of fitness.
PMCID: PMC3697077  PMID: 23340029
fitness; obesity; metabolic syndrome; liver fat; inflammation
3.  Increased Incidence of Tuberculosis in Zimbabwe, in Association with Food Insecurity, and Economic Collapse: An Ecological Analysis 
PLoS ONE  2014;9(2):e83387.
Zimbabwe underwent a socioeconomic crisis and resultant increase in food insecurity in 2008–9. The impact of the crisis on Tuberculosis (TB) incidence is unknown.
Prospective databases from two mission hospitals, which were geographically widely separated, and remained open during the crisis, were reviewed.
At the Howard Hospital (HH) in northern Zimbabwe, TB incidence increased 35% in 2008 from baseline rates in 2003–2007 (p<0.01) and remained at that level in 2009. Murambinda Hospital (MH) in Eastern Zimbabwe also demonstrated a 29% rise in TB incidence from 2007 to 2008 (p<0.01) and remained at that level in 2009. Data collected post-crisis at HH showed a decrease of 33% in TB incidence between 2009 to 2010 (p<0.001) and 2010/2011 TB incidence remained below that of the crisis years of 2008/2009 (p<0.01). Antenatal clinic HIV seroprevalence at HH decreased between 2001(23%) to 2011(11%) (p<0.001). Seasonality of TB incidence was analyzed at both MH and HH. There was a higher TB incidence in the dry season when food is least available (September-November) compared to post harvest (April-June) (p<0.001).
This study suggests that an epidemic of TB mirrored socioeconomic collapse and recovery in Zimbabwe. The seasonal data suggests that food security may have been associated with TB incidence both annually and during the crisis in this high HIV prevalence country.
PMCID: PMC3914787  PMID: 24505245
4.  CF102 for the Treatment of Hepatocellular Carcinoma: A Phase I/II, Open-Label, Dose-Escalation Study 
The Oncologist  2013;18(1):25-26.
The A3 adenosine receptor (A3AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A3AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC.
The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A3AR as a biological predictive marker of response to CF102 were the secondary objectives.
Eighteen patients received CF102—six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102.
CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.
PMCID: PMC3556251  PMID: 23299770
5.  Relation of Uric Acid to Serum Levels of High-Sensitivity C-Reactive Protein, Triglycerides, and High-Density Lipoprotein Cholesterol and to Hepatic Steatosis 
The American journal of cardiology  2012;110(12):1787-1792.
Increased uric acid (UA) is strongly linked to cardiovascular disease. However, the independent role of UA is still debated because it is associated with several cardiovascular risk factors including obesity and metabolic syndrome. This study assessed the association of UA with increased high-sensitivity C-reactive protein (hs-CRP), increased ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL), sonographically detected hepatic steatosis, and their clustering in the presence and absence of obesity and metabolic syndrome. We evaluated 3,518 employed subjects without clinical cardiovascular disease from November 2008 through July 2010. Prevalence of hs-CRP ≥3 mg/L was 19%, that of TG/HDL ≥3 was 44%, and that of hepatic steatosis was 43%. In multivariable logistic regression after adjusting for traditional cardiovascular risk factors and confounders, highest versus lowest UA quartile was associated with hs-CRP ≥3 mg/L (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.01 to 2.28, p = 0.04), TG/HDL ≥3 (OR 3.29, 95% CI 2.36 to 4.60, p <0.001), and hepatic steatosis (OR 3.10, 95% CI 2.22 to 4.32, p <0.001) independently of obesity and metabolic syndrome. Association of UA with hs-CRP ≥3 mg/L became nonsignificant in analyses stratified by obesity. Ascending UA quartiles compared to the lowest UA quartile demonstrated a graded increase in the odds of having 2 or 3 of these risk conditions and a successive decrease in the odds of having none. In conclusion, high UA levels were associated with increased TG/HDL and hepatic steatosis independently of metabolic syndrome and obesity and with increased hs-CRP independently of metabolic syndrome.
PMCID: PMC3766845  PMID: 22975466
6.  Amyloid-β oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons 
Molecular Biology of the Cell  2013;24(16):2494-2505.
The role of tau in axonal transport disruption during early-stage Alzheimer disease is controversial. The amyloid-β oligomers markedly impair BDNF transport in primary wild-type and tau-knockout neurons. This occurs by nonexcitotoxic activation of calcineurin, and inhibition of calcineurin rescues transport defects independent of tau.
Disruption of fast axonal transport (FAT) is an early pathological event in Alzheimer's disease (AD). Soluble amyloid-β oligomers (AβOs), increasingly recognized as proximal neurotoxins in AD, impair organelle transport in cultured neurons and transgenic mouse models. AβOs also stimulate hyperphosphorylation of the axonal microtubule-associated protein, tau. However, the role of tau in FAT disruption is controversial. Here we show that AβOs reduce vesicular transport of brain-derived neurotrophic factor (BDNF) in hippocampal neurons from both wild-type and tau-knockout mice, indicating that tau is not required for transport disruption. FAT inhibition is not accompanied by microtubule destabilization or neuronal death. Significantly, inhibition of calcineurin (CaN), a calcium-dependent phosphatase implicated in AD pathogenesis, rescues BDNF transport. Moreover, inhibition of protein phosphatase 1 and glycogen synthase kinase 3β, downstream targets of CaN, prevents BDNF transport defects induced by AβOs. We further show that AβOs induce CaN activation through nonexcitotoxic calcium signaling. Results implicate CaN in FAT regulation and demonstrate that tau is not required for AβO-induced BDNF transport disruption.
PMCID: PMC3744947  PMID: 23783030
8.  Cognitive Outcome of Offspring from Dexamethasone-Treated Pregnancies at Risk for Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency 
European Journal of Endocrinology  2012;167(1):103-110.
To test whether dexamethasone (DEX) treatment of pregnancies at risk for congenital adrenal hyperplasia (CAH) impairs cognitive functioning in the offspring.
Observational follow-up of prenatally DEX-exposed offspring and controls.
Study 1 included 140 children age 5-12 years: 67 DEX-exposed (long-term: 8 CAH girls) and 73 unexposed (with 15 CAH girls). Study 2 included 20 participants age 11-24 years: 7 DEX-exposed (long-term: 1 CAH woman) and 13 unexposed (with 4 CAH women). Neuropsychological testing was done in hospital settings or patients' homes. Data analysis aimed at maximizing detection of effects of DEX exposure.
The vast majority of group comparisons were not marginally or conventionally significant. The few significant findings on short-term prenatal DEX exposure suggested more positive than adverse outcomes. By contrast, the few significant findings in females with CAH and long-term DEX exposure indicated slower mental processing than in controls on several neuropsychological variables, although partial correlations of DEX-exposure duration with cognitive outcome did not corroborate this association.
Our studies do not replicate a previously reported adverse effect of short-term prenatal DEX exposure on working memory, while our findings on cognitive function in CAH girls with long-term DEX exposure contribute to concerns about potentially adverse cognitive aftereffects of such exposure. Yet, our studies are not definitive, and replications in larger samples are required.
PMCID: PMC3383400  PMID: 22549088
9.  Treatment of Dry Eye Syndrome with Orally Administered CF101: Data from a Phase 2 Clinical Trial 
Ophthalmology  2010;117(7):1287-1293.
To explore the safety and efficacy of CF101, an A3 adenosine receptor agonist, in patients with moderate-to-severe dry eye syndrome
Phase 2, multicenter, randomized, double-masked, placebo-controlled, parallel-group study.
68 patients completed the study, 35 patients in the placebo group and 33 patients in the CF101 group.
Patients were orally treated with either 1 mg CF101 pills or matching vehicle-filled placebo pills, given twice daily for 12 weeks, followed by a 2-week post-treatment observation.
Main Outcome Measures
an improvement of >25% over baseline at week 12 in one of the following parameters: (a) tear break-up time (BUT); (b) superficial punctate keratitis assessed by fluorescein staining (FS); (c) Schirmer tear test 1 (ST1).
clinical laboratory safety tests, ophthalmic examinations, intraocular pressure (IOP) measurements, electrocardiographic evaluations, vital sign measurements and monitoring of adverse events.
A statistically significant increase in the proportion of patients who achieved more than 25% improvement in the corneal staining and in the clearance of corneal staining was noted between the CF101-treated group and the placebo group. Treatment with CF101 resulted in a statistically significant improvement in the mean change from baseline at week 12 of the corneal staining, BUT, and tear meniscus (TM) height in the CF101-treated group CF101 was well tolerated and exhibited an excellent safety profile with no serious adverse events. A statistically significant decrease from baseline was observed in the IOP of the CF101-treated group in comparison with the placebo group.
CF101, given orally, induced a statistically significant improvement in the corneal staining and an improvement in the BUT and TM in patients with moderate-to-severe dry eye syndrome. The drug was very well tolerated. These data and the anti-inflammatory characteristic of CF101 support further study of the drug as a potential treatment for the signs and symptoms of dry eye syndrome.
PMCID: PMC3668568  PMID: 20304499
10.  Potential Implications of Coronary Artery Calcium Testing for Guiding Aspirin Use Among Asymptomatic Individuals With Diabetes 
Diabetes Care  2012;35(3):624-626.
It is unclear whether coronary artery calcium (CAC) is effective for risk stratifying patients with diabetes in whom treatment decisions are uncertain.
Of 44,052 asymptomatic individuals referred for CAC testing, we studied 2,384 individuals with diabetes. Subjects were followed for a mean of 5.6 ± 2.6 years for the end point of all-cause mortality.
There were 162 deaths (6.8%) in the population. CAC was a strong predictor of mortality across age-groups (age <50, 50–59, ≥60), sex, and risk factor burden (0 vs. ≥1 additional risk factor). In individuals without a clear indication for aspirin per current guidelines, CAC stratified risk, identifying patients above and below the 10% risk threshold of presumed aspirin benefit.
CAC can help risk stratify individuals with diabetes and may aid in selection of patients who may benefit from therapies such as low-dose aspirin for primary prevention.
PMCID: PMC3322717  PMID: 22228745
11.  Eastern Equine Encephalitis in Children, Massachusetts and New Hampshire,USA, 1970–2010 
Emerging Infectious Diseases  2013;19(2):194-201.
A short prodrome in children is associated with more severe disease and increased risk for death.
PMCID: PMC3559032  PMID: 23343480
Encephalitis; arbovirus; Eastern equine encephalitis; Eastern equine encephalitis virus; pediatric; Massachusetts; New Hampshire; children; viruses
12.  Toward an Understanding of Changes in Diversity Associated with Fecal Microbiome Transplantation Based on 16S rRNA Gene Deep Sequencing 
mBio  2012;3(5):e00338-12.
Fecal microbiome transplantation by low-volume enema is an effective, safe, and inexpensive alternative to antibiotic therapy for patients with chronic relapsing Clostridium difficile infection (CDI). We explored the microbial diversity of pre- and posttransplant stool specimens from CDI patients (n = 6) using deep sequencing of the 16S rRNA gene. While interindividual variability in microbiota change occurs with fecal transplantation and vancomycin exposure, in this pilot study we note that clinical cure of CDI is associated with an increase in diversity and richness. Genus- and species-level analysis may reveal a cocktail of microorganisms or products thereof that will ultimately be used as a probiotic to treat CDI.
Antibiotic-associated diarrhea (AAD) due to Clostridium difficile is a widespread phenomenon in hospitals today. Despite the use of antibiotics, up to 30% of patients are unable to clear the infection and suffer recurrent bouts of diarrheal disease. As a result, clinicians have resorted to fecal microbiome transplantation (FT). Donor stool for this type of therapy is typically obtained from a spouse or close relative and thoroughly tested for various pathogenic microorganisms prior to infusion. Anecdotal reports suggest a very high success rate of FT in patients who fail antibiotic treatment (>90%). We used deep-sequencing technology to explore the human microbial diversity in patients with Clostridium difficile infection (CDI) disease after FT. Genus- and species-level analysis revealed a cocktail of microorganisms in the Bacteroidetes and Firmicutes phyla that may ultimately be used as a probiotic to treat CDI.
PMCID: PMC3482503  PMID: 23093385
13.  Alveolarization Continues during Childhood and Adolescence 
Rationale: The current hypothesis that human pulmonary alveolarization is complete by 3 years is contradicted by new evidence of alveolarization throughout adolescence in mammals.
Objectives: We reexamined the current hypothesis using helium-3 (3He) magnetic resonance (MR) to assess alveolar size noninvasively between 7 and 21 years, during which lung volume nearly quadruples. If new alveolarization does not occur, alveolar size should increase to the same extent.
Methods: Lung volumes were measured by spirometry and plethysmography in 109 healthy subjects aged 7–21 years. Using 3HeMR we determined two independent measures of peripheral airspace dimensions: apparent diffusion coefficient (ADC) of 3He at FRC (n = 109), and average diffusion distance of helium (Xrms¯) by q-space analysis (n = 46). We compared the change in these parameters with lung growth against a model of lung expansion with no new alveolarization.
Measurements and Main Results: ADC increased by 0.19% for every 1% increment in FRC (95% confidence interval [CI], 0.13–0.25), whereas the expected change in the absence of neoalveolarization is 0.41% (95% CI, 0.31–0.52). Similarly, increase of (Xrms¯) with FRC was significantly less than the predicted increase in the absence of neoalveolarization. The number of alveoli is estimated to increase 1.94-fold (95% CI, 1.64–2.30) across the age range studied.
Conclusions: Our observations are best explained by postulating that the lungs grow partly by neoalveolarization throughout childhood and adolescence. This has important implications: developing lungs have the potential to recover from early life insults and respond to emerging alveolar therapies. Conversely, drugs, diseases, or environmental exposures could adversely affect alveolarization throughout childhood.
PMCID: PMC3410735  PMID: 22071328
growth and development; lung development; alveolarization
14.  The Epidemiology of Hospitalized Postpartum Depression in New York State, 1995–2004 
Annals of epidemiology  2011;21(6):399-406.
The purpose of this study is to describe the patterns of hospitalization for depression in the year following delivery in relation to social, demographic, and behavioral characteristics.
Data on fetal deliveries were linked to hospitalizations for depression over the subsequent year in order to describe the frequency and patterns of hospitalized postpartum depression among 2,355,886 deliveries in New York State from 1995 – 2004. We identified “definite postpartum depression” based on ICD codes indicative of “mental disorders specific to pregnancy,” and “possible postpartum depression” by ICD codes for hospitalization with any depressive disorders.
In New York State, we identified 1,363 women (5.8 per 10,000) who were hospitalized with definite postpartum depression, and 6,041 women (25.6 per 10,000) with possible postpartum depression, with lower risks in the New York City area. Postpartum depression was more common in later years and among mothers who were older, Black, smokers, lacking private insurance, and with multiple gestations, and was rarer among Asians. For possible postpartum depression, socioeconomic gradients were enhanced.
Risk of hospitalized postpartum depression is strongly associated with socioeconomic deprivation and varies markedly by ethnicity, with direct implications for screening and health services, also providing suggestions for etiologic studies.
PMCID: PMC3090997  PMID: 21549277
postpartum depression; pregnancy; ethnicity
15.  An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers 
The Journal of Clinical Investigation  2012;122(4):1339-1353.
Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer’s disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.
PMCID: PMC3314445  PMID: 22476196
16.  A glycine zipper motif mediates the formation of toxic β-amyloid oligomers in vitro and in vivo 
The β-amyloid peptide (Aβ) contains a Gly-XXX-Gly-XXX-Gly motif in its C-terminal region that has been proposed to form a "glycine zipper" that drives the formation of toxic Aβ oligomers. We have tested this hypothesis by examining the toxicity of Aβ variants containing substitutions in this motif using a neuronal cell line, primary neurons, and a transgenic C. elegans model.
We found that a Gly37Leu substitution dramatically reduced Aβ toxicity in all models tested, as measured by cell dysfunction, cell death, synaptic alteration, or tau phosphorylation. We also demonstrated in multiple models that Aβ Gly37Leu is actually anti-toxic, thereby supporting the hypothesis that interference with glycine zipper formation blocks assembly of toxic Aβ oligomers. To test this model rigorously, we engineered second site substitutions in Aβ predicted by the glycine zipper model to compensate for the Gly37Leu substitution and expressed these in C. elegans. We show that these second site substitutions restore in vivo Aβtoxicity, further supporting the glycine zipper model.
Our structure/function studies support the view that the glycine zipper motif present in the C-terminal portion of Aβ plays an important role in the formation of toxic Aβ oligomers. Compounds designed to interfere specifically with formation of the glycine zipper could have therapeutic potential.
PMCID: PMC3178497  PMID: 21861874
Alzheimer's disease; C. elegans; pore-forming toxin; glycine motif
17.  Live Imaging of Dense-core Vesicles in Primary Cultured Hippocampal Neurons 
Observing and characterizing dynamic cellular processes can yield important information about cellular activity that cannot be gained from static images. Vital fluorescent probes, particularly green fluorescent protein (GFP) have revolutionized cell biology stemming from the ability to label specific intracellular compartments and cellular structures. For example, the live imaging of GFP (and its spectral variants) chimeras have allowed for a dynamic analysis of the cytoskeleton, organelle transport, and membrane dynamics in a multitude of organisms and cell types [1-3]. Although live imaging has become prevalent, this approach still poses many technical challenges, particularly in primary cultured neurons. One challenge is the expression of GFP-tagged proteins in post-mitotic neurons; the other is the ability to capture fluorescent images while minimizing phototoxicity, photobleaching, and maintaining general cell health. Here we provide a protocol that describes a lipid-based transfection method that yields a relatively low transfection rate (~0.5%), however is ideal for the imaging of fully polarized neurons. A low transfection rate is essential so that single axons and dendrites can be characterized as to their orientation to the cell body to confirm directionality of transport, i.e., anterograde v. retrograde. Our approach to imaging GFP expressing neurons relies on a standard wide-field fluorescent microscope outfitted with a CCD camera, image capture software, and a heated imaging chamber. We have imaged a wide variety of organelles or structures, for example, dense-core vesicles, mitochondria, growth cones, and actin without any special optics or excitation requirements other than a fluorescent light source. Additionally, spectrally-distinct, fluorescently labeled proteins, e.g., GFP and dsRed-tagged proteins, can be visualized near simultaneously to characterize co-transport or other coordinated cellular events. The imaging approach described here is flexible for a variety of imaging applications and can be adopted by a laboratory for relatively little cost provided a microscope is available.
PMCID: PMC2762918  PMID: 19488029
18.  Clinical importance of delayed MRI contrast enhancement of primary central nervous system lymphoma in AIDS 
BMJ Case Reports  2009;2009:bcr10.2008.1043.
Accurately distinguishing between cerebral toxoplasmosis and primary central nervous system lymphoma (PCNSL), still the most common secondary CNS mass lesion complications of AIDS, has long represented a diagnostic challenge in those with HIV. A young adult male with AIDS presented with evolving ophthalmoplegias, Parinaud’s syndrome and gait dysfunction. MRI with gadolinium contrast revealed a brainstem lesion failing to enhance on initially obtained post-contrast images yet prominently enhancing on images acquired endmost within the same scanning session. Biopsy ultimately confirmed lesion aetiology as PCNSL. While the definitive diagnosis of PCNSL generally requires brain biopsy, different MRI contrast-enhancement time courses of PCNSL versus toxoplasmosis (PCNSL tends to peak-enhance sooner than toxoplasmosis) can provide differential diagnostic insight. These images underscore the delayed nature of PCNSL contrast enhancement and demonstrate the diagnostic importance of attending to post-gadolinium image acquisition timing to help inform utilisation of MRI for PCNSL identification.
PMCID: PMC3027744  PMID: 21686485
19.  A parent‐completed respiratory questionnaire for 1‐year‐old children: repeatability 
Archives of Disease in Childhood  2007;92(10):861-865.
Background and aims
There are few standardised questionnaires for the assessment of respiratory symptoms in preschool children. We have developed and tested the short‐term repeatability of a postal questionnaire on respiratory symptoms for 1‐year‐old children.
A newly developed postal questionnaire for the assessment of wheeze and other respiratory symptoms was sent to parents of a population‐based random sample of 4300 children aged 12–24 months. After an interval of 3 months, a random sample of 800 respondents received the questionnaire a second time. The responses were compared using Cohen's kappa (κ) to assess agreement corrected for chance.
The first questionnaire was returned by 3194 (74%) families, the second one by 460/800 (58%). Repeatability was excellent (κ 0.80–0.96) for questions on household characteristics, environmental exposures and family history, good (κ 0.61–0.80) for questions on prevalence, severity and treatment of wheeze, and moderate (κ 0.39–0.66) for chronic cough and upper respiratory symptoms.
This short postal questionnaire designed for use in population‐based studies has excellent repeatability for family and household characteristics and good repeatability for questions on wheeze. Short‐term changes in symptom status might be responsible for variable answers on recent chronic cough and upper respiratory symptoms. Overall, the questionnaire is a valuable instrument for community‐based research on respiratory symptoms in 1 to 2‐year‐old children.
PMCID: PMC2083231  PMID: 17502330
preschool; asthma; kappa; repeatability; questionnaire
20.  A Disease Model for Wheezing Disorders in Preschool Children Based on Clinicians' Perceptions 
PLoS ONE  2009;4(12):e8533.
Wheezing disorders in childhood vary widely in clinical presentation and disease course. During the last years, several ways to classify wheezing children into different disease phenotypes have been proposed and are increasingly used for clinical guidance, but validation of these hypothetical entities is difficult.
Methodology/Principal Findings
The aim of this study was to develop a testable disease model which reflects the full spectrum of wheezing illness in preschool children. We performed a qualitative study among a panel of 7 experienced clinicians from 4 European countries working in primary, secondary and tertiary paediatric care. In a series of questionnaire surveys and structured discussions, we found a general consensus that preschool wheezing disorders consist of several phenotypes, with a great heterogeneity of specific disease concepts between clinicians. Initially, 24 disease entities were described among the 7 physicians. In structured discussions, these could be narrowed down to three entities which were linked to proposed mechanisms: a) allergic wheeze, b) non-allergic wheeze due to structural airway narrowing and c) non-allergic wheeze due to increased immune response to viral infections. This disease model will serve to create an artificial dataset that allows the validation of data-driven multidimensional methods, such as cluster analysis, which have been proposed for identification of wheezing phenotypes in children.
While there appears to be wide agreement among clinicians that wheezing disorders consist of several diseases, there is less agreement regarding their number and nature. A great diversity of disease concepts exist but a unified phenotype classification reflecting underlying disease mechanisms is lacking. We propose a disease model which may help guide future research so that proposed mechanisms are measured at the right time and their role in disease heterogeneity can be studied.
PMCID: PMC2795203  PMID: 20046874
21.  Fertility Desires and Intentions of HIV-Positive Women of Reproductive Age in Ontario, Canada: A Cross-Sectional Study 
PLoS ONE  2009;4(12):e7925.
Improvements in life expectancy and quality of life for HIV-positive women coupled with reduced vertical transmission will likely lead numerous HIV-positive women to consider becoming pregnant. In order to clarify the demand, and aid with appropriate health services planning for this population, our study aims to assess the fertility desires and intentions of HIV-positive women of reproductive age living in Ontario, Canada.
Methodology/Principal Findings
A cross-sectional study with recruitment stratified to match the geographic distribution of HIV-positive women of reproductive age (18–52) living in Ontario was carried out. Women were recruited from 38 sites between October 2007 and April 2009 and invited to complete a 189-item self-administered survey entitled “The HIV Pregnancy Planning Questionnaire” designed to assess fertility desires, intentions and actions. Logistic regression models were fit to calculate unadjusted and adjusted odds ratios of significant predictors of fertility intentions. The median age of the 490 participating HIV-positive women was 38 (IQR, 32–43) and 61%, 52%, 47% and 74% were born outside of Canada, living in Toronto, of African ethnicity and currently on antiretroviral therapy, respectively. Of total respondents, 69% (95% CI, 64%–73%) desired to give birth and 57% (95% CI, 53%–62%) intended to give birth in the future. In the multivariable model, the significant predictors of fertility intentions were: younger age (age<40) (p<0.0001), African ethnicity (p<0.0001), living in Toronto (p = 0.002), and a lower number of lifetime births (p = 0.02).
The proportions of HIV-positive women of reproductive age living in Ontario desiring and intending pregnancy were higher than reported in earlier North American studies. Proportions were more similar to those reported from African populations. Healthcare providers and policy makers need to consider increasing services and support for pregnancy planning for HIV-positive women. This may be particularly significant in jurisdictions with high levels of African immigration.
PMCID: PMC2785467  PMID: 19997556
22.  The β amyloid peptide can act as a modular aggregation domain 
Neurobiology of disease  2008;32(3):420-425.
Although there is compelling evidence that the β amyloid peptide (Aβ) can be centrally involved in Alzheimer’s disease, the natural role (if any) of this peptide remains unclear. Here we use green fluorescent protein (GFP) fusions to demonstrate that the Aβ sequence, like prion domains, can act as a modular aggregation domain when terminally appended to a normally soluble protein. We find that a single amino acid substitution (Leu17 to Pro) in the β peptide sequence can abolish this cis capacity to induce aggregation. Introduction of this substitution into full-length APP (i.e., a Leu613Pro substitution in APP695) alters the processing of APP leading to the accumulation of the C99 C-terminal fragment (CTF). We suggest that in at least some aggregation disease-related proteins the presence of an aggregation domain is not “accidental”, but reflects a selected role of these domains in modulating the trafficking or metabolism of the parental protein.
PMCID: PMC2646107  PMID: 18778773
Alzheimer’s disease; C. elegans; transgenic; neurodegeneration; γ-secretase; α-secretase; AICD
23.  The Impact of Socioeconomic Status on the Neural Substrates Associated with Pleasure 
Low socio-economic status (SES) is associated with increased morbidity and premature mortality. Because tonic adversity relates to a diminished ability to experience pleasure, we hypothesized that subjects living in poverty would show diminished neural responsivity to positive stimuli in regions associated with positive experience and reward. Visual images were presented to twenty-two subjects in the context of a EPI-BOLD fMRI paradigm. Significant differences in neural responses between SES groups to poverty vs. neutral images were assessed, examining group, condition, and interaction effects. The data suggest that persons living in low-SES have neural experiences consistent with diminished interest in things generally enjoyed and point toward a possible explanation for the relationship between socioeconomic inequalities and mood disorders, such as depression, by SES.
PMCID: PMC2731107  PMID: 19718457
fMRI; depression; mood; stress; socio-economic status.
24.  Antimalarial Therapy Selection for Quinolone Resistance among Escherichia coli in the Absence of Quinolone Exposure, in Tropical South America 
PLoS ONE  2008;3(7):e2727.
Bacterial resistance to antibiotics is thought to develop only in the presence of antibiotic pressure. Here we show evidence to suggest that fluoroquinolone resistance in Escherichia coli has developed in the absence of fluoroquinolone use.
Over 4 years, outreach clinic attendees in one moderately remote and five very remote villages in rural Guyana were surveyed for the presence of rectal carriage of ciprofloxacin-resistant Gram-negative bacilli (GNB). Drinking water was tested for the presence of resistant GNB by culture, and the presence of antibacterial agents and chloroquine by HPLC. The development of ciprofloxacin resistance in E. coli was examined after serial exposure to chloroquine. Patient and laboratory isolates of E. coli resistant to ciprofloxacin were assessed by PCR-sequencing for quinolone-resistance-determining-region (QRDR) mutations.
In the very remote villages, 4.8% of patients carried ciprofloxacin-resistant E. coli with QRDR mutations despite no local availability of quinolones. However, there had been extensive local use of chloroquine, with higher prevalence of resistance seen in the villages shortly after a Plasmodium vivax epidemic (p<0.01). Antibacterial agents were not found in the drinking water, but chloroquine was demonstrated to be present. Chloroquine was found to inhibit the growth of E. coli in vitro. Replica plating demonstrated that 2-step QRDR mutations could be induced in E. coli in response to chloroquine.
In these remote communities, the heavy use of chloroquine to treat malaria likely selected for ciprofloxacin resistance in E. coli. This may be an important public health problem in malarious areas.
PMCID: PMC2481278  PMID: 18648533
25.  On the Origin of the Treponematoses: A Phylogenetic Approach 
Since the first recorded epidemic of syphilis in 1495, controversy has surrounded the origins of the bacterium Treponema pallidum subsp. pallidum and its relationship to the pathogens responsible for the other treponemal diseases: yaws, endemic syphilis, and pinta. Some researchers have argued that the syphilis-causing bacterium, or its progenitor, was brought from the New World to Europe by Christopher Columbus and his men, while others maintain that the treponematoses, including syphilis, have a much longer history on the European continent.
Methodology/Principal Findings
We applied phylogenetics to this problem, using data from 21 genetic regions examined in 26 geographically disparate strains of pathogenic Treponema. Of all the strains examined, the venereal syphilis-causing strains originated most recently and were more closely related to yaws-causing strains from South America than to other non-venereal strains. Old World yaws-causing strains occupied a basal position on the tree, indicating that they arose first in human history, and a simian strain of T. pallidum was found to be indistinguishable from them.
Our results lend support to the Columbian theory of syphilis's origin while suggesting that the non-sexually transmitted subspecies arose earlier in the Old World. This study represents the first attempt to address the problem of the origin of syphilis using molecular genetics, as well as the first source of information regarding the genetic make-up of non-venereal strains from the Western hemisphere.
Author Summary
For 500 years, controversy has raged around the origin of T. pallidum subsp. pallidum, the bacterium responsible for syphilis. Did Christopher Columbus and his men introduce this pathogen into Renaissance Europe, after contracting it during their voyage to the New World? Or does syphilis have a much older history in the Old World? This paper represents the first attempt to use a phylogenetic approach to solve this question. In addition, it clarifies the evolutionary relationships between the pathogen that causes syphilis and the other T. pallidum subspecies, which cause the neglected tropical diseases yaws and endemic syphilis. Using a collection of pathogenic Treponema strains that is unprecedented in size, we show that yaws appears to be an ancient infection in humans while venereal syphilis arose relatively recently in human history. In addition, the closest relatives of syphilis-causing strains identified in this study were found in South America, providing support for the Columbian theory of syphilis's origin.
PMCID: PMC2217670  PMID: 18235852

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