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1.  Feature Selection in Computer-Aided Breast Cancer Diagnosis via Dynamic Contrast-Enhanced Magnetic Resonance Images 
Journal of Digital Imaging  2012;26(2):198-208.
The accuracy of computer-aided diagnosis (CAD) for early detection and classification of breast cancer in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is dependent upon the features used by the CAD classifier. Here, we show that fast orthogonal search (FOS), which provides a more efficient iterative manner of computing stepwise regression feature selection, can select features with predictive value from a set of kinetic and texture candidate features computed from dynamic contrast-enhanced magnetic resonance images. FOS can in minutes search candidate feature sets of millions of terms, which may include cross-products of features up to second-, third- or fourth-order. This method is tested on a set of 83 DCE-MRI images, of which 20 are for cancerous and 63 for benign cases, using a leave-one-out trial. The features selected by FOS were used in a FOS predictor and nearest-neighbour predictor and had an area under the receiver operating curve (AUC) of 0.889 and 0.791 respectively. The FOS predictor AUC is significantly improved over the signal enhancement ratio predictor with an AUC of 0.706 (p = 0.0035 for the difference in the AUCs). Moreover, using FOS-selected features in a support vector machine increased the AUC over that resulting when the features were manually selected.
PMCID: PMC3597958  PMID: 22828783
Breast cancer; Computer-aided diagnosis; Stepwise regression; Fast orthogonal search
2.  Temporal relationship of conduction system disease and ventricular dysfunction in LMNA cardiomyopathy 
Journal of cardiac failure  2013;19(4):233-239.
LMNA cardiomyopathy presents with ECG abnormalities, conduction system disease (CSD) and/or arrhythmias prior to the onset of dilated cardiomyopathy (DCM). The time interval between the onset of CSD and its progression to DCM, if known, would help to guide clinical care.
Methods and Results
We evaluated family members from 16 pedigrees previously identified to carry LMNA mutations for the ages of onset of ECG abnormalities, CSD or arrhythmia, and of left ventricular enlargement (LVE), systolic dysfunction or both. Of 103 subjects, 64 carried their family LMNA mutation, and 51 (79%) had ECG abnormalities with a mean age of onset of 41.2 years (range 18-76). Ventricular dysfunction was observed in 26 with a mean age of onset of 47.6 (range 28-82); at diagnosis 9 had systolic dysfunction but no LVE, 5 had LVE but no systolic dysfunction, and 11 had DCM. Of 16 subjects identified with ECG abnormalities who later developed ventricular dysfunction, the median ages of onset by log rank analyses were 41 and 48 years, respectively.
ECG abnormalities preceded DCM with a median difference of seven years. Clinical surveillance should occur at least annually in those at risk for LMNA cardiomyopathy with any ECG findings.
PMCID: PMC3699310  PMID: 23582089
3.  Predictors of High-Grade Esophagitis after Definitive 3D Conformal Therapy, Intensity Modulated Radiation Therapy, or Proton Beam Therapy for Non-Small Cell Lung Cancer 
We analyzed the ability of various patient- and treatment-related factors to predict radiation-induced esophagitis (RE) in patients with non-small cell lung cancer (NSCLC) treated with three-dimensional (3D) conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or proton beam therapy (PBT).
Methods and Materials
Patients were treated for NSCLC with 3D-CRT, IMRT, or PBT at MD Anderson from 2000 to 2008 and had full dose-volume histogram (DVH) data available. The endpoint was severe (grade ≥3) RE. The Lyman-Kutcher-Burman (LKB) model was used to analyze RE as a function of the fractional esophageal DVH, with clinical variables included as dose-modifying factors.
Overall, 652 patients were included: 405 treated with 3D-CRT, 139 with IMRT, and 108 with PBT; corresponding rates of grade ≥3 RE were 8%, 28%, and 6%, with a median time to onset of 42 days (range 11–93 days). A fit of the fractional-DVH LKB model demonstrated that the volume parameter n was significantly different (p=0.046) than 1, indicating that high doses to small volumes are more predictive than mean esophageal dose. The model fit was better for 3D-CRT and PBT than for IMRT. Including receipt of concurrent chemotherapy as a dose-modifying factor significantly improved the LKB model (p=0.005), and the model was further improved by including a variable representing treatment with >30 fractions. Examining individual types of chemotherapy agents revealed a trend toward receipt of concurrent taxanes and increased risk of RE (p=0.105).
The fractional dose (dose rate) and number of fractions (total dose) distinctly affect the risk of severe RE estimated using the LKB model, and concurrent chemotherapy improves the model fit. This risk of severe RE is underestimated by this model in patients receiving IMRT.
PMCID: PMC3951751  PMID: 22920974
intensity modulated radiation therapy; esophagitis; chemotherapy; DVH modeling
4.  Probability of Cancer in Pulmonary Nodules Detected on First Screening CT 
The New England journal of medicine  2013;369(10):910-919.
Major issues in the implementation of screening for lung cancer by means of low-dose computed tomography (CT) are the definition of a positive result and the management of lung nodules detected on the scans. We conducted a population-based prospective study to determine factors predicting the probability that lung nodules detected on the first screening low-dose CT scans are malignant or will be found to be malignant on follow-up.
We analyzed data from two cohorts of participants undergoing low-dose CT screening. The development data set included participants in the Pan-Canadian Early Detection of Lung Cancer Study (PanCan). The validation data set included participants involved in chemoprevention trials at the British Columbia Cancer Agency (BCCA), sponsored by the U.S. National Cancer Institute. The final outcomes of all nodules of any size that were detected on baseline low-dose CT scans were tracked. Parsimonious and fuller multivariable logistic-regression models were prepared to estimate the probability of lung cancer.
In the PanCan data set, 1871 persons had 7008 nodules, of which 102 were malignant, and in the BCCA data set, 1090 persons had 5021 nodules, of which 42 were malignant. Among persons with nodules, the rates of cancer in the two data sets were 5.5% and 3.7%, respectively. Predictors of cancer in the model included older age, female sex, family history of lung cancer, emphysema, larger nodule size, location of the nodule in the upper lobe, part-solid nodule type, lower nodule count, and spiculation. Our final parsimonious and full models showed excellent discrimination and calibration, with areas under the receiver-operating-characteristic curve of more than 0.90, even for nodules that were 10 mm or smaller in the validation set.
Predictive tools based on patient and nodule characteristics can be used to accurately estimate the probability that lung nodules detected on baseline screening low-dose CT scans are malignant. (Funded by the Terry Fox Research Institute and others; number, NCT00751660.)
PMCID: PMC3951177  PMID: 24004118
5.  Aortic Dose Constraints when Reirradiating Thoracic Tumors 
Background and Purpose
Improved radiation delivery and planning has allowed, in some instances, for the retreatment of thoracic tumors. We investigated the dose limits of the aorta wherein grade 5 aortic toxicity was observed after reirradiation of lung tumors.
Material and Methods
In a retrospective analysis, 35 patients were identified, between 1993 and 2008, who received two rounds of external beam irradiation that included the aorta in the radiation fields of both the initial and retreatment plans. We determined the maximum cumulative dose to 1 cm3 of the aorta (the composite dose) for each patient, normalized these doses to 1.8 Gy/fraction, and corrected them for long-term tissue recovery between treatments (NIDR).
The median time interval between treatments was 30 months (range, 1–185 months). The median follow-up of patients alive at analysis was 42 months (range, 14–70 months). Two of the 35 patients (6%) were identified as having grade 5 aortic toxicities. There was a 25% rate of grade 5 aortic toxicity for patients receiving composite doses ≥120.0 Gy (vs. 0% for patients receiving <120.0 Gy) (P=0.047).
Grade 5 aortic toxicities were observed with composite doses ≥120.0 Gy (NIDR ≥90.0 Gy) to 1 cm3 of the aorta.
PMCID: PMC3921976  PMID: 23453540
reirradiation; aortic toxicity; radiation toxicity; lung cancer
6.  Retrotaxis of Human Neutrophils during Mechanical Confinement inside Microfluidic Channels 
The current paradigm of unidirectional migration of neutrophils from circulation to sites of injury in tissues has been recently challenged by observations in zebrafish showing that neutrophils can return from tissues back into the circulation. However, the relevance of these observations to human neutrophils remains unclear, the forward and reversed migration of neutrophils is difficult to quantify, and the precise conditions modulating the reverse migration cannot be isolated. Here, we designed a microfluidic platform inside which we observed human neutrophil migration in response to chemoattractant sources inside channels, simulating the biochemical and mechanical confinement conditions at sites of injury in tissues. We observed that, after initially following the direction of chemoattractant gradients, more than 90% of human neutrophils can reverse their direction and migrate persistently and for distances longer than one thousand micrometers micrometers away from chemoattractant sources (retrotaxis). Retrotaxis is enhanced in the presence of lipoxin A4 (LXA4), a well-established mediator of inflammation resolution, or Tempol, a standard antioxidant. Retrotaxis stops after neutrophils encounter targets which they phagocytise or on surfaces presenting high concentrations of fibronectin. Our microfluidic model suggests a new paradigm for neutrophil accumulation at sites of inflammation, which depends on the balance of three simultaneous processes: chemotaxis along diffusion gradients, retrotaxis following mechanical guides, and stopping triggered by phagocytosis.
PMCID: PMC3928968  PMID: 24419464
7.  Prospective Associations between Plasma Saturated, Monounsaturated and Polyunsaturated Fatty Acids and Overall and Breast Cancer Risk – Modulation by Antioxidants: A Nested Case-Control Study 
PLoS ONE  2014;9(2):e90442.
Mechanistic data suggest that different types of fatty acids play a role in carcinogenesis and that antioxidants may modulate this relationship but epidemiologic evidence is lacking. Our aim was to investigate the association between plasma saturated, monounsaturated and polyunsaturated fatty acids (SFAs, MUFAs and PUFAs) and overall and breast cancer risk and to evaluate the potential modulatory effect of an antioxidant supplementation on these relationships.
A nested case-control study included all first incident cancer cases diagnosed in the SU.VI.MAX study between 1994 and 2002 (n = 250 cases, one matched control/case). Participants to the SU.VI.MAX randomized controlled trial received either vitamin/mineral antioxidants or placebo during this intervention period. Baseline fatty acid composition of plasma total lipids was measured by gas chromatography. Conditional logistic regression was performed overall and stratified by intervention group.
Dihomo-γ-linolenic acid (Ptrend = 0.002), the dihomo-γ-linolenic/linoleic acids ratio (Ptrend = 0.001), mead acid (Ptrend = 0.0004), and palmitoleic acid (Ptrend = 0.02) were inversely associated with overall cancer risk. The arachidonic/dihomo-γ-linolenic acids ratio (Ptrend = 0.02) and linoleic acid (Ptrend = 0.02) were directly associated with overall cancer risk. Similar results were observed for breast cancer specifically. In stratified analyses, associations were only observed in the placebo group. Notably, total PUFAs were directly associated with overall (Ptrend = 0.02) and breast cancer risk in the placebo group only.
Specific SFAs, MUFAs and PUFAs were prospectively differentially associated with cancer risk. In addition, this study suggests that antioxidants may modulate these associations by counteracting the potential effects of these fatty acids on carcinogenesis.
PMCID: PMC3937383  PMID: 24587366
8.  Republished: Value of biomarkers in osteoarthritis: current status and perspectives 
Postgraduate Medical Journal  2013;90(1061):171-178.
Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the ‘omics’ (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis.
PMCID: PMC3934547  PMID: 24534711
Osteoarthritis; Outcomes research; Inflammation
9.  Drug Delivery by Tattooing to Treat Cutaneous Leishmaniasis 
Scientific Reports  2014;4:4156.
This study establishes a proof-of-concept that a tattoo device can target intra-dermal drug delivery against cutaneous leishmaniasis (CL). The selected drug is oleylphosphocholine (OlPC) formulated as liposomes, particles known to be prone to macrophage ingestion. We first show that treatment of cultured Leishmania-infected macrophages with OlPC-liposomes results in a direct dose-dependent killing of intracellular parasites. Based on this, in vivo efficacy is demonstrated using a 10 day tattooing-mediated treatment in mice infected with L. major and L. mexicana. In both models this regimen results in rapid clinical recovery with complete regression of skin lesions by Day 28. Parasite counts and histopathology examination confirm high treatment efficacy at the parasitic level. Low amount of drug required for tattooing combined with fast clinical recovery may have a positive impact on CL patient management. This first example of tattoo-mediated drug delivery could open to new therapeutic interventions in the treatment of skin diseases.
PMCID: PMC3932479  PMID: 24561704
10.  The Impact of Fusarium Mycotoxins on Human and Animal Host Susceptibility to Infectious Diseases 
Toxins  2014;6(2):430-452.
Contamination of food and feed with mycotoxins is a worldwide problem. At present, acute mycotoxicosis caused by high doses is rare in humans and animals. Ingestion of low to moderate amounts of Fusarium mycotoxins is common and generally does not result in obvious intoxication. However, these low amounts may impair intestinal health, immune function and/or pathogen fitness, resulting in altered host pathogen interactions and thus a different outcome of infection. This review summarizes the current state of knowledge about the impact of Fusarium mycotoxin exposure on human and animal host susceptibility to infectious diseases. On the one hand, exposure to deoxynivalenol and other Fusarium mycotoxins generally exacerbates infections with parasites, bacteria and viruses across a wide range of animal host species. Well-known examples include coccidiosis in poultry, salmonellosis in pigs and mice, colibacillosis in pigs, necrotic enteritis in poultry, enteric septicemia of catfish, swine respiratory disease, aspergillosis in poultry and rabbits, reovirus infection in mice and Porcine Reproductive and Respiratory Syndrome Virus infection in pigs. However, on the other hand, T-2 toxin has been shown to markedly decrease the colonization capacity of Salmonella in the pig intestine. Although the impact of the exposure of humans to Fusarium toxins on infectious diseases is less well known, extrapolation from animal models suggests possible exacerbation of, for instance, colibacillosis and salmonellosis in humans, as well.
PMCID: PMC3942744  PMID: 24476707
deoxynivalenol; fumonisin; Fusarium mycotoxins; human; infectious diseases; mouse; pig; poultry; T-2 toxin; zearalenone
To determine whether single nucleotide polymorphisms (SNPs) in genes associated with DNA repair, cell cycle, transforming growth factor beta, tumor necrosis factor and receptor, folic acid metabolism, and angiogenesis can significantly improve the fit of the Lyman-Kutcher-Burman (LKB) normal-tissue complication probability (NTCP) model of radiation pneumonitis (RP) risk among patients with non-small cell lung cancer (NSCLC).
Methods and Materials
Sixteen SNPs from 10 different genes (XRCC1, XRCC3, APEX1, MDM2, TGFβ, TNFα, TNFR, MTHFR, MTRR, and VEGF) were genotyped in 141 NSCLC patients treated with definitive radiotherapy, with or without chemotherapy. The LKB model was used to estimate the risk of severe (Grade ≥3) RP as a function of mean lung dose (MLD), with SNPs and patient smoking status incorporated into the model as dose-modifying factors. Multivariate (MV) analyses were performed by adding significant factors to the MLD model in a forward stepwise procedure, with significance assessed using the likelihood-ratio test. Bootstrap analyses were used to assess the reproducibility of results under variations in the data.
Five SNPs were selected for inclusion in the multivariate NTCP model based on MLD alone. SNPs associated with an increased risk of severe RP were in genes for TGFβ, VEGF, TNFα, XRCC1 and APEX1. With smoking status included in the MV model, the SNPs significantly associated with increased risk of RP were in genes for TGFβ, VEGF, and XRCC3. Bootstrap analyses selected a median of 4 SNPs per model fit, with the 6 genes listed above selected most often.
This study provides evidence that SNPs can significantly improve the predictive ability of the Lyman MLD model. With a small number of SNPs, it was possible to distinguish cohorts with >50% risk versus <10% risk of RP when exposed to high MLDs.
PMCID: PMC3521878  PMID: 22541966
SNP; NTCP; biomarker; non-small cell lung cancer
12.  Association Between Prediagnostic Biomarkers of Inflammation and Endothelial Function and Cancer Risk: A Nested Case-Control Study 
Experimental and prevalent case-control studies suggest an association between biomarkers of inflammation, endothelial function, and adiposity and cancer risk, but results from prospective studies have been limited. The authors’ objective was to prospectively examine the relations between these biomarkers and cancer risk. A nested case-control study was designed within the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) Study, a nationwide French cohort study, to include all first primary incident cancers diagnosed between 1994 and 2007 (n = 512). Cases were matched with randomly selected controls (n = 1,024) on sex, age (in 2-year strata), body mass index (weight (kg)/height (m)2; <25 vs. ≥25), and SU.VI.MAX intervention group. Conditional logistic regression was used to study the associations between prediagnostic levels of high-sensitivity C-reactive protein (hs-CRP), adiponectin, leptin, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1, soluble E-selectin, and monocyte chemoattractant protein 1 and cancer risk. All statistical tests were 2-sided. Plasma sICAM-1 level was positively associated with breast cancer risk (for quartile 4 vs. quartile 1, multivariate odds ratio (OR) = 1.86, 95% confidence interval (CI): 1.06, 3.26; Ptrend = 0.048). Plasma hs-CRP level was positively associated with prostate cancer risk (for quartile 4 vs. quartile 1, multivariate OR = 3.04, 95% CI: 1.28, 7.23; Ptrend = 0.03). These results suggest that prediagnostic hs-CRP and sICAM-1 levels are associated with increased prostate and breast cancer risk, respectively.
PMCID: PMC3529490  PMID: 23171880
breast neoplasms; case-control studies; C-reactive protein; intercellular adhesion molecule 1; neoplasms; prostatic neoplasms
13.  Identification of a New P335 Subgroup through Molecular Analysis of Lactococcal Phages Q33 and BM13 
Applied and Environmental Microbiology  2013;79(14):4401-4409.
Lactococcal dairy starter strains are under constant threat from phages in dairy fermentation facilities, especially by members of the so-called 936, P335, and c2 species. Among these three phage groups, members of the P335 species are the most genetically diverse. Here, we present the complete genome sequences of two P335-type phages, Q33 and BM13, isolated in North America and representing a novel lineage within this phage group. The Q33 and BM13 genomes exhibit homology, not only to P335-type, but also to elements of the 936-type phage sequences. The two phage genomes also have close relatedness to phages infecting Enterococcus and Clostridium, a heretofore unknown feature among lactococcal P335 phages. The Q33 and BM13 genomes are organized in functionally related clusters with genes encoding functions such as DNA replication and packaging, morphogenesis, and host cell lysis. Electron micrographic analysis of the two phages highlights the presence of a baseplate more reminiscent of the baseplate of 936 phages than that of the majority of members of the P335 group, with the exception of r1t and LC3.
PMCID: PMC3697491  PMID: 23666331
14.  Persistent pain in postmastectomy patients: Comparison of psychophysical, medical, surgical, and psychosocial characteristics between patients with and without pain 
Pain  2012;154(5):10.1016/j.pain.2012.11.015.
Persistent postmastectomy pain (PPMP) is a major individual and public health problem. Increasingly, psychosocial factors such as anxiety and catastrophizing are being revealed as crucial contributors to individual differences in pain processing and outcomes. Furthermore, differences in patients’ responses to standardized quantitative sensory testing (QST) may aid in the discernment of who is at risk for acute and chronic pain after surgery. However, characterization of the variables that differentiate those with PPMP from those whose acute postoperative pain resolves is currently incomplete. The purpose of this study was to investigate important surgical, treatment-related, demographic, psychophysical, and psychosocial factors associated with PPMP by comparing PPMP cases with PPMP-free controls. Pain was assessed using the breast cancer pain questionnaire to determine the presence and extent of PPMP. Psychosocial and demographic information were gathered via phone interview, and women underwent a QST session. Consistent with most prior research, surgical and disease-related variables did not differ significantly between cases and controls. Furthermore, treatment with radiation, chemotherapy, or hormone therapy was also not more common among those with PPMP. In contrast, women with PPMP did show elevated levels of distress-related psychosocial factors such as anxiety, depression, catastrophizing, and somatization. Finally, QST in nonsurgical body areas revealed increased sensitivity to mechanical stimulation among PPMP cases, while thermal pain responses were not different between the groups. These findings suggest that an individual’s psychophysical and psychosocial profile may be more strongly related to PPMP than their surgical treatment.
PMCID: PMC3863788  PMID: 23290256
Mastectomy; Chronic pain/persistent pain; Quantitative sensory testing/QST; Psychosocial; Catastrophizing; Breast cancer survivors
15.  Randomized trial in malignant biliary obstruction: Plastic vs partially covered metal stents 
AIM: To compare efficacy and complications of partially covered self-expandable metal stent (pcSEMS) to plastic stent (PS) in patients treated for malignant, infrahilar biliary obstruction.
METHODS: Multicenter prospective randomized clinical trial with treatment allocation to a pcWallstent® (SEMS) or a 10 French PS. Palliative patients aged ≥ 18, for infrahilar malignant biliary obstruction and a Karnofsky performance scale index > 60% from 6 participating North American university centers. Primary endpoint was time to stent failure, with secondary outcomes of death, adverse events, Karnofsky performance score and short-form-36 scale administered on a three-monthly basis for up to 2 years. Survival analyses were performed for stent failure and death, with Cox proportional hazards regression models to determine significant predictive characteristics.
RESULTS: Eighty-five patients were accrued over 37 mo, 42 were randomized to the SEMS group and 83 patients were available for analyses. Time to stent failure was 385.3 ± 52.5 d in the SEMS and 153.3 ± 19.8 d in the PS group, P = 0.006. Time to death did not differ between groups (192.3 ± 23.4 d for SEMS vs 211.5 ± 28.0 d for PS, P = 0.70). The only significant predictor was treatment allocation, relating to the time to stent failure (P = 0.01). Amongst other measured outcomes, only cholangitis differed, being more common in the PS group (4.9% vs 24.5%, P = 0.029). The small number of patients in follow-up limits longitudinal assessments of performance and quality of life. From an initially planned 120 patients, only 85 patients were recruited.
CONCLUSION: Partially covered SEMS result in a longer duration till stent failure without increased complication rates, yet without accompanying measurable benefits in survival, performance, or quality of life.
PMCID: PMC3870509  PMID: 24379581
Randomized; Biliary; Obstruction; Stent; Plastic; Metal; Palliative; Common bile duct
16.  Do Plain Radiographs Correlate With CT for Imaging of Cam-type Femoroacetabular Impingement? 
Three-dimensional imaging (CT and MRI) is the gold standard for detecting femoral head-neck junction malformations in femoroacetabular impingement, yet plain radiographs are used for initial diagnostic evaluation. It is unclear, however, whether the plain radiographs accurately reflect the findings on three-dimensional imaging.
We therefore: (1) investigated the correlation of alpha angle measurements on plain radiographs and radial reformats of CT scans; (2) determined which radiographic views are most sensitive and specific in detecting head-neck deformities present on CT scans; and (3) determined if specific radiographic views correlated with specific locations on the radial oblique CT scan.
We retrospectively reviewed 41 surgical patients with preoperative CT scans (radial oblique reformats) and plain radiographs (AP pelvis, 45° Dunn, frog lateral, and crosstable lateral). Alpha angles were measured on plain radiographs and CT reformats.
The complete radiographic series was 86% to 90% sensitive in detecting abnormal alpha angles on CT. The maximum alpha angle on plain radiographs was greater than that of CT reformats in 61% of cases. Exclusion of the crosstable lateral did not affect the sensitivity (86%–88%). The Dunn view was most sensitive (71%–80%). The frog lateral showed the best specificity (91%–100%). Substantial correlations (intraclass correlation coefficients, 0.64–0.75) between radiograph and radial oblique CT position were observed, including AP/12:00 (superior), Dunn/1:00 (anterolateral), frog/3:00 (anterior), and crosstable/3:00 (anterior).
For diagnostic and treatment purposes, a three-view radiographic hip series (AP pelvis, 45° Dunn, and frog lateral) effectively characterizes femoral head-neck junction malformations.
Level of Evidence
Level II, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3492627  PMID: 22930210
17.  How to define responders in osteoarthritis 
Osteoarthritis is a clinical syndrome of failure of the joint accompanied by varying degrees of joint pain, functional limitation, and reduced quality of life due to deterioration of articular cartilage and involvement of other joint structures.
Regulatory agencies require relevant clinical benefit on symptoms and structure modification for registration of a new therapy as a disease-modifying osteoarthritis drug (DMOAD). An international Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and International Osteoporosis Foundation was convened to explore the current burden of osteoarthritis, review current regulatory guidelines for the conduct of clinical trials, and examine the concept of responder analyses for improving drug evaluation in osteoarthritis.
The ESCEO considers that the major challenges in DMOAD development are the absence of a precise definition of the disease, particularly in the early stages, and the lack of consensus on how to detect structural changes and link them to clinically meaningful endpoints. Responder criteria should help identify progression of disease and be clinically meaningful. The ideal criterion should be sensitive to change over time and should predict disease progression and outcomes such as joint replacement.
The ESCEO considers that, for knee osteoarthritis, clinical trial data indicate that radiographic joint space narrowing >0.5 mm over 2 or 3 years might be a reliable surrogate measure for total joint replacement. On-going research using techniques such as magnetic resonance imaging and biochemical markers may allow the identification of these patients earlier in the disease process.
PMCID: PMC3690437  PMID: 23557069
magnetic resonance imaging; osteoarthritis; X-ray; responder; structure-modifying drug; pain
18.  Loss of DNMT1o Disrupts Imprinted X Chromosome Inactivation and Accentuates Placental Defects in Females 
PLoS Genetics  2013;9(11):e1003873.
The maintenance of key germline derived DNA methylation patterns during preimplantation development depends on stores of DNA cytosine methyltransferase-1o (DNMT1o) provided by the oocyte. Dnmt1omat−/− mouse embryos born to Dnmt1Δ1o/Δ1o female mice lack DNMT1o protein and have disrupted genomic imprinting and associated phenotypic abnormalities. Here, we describe additional female-specific morphological abnormalities and DNA hypomethylation defects outside imprinted loci, restricted to extraembryonic tissue. Compared to male offspring, the placentae of female offspring of Dnmt1Δ1o/Δ1o mothers displayed a higher incidence of genic and intergenic hypomethylation and more frequent and extreme placental dysmorphology. The majority of the affected loci were concentrated on the X chromosome and associated with aberrant biallelic expression, indicating that imprinted X-inactivation was perturbed. Hypomethylation of a key regulatory region of Xite within the X-inactivation center was present in female blastocysts shortly after the absence of methylation maintenance by DNMT1o at the 8-cell stage. The female preponderance of placental DNA hypomethylation associated with maternal DNMT1o deficiency provides evidence of additional roles beyond the maintenance of genomic imprints for DNA methylation events in the preimplantation embryo, including a role in imprinted X chromosome inactivation.
Author Summary
During oocyte growth and maturation, vital proteins and enzymes are produced to ensure that, when fertilized, a healthy embryo will arise. When this natural process is interrupted, one or more of these essential elements can fail to be produced thus compromising the health of the future embryo. We are using a mouse model, lacking an enzyme (DNMT1o) produced in the oocyte and only required post-fertilization in the early embryo for the maintenance of inherited DNA methylation marks. Here, we reveal that oocytes lacking DNMT1o, when fertilized, generated conceptuses with a wide variety of placental abnormalities. These placental abnormalities were more frequent and severe in females, and showed specific genomic regions constantly deprived of their normal methylation marks. The affected genomic regions were concentrated on the X chromosome. Interestingly, we also found that a region important for the regulation of the X chromosome inactivation process was hypomethylated in female blastocysts and was associated with sex-specific abnormalities in the placenta, relaxation of imprinted X chromosome inactivation, and disruption of DNA methylation later in development. Our findings provide a novel unanticipated role for DNA methylation events taking place within the first few days of life specifically in female preimplantation embryos.
PMCID: PMC3836718  PMID: 24278026
19.  NFAT3 and TGF-β/SMAD3 regulate the expression of miR-140 in osteoarthritis 
Arthritis Research & Therapy  2013;15(6):R197.
MicroRNAs (miRNAs) down-regulate their target genes. The intronic miR-140, present in the WW domain containing E3 ubiquitin protein ligase 2 (WWP2) gene, decreases the expression of genes that play detrimental roles in osteoarthritis (OA). As the expression level of miR-140 is significantly decreased in human OA chondrocytes, we investigated its regulation in those cells.
Gene expression in human chondrocytes was determined by quantitative polymerase chain reaction (qPCR) and gene silencing was done in OA chondrocytes by transient transfection with specific small interfering RNAs (siRNAs). Binding sites of the miR-140 regulatory sequence (rsmiR-140) were identified by mutagenesis and chromatin immunoprecipitation (ChIP) in OA chondrocytes. The effects of translocation on OA chondrocytes were determined by immunocytochemistry and qPCR.
In contrast to miR-140, the expression of WWP2 was similar in both normal and OA cells, suggesting that miR-140 has an additional level of regulation. rsmiR-140 showed activity and predicted binding sites for nuclear matrix transcription factor 4 (NMP4), myc-associated zinc (MAZ), nuclear factor of activated T-cells (NFAT), and mothers against decapentaplegic homolog 3 (SMAD3). Silencing NFAT3 (P ≤0.01) and SMAD3 (P ≤0.05) differentially regulated miR-140 independently of WWP2. Silencing NFAT5 decreased both miR-140 and WWP2 (P ≤0.003 and P ≤0.05, respectively). NFAT3 activation increased and transforming growth factor-β (TGF-β) decreased rsmiR-140 activity. Mutagenesis of rsmiR-140 and ChIP assays identified binding sites at which NFAT3 (activator) and SMAD3 (repressor) directly regulated miR-140. TGF-β interfered with NFAT3 translocation, and subsequently with miR-140 expression.
This is the first study to provide evidence of a regulatory mechanism of miR-140 independent of WWP2, and new and differential roles for NFAT3 and SMAD3 in the OA process in the regulation of miR-140 transcription. Such knowledge could advance therapeutic strategies targeting OA.
PMCID: PMC3978709  PMID: 24257415
20.  Sex differences in the stability of conditioned pain modulation (CPM) among patients with chronic pain 
Pain medicine (Malden, Mass.)  2013;14(11):10.1111/pme.12220.
To examine the temporal stability of conditioned pain modulation (CPM), formerly termed diffuse noxious inhibitory controls (DNIC), among a sample of patients with chronic pain. The study also examined the factors that might be responsible for the stability of CPM.
Design & subjects, and methods
In this test-retest study, patients underwent a series of standardized psychophysical pain testing procedures designed to assess CPM on two separate occasions (i.e., baseline, follow-up). Patients also completed self-report measures of catastrophizing (PCS) and negative affect (NA).
Overall, results provided evidence for the stability of CPM among patients with chronic pain. Results, however, revealed considerable sex differences in the stability of CPM. For women, results revealed a significant test-retest correlation between baseline and follow-up CPM scores. For men, however, the test-retest correlation between baseline and follow-up CPM scores was not significant. Results of a Fisher’s Z-test revealed that the stability of CPM was significantly greater for women than for men. Follow-up analyses revealed that the difference between men and women in the stability of CPM could not be accounted for by any demographic (e.g., age) and/or psychologic factors (PCS, NA).
Our findings suggest that CPM paradigms possess sufficient reliability to be incorporated into bedside clinical evaluation of patients with chronic pain, but only among women. The lack of CPM reproducibility/stability observed among men places limits on the potential use of CPM paradigms in clinical settings for the assessment of men’s endogenous pain-inhibitory function.
PMCID: PMC3833959  PMID: 23924369
Conditioned pain modulation; DNIC; catastrophizing; negative affect; chronic pain
21.  Comparing life expectancy and health-adjusted life expectancy by body mass index category in adult Canadians: a descriptive study 
While many studies have examined differences between body mass index (BMI) categories in terms of mortality risk and health-related quality of life (HRQL), little is known about the effect of body weight on health expectancy. We examined life expectancy (LE), health-adjusted life expectancy (HALE), and proportion of LE spent in nonoptimal (or poor) health by BMI category for the Canadian adult population (age ≥ 20).
Respondents to the National Population Health Survey (NPHS) were followed for mortality outcomes from 1994 to 2009. Our study population at baseline (n=12,478) was 20 to 100 years old with an average age of 47. LE was produced by building abridged life tables by sex and BMI category using data from the NPHS and the Canadian Chronic Disease Surveillance System. HALE was estimated using the Health Utilities Index from the Canadian Community Health Survey as a measure of HRQL. The contribution of HRQL to loss of healthy life years for each BMI category was also assessed using two methods: by calculating differences between LE and HALE proportional to LE and by using a decomposition technique to separate out mortality and HRQL contributions to loss of HALE.
At age 20, for both sexes, LE is significantly lower in the underweight and obesity class 2+ categories, but significantly higher in the overweight category when compared to normal weight (obesity class 1 was nonsignificant). HALE at age 20 follows these same associations and is significantly lower for class 1 obesity in women. Proportion of life spent in nonoptimal health and decomposition of HALE demonstrate progressively higher losses of healthy life associated with lowered HRQL for BMI categories in excess of normal weight.
Although being in the overweight category for adults may be associated with a gain in life expectancy as compared to normal weight adults, overweight individuals also experience a higher proportion of these years of life in poorer health. Due to the descriptive nature of this study, further research is needed to explore the causal mechanisms which explain these results, including the important differences we observed between sexes and within obesity subcategories.
PMCID: PMC3842774  PMID: 24252500
Overweight; Obesity; Underweight; Body mass index; Life expectancy; Health expectancy; Mortality; Health-related quality of life
22.  Prospective Association between Dietary Fiber Intake and Breast Cancer Risk 
PLoS ONE  2013;8(11):e79718.
Mechanistic hypotheses suggest a potential effect of dietary fiber on breast carcinogenesis through the modulation of insulin-like growth factor bioactivity, estrogen metabolism and inflammation. An association between dietary fiber intake and breast cancer risk has been suggested in epidemiological studies but remains inconclusive. In particular, data is lacking regarding the different types of dietary fibers.
The objective was to investigate the prospective relationship between dietary fiber intake and breast cancer risk, taking into account different types of dietary fiber (overall, insoluble, soluble and from different food sources: cereals, vegetables, fruits and legumes).
4684 women from the SU.VI.MAX cohort were included in this analysis as they completed at least three 24h-dietary records within the first two years of follow-up. Among them, 167 incident invasive breast cancers were diagnosed during a median follow-up of 12.6 years (between 1994 and 2007). The associations between quartiles of dietary fiber intake and breast cancer risk were characterized using multivariate Cox proportional hazards models.
Total fiber intake was not associated with breast cancer risk (HRQuartile4vs.Quartile1 = 1.29 (95%CI 0.66–2.50), P-trend = 0.5), nor was fiber intake from cereals (P-trend = 0.1), fruits (P-trend = 0.9) and legumes (P-trend = 0.3). In contrast, vegetable fiber intake was related to a decreased risk of breast cancer (HRQ4vs.Q1 = 0.50 (0.29-0.88), P-trend = 0.03). Overall vegetable intake (in g/day) was not associated with breast cancer risk (P-trend = 0.2).
This prospective study suggests that vegetable fiber intake may contribute to reduce breast cancer risk, in line with experimental mechanistic data.
PMCID: PMC3828192  PMID: 24244548
23.  Temperament and Common Disruptive Behavior Problems in Preschool 
The study evaluated trait associations with common Disruptive Behavior Disorders (DBD), Oppositional Defiant Disorder (ODD) and Attention-Deficit/Hyperactivity Disorder (ADHD), during an understudied developmental period: Preschool. Participants were 109 children ages 3 to 6 and their families. DBD symptoms were available via parent and teacher/caregiver report on the Disruptive Behavior Rating Scale. Traits were measured using observational coding paradigms, and parent and examiner report on the Child Behavior Questionnaire and the California Q-Sort. The DBD groups exhibited significantly higher negative affect, higher surgency, and lower effortful control. Negative affect was associated with most DBD symptom domains; surgency and reactive control were associated with hyperactivity-impulsivity; and effortful control was associated with ADHD and inattention. Interactive effects between effortful control and negative affect and curvilinear associations of reactive control with DBD symptoms were evident. Temperament trait associations with DBD during preschool are similar to those seen during middle childhood. Extreme levels of temperament traits are associated with DBD as early as preschool.
PMCID: PMC3489497  PMID: 23139437
preschool children; behavior problems; Attention-Deficit/Hyperactivity Disorder (ADHD); temperament
24.  Serum and Lymphocytic Neurotrophins Profiles in Systemic Lupus Erythematosus: a Case-Control Study 
PLoS ONE  2013;8(11):e79414.
Neurotrophins play a central role in the development and maintenance of the nervous system. However, neurotrophins can also modulate B and T cell proliferation and activation, especially via autocrine loops. We hypothesized that both serum and lymphocytic neurotrophin levels may be deregulated in systemic Lupus erythematosus (SLE) and may reflect clinical symptoms of the disease.
Neurotrophins in the serum (ELISA tests) and lymphocytes (flow cytometry) were measured in 26 SLE patients and 26 control subjects. Th1 (interferon-γ) and Th2 (IL-10) profiles and serum concentration of BAFF were assessed by ELISA in the SLE and control subjects.
We have demonstrated that both NGF and BDNF serum levels are higher in SLE patients than healthy controls (p=0.003 and p<0.001), independently of Th1 or Th2 profiles. Enhanced serum NT-3 levels (p=0.003) were only found in severe lupus flares (i.e. SLEDAI ≥ 10) and significantly correlated with complement activation (decreased CH 50, Γ=-0.28, p=0.03). Furthermore, there was a negative correlation between serum NGF levels and the number of circulating T regulatory cells (Γ=0.48, p=0.01). In circulating B cells, production of both NGF and BDNF was greater in SLE patients than in healthy controls. In particular, the number of NGF-secreting B cells correlated with decreased complement levels (p=0.05). One month after SLE flare treatment, BDNF levels decreased; in contrast, NGF and NT-3 levels remained unchanged.
This study demonstrates that serum and B cell levels of both NGF and BDNF are increased in SLE, suggesting that the neurotrophin production pathway is deregulated in this disease. These results must be confirmed in a larger study with naive SLE patients, in order to avoid the potential confounding influence of prior immune-modulating treatments on neurotrophin levels.
PMCID: PMC3815153  PMID: 24223945
25.  A Posteriori Comparison of Natural and Surgical Destabilization Models of Canine Osteoarthritis 
BioMed Research International  2013;2013:180453.
For many years Canis familiaris, the domestic dog, has drawn particular interest as a model of osteoarthritis (OA). Here, we optimized the dog model of experimental OA induced by cranial cruciate ligament sectioning. The usefulness of noninvasive complementary outcome measures, such as gait analysis for the limb function and magnetic resonance imaging for structural changes, was demonstrated in this model. Relationships were established between the functional impairment and the severity of structural changes including the measurement of cartilage thinning. In the dog model of naturally occurring OA, excellent test-retest reliability was denoted for the measurement of the limb function. A criterion to identify clinically meaningful responders to therapy was determined for privately owned dogs undergoing clinical trials. In addition, the recording of accelerometer-based duration of locomotor activity showed strong and complementary agreement with the biomechanical limb function. The translation potential of these models to the human OA condition is underlined. A preclinical testing protocol which combines the dog model of experimental OA induced by cranial cruciate ligament transection and the Dog model of naturally occurring OA offers the opportunity to further investigate the structural and functional benefits of disease-modifying strategies. Ultimately, a better prediction of outcomes for human clinical trials would be brought.
PMCID: PMC3833019  PMID: 24288664

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