Clinical Features, Virus Identification, and Sinusitis as a Complication of Upper Respiratory Tract Illness in Children Ages 4-7 Years.

OBJECTIVE: To determine the rate of sinusitis complicating upper respiratory tract illnesses (URIs) in children. We prospectively identified the clinical, virologic, and epidemiologic characteristics of URIs in a population of 4- to 7-year-old children followed for 1 year. STUDY DESIGN: This was an observational cohort study in 2 primary care pediatric practices in Madison, Wisconsin. Nasal samples were obtained during 4 asymptomatic surveillance visits and during symptomatic URIs. A polymerase chain reaction-based assay for 9 respiratory viruses was performed on nasal samples. A diagnosis of sinusitis was based on published criteria. RESULTS: Two hundred thirty-six children ages 48-96 months were enrolled. A total of 327 URIs were characterized. The mean number of URIs per child was 1.3 (range 0-9) per year. Viruses were detected in 81% of URIs; rhinovirus (RV) was most common. Seventy-two percent of URIs were resolved clinically by the 10th day. RV-A and RV-C were detected more frequently at URI visits; RV-B was detected at the same rate for both asymptomatic surveillance visits and URI visits. Sinusitis was diagnosed in 8.8% of symptomatic URIs. Viruses were detected frequently (33%) in samples from asymptomatic children. CONCLUSIONS: Sinusitis occurred in 8.8% of symptomatic URIs in our study. The virus most frequently detected with URIs in children was RV; RV-A and RV-C detection but not RV-B detection were associated with illness. Viruses, especially RV, are detected frequently in asymptomatic children. Most URIs have improved or resolved by the 10th day after onset. Children experienced a mean of 1.3 URIs per year, which was lower than expected.

Cross-Sectional Survey on Newborn Screening in Wisconsin Amish and Mennonite Communities.

Old Order Amish and Mennonites, or Plain populations, are a growing minority in North America with unique health care delivery and access challenges coupled with higher frequencies of genetic disorders. The objective of this study was to determine newborn screening use and attitudes from western Wisconsin Plain communities. A cross-sectional survey, with an overall response rate of 25 %, provided data representing 2010 children. In households with children (n = 297), the rate of newborn screening was 74 % and all children were screened in 40 % of these households. Lack of access to testing was the most common reason for not screening all children and parental age was inversely associated with testing. The majority of respondents reported some or more knowledge of screening, viewed screening as important, and had access to screening in their communities. Households with children who had never received newborn screening (26 %) reported lower frequencies of favorable responses in all categories compared to households that had at least one child screened. The difference in access to newborn screening was less marked between the groups compared to differences on knowledge and consideration of its importance. Moreover, 55 % of households who had never screened any of their children reported being unlikely or unsure of screening any future children. A focus on improving access to newborn screening alongside establishing approaches to change parental perceptions on the importance of newborn screening is necessary for increasing newborn screening in these Plain communities.

Plasma diacylglycerol composition is a biomarker of metabolic syndrome onset in rhesus monkeys.

Metabolic syndrome is linked with obesity and is often first identified clinically by elevated BMI and elevated levels of fasting blood glucose that are generally secondary to insulin resistance. Using the highly translatable rhesus monkey (Macaca mulatta) model, we asked if metabolic syndrome risk could be identified earlier. The study involved 16 overweight but healthy, euglycemic monkeys, one-half of which spontaneously developed metabolic syndrome over the course of 2 years while the other half remained healthy. We conducted a series of biometric and plasma measures focusing on adiposity, lipid metabolism, and adipose tissue-derived hormones, which led to a diagnosis of metabolic syndrome in the insulin-resistant animals. Plasma fatty acid composition was determined by gas chromatography for cholesteryl ester, FFA, diacylglycerol (DAG), phospholipid, and triacylglycerol lipid classes; plasma lipoprotein profiles were generated by NMR; and circulating levels of adipose-derived signaling peptides were determined by ELISA. We identified biomarker models including a DAG model, two lipoprotein models, and a multiterm model that includes the adipose-derived peptide adiponectin. Correlations among circulating lipids and lipoproteins revealed shifts in lipid metabolism during disease development. We propose that lipid profiling may be valuable for early metabolic syndrome detection in a clinical setting.

A frequency-duty cycle equation for the ACGIH hand activity level.

A new equation for predicting the hand activity level (HAL) used in the American Conference for Government Industrial Hygienists threshold limit value®(TLV®) was based on exertion frequency (F) and percentage duty cycle (D). The TLV® includes a table for estimating HAL from F and D originating from data in Latko et al. (Latko WA, Armstrong TJ, Foulke JA, Herrin GD, Rabourn RA, Ulin SS, Development and evaluation of an observational method for assessing repetition in hand tasks. American Industrial Hygiene Association Journal, 58(4):278-285, 1997) and post hoc adjustments that include extrapolations outside of the data range. Multimedia video task analysis determined D for two additional jobs from Latko's study not in the original data-set, and a new nonlinear regression equation was developed to better fit the data and create a more accurate table. The equation, HAL = 6:56 ln D[F(1:31) /1+3:18 F(1:31), generally matches the TLV® HAL lookup table, and is a substantial improvement over the linear model, particularly for F>1.25 Hz and D>60% jobs. The equation more closely fits the data and applies the TLV® using a continuous function.

The accuracy of conventional 2D video for quantifying upper limb kinematics in repetitive motion occupational tasks.

Marker-less 2D video tracking was studied as a practical means to measure upper limb kinematics for ergonomics evaluations. Hand activity level (HAL) can be estimated from speed and duty cycle. Accuracy was measured using a cross-correlation template-matching algorithm for tracking a region of interest on the upper extremities. Ten participants performed a paced load transfer task while varying HAL (2, 4, and 5) and load (2.2 N, 8.9 N and 17.8 N). Speed and acceleration measured from 2D video were compared against ground truth measurements using 3D infrared motion capture. The median absolute difference between 2D video and 3D motion capture was 86.5 mm/s for speed, and 591 mm/s(2) for acceleration, and less than 93 mm/s for speed and 656 mm/s(2) for acceleration when camera pan and tilt were within ± 30 degrees. Single-camera 2D video had sufficient accuracy (< 100 mm/s) for evaluating HAL. Practitioner Summary: This study demonstrated that 2D video tracking had sufficient accuracy to measure HAL for ascertaining the American Conference of Government Industrial Hygienists Threshold Limit Value(®) for repetitive motion when the camera is located within ± 30 degrees off the plane of motion when compared against 3D motion capture for a simulated repetitive motion task.

Pubertal height velocity and associations with prepubertal and adult heights in cystic fibrosis.

OBJECTIVES: To test the hypothesis that pubertal peak height velocity (PHV) in cystic fibrosis (CF) has improved and is influenced by prepubertal growth and genetic potential. STUDY DESIGN: PHV from 1862 children born in 1984-87 and documented in the 1986-2008 US CF Foundation Registry was determined by statistical modeling and classified into normal, delayed (2-SD > average age), attenuated (magnitude <5th percentile), or both delayed and attenuated (D&A). Genetic potential for height was estimated by parental stature. RESULTS: PHV averaged 8.4 cm/year at age 14.0 years in boys and 7.0 cm/year at age 12.1 years in girls, ∼6-month delay and ∼15% reduction compared with healthy children. PHV was normal in 60%, delayed in 9%, attenuated in 21%, and D&A in 5%. Patients with delayed PHV reached similar adult height percentile (boys: 34th, girls: 46th) to those with normal PHV (boys: 33rd, girls: 34th); both were significantly taller than the attenuated (boys: 11th, girls: 19th) and D&A PHV subgroups (boys: 8th, girls: 14th). Pancreatic-sufficient patients had taller prepubertal and adult heights but similar PHV compared with pancreatic-insufficient or meconium ileus patients. Adjusting for genetic potential reduced adult height percentiles more in boys (from 25th to 16th) than girls (from 28th to 24th). Height at age 7 years, PHV age and magnitude, and parental stature significantly predicted adult height. CONCLUSIONS: Pubertal PHV has improved in children with CF born after mid-1980s compared with older cohorts but remains below normal. Suboptimal prepubertal and pubertal growth led to adult height below genetic potential in CF.

Comparison of hepatitis C virus treatment between incarcerated and community patients.

UNLABELLED: The prevalence of chronic hepatitis C virus (HCV) infection among incarcerated individuals in the United States is estimated to be between 12% and 31%. HCV treatment during incarceration is an attractive option because of improved access to health care and directly observed therapy. We compared incarcerated and nonincarcerated HCV-infected patients evaluated for treatment at a single academic center between January 1, 2002 and December 31, 2007. During this period, 521 nonincarcerated and 388 incarcerated patients were evaluated for HCV treatment. Three hundred and nineteen (61.2%) nonincarcerated patients and 234 (60.3%) incarcerated patients underwent treatment with pegylated interferon and ribavirin. Incarcerated patients were more likely to be male, African-American race, and have a history of alcohol or intravenous drug use. Treated incarcerated patients were less likely to have genotype 1 virus and were less likely to have undergone previous treatment. There was a similar prevalence of coinfection with human immunodeficiency virus (HIV) in both groups. A sustained viral response (SVR) was achieved in 97 (42.9%) incarcerated patients, compared to 115 (38.0%) nonincarcerated patients (P = 0.304). Both groups had a similar proportion of patients that completed a full treatment course. Stepwise logistic regression was conducted, and the final model included full treatment course, non-genotype 1 virus, younger age at treatment start, and negative HIV status. Incarceration status was not a significant predictor when added to this model (P = 0.075). CONCLUSION: In a cohort of HCV-infected patients managed in an academic medical center ambulatory clinic, incarcerated patients were as likely to be treated for HCV and as likely to achieve an SVR as nonincarcerated patients.

Diagnostics for repeated measurements in linear mixed effects models.

Most currently available methods for detecting discordant subjects and observations in linear mixed effects model fits adapt existing methods for single-level regression data. The most common methods are generalizations of deletion-based approaches, primarily Cook's distance. This article describes the limitations of modifications to Cook's distance and local influence, and suggests a new nondeletion subject-level method, studentized residual sum of squares (TRSS) plots. We also suggest a new observation-level deletion method that detects discordant observations as an application of TRSS plots. The proposed method provides greater information on repeated measurements by utilizing revised residuals and efficiently evaluating the effect of discordant subjects and observations on the estimation of parameters including variance components. We compare the performance of the proposed methods with current methods by using the orthodontic growth data: a longitudinal dataset with 27 subjects each observed four times. TRSS plots successfully identified discordant subjects that were missed by modified Cook's distance methods and the local influence approach. Extensions of TRSS plots are also described.

Speech in ALS: Longitudinal Changes in Lips and Jaw Movements and Vowel Acoustics.

PURPOSE: The goal of this exploratory study was to investigate longitudinally the changes in facial kinematics, vowel formant frequencies, and speech intelligibility in individuals diagnosed with bulbar amyotrophic lateral sclerosis (ALS). This study was motivated by the need to understand articulatory and acoustic changes with disease progression and their subsequent effect on deterioration of speech in ALS. METHOD: Lip and jaw movements and vowel acoustics were obtained for four individuals with bulbar ALS during four consecutive recording sessions with an average interval of three months between recordings. Participants read target words embedded into sentences at a comfortable speaking rate. Maximum vertical and horizontal mouth opening and maximum jaw displacements were obtained during corner vowels. First and second formant frequencies were measured for each vowel. Speech intelligibility and speaking rate score were obtained for each session as well. RESULTS: Transient, non-vowel-specific changes in kinematics of the jaw and lips were observed. Kinematic changes often preceded changes in vowel acoustics and speech intelligibility. CONCLUSIONS: Nonlinear changes in speech kinematics should be considered in evaluation of the disease effects on jaw and lip musculature. Kinematic measures might be most suitable for early detection of changes associated with bulbar ALS.

MRI appearance of the proximal hamstring tendons in patients with and without symptomatic proximal hamstring tendinopathy.

OBJECTIVE: The purpose of our study was to determine if six MRI findings of the proximal hamstrings differ in frequency in hamstrings with and without symptoms of tendinopathy. MATERIALS AND METHODS: We reviewed the MRI examinations of 118 consecutive patients who had undergone pelvis MRI and evaluation by a musculoskeletal clinical specialist. The proximal hamstrings were evaluated at four consecutive axial locations for tendon size, internal T1 and T2 signal, peritendinous T2 signal, and ischial tuberosity edema. Statistical analysis was performed to determine the association of the MRI findings with symptomatic hamstring tendinopathy. RESULTS: Twenty-one patients had a clinical diagnosis of unilateral proximal hamstring tendinopathy. The mean width or anteroposterior size was significantly larger in symptomatic hamstrings at all three proximal levels (p = 0.002-0.040). More than 90% of hamstring tendons had increased internal T1 or T2 signal that was not associated with hamstring symptoms. Both hamstrings with and without symptoms of tendinopathy had peritendinous T2 signal, but this was significantly more common in hamstrings with tendinopathy symptoms at the three most distal levels (p = 0.001-0.041). Ischial tuberosity edema and a feathery appearance of the peritendinous T2 signal distally were significantly more common in symptomatic hamstrings (p = 0.004 and 0.001, respectively). CONCLUSION: Increased T1 and T2 signal is commonly seen within the proximal hamstrings but is not associated with symptoms of hamstring tendinopathy. Increased tendon size, peritendinous T2 signal with a distal feathery appearance, and ischial tuberosity edema are significantly associated with symptomatic hamstring tendinopathy but can be seen in asymptomatic individuals.

Ankylosing spondylitis macrophage production of higher levels of interleukin-23 in response to lipopolysaccharide without induction of a significant unfolded protein response.

OBJECTIVE: Previous studies of the HLA-B27-transgenic rat model of ankylosing spondylitis (AS) suggested that macrophages develop an intracellular stress response called the unfolded protein response (UPR) and, as a result, secrete increased amounts of cytokines in response to Toll-like receptor agonists such as lipopolysaccharide (LPS). Our objective was to determine whether macrophages from AS patients also undergo a UPR and secrete increased cytokines/chemokines in response to LPS. METHODS: Peripheral blood monocytes isolated from 10 AS patients and 10 healthy controls were differentiated in vitro with macrophage colony-stimulating factor. Select samples were treated with interferon-γ (IFNγ) to up-regulate class I major histocompatibility complex (HLA-B) expression prior to stimulation with LPS for either 3 hours (for RNA) or 8-24 hours (for supernatant). UPR induction was assessed by measuring the expression of messenger RNA for ERdj4, BiP, and CCAAT/enhancer binding protein homologous protein 10 (CHOP). RESULTS: Although IFNγ treatment up-regulated HLA-B expression (2-fold; P < 0.0001), neither IFNγ nor LPS substantially enhanced BiP or CHOP expression (<1.3-fold). ERdj4 expression increased weakly, but not significantly, in AS samples treated with IFNγ plus LPS (2.2-fold; P = 0.31). In response to LPS, AS macrophages secreted more CXCL9, interleukin-10 (IL-10), IL-12p70, IL-23, and tumor necrosis factor α than did control macrophages (P ≤ 0.025). The most striking difference was observed for IL-23 (median 265 pg/ml in AS patients versus 9 pg/ml in controls; P = 0.0007). We did not detect significant differences in IL-6, IL-8, or IFNß production. CONCLUSION: The greater production of IL-23 by AS patient macrophages in response to LPS provides further support for the development of Th17/IL-23-directed therapy. Since significant UPR induction was not detected in AS patient macrophages, the relationship between UPR and inflammatory cytokine production remains unclear.

Effects of postprandial state and mesenteric blood flow on the repeatability of MR elastography in asymptomatic subjects.

PURPOSE: To determine the repeatability of stiffness measurements in the liver using MR elastography (MRE) during the fasted and fed states. MRE has gained increased recognition as a noninvasive method to quantify fibrotic changes in the liver. It is well known that eating increases splanchnic blood flow, and fasting status of patients has been recognized as a factor that may affect hepatic stiffness measured with MRE. MATERIALS AND METHODS: Hepatic MRE stiffness and flow through the superior mesenteric vein (SMV) were measured in 12 healthy subjects in fasted and fed states, and measurements were repeated 5 weeks later. A linear mixed effects model was used to estimate the sources of variability in the data, which included day (exams on different days) and subject. Sources were combined to calculate the overall standard deviation of a single MRE measurement. RESULTS: The total within-subject standard deviation of an MRE exam is 8.5% (standard error [SE] = 1.7%) or 9.0% (SE = 1.8%) for fasted and fed states, respectively. No significant differences between fasted/fed state stiffness and no correlation between hepatic stiffness and SMV flow were observed. CONCLUSION: As seen in this smaller population, healthy subjects scanned in a known fasted or fed state provide repeatable stiffness estimates with no relationship to SMV flow.

Women's health training in gastroenterology fellowship: a national survey of fellows and program directors.

BACKGROUND AND AIMS: The Gastroenterology Core Curriculum requires training in women's digestive disorders; however, requirements do not necessarily produce knowledge and competence. Our study goals were: (1) to compare perceptions of education, fellow-reported levels of competence, and attitudes towards training in women's gastrointestinal (GI) health issues during fellowship between gastroenterology fellows and program directors, and (2) to determine the barriers for meeting training requirements. METHODS: A national survey assessing four domains of training was conducted. All GI program directors in the United States (n = 153) and a random sample of gastroenterology fellows (n = 769) were mailed surveys. Mixed effects linear modeling was used to estimate all mean scores and to assess differences between the groups. Cronbach's alpha was used to assess the consistency of the measures which make up the means. RESULTS: Responses were received from 61% of program directors and 31% of fellows. Mean scores in perceived didactic education, clinical experiences, and competence in women's GI health were low and significantly differed between the groups (P < 0.0001). Fellows' attitudes towards women's GI health issues were more positive compared to program directors' (P = 0.004). Barriers to training were: continuity clinic at a Veteran's Administration hospital, low number of pregnant patients treated, low number of referrals from obstetrics and gynecology, and lack of faculty interest in women's health. CONCLUSIONS: (1) Fellows more so than program directors perceive training in women's GI health issues to be low. (2) Program directors more so than fellows rate fellows to be competent in women's GI health. (3) Multiple barriers to women's health training exist.

Repeatability of magnetic resonance elastography for quantification of hepatic stiffness.

PURPOSE: To determine the sources of variability of MRE hepatic stiffness measurements using healthy volunteers and patients and to calculate the minimum change required for statistical significance. Hepatic stiffness measured with magnetic resonance elastography (MRE) has demonstrated tremendous potential as a noninvasive surrogate of hepatic fibrosis, although the underlying repeatability of MRE for longitudinal tracking of liver disease has not been documented. MATERIALS AND METHODS: MRE stiffness measurements from 20 healthy volunteers and 10 patients were obtained twice on the same day, and repeated 2-4 weeks later for volunteers in this institutional review board-approved study. A linear mixed effects model was used to estimate the component sources of variability in the data. RESULTS: The standard deviation of MRE measurements of the same individual on different days is 11.9% (percent of the measured stiffness) using the same reader and 12.0% using different readers. The standard deviation of the difference between two measurements (i.e., longitudinal change in an individual) is 17.4%; the corresponding 95% confidence interval for zero change is (-27.0%, 37.0%). CONCLUSION: MRE is a repeatable method for quantifying liver stiffness. Using the described MRE technique, changes greater than 37.0% of the smaller measured stiffness value represent meaningful changes in longitudinal liver stiffness measurements.

Hepatic steatosis (fatty liver disease) in asymptomatic adults identified by unenhanced low-dose CT.

OBJECTIVE: The purpose of this study was to investigate the prevalence of hepatic steatosis in an asymptomatic U.S. adult population using attenuation values at unenhanced CT as the reference standard. We also assessed the utility of known clinical risk factors for diagnosis. MATERIALS AND METHODS: For 3,357 consecutive asymptomatic adults (1,865 women and 1,492 men; mean age, 57.0 years), hepatic and splenic CT attenuation values (Hounsfield units) were obtained by unenhanced CT using a low-dose colonography technique for colorectal cancer screening. Multiple attenuation criteria for steatosis were applied, including liver thresholds and comparison of liver and spleen attenuation. Relevant clinical risk factors were compared against a CT liver attenuation < or = 40 HU, which has been shown to exclude mild steatosis. RESULTS: Mean liver attenuation was 58.8 +/- 10.8 (SD) HU. The prevalence of moderate-to-severe hepatic steatosis (defined by liver attenuation < or = 40 HU) was 6.2% (208/3,357). For CT attenuation criteria that include milder degrees of steatosis, prevalence increased to as high as 45.9% (1,542/3,357) for a liver-to-spleen attenuation ratio of < or = 1.1. Overweight status (body mass index > 25) was a sensitive indicator for moderate-to-severe steatosis (92.8%) but was highly nonspecific (37.5%). Other clinical risk factors, such as diabetes, dyslipidemia, hypertension, alcohol overuse, and hepatitis, were more specific (77.6-92.4%) but highly insensitive (1.9-37.5%). Combining clinical risk factors did not substantially increase the accuracy for screening. CONCLUSION: Assessment of liver attenuation by use of unenhanced CT represents an objective and noninvasive means for detection of asymptomatic hepatic steatosis, whereas clinical risk factor assessment is unreliable. Further longitudinal investigation is needed to determine the most appropriate attenuation threshold and the risk for disease progression to steatohepatitis and cirrhosis.

Probabilistic computer model developed from clinical data in national mammography database format to classify mammographic findings.

PURPOSE: To determine whether a Bayesian network trained on a large database of patient demographic risk factors and radiologist-observed findings from consecutive clinical mammography examinations can exceed radiologist performance in the classification of mammographic findings as benign or malignant. MATERIALS AND METHODS: The institutional review board exempted this HIPAA-compliant retrospective study from requiring informed consent. Structured reports from 48 744 consecutive pooled screening and diagnostic mammography examinations in 18 269 patients from April 5, 1999 to February 9, 2004 were collected. Mammographic findings were matched with a state cancer registry, which served as the reference standard. By using 10-fold cross validation, the Bayesian network was tested and trained to estimate breast cancer risk by using demographic risk factors (age, family and personal history of breast cancer, and use of hormone replacement therapy) and mammographic findings recorded in the Breast Imaging Reporting and Data System lexicon. The performance of radiologists compared with the Bayesian network was evaluated by using area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. RESULTS: The Bayesian network significantly exceeded the performance of interpreting radiologists in terms of AUC (0.960 vs 0.939, P = .002), sensitivity (90.0% vs 85.3%, P < .001), and specificity (93.0% vs 88.1%, P < .001). CONCLUSION: On the basis of prospectively collected variables, the evaluated Bayesian network can predict the probability of breast cancer and exceed interpreting radiologist performance. Bayesian networks may help radiologists improve mammographic interpretation.

Knee joint: comprehensive assessment with 3D isotropic resolution fast spin-echo MR imaging--diagnostic performance compared with that of conventional MR imaging at 3.0 T.

PURPOSE: To determine whether a three-dimensional isotropic resolution fast spin-echo sequence (FSE-Cube) has similar diagnostic performance as a routine magnetic resonance (MR) imaging protocol for evaluating the cartilage, ligaments, menisci, and osseous structures of the knee joint in symptomatic patients at 3.0 T. MATERIALS AND METHODS: This prospective, HIPAA-compliant, institutional review board-approved study was performed with a waiver of informed consent. FSE-Cube was added to the routine 3.0-T MR imaging protocol performed in 100 symptomatic patients (54 male patients with a median age of 32 years and 46 female patients with a median age of 33 years) who subsequently underwent arthroscopic knee surgery. All MR imaging studies were independently reviewed twice by two musculoskeletal radiologists. During the first review, the routine MR imaging protocol was used to detect cartilage lesions, ligament tears, meniscal tears, and bone marrow edema lesions. During the second review, FSE-Cube with multiplanar reformations was used to detect these joint abnormalities. With arthroscopic results as the reference standard, the sensitivity and specificity of FSE-Cube and the routine MR imaging protocol in the detection of cartilage lesions, anterior cruciate ligament tears, and meniscal tears were calculated. Permutation tests were used to compare sensitivity and specificity values. RESULTS: FSE-Cube had significantly higher sensitivity (P = .039) but significantly lower specificity (P = .003) than the routine MR imaging protocol for detecting cartilage lesions. There were no significant differences (P = .183-.999) in sensitivity and specificity between FSE-Cube and the routine MR imaging protocol in the detection of anterior cruciate ligament tears, medial meniscal tears, or lateral meniscal tears. FSE-Cube depicted 96.2% of medial collateral ligament tears, 100% of lateral collateral ligament tears, and 85.3% of bone marrow edema lesions identified on images obtained with the routine MR imaging protocol. CONCLUSION: FSE-Cube has similar diagnostic performance as a routine MR imaging protocol for detecting cartilage lesions, cruciate ligament tears, collateral ligament tears, meniscal tears, and bone marrow edema lesions within the knee joint at 3.0 T.

A logistic regression model based on the national mammography database format to aid breast cancer diagnosis.

OBJECTIVE: The purpose of our study was to create a breast cancer risk estimation model based on the descriptors of the National Mammography Database using logistic regression that can aid in decision making for the early detection of breast cancer. MATERIALS AND METHODS: We created two logistic regression models based on the mammography features and demographic data for 62,219 consecutive mammography records from 48,744 studies in 18,269 [corrected] patients reported using the Breast Imaging Reporting and Data System (BI-RADS) lexicon and the National Mammography Database format between April 5, 1999 and February 9, 2004. State cancer registry outcomes matched with our data served as the reference standard. The probability of cancer was the outcome in both models. Model 2 was built using all variables in Model 1 plus radiologists' BI-RADS assessment categories. We used 10-fold cross-validation to train and test the model and to calculate the area under the receiver operating characteristic curves (A(z)) to measure the performance. Both models were compared with the radiologists' BI-RADS assessments. RESULTS: Radiologists achieved an A(z) value of 0.939 +/- 0.011. The A(z) was 0.927 +/- 0.015 for Model 1 and 0.963 +/- 0.009 for Model 2. At 90% specificity, the sensitivity of Model 2 (90%) was significantly better (p < 0.001) than that of radiologists (82%) and Model 1 (83%). At 85% sensitivity, the specificity of Model 2 (96%) was significantly better (p < 0.001) than that of radiologists (88%) and Model 1 (87%). CONCLUSION: Our logistic regression model can effectively discriminate between benign and malignant breast disease and can identify the most important features associated with breast cancer.

Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction.

PURPOSE: To test the efficacy of resveratrol, a nontoxic plant product, in the treatment of uveal melanoma. METHODS: The effect of oral administration and peritumor injection of resveratrol was tested on tumor growth in two animal models of uveal melanoma. The mechanism of resveratrol action on uveal melanoma cells was studied in vitro in a cell-viability assay: with JC-1 dye, to measure mitochondrial membrane potential; by Western blot analysis, to analyze the cellular redistribution of cytochrome c and Smac/diablo; and in a fluorescence assay with specific substrates, to measure activation of different caspases. RESULTS: Resveratrol treatment inhibited tumor growth in animal models of uveal melanoma. Since oral administration resulted in relatively low bioavailability of resveratrol, the effect of increased local levels was tested by peritumor injection of the drug. This method resulted in tumor cell death and tumor regression. In vitro experiments with multiple uveal melanoma cell lines demonstrate that resveratrol causes a decrease in cell viability, resulting at least in part from an increase in apoptosis through a mitochondrial pathway. An early event in drug action is the direct targeting of mitochondria by resveratrol, which leads to a decrease in mitochondrial membrane potential and the eventual activation of caspase-3. CONCLUSION: These data suggest that resveratrol can inhibit tumor growth and can induce apoptosis via the intrinsic mitochondrial pathway and that by further increasing bioavailability of resveratrol the potency of the drug can be increased, leading to tumor regression. The nontoxic nature of the drug at levels needed for therapy make resveratrol an attractive candidate for the treatment of uveal melanoma.

Resveratrol inhibits tumor growth of human neuroblastoma and mediates apoptosis by directly targeting mitochondria.

PURPOSE: Neuroblastoma is an aggressive childhood disease of the sympathetic nervous system. Treatments are often ineffective and have serious side effects. Because resveratrol, a natural plant product, has been reported to have limited toxicity at chemotherapeutic levels, we investigated its efficacy in the treatment of neuroblastoma as well as its underlying mechanism of action. EXPERIMENTAL DESIGN: Resveratrol was tested in mouse xenograft models of human neuroblastoma and in vitro using human cell lines. RESULTS: Resveratrol inhibited the outgrowth of tumors by as much as 80%. The bioavailability of the drug in serum was in the low micromolar range (2-10 micromol/L) and no accumulation was observed in tumor tissue. When resveratrol levels were increased by peritumor injection, rapid tumor regression occurred. Resveratrol decreased tumor cell viability in vitro by 75% to 90%, resulting from an inhibition of cell proliferation and an induction of apoptosis. Loss of mitochondrial membrane potential was an early response to resveratrol. In addition, resveratrol treatment of isolated mitochondria also led to depolarization, suggesting that the drug may target mitochondria directly. Following depolarization, resveratrol caused the release of cytochrome c and Smac/Diablo from the mitochondria and subsequently the activation of caspase-9 (4- to 8-fold) and caspase-3 (4- to 6-fold). CONCLUSIONS: These studies indicate that, despite low bioavailability, resveratrol is effective at inhibiting tumor growth. Elevated levels of resveratrol enhance its antitumor potency leading to tumor regression, associated with widespread tumor cell death, the underlying mechanism of which involves the direct activation of the mitochondrial intrinsic apoptotic pathway.