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The goal of this study is to spatially discriminate tumor from treatment effect (TE), within the contrast-enhancing lesion, for brain tumor patients at all stages of treatment. To this end, the diagnostic accuracy of MRI-derived diffusion and perfusion parameters to distinguish pure TE from pure glioblastoma (GBM) was determined utilizing spatially-correlated biopsy samples. From July 2010 through June 2015, brain tumor patients who underwent pre-operative DWI and DSC-MRI and stereotactic image-guided biopsy were considered for inclusion in this IRB-approved study. MRI-derived parameter maps included apparent diffusion coefficient (ADC), normalized cerebral blood flow (nCBF), normalized and standardized relative cerebral blood volume (nRCBV, sRCBV), peak signal-height (PSR) and percent signal-recovery (PSR). These were co-registered to the Stealth MRI and median values extracted from the spatially-matched biopsy regions. A ROC analysis accounting for multiple subject samples was performed, and the optimal threshold for distinguishing TE from GBM determined for each parameter. Histopathologic diagnosis of pure TE (n = 10) or pure GBM (n = 34) was confirmed in tissue samples from 15 consecutive subjects with analyzable data. Perfusion thresholds of sRCBV (3575; SN/SP% = 79.4/90.0), nRCBV (1.13; SN/SP% = 82.1/90.0), and nCBF (1.05; SN/SP% = 79.4/80.0) distinguished TE from GBM (P 0.05), whereas ADC, PSR, and PH could not (P 0.05). The thresholds for CBF and CBV can be applied to lesions with any admixture of tumor or treatment effect, enabling the identification of true tumor burden within enhancing lesions. This approach overcomes current limitations of averaging values from both tumor and TE for quantitative assessments.

Objective To describe preschool neurodevelopmental outcomes of children with complex congenital heart disease (CHD), who were evaluated as part of a longitudinal cardiac neurodevelopmental follow-up program, as recommended by the American Heart Association and the American Academy of Pediatrics, and identify predictors of neurodevelopmental outcomes in these children. Study design Children with CHD meeting the American Heart Association/American Academy of Pediatrics high-risk criteria for neurodevelopmental delay were evaluated at 4-5 years of age. Testing included standardized neuropsychological measures. Parents completed measures of child functioning. Scores were compared by group (single ventricle [1V]; 2 ventricles [2V]; CHD plus known genetic condition) to test norms and classified as: normal (within 1 SD of mean); at risk (1-2 SD from mean); and impaired (>2 SD from mean). Results Data on 102 patients were analyzed. Neurodevelopmental scores did not differ based on cardiac anatomy (1V vs 2V); both groups scored lower than norms on fine motor and adaptive behavior skills, but were within 1 SD of norms. Patients with genetic conditions scored significantly worse than 1V and 2V groups and test norms on most measures. Conclusions Children with CHD and genetic conditions are at greatest neurodevelopmental risk. Deficits in children with CHD without genetic conditions were mild and may not be detected without formal longitudinal testing. Parents and providers need additional education regarding the importance of developmental follow-up for children with CHD.

Approximately 20% to 25% of patients with von Willebrand disease (VWD) have a qualitative defect of the von Willebrand factor (VWF) protein activities. Variant VWD typically is classified as type 1C, 2A, 2B, 2M, or 2N depending on the VWF activity defect. Traditionally, diagnosis has relied on multiple clinical laboratory assays to assign VWD phenotype. We developed an enzyme-linked immunosorbent assay (ELISA) to measure the various activities of VWF on a single plate and evaluated 160 patient samples enrolled in the Zimmerman Program for the Molecular and Clinical Biology of von Willebrand Disease with type 2 VWD. Using linear discriminate analysis (LDA), this assay was able to identify type 1C, 2A, 2B, 2M, or 2N VWD with an overall accuracy of 92.5% in the patient study cohort. LDA jackknife analysis, a statistical resampling technique, identified variant VWD with an overall accuracy of 88.1%, which predicts the assay's performance in the general population. In addition, this assay demonstrated correlation with traditional clinical laboratory VWF assays. The VWF multiplex activity assay may be useful as a same-day screening assay when considering the diagnosis of variant VWD in an individual patient.

Study objective The J-Tip (National Medical Products Inc, Irvine, CA) uses air instead of a needle to push lidocaine into the skin. To our knowledge, no studies have investigated its use for venipuncture in young children. We determine whether the J-Tip decreased venipuncture pain in young children compared with vapocoolant spray. Methods Children aged 1 to 6 years were randomized into 3 groups: intervention (J-Tip), control (vapocoolant spray), and sham (vapocoolant spray and pop of an empty J-Tip). The procedure was videotaped and scored with the Face, Legs, Activity, Cry and Consolability (FLACC) tool at 3 points; baseline, before approach; device, at J-Tip deployment; and at venipuncture. The FLACC tool was scored 0 (none) to 10 (severe). Comparisons of pain scores over time were made with the generalized estimating equation. Venipuncture success and adverse effects were assessed and compared with χ 2 . Results Two hundred five children enrolled: intervention 96, control 53, and sham 56. There were no between-group differences in baseline characteristics. There was no mean change in pain scores from device to venipuncture in the intervention group (0.26; 95% confidence interval [CI] –0.31 to 0.82), but there was an increase in pain in the control (2.82; 95% CI 1.91 to 3.74) and sham (1.68; 95% CI 0.83 to 2.52) groups. This change was greater for the control and sham compared to the intervention group. There was no difference in venipuncture success between groups. No severe adverse events occurred. Minor adverse events were the same between groups. Conclusion Use of the J-Tip for children aged 1 to 6 years reduced venipuncture pain compared with vapocoolant spray or sham treatment.

BACKGROUND: In glioblastoma (GBM), pseudoprogression (PsP) appears as increased enhancement on T1-weighted imaging following concurrent chemoradiotherapy (CRT), making it difficult to distinguish from true progression. This increased enhancement, due to radiation and necrotic induced changes, is associated with effective treatment response. The goal of this study was to determine the ability of measures derived from dynamic susceptibility contrast (DSC) MRI to distinguish radiation effect (RE) and necrosis from GBM. METHODS: All patients gave informed written consent according to IRB policy. Thirty-three tissue samples from 11 previously treated patients were spatially correlated to MRI with a median = 13 days between surgery and MRI. Preload and leakage-corrected metrics of DSC-MRI were co-registered with the pre-surgical Stealth exam, and positive, median values of standardized (sRCBV) or normalized (nRCBV) relative cerebral blood volume, and normalized relative cerebral blood flow (nRCBF) were obtained within 3-mm regions precisely matched to the surgically recorded biopsy locations. Statistical analysis included generalized estimating equations (to account for multiple samples from the same subject) with receiver operator characteristic curves. RESULTS: Gender and median age were similar between tissue groups. Pathologic diagnosis confirmed 11 samples with pure RE/Necrosis and 22 samples with pure GBM. All metrics showed significant differences between RE/Necrosis and GBM (p < 0.001). Interestingly, both sRCBV and nRCBV showed equally higher sensitivity and specificity (81.8%/90.9%, thresholds = 4287 and 1.32, respectively) than nRCBF (72.7%/81.8%, threshold = 1.13) for differentiating RE/Necrosis and GBM. CONCLUSIONS: Accurate assessment of treatment response using measures of DSC-MRI is promising, as these measures show high sensitivity and specificity for differentiating RE/Necrosis and GBM. Both nRCBV and sRCBV provide equally greater accuracy than nRCBF. Visualizing these differentiated regions on imaging could help clinicians better assess treatment response following CRT, with potential to impact treatment management decisions.

International audience; X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1delta4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials.

The diagnosis of von Willebrand disease (VWD) is complicated by issues with current laboratory testing, particularly the ristocetin cofactor activity assay (VWF:RCo). We have recently reported a sequence variation in the von Willebrand factor (VWF) A1 domain, p.D1472H (D1472H), associated with a decrease in the VWF:RCo/VWF antigen (VWF:Ag) ratio but not associated with bleeding in healthy control subjects. This report expands the previous study to include subjects with symptoms leading to the diagnosis of type 1 VWD. Type 1 VWD subjects with D1472H had a significant decrease in the VWF:RCo/VWF:Ag ratio compared with those without D1472H, similar to the findings in the healthy control population. No increase in bleeding score was observed, however, for VWD subjects with D1472H compared with those without D1472H. These results suggest that the presence of the D1472H sequence variation is not associated with a significant increase in bleeding symptoms, even in type 1 VWD subjects.

Studies of the pressure response of the upper esophageal sphincter (UES) to simulated or spontaneous gastroesophageal reflux have shown conflicting results. These discrepancies could result from uncontrolled influence of variables such as posture, volume, and velocity of distension. We characterized in humans the effects of these variables on UES pressure response to esophageal distension.We studied 12 healthy volunteers (average, 27 ± 5 years old; 6 male) using concurrent esophageal infusion and high-resolution manometry to determine UES, lower esophageal sphincter, and intraesophageal pressure values. Reflux events were simulated by distal esophageal injections of room temperature air and water (5, 10, 20, and 50 mL) in individuals in 3 positions (upright, supine, and semisupine). Frequencies of various UES responses were compared using χ(2) analysis. Multinomial logistical regression analysis was used to identify factors that determine the UES response.UES contraction and relaxation were the overriding responses to esophageal water and air distension, respectively, in a volume-dependent fashion (P.001). Water-induced UES contraction and air-induced UES relaxation were the predominant responses among individuals in supine and upright positions, respectively (P.001). The prevalence of their respective predominant response significantly decreased in the opposite position. Proximal esophageal dp/dt significantly and independently differentiated the UES response to infusion with water or air.The UES response to esophageal distension is affected by combined effects of posture (spatial orientation of the esophagus), physical properties, and volume of refluxate, as well as the magnitude and rate of increase in intraesophageal pressure. The UES response to esophageal distension can be predicted using a model that incorporates these factors.

Background In sickle cell disease (SCD), pulmonary hypertension (assessed by tricuspid regurgitant jet [TRJ] velocity ≥ 2.5 m/sec) is associated with increased mortality. The relationships among TRJ velocity and left ventricular (LV) and right ventricular (RV) systolic and diastolic function (i.e., relaxation and compliance) have not been well characterized in SCD. Methods A prospective study was conducted in 53 ambulatory adults with SCD (mean age, 34 years; range, 21–65 years) and 33 African American controls to define the relationship between LV and RV function and TRJ velocity using echocardiography. Results Subjects with SCD had larger left and right atrial volumes and increased LV mass compared with controls. When patients with SCD were compared with controls, LV and RV relaxation (i.e., E′) were similar. Among subjects with SCD, pulmonary hypertension (TRJ ≥ 2.5 m/sec) was present in 40%. Higher TRJ velocity was correlated with larger left atrial volumes in patients with SCD. Additionally, some measures of LV (peak A, lateral and septal annular E/E′ ratio) and RV (tricuspid valve E/E′ ratio) compliance were correlated with TRJ velocity. No other measures of LV and RV systolic function or LV diastolic function (i.e., relaxation and compliance) were associated with TRJ velocity. Conclusions Ambulatory adults with SCD exhibited structural (i.e., LV and RV chamber enlargement) and functional (i.e., higher surrogate measures of LV and RV filling pressure) abnormalities compared with the control group. In subjects with SCD, few abnormalities of LV and RV structure and function were associated with TRJ velocity.

von Willebrand disease (VWD) is a common bleeding disorder, but diagnosis is sometimes challenging because of issues with the current von Willebrand factor (VWF) assays, VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:RCo), used for diagnosis. We evaluated 113 healthy controls and 164 VWD subjects enrolled in the T.S. Zimmerman Program for the Molecular and Clinical Biology of VWD for VWF:Ag, VWF:RCo, and a new enzyme-linked immunosorbent assay (ELISA)–based assay of VWF-glycoprotein Ib (GPIb) interactions using a gain-of-function GPIb construct (tGPIbα235Y;239V) as a receptor to bind its ligand VWF in an assay independent of ristocetin (VWF:IbCo ELISA). Healthy controls, type 1, 2A, 2M, and 2N subjects had VWF:RCo/VWF:Ag ratios similar to the ratio obtained with VWF:IbCo ELISA/VWF:Ag. Type 2B VWD subjects, however, had elevated VWF:IbCo ELISA/VWF:Ag ratios. Type 3 VWD subjects had undetectable (< 1.6 U/dL) VWF:IbCo ELISA values. As previously reported, VWF:RCo/VWF:Ag ratio was decreased with a common A1 domain polymorphism, D1472H, as was direct binding to ristocetin for a 1472H A1 loop construct. The VWF:IbCo ELISA, however, was not affected by D1472H. The VWF:IbCo ELISA may be useful in testing VWF binding to GPIb, discrimination of type 2 variants, and in the diagnosis of VWD as it avoids some of the pitfalls of VWF:RCo assays.

The quinones duroquinone (DQ) and coenzyme Q1(CoQ1) and quinone reductase inhibitors have been used to identify reductases involved in quinone reduction on passage through the pulmonary circulation. In perfused rat lung, NAD(P)H:quinone oxidoreductase 1 (NQO1) was identified as the predominant DQ reductase and NQO1 and mitochondrial complex I as the CoQ1reductases. Since inhibitors have nonspecific effects, the goal was to use Nqo1-null (NQO1−/−) mice to evaluate DQ as an NQO1 probe in the lung. Lung homogenate cytosol NQO1 activities were 97 ± 11, 54 ± 6, and 5 ± 1 (SE) nmol dichlorophenolindophenol reduced·min−1·mg protein−1for NQO1+/+, NQO1+/−, and NQO1−/−lungs, respectively. Intact lung quinone reduction was evaluated by infusion of DQ (50 μM) or CoQ1(60 μM) into the pulmonary arterial inflow of the isolated perfused lung and measurement of pulmonary venous effluent hydroquinone (DQH2or CoQ1H2). DQH2efflux rates for NQO1+/+, NQO1+/−, and NQO1−/−lungs were 0.65 ± 0.08, 0.45 ± 0.04, and 0.13 ± 0.05 (SE) μmol·min−1·g dry lung−1, respectively. DQ reduction in NQO1+/+lungs was inhibited by 90 ± 4% with dicumarol; there was no inhibition in NQO1−/−lungs. There was no significant difference in CoQ1H2efflux rates for NQO1+/+and NQO1−/−lungs. Differences in DQ reduction were not due to differences in lung dry weights, wet-to-dry weight ratios, perfusion pressures, perfused surface areas, or total DQ recoveries. The data provide genetic evidence implicating DQ as a specific NQO1 probe in the perfused rodent lung.

Obesity is associated with impaired endothelial-dependent flow-mediated dilation, a precursor to hypertension and atherosclerosis. Although dieting generally improves cardiovascular risk factors, the direct effect of different dietary strategies on vascular endothelial function is not known. The purpose of this study was to test the hypothesis that a low-fat (LF) diet improves endothelial function compared with an isocaloric low-carbohydrate (LC) diet. Obese (n=20; body mass index: 29 to 39; mean systolic blood pressure: 107 to 125 mm Hg) and otherwise healthy volunteers were randomly assigned to either the American Heart Association modeled LF (30% fat calories) diet or an isocaloric LC Atkins’ style diet (20 g of carbohydrates) for 6 weeks (4-week weight loss and 2-week maintenance phase). Brachial flow-mediated dilation and dilation to nitroglycerin were measured with ultrasound using automated edge detection technology (baseline, week 2, and week 6). Blood pressure, weight loss, and cholesterol profiles were measured throughout the study. Weight loss was similar in LF (100±4 to 96.1±4 kg; P P P P

FMRI voxel time series are complex-valued with real and imaginary parts that are usually converted to magnitude-phase polar coordinates. Magnitude-only data models that discard the phase portion of the data have dominated fMRI analysis. However, when such analyses are performed, the data that is discarded may contain valuable biologic information that is not in the magnitude data. This biologic information from BOLD fMRI data may be vascular [Menon RS. Postacquisition suppression of large-vessel BOLD signals in high-resolution fMRI. Magn Reson Med 2002;47(1):1-9] or neuronal [Bodurka J, Jesmanowicz A, Hyde JS, Xu H, Estowski L, Li S-J. Current-induced magnetic resonance phase imaging. J Magn Reson 1999;137(1):265-71] in origin. When phase-only time series that discard the magnitude portion of the data have been analyzed, ordinary least squares (OLS) regression has been the technique of choice. However, OLS models may fit poorly when phase-wrap or low signal-to-noise ratio (SNR) is present. We have explored alternatives to the OLS model which will account for the angular response of the phase while also allowing us the flexibility to develop similar hypothesis tests. We adopt an angular regression model by Fisher and Lee [Fisher NI, Lee AJ. Regression models for an angular response. Biometrics 1992;48:665-77] for our analysis and show its improvement over the OLS model at low SNR in terms of both parameter estimation and inferences. We found an improvement in parameter estimation along with modeling for the Fisher and Lee method in simulated data while detailing potential benefits when used with experimentally acquired data. Finally, we look at a map of the statistics testing the association of the observed voxel phase time course and the reference function in our acquired data. This shows the possible detection of biological information in the generally discarded phase.

The drug use of 97 adult regular marijuana-user volunteers who were interviewed in 1970 and were re-interviewed in 1976 is presented. At the original interview the majority were using marijuana one to four times per week. By follow-up, most had either decreased to only occasional use or had increased to near daily use. Use of cigarettes, hallucinogens, stimulants, barbiturates, and opiates had declined. Alcohol was being more frequently used at follow-up. Use of nearly all substances reported at the original interview was correlated with the use reported at follow-up. Five global levels of drug use were examined, from those using very little alcohol and no cigarettes (level 1) to marijuana use (level 3) to use of substances from among four categories of “harder” drugs (level 5). The majority of persons had moved to a lower level by follow-up, with only 10% moving to a higher level. Marijuana-use frequency was related to extent of other drug use at the original but not at the follow-up interview. Cessation of harder drug use was found to be best predicted by marriage, and by having friends who were not marijuana users.

Endemic pemphigus foliaceus or Fogo selvagem (FS) is an epidermal organ-specific autoimmune disease mediated by autoantibodies. Individuals at risk are peasants who live and work on farms located in the interior of certain endemic states of Brazil. This case-control study compares a group of 52 FS patients with 52 patients suffering from other dermatoses admitted and followed at the hospital for pemphigus (Hospital do Penfigo) in the city of Goiania, state of Goias. Patients and controls matched 1:1 by age, sex, and occupation were examined by two dermatologists at the time of admission and asked to respond to a prepared questionnaire. This questionnaire concerned current and past (1 and 5 years) exposure to environmental risk factors. The following risk factors were assessed: black fly bites, presence of rodents at home, exposure to cereal dust, exposure to fumes or dust released by tree and shrub removal, and exposure to insecticides. Relative risks were estimated from tabulated data by the odds ratio and tested for significance by the chi-square test. The 95% confidence interval for the odds ratio was also calculated for each of the risk factors. The only risk factor showing an odds ratio significantly different from one was exposure to simuliidae bites (odds ratio 4.7, p less than 0.001). This study reinforces the hypothesis that chronic exposure to black fly antigens may precipitate IgG4 antibody formation in predisposed individuals. These antibodies in turn may cross-react with epidermal antigens and cause acantholysis and the clinical expression of the disease known as FS.

Pentobarbital-anesthetized dogs were studied to determine the relative efficacy of monophasic and biphasic truncated exponential shocks employing a nonthoracotomy internal defibrillation pathway that consisted of a right ventricular catheter electrode (cathode) and a subcutaneous chest wall patch electrode (anode). In part 1 of the experiments, six dogs (19.6 ± 1.1 kg) were utilized. Monophasic pulses of 5, 7.5, 10 and 12.5 ms duration were compared with biphasic pulses of the same total duration. The biphasic pulses had an initial positive phase (P1) followed by a terminal negative phase (P2) with the initial voltage equal for each phase. For each biphasic total pulse width, five relative P1versus P2durations were tested (50 and 50%, 75 and 25%, 90 and 10%, 25 and 75%, 10 and 90%). Ventricular fibrillation was induced by alternating current and pulse configurations were tested randomly to determine the minimal voltage and energy for defibrillation (threshold). Biphasic shocks with P1longer than P2were associated with significantly tower (p < 0.01) energy thresholds than were monophasic shocks. Additionally, there was no significant relation between pulse width and voltage or energy thresholds. In part 2 of the experiments, six dogs (20.2 ± 1.6 kg) were studied. Monophasic shocks were compared with biphasic shocks with P1versus P2durations of 75 aud 25% and 90 and 10% for total puke widths of 7.5, 10 and 12.5 ms. Threshold determinations were performed as in part 1. Subsequently, five initial voltages clustered about threshold were randomly tested four times and dose-response curves constructed for each pulse configuration with the use of stepwise logistic regression. Biphasic shocks resulted in significantly lower energy (p < 0.0001) and voltage (p < 0.001) requirements than did monophasic shocks. There was no difference in energy requirements between the 75 and 25% and 90 and 10% biphasic shocks, although the 75 and 25% shocks were associated with significantly lower (p < 0.001) voltage requirements than the 90 and 10% shocks. These results indicate that biphasic shocks with P1(initial positive phase) longer than P2(terminal negative phase) markedly reduce energy requirements for nonthoracotomy canine defibrilation and may, therefore, facilitate development of nonthoracotomy devices for clinical application.