Metabolic imaging of atrophic muscle tissue using appropriate markers in 1H and 31P NMR spectroscopy

Introduction The purpose of this feasibility study was to demonstrate non-invasive metabolic imaging of human muscular atrophy using significant changes of NMR signals that are related directly or indirectly to fiber necrosis.Methods Single-voxel ¹H NMR spectroscopy and two-dimensional ³¹P spectroscopic imaging on a 1.5-T whole-body scanner were used for in vivo mapping of areas of muscle damage in two cases of differently localized and pronounced atrophy. Spectral patterns affiliated with severe and intermediate stages of degeneration were compared to data of healthy control tissue to derive appropriate metabolic markers related to lipid infiltration or high-energy ³¹P metabolism.Results Reliable detection of atrophic tissue was achieved by the following parameters: (1) liposclerotic turnover is related to a drastic reduction in the water/lipid ¹H signal intensity ratio (up to a factor of 74 compared to adjacent healthy tissue); (2) the ³¹P resonance of phosphocreatine (PCr) is an adequate marker for differentiation of intact myocells with high-energy metabolism from regions dominated by terminal fiber necrosis (PCr signal vanished nearly completely or intensity was reduced by a factor of 3 in affected muscles). Metabolic images based on this signal allowed accurate non-invasive localization of atrophic tissue.Conclusion The molecular information provided by NMR spectroscopy—previously only used with poor localization in atrophy studies—enables access to both the myocell-specific high-energy metabolism and the result of lipid infiltration allowing non-invasive mapping of degenerate tissue. The ability to investigate the results of these advanced levels of atrophy would also be useful for studies of more subtle degrees of denervation.     

Patterns of locoregional failure in locally advanced non-small cell lung cancer treated with definitive conformal radiotherapy: Results from the Gating 2006 trial

Purpose

To determine the patterns of locoregional failure (LRF) in patients with locally advanced non-small cell lung cancer treated with definitive radiotherapy (RT).

Optimization of Sample Preparation for the Identification and Quantification of Saxitoxin in Proficiency Test Mussel Sample using Liquid Chromatography-Tandem Mass Spectrometry

Saxitoxin (STX) and some selected paralytic shellfish poisoning (PSP) analogues in mussel samples were identified and quantified with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Sample extraction and purification methods of mussel sample were optimized for LC-MS/MS analysis. The developed method was applied to the analysis of the homogenized mussel samples in the proficiency test (PT) within the EQuATox project (Establishment of Quality Assurance for the Detection of Biological Toxins of Potential Bioterrorism Risk). Ten laboratories from eight countries participated in the STX PT. Identification of PSP toxins in naturally contaminated mussel samples was performed by comparison of product ion spectra and retention times with those of reference standards. The quantitative results were obtained with LC-MS/MS by spiking reference standards in toxic mussel extracts. The results were within the z-score of ±1 when compared to the results measured with the official AOAC (Association of Official Analytical Chemists) method 2005.06, pre-column oxidation high-performance liquid chromatography with fluorescence detection (HPLC-FLD).     

Contrast-enhanced Ultrasound in Dermatomyositis- and Polymyositis

Objective To evaluate prospectively contrast-enhanced ultrasound (CEUS) in patients suspected of having dermatomyositis or polymyositis. Methods In 35 patients (23 women, 12 men; mean age, 51 years ± 16 years) who were suspected of having dermatomyositis or polymyositis, perfusion in clinically affected skeletal muscles was quantified with contrast-enhanced intermittent power Doppler ultrasound. By applying a modified model that analyzed the replenishment kinetics of microbubbles, the perfusion-related parameters blood flow, local blood volume and blood flow velocity were measured. Findings were compared with muscle biopsy appearances and with the results of MRI that was performed with a 1.5-Tesla unit. Receiver operating characteristic analysis was performed and optimum thresholds for diagnosis of myositis were determined. Results Eleven patients had histologically confirmed dermatomyositis or polymyositis and showed significantly higher blood flow velocity (P = .01 for dermato- and P < .001 for polymyositis), blood flow (P < .001 for dermato- and polymyositis), and blood volume (P = .007 for dermato- and P < .001 for polymyositis) on contrast-enhanced ultrasound than those who did not have myositis. An increase in signal intensity on T2-weighted MR images was found in all patients with myositis. MRI had a sensitivity, specificity, positive (PPV), and negative predicting values (NPV) of 100%, 88%, 77%, and 100% for diagnosis of myositis, respectively. CEUS blood flow was the best ultrasound measure for diagnosis of dermato- or polymyositis with sensitivity, specificity, PPV, and NPV of 73%, 91%, 80%, and 88%, respectively. Conclusions Increased skeletal muscle perfusion measured by CEUS could serve as an additional measurer for the diagnosis of an inflammatory myopathy. Received in revised form: 6 June 2006 An erratum to this article is available at .     

Associations of Perfluoroalkyl Substances (PFAS) with Lower Birth Weight: An Evaluation of Potential Confounding by Glomerular Filtration Rate Using a Physiologically Based Pharmacokinetic Model (PBPK)

Background

Prenatal exposure to perfluoroalkyl substances (PFAS) has been associated with lower birth weight in epidemiologic studies. This association could be attributable to glomerular filtration rate (GFR), which is related to PFAS concentration and birth weight.

Objectives

We used a physiologically based pharmacokinetic (PBPK) model of pregnancy to assess how much of the PFAS–birth weight association observed in epidemiologic studies might be attributable to GFR.

Methods

We modified a PBPK model to reflect the association of GFR with birth weight (estimated from three studies of GFR and birth weight) and used it to simulate PFAS concentrations in maternal and cord plasma. The model was run 250,000 times, with variation in parameters, to simulate a population. Simulated data were analyzed to evaluate the association between PFAS levels and birth weight due to GFR. We compared simulated estimates with those from a meta-analysis of epidemiologic data.

Results

The reduction in birth weight for each 1-ng/mL increase in simulated cord plasma for perfluorooctane sulfonate (PFOS) was 2.72 g (95% CI: –3.40, –2.04), and for perfluorooctanoic acid (PFOA) was 7.13 g (95% CI: –8.46, –5.80); results based on maternal plasma at term were similar. Results were sensitive to variations in PFAS level distributions and the strength of the GFR–birth weight association. In comparison, our meta-analysis of epidemiologic studies suggested that each 1-ng/mL increase in prenatal PFOS and PFOA levels was associated with 5.00 g (95% CI: –21.66, –7.78) and 14.72 g (95% CI: –8.92, –1.09) reductions in birth weight, respectively.

Conclusion

Results of our simulations suggest that a substantial proportion of the association between prenatal PFAS and birth weight may be attributable to confounding by GFR and that confounding by GFR may be more important in studies with sample collection later in pregnancy.

Citation

Verner MA, Loccisano AE, Morken NH, Yoon M, Wu H, McDougall R, Maisonet M, Marcus M, Kishi R, Miyashita C, Chen MH, Hsieh WS, Andersen ME, Clewell HJ III, Longnecker MP. 2015. Associations of perfluoroalkyl substances (PFAS) with lower birth weight: an evaluation of potential confounding by glomerular filtration rate using a physiologically based pharmacokinetic model (PBPK). Environ Health Perspect 123:1317–1324; http://dx.doi.org/10.1289/ehp.1408837     

Measured Prenatal and Estimated Postnatal Levels of Polychlorinated Biphenyls (PCBs) and ADHD-Related Behaviors in 8-Year-Old Children

Background

Epidemiologic studies of postnatal PCB exposure and behavior have not reported consistent evidence of adverse associations, possibly because of challenges in exposure estimation. We previously developed a pharmacokinetic model to improve estimation of children’s PCB exposure.

Objectives

We aimed to assess whether estimated serum PCB levels in infancy are associated with attention deficit/hyperactivity disorder (ADHD)–related behaviors at 8 years of age among children whose cord serum PCB levels were previously shown to be associated with ADHD-related behaviors.

Methods

We used a pharmacokinetic model to estimate monthly serum polychlorinated biphenyl (PCB)–153 levels in 441 infants (ages 1–12 months) based on parameters such as breastfeeding and cord serum PCB-153 levels. Behavior was evaluated at age 8 using the Conners’ Rating Scale for Teachers (CRS-T). Associations between PCB-153 levels and ADHD-related CRS-T indices were assessed using multivariable quantile regression at the 50th and 75th percentiles of CRS-T scores, where higher percentiles reflect more adverse behaviors.

Results

Cord serum PCB-153 levels (median, 38 ng/g lipids) were associated with ADHD-related behaviors, although statistical significance was observed with quantile regression models only at the 75th percentile. Associations with postnatal exposure estimates were attenuated. For example, hyperactive-impulsive behavior scores at age 8 years were 0.9 points (95% CI: 0.2, 2.5), 0.5 points (95% CI: 0.3, 2.3), and 0.3 points (95% CI: –0.2, 1.5) higher in association with interquartile range increases in serum PCB-153 at birth, 2 months, and 12 months of age, respectively.

Conclusions

Associations between estimated postnatal PCB-153 exposures and ADHD-related behaviors at 8 years of age were weaker than associations with PCB-153 concentrations measured in cord serum at birth.

Citation

Verner MA, Hart JE, Sagiv SK, Bellinger DC, Altshul LM, Korrick SA. 2015. Measured prenatal and estimated postnatal levels of polychlorinated biphenyls (PCBs) and ADHD-related behaviors in 8-year-old children. Environ Health Perspect 123:888–894; http://dx.doi.org/10.1289/ehp.1408084