Individual heat map assessments demonstrate vestronidase alfa treatment response in a highly heterogeneous mucopolysaccharidosis VII study population.

Mucopolysaccharidosis (MPS) VII is an ultra-rare, progressively debilitating, life-threatening lysosomal disease caused by deficiency of the enzyme, β-glucuronidase. Vestronidase alfa is an approved enzyme replacement therapy for MPS VII. UX003-CL301 was a phase 3, randomized, placebo-controlled, blind-start study examining the efficacy and safety of vestronidase alfa 4 mg/kg intravenously administered every 2 weeks to 12 patients with MPS VII. Due to the rarity of disease, broad eligibility criteria resulted in a highly heterogeneous population with variable symptoms. For an integrated view of the diverse data, the changes from baseline (or randomization for the placebo period) in clinical endpoints were grouped into three functional domains (mobility, fatigue, and fine motor + self-care) and analyzed post-hoc as subject-level heat maps. Mobility assessments included the 6-minute walk test, 3-minute stair climb test, Bruininks-Oseretsky test (BOT-2) gross motor function subtests, and patient-reported outcome assessments (PROs) related to movement, pain, and ambulation. Fatigue assessments included the Pediatric Quality of Life Multidimensional Fatigue Scale and other fatigue-related PROs. Fine motor + self-care assessments included BOT-2 fine motor function subtests and PROs for eating, dressing, hygiene, and caregiver assistance. Most subjects showed improvement in at least one domain. Two subjects improved in two or more domains and two subjects did not show clear improvement in any domain. Both severely and mildly affected subjects improved with vestronidase alfa in clinical assessments, PRO results, or both. Heat map analysis demonstrates how subjects responded to treatment across multiple domains, providing a useful visual tool for studying rare diseases with variable symptoms

Immune-Mediated Inflammation May Contribute to the Pathogenesis of Cardiovascular Disease in Mucopolysaccharidosis Type I.

BackgroundCardiovascular disease, a progressive manifestation of α-L-iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. Few studies have examined the effects of α-L-iduronidase deficiency and subsequent glycosaminoglycan storage upon arterial gene expression to understand the pathogenesis of cardiovascular disease.MethodsGene expression in carotid artery, ascending, and descending aortas from four non-tolerized, non-enzyme treated 19 month-old mucopolysaccharidosis type I dogs was compared with expression in corresponding vascular segments from three normal, age-matched dogs. Data were analyzed using R and whole genome network correlation analysis, a bias-free method of categorizing expression level and significance into discrete modules. Genes were further categorized based on module-trait relationships. Expression of clusterin, a protein implicated in other etiologies of cardiovascular disease, was assessed in canine and murine mucopolysaccharidosis type I aortas via Western blot and in situ immunohistochemistry.ResultsGene families with more than two-fold, significant increased expression involved lysosomal function, proteasome function, and immune regulation. Significantly downregulated genes were related to cellular adhesion, cytoskeletal elements, and calcium regulation. Clusterin gene overexpression (9-fold) and protein overexpression (1.3 to 1.62-fold) was confirmed and located specifically in arterial plaques of mucopolysaccharidosis-affected dogs and mice.ConclusionsOverexpression of lysosomal and proteasomal-related genes are expected responses to cellular stress induced by lysosomal storage in mucopolysaccharidosis type I. Upregulation of immunity-related genes implicates the potential involvement of glycosaminoglycan-induced inflammation in the pathogenesis of mucopolysaccharidosis-related arterial disease, for which clusterin represents a potential biomarker

Calorimetric Investigation of CeRu2Ge2 up to 8 GPa

We have developed a calorimeter able to give a qualitative picture of the specific heat of a sample under high pressure up to approximately 10 GPa. The principle of ac-calorimetry was adapted to the conditions in a high pressure clamp. The performance of this technique was successfully tested with the measurement of the specific heat of CeRu2Ge2 in the temperature range 1.5 K<T<12 K. The phase diagram of its magnetic phases is consistent with previous transport measurements.Comment: 5 pages, 4 figure

Improved navigator-gated motion compensation in cardiac MR using additional constraint of magnitude of motion-corrupted data

Background. In conventional prospective respiratory navigator (NAV) acquisitions, 40-60% of the acquired data are discarded resulting in low efficiency and long scan times [1,2].Compressed-sensing Motion Compensation (CosMo) has a shorter fixed scan time by acquiring the full inner k-space and estimating the NAV-rejected outer k-space lines [3]. Respiratory motion will mainly manifest itself as phase variation in the acquired k-space data. We sought to determine if the addition of the magnitude of the rejected k-space lines as a constraint in image reconstruction will improve the performance of CosMo. Methods. To investigate the variability of the magnitude of kspace lines at different respiratory phases, free-breathing, ECG-triggered, targeted right coronary images with multiple averages were acquired from 10 healthy adult subjects. Magnitude variability was investigated quantitatively by calculating the cross-correlation between accepted and rejected k-space lines. CosMo was implemented retrospectively on one acquisition from each subject. The inner k-space (31 ky by 7 kz lines) was filled with lines acquired within the 5mm gating window from all acquisitions. The outer kspace was then filled only with lines from the first average acquired within the 5 mm gating window, resulting in an undersampled k-space with a fully sampled center. For reliable image reconstruction with CosMo, 10-20% of the inner k-space must be fully-sampled. The missing outer k-space lines were then estimated using LOST with an additional magnitude constraint within each estimation iteration or in the final iteration for each coil [4]. The results were compared with prospective NAVgating with a gating window of 5 mm and CosMo reconstruction without the magnitude constraint. Results. Figure 1 shows the cross-correlation between the accepted and worst rejected k-space lines for each position. The correlation is close to 1 at the center of kspace where the majority of image information is contained, indicating low variability in magnitude information at different respiratory phases. Figure 2 shows right coronary images acquired using a) fully-sampled, 5-mm gated data, b) the original CosMo, and CosMo with the additional magnitude constraint c) inside each iteration and d) in the final iteration. The relative signal-to-noise in the left ventricle blood pool is: $30.71 \pm 6.5; 40.32 \pm 14.2; 53.9 \pm 26.8; 56.8 \pm 25.9$ for each reconstruction, respectively. Significant differences (p<0.05) are present for all measurements except between the original CosMo and the CosMo image with the magnitude constraint in each iteration (p=0.09). Conclusions. The addition of the magnitude of rejected lines, readily available in all navigator-gated scans, as a constraint in CosMo results in improved image quality as measured by relative SNR. Funding. NIH R01EB008743-01A2

An In Silico Approach for Evaluating a Fraction-Based, Risk Assessment Method for Total Petroleum Hydrocarbon Mixtures

Both the Massachusetts Department of Environmental Protection (MADEP) and the Total Petroleum Hydrocarbon Criteria Working Group (TPHCWG) developed fraction-based approaches for assessing human health risks posed by total petroleum hydrocarbon (TPH) mixtures in the environment. Both organizations defined TPH fractions based on their expected environmental fate and by analytical chemical methods. They derived toxicity values for selected compounds within each fraction and used these as surrogates to assess hazard or risk of exposure to the whole fractions. Membership in a TPH fraction is generally defined by the number of carbon atoms in a compound and by a compound's equivalent carbon (EC) number index, which can predict its environmental fate. Here, we systematically and objectively re-evaluate the assignment of TPH to specific fractions using comparative molecular field analysis and hierarchical clustering. The approach is transparent and reproducible, reducing inherent reliance on judgment when toxicity information is limited. Our evaluation of membership in these fractions is highly consistent (˜80% on average across various fractions) with the empirical approach of MADEP and TPHCWG. Furthermore, the results support the general methodology of mixture risk assessment to assess both cancer and noncancer risk values after the application of fractionation

Controlling laser spectra in a phaseonium photonic crystal using maser

We study the control of quantum resonances in photonic crystals with electromagnetically induced transparency driven by microwave field. In addition to the control laser, the intensity and phase of the maser can alter the transmission and reflection spectra in interesting ways, producing hyperfine resonances through the combined effects of multiple scattering in the superstructure.Comment: 7 pages, 4 figure

Dual electronic states in thermoelectric cobalt oxide

We investigate the low temperature magnetic field dependence of the resistivity in the thermoelectric misfit cobalt oxide [Bi1.7Ca2O4]0.59CoO2 from 60 K down to 3 K. The scaling of the negative magnetoresistance demonstrates a spin dependent transport mechanism due to a strong Hund's coupling. The inferred microscopic description implies dual electronic states which explain the coexistence between localized and itinerant electrons both contributing to the thermopower. By shedding a new light on the electronic states which lead to a high thermopower, this result likely provides a new potential way to optimize the thermoelectric properties

Effects of Neutron Irradiation on Carbon Doped MgB2 Wire Segments

We have studied the evolution of superconducting and normal state properties of neutron irradiated Mg(B$_{.962}$C$_{.038}$)$_2$ wire segments as a function of post exposure annealing time and temperature. The initial fluence fully suppressed superconductivity and resulted in an anisotropic expansion of the unit cell. Superconductivity was restored by post-exposure annealing. The upper critical field, H$_{c2}$(T=0), approximately scales with T$_c$ starting with an undamaged T$_c$ near 37 K and H$_{c2}$(T=0) near 32 T. Up to an annealing temperature of 400 $^ o$C the recovery of T$_c$ tends to coincide with a decrease in the normal state resistivity and a systematic recovery of the lattice parameters. Above 400 $^ o$C a decrease in order along the c- direction coincides with an increase in resistivity, but no apparent change in the evolution of T$_c$ and H$_{c2}$. To first order, it appears that carbon doping and neutron damaging effect the superconducting properties of MgB$_2$ independently

Supernova Remnants in the Magellanic Clouds III: An X-ray Atlas of LMC Supernova Remnants

We have used archival ROSAT data to present X-ray images of thirty-one supernova remnants (SNRs) in the Large Magellanic Cloud (LMC). We have classified these remnants according to their X-ray morphologies, into the categories of Shell-Type, Diffuse Face, Centrally Brightened, Point-Source Dominated, and Irregular. We suggest possible causes of the X-ray emission for each category, and for individual features of some of the SNRs.Comment: 27 pages, 6 figures (9 figure files). To appear in the Supplement Series of the Astrophysical Journal, August 1999 Vol. 123 #