B cell acute lymphoblastic leukemia associated with t(8;22)(p11.2q11.2): Role of additional cytogenic anomalies

B lymphoblastic leukemia (B-ALL) may be associated with recurrent cytogenetic and molecular abnormalities. We describe the fourth-known case of B-ALL associated with the t(8;22)(p11.2q11.2) – a translocation seen more frequently in T lymphoblastic leukemia and acute myelogenous leukemia. This patient’s leukemia involves a combination of additional cytogenetic anomalies not yet described in the literature, including del(11)(q13q23), add(9)(p22), and monosomy 7. Given the role in B cell differentiation of genes in the affected regions, including MEN1 (11q13), ATM (11q22), ETS1(11q23), MLL (11q23), AF9 (9p22), and IKZ-F1 (7p12), this case may provide further insight into B cell leukemogenesis associated with the t(8;22). Deletion or mutation of these genes may be critical in targeting the B cell population, and this cytogenetic profile of a B-ALL suggests additional gene targets for diagnostic and therapeutic consideration

The Regional Exchange: From Main Street to Shopping Mall to App Info-Structure

The current switch that has now made the shopping center model vulnerable to yet another evolution is the smartphone, which, since its introduction has become an essential component to American lifestyle even more quickly than the car, changing the way in which people engage in both social and commercial activity. Unlike their response to the automobile switch, if architects can recognize and accept the smartphone as a evolutionary tool, then they can take a center role in designing the next major regional exchange. This new social and commercial regional spatial organizer is still desired to be a physical place, however it would be reorganized around the role of the smartphone in this place. It would accept the recent movement of people back to urban cores, maximize a desire for not just physical mobility but also access to information, and balance regional diversity with global demands. It would consist of a range of specialized functions, or “Apps,” that assist, enhance and adapt to everyday activities at multiple scales. If the automobile was able to shift the center of American social and commercial interests from Main Street to Shopping Mall developments, then the smartphone could serve as the switch for the next Regional Exchange: an appbased information infrastructure, an “App Info-Structure.

Ferritin and Percent Transferrin Saturation Levels Predict Type 2 Diabetes Risk and Cardiovascular Disease Outcomes

Introduction: Type 2 diabetes (T2D) and cardiovascular disease (CVD) risk associate withferritin and percent transferrin saturation (%TS) levels. However, increased risk has been observed at levels considered within the “normal range” for these markers. Objective: To define normative ferritin and %TS levels associated with T2D and CVD risk. Methods: Six-monthly ferritin, %TS and hemoglobin levels from 1,277 iron reduction clinical trial participants with CVD (peripheral arterial disease, 37% diabetic) permitted pair-wise analysis using Loess Locally Weighted Smoothing plots. Curves showed continuous quantitative ferritin, hemoglobin (reflecting physiologic iron requirements), and %TS (reflecting iron transport and sequestration) levels over a wide range of values. Inflection points in the curves were compared to ferritin and %TS levels indicating increased T2D and CVD risk in epidemiologic and intervention studies. Results: Increasing ferritin up to about 80 ng/mL and %TS up to about 25% TS corresponded to increasing hemoglobin levels, and minimal T2D and CVD risk. Displaced Loess trajectories reflected lower hemoglobin levels in diabetics compared to non-diabetics. Ferritin levels up to about 100 ng/mL paralleled proportionately increasing %TS levels up to about 55%TS corresponding to further limitation of T2D and CVD risk. Ferritin levels over 100 ng/mL did not associate with hemoglobin levels and coincided with increased T2D and CVD risk. Conclusions: Recognition of modified normal ranges for ferritin from about 15 ng/mL up to about 80- 100 ng/mL and %TS from about 15% up to about 25-55% may improve the value of iron biomarkers to assess and possibly lower T2D and CVD risk

Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

Most traumatic brain injuries (TBIs) during military deployment or training are clinically “mild” and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation

Identification and quantification of particle growth channels during new particle formation

Atmospheric new particle formation (NPF) is a key source of ambient ultrafine particles that may contribute substantially to the global production of cloud condensation nuclei (CCN). While NPF is driven by atmospheric nucleation, its impact on CCN concentration depends strongly on atmospheric growth mechanisms since the growth rate must exceed the loss rate due to scavenging in order for the particles to reach the CCN size range. In this work, chemical composition measurements of 20 nm diameter particles during NPF in Hyytiälä, Finland, in March–April 2011 permit identification and quantitative assessment of important growth channels. In this work we show the following: (A) sulfuric acid, a key species associated with atmospheric nucleation, accounts for less than half of particle mass growth during this time period; (B) the sulfate content of a growing particle during NPF is quantitatively explained by condensation of gas-phase sulfuric acid molecules (i.e., sulfuric acid uptake is collision-limited); (C) sulfuric acid condensation substantially impacts the chemical composition of preexisting nanoparticles before new particles have grown to a size sufficient to be measured; (D) ammonium and sulfate concentrations are highly correlated, indicating that ammonia uptake is driven by sulfuric acid uptake; (E) sulfate neutralization by ammonium does not reach the predicted thermodynamic end point, suggesting that a barrier exists for ammonia uptake; (F) carbonaceous matter accounts for more than half of the particle mass growth, and its oxygen-to-carbon ratio (~ 0.5) is characteristic of freshly formed secondary organic aerosol; and (G) differences in the overall growth rate from one formation event to another are caused by variations in the growth rates of all major chemical species, not just one individual species

Phenotype-genotype association grid: a convenient method for summarizing multiple association analyses

BACKGROUND: High-throughput genotyping generates vast amounts of data for analysis; results can be difficult to summarize succinctly. A single project may involve genotyping many genes with multiple variants per gene and analyzing each variant in relation to numerous phenotypes, using several genetic models and population subgroups. Hundreds of statistical tests may be performed for a single SNP, thereby complicating interpretation of results and inhibiting identification of patterns of association. RESULTS: To facilitate visual display and summary of large numbers of association tests of genetic loci with multiple phenotypes, we developed a Phenotype-Genotype Association (PGA) grid display. A database-backed web server was used to create PGA grids from phenotypic and genotypic data (sample sizes, means and standard errors, P-value for association). HTML pages were generated using Tcl scripts on an AOLserver platform, using an Oracle database, and the ArsDigita Community System web toolkit. The grids are interactive and permit display of summary data for individual cells by a mouse click (i.e. least squares means for a given SNP and phenotype, specified genetic model and study sample). PGA grids can be used to visually summarize results of individual SNP associations, gene-environment associations, or haplotype associations. CONCLUSION: The PGA grid, which permits interactive exploration of large numbers of association test results, can serve as an easily adapted common and useful display format for large-scale genetic studies. Doing so would reduce the problem of publication bias, and would simplify the task of summarizing large-scale association studies

THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage

Background and Purpose A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage (SAH). This study seeks to define a specific gene whose mutation leads to disease. Methods More than 500 IA probands and 100 affected families were enrolled and clinically characterized. Whole exome sequencing was performed on a large family, revealing a segregating THSD1 mutation. THSD1 was sequenced in other probands and controls. Thsd1 loss-of-function studies in zebrafish and mice were used for in vivo analyses, and functional studies performed using an in vitro endothelial cell model. Results A nonsense mutation in THSD1 (thrombospondin type-1 domain-containing protein 1) was identified that segregated with the 9 affected (3 suffered SAH; 6 had unruptured IA) and 13 unaffected family members (LOD score 4.69). Targeted THSD1 sequencing identified mutations in 8 of 507 unrelated IA probands, including 3 who had suffered SAH (1.6% [95% CI, 0.8%–3.1%]). These THSD1 mutations/rare variants were highly enriched in our IA patient cohort relative to 89,040 chromosomes in ExAC database (p\u3c0.0001). In zebrafish and mice, Thsd1 loss-of-function caused cerebral bleeding (which localized to the subarachnoid space in mice) and increased mortality. Mechanistically, THSD1 loss impaired endothelial cell focal adhesion to the basement membrane. These adhesion defects could be rescued by expression of wild-type THSD1 but not THSD1 mutants identified in IA patients. Conclusions This report identifies THSD1 mutations in familial and sporadic IA patients, and shows that THSD1 loss results in cerebral bleeding in two animal models. This finding provides new insight into IA and SAH pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion

Cardiac Repolarization Abnormalities and Potential Evidence for Loss of Cardiac Sodium Currents on ECGs of Patients with Chagas' Heart Disease

Some individuals with Chagas disease develop right precordial lead ST segment elevation in response to an ajmaline challenge test, and the prevalence of right bundle branch block (RBBB) is also high in Chagas disease. Because these same electrocardiographic abnormalities occur in the Brugada syndrome, which involves genetically defective cardiac sodium channels, acquired damage to cardiac sodium channels may also occur in Chagas disease. We studied several conventional and advanced resting 12-lead/derived Frank-lead ECG parameters in 34 patients with Chagas -related heart disease (mean age 39 14 years) and in 34 age-/gender-matched healthy controls. All ECG recordings were of 5-10 min duration, obtained in the supine position using high fidelity hardware/software (CardioSoft, Houston, TX). Even after excluding those Chagas patients who had resting BBBs, tachycardia and/or pathologic arrhythmia (n=8), significant differences remained in multiple conventional and advanced ECG parameters between the Chagas and control groups (n=26/group), especially in their respective QT interval variability indices, maximal spatial QRS-T angles and low frequency HRV powers (p=0.0006, p=0.0015 and p=0.0314 respectively). In relation to the issue of potential damage to cardiac sodium channels, the Chagas patients had: 1) greater than or equal to twice the incidence of resting ST segment elevation in leads V1-V3 (n=10/26 vs. n=5/26) and of both leftward (n=5/26 versus n=0/26) and rightward (n=7/26 versus n=3/26) QRS axis deviation than controls; 2) significantly increased filtered (40-250 Hz) QRS interval durations (92.1 8.5 versus 85.3 plus or minus 9.0 ms, p=0.022) versus controls; and 3) significantly decreased QT and especially JT interval durations versus controls (QT interval: 387.5 plus or minus 26.4 versus 408.9 plus or minus 34.6 ms, p=0.013; JT interval: 290.5 plus or minus 26.3 versus 314.8 plus or minus 31.3 ms; p=0.0029). Heart rates and Bazett-corrected QTc/JTc intervals were not significantly different between groups. Patients with Chagas heart disease have increased cardiac repolarization abnormalities, especially by advanced ECG. Moreover, as a group, they have decreased uncorrected JT and QT interval durations and increased filtered QRS interval durations (versus age/gender-matched controls), all suggesting a potential loss of cardiac sodium channel function that might be mediated, in part, by cardiac autonomic damage. Overall findings support Brugada et al's recent hypothesis that the pathway leading to sudden death may often be similar in Chagas' disease and Brugada syndrome i.e., damage to the sodium channel (infectious/immunologic/autonomic in Chagas' genetic in Brugada) with consequent loss of sodium currents may facilitate a phase II-reentry based arrhythmic substrate for ventricular fibrillation in both conditions. In general, JT interval-related results have been underreported in the Chagas literature