Retinal Dysplasia Mimicking Retinoblastoma.

Retinal dysplasia represents a congenital disorder characterized by abnormal proliferation of retinal tissue causing leukocoria. We present a case of an infant with bilateral leukocoria, clinically diagnosed as retinoblastoma, followed by enucleation of the left eye. Microscopy however, demonstrated retinal dysplasia consisting of a disorderly proliferation of retinal tissue with formation of rosettes, mimicking retinoblastoma. Microscopic features that aid in differentiating this lesion from retinoblastoma are discussed

Dynamical Jahn-Teller Effect in Spin-Orbital Coupled System

Dynamical Jahn-Teller (DJT) effect in a spin-orbital coupled system on a honeycomb lattice is examined, motivated from recently observed spin-liquid behavior in Ba$_3$CuSb$_2$O$_9$. An effective vibronic Hamiltonian, where the superexchange interaction and the DJT effect are taken into account, is derived. We find that the DJT effect induces a spin-orbital resonant state where local spin-singlet states and parallel orbital configurations are entangled with each other. This spin-orbital resonant state is realized in between an orbital ordered state, where spin-singlet pairs are localized, and an antiferromagnetic ordered state. Based on the theoretical results, a possible scenario for Ba$_3$CuSb$_2$O$_9$ is proposed.Comment: 13 pages, 8 figures, to be published in PR

Acoustic-Structure Interaction in Rocket Engines: Validation Testing

While analyzing a rocket engine component, it is often necessary to account for any effects that adjacent fluids (e.g., liquid fuels or oxidizers) might have on the structural dynamics of the component. To better characterize the fully coupled fluid-structure system responses, an analytical approach that models the system as a coupled expansion of rigid wall acoustic modes and in vacuo structural modes has been proposed. The present work seeks to experimentally validate this approach. To experimentally observe well-coupled system modes, the test article and fluid cavities are designed such that the uncoupled structural frequencies are comparable to the uncoupled acoustic frequencies. The test measures the natural frequencies, mode shapes, and forced response of cylindrical test articles in contact with fluid-filled cylindrical and/or annular cavities. The test article is excited with a stinger and the fluid-loaded response is acquired using a laser-doppler vibrometer. The experimentally determined fluid-loaded natural frequencies are compared directly to the results of the analytical model. Due to the geometric configuration of the test article, the analytical model is found to be valid for natural modes with circumferential wave numbers greater than four. In the case of these modes, the natural frequencies predicted by the analytical model demonstrate excellent agreement with the experimentally determined natural frequencies

Reversal of oral anticoagulation in patients with acute intracerebral hemorrhage

In light of an aging population with increased cardiovascular comorbidity, the use of oral anticoagulation (OAC) is steadily expanding. A variety of pharmacological alternatives to vitamin K antagonists (VKA) have emerged over recent years (direct oral anticoagulants, DOAC, i.e., dabigatran, rivaroxaban, apixaban, and edoxaban) which show a reduced risk for the occurrence of intracerebral hemorrhage (ICH). Yet, in the event of ICH under OAC (OAC-ICH), hematoma characteristics are similarly severe and clinical outcomes likewise substantially limited in both patients with VKA- and DOAC-ICH, which is why optimal acute hemostatic treatment in all OAC-ICH needs to be guaranteed. Currently, International Guidelines for the hemostatic management of patients with OAC-ICH are updated as several relevant large-sized observational studies and recent trials have established treatment approaches for both VKA- and DOAC-ICH. While the management of VKA-ICH is mainly based on the immediate reversal of elevated levels of international normalized ratio using prothrombin complex concentrates, hemostatic management of DOAC-associated ICH is challenging requiring specific antidotes, notably idarucizumab and andexanet alfa. This review will provide an overview of the latest studies and trials on hemostatic reversal agents and timing and summarizes the effects on hemorrhage progression and clinical outcomes in patients with OAC-ICH

Tracking Single Cells in Live Animals Using a Photoconvertible Near-Infrared Cell Membrane Label

We describe a novel photoconversion technique to track individual cells in vivo using a commercial lipophilic membrane dye, DiR. We show that DiR exhibits a permanent fluorescence emission shift (photoconversion) after light exposure and does not reacquire the original color over time. Ratiometric imaging can be used to distinguish photoconverted from non-converted cells with high sensitivity. Combining the use of this photoconvertible dye with intravital microscopy, we tracked the division of individual hematopoietic stem/progenitor cells within the calvarium bone marrow of live mice. We also studied the peripheral differentiation of individual T cells by tracking the gain or loss of FoxP3-GFP expression, a marker of the immune suppressive function of CD4+ T cells. With the near-infrared photoconvertible membrane dye, the entire visible spectral range is available for simultaneous use with other fluorescent proteins to monitor gene expression or to trace cell lineage commitment in vivo with high spatial and temporal resolution

Peak Troponin I Levels Are Associated with Functional Outcome in Intracerebral Hemorrhage

Background: Troponin I is a widely used and reliable marker of myocardial damage and its levels are routinely measured in acute stroke care. So far, the influence of troponin I elevations during hospital stay on functional outcome in patients with atraumatic intracerebral hemorrhage (ICH) is unknown. Methods: Observational single-center study including conservatively treated ICH patients over a 9-year period. Patients were categorized according to peak troponin I level during hospital stay (≤0.040, 0.041–0.500, > 0.500 ng/mL) and compared regarding baseline and hematoma characteristics. Multivariable analyses were performed to investigate independent associations of troponin levels during hospital stay with functional outcome – assessed using the modified Rankin Scale (mRS; favorable 0–3/unfavorable 4–6) – and mortality after 3 and 12 months. To account for possible confounding propensity score (PS)-matching (1: 1; caliper 0.1) was performed accounting for imbalances in baseline characteristics to investigate the impact of troponin I values on outcome. Results: Troponin elevations (> 0.040 ng/mL) during hospital stay were observed in 308 out of 745 (41.3%) patients and associated with poorer status on admission (Glasgow Coma Scale/National Institute of Health Stroke Scale). Multivariable analysis revealed troponin I levels during hospital stay to be independently associated with unfavorable outcome after 12 months (risk ratio [95% CI]: 1.030 [1.009–1.051] per increment of 1.0 ng/mL; p = 0.005), but not with mortality. After PS-matching, patients with troponin I elevation (≥0.040 ng/mL) versus those without had a significant higher rate of ­unfavorable outcome after 3 and 12 months (mRS 4–6 at 3 months: < 0.04 ng/mL: 159/265 [60.0%] versus ≥0.04 ng/mL: 199/266 [74.8%]; p < 0.001; at 12 months: < 0.04 ng/mL: 141/248 [56.9%] versus ≥0.04 ng/mL: 179/251 [71.3%]; p = 0.001). Conclusions: Troponin I elevations during hospital stay occur frequently in ICH patients and are independently associated with functional outcome after 3 and 12 months but not with mortality

Clinic Blood Pressure Underestimates Ambulatory Blood Pressure in an Untreated Employer-Based US Population: Results From the Masked Hypertension Study

Background: Ambulatory blood pressure (ABP) is consistently superior to clinic blood pressure (CBP) as a predictor of cardiovascular morbidity and mortality risk. A common perception is that ABP is usually lower than CBP. The relationship of the CBP minus ABP difference to age has not been examined in the United States. Methods: Between 2005 and 2012, 888 healthy, employed, middle-aged (mean±SD age, 45±10.4 years) individuals (59% female, 7.4% black, 12% Hispanic) with screening BP <160/105 mm Hg and not taking antihypertensive medication completed 3 separate clinic BP assessments and a 24-hour ABP recording for the Masked Hypertension Study. The distributions of CBP, mean awake ABP (aABP), and the CBP−aABP difference in the full sample and by demographic characteristics were compared. Locally weighted scatterplot smoothing was used to model the relationship of the BP measures to age and body mass index. The prevalence of discrepancies in ABP- versus CBP-defined hypertension status—white-coat hypertension and masked hypertension—were also examined. Results: Average systolic/diastolic aABP (123.0/77.4±10.3/7.4 mm Hg) was significantly higher than the average of 9 CBP readings over 3 visits (116.0/75.4±11.6/7.7 mm Hg). aABP exceeded CBP by >10 mm Hg much more frequently than CBP exceeded aABP. The difference (aABP>CBP) was most pronounced in young adults and those with normal body mass index. The systolic difference progressively diminished, but did not disappear, at older ages and higher body mass indexes. The diastolic difference vanished around age 65 and reversed (CBP>aABP) for body mass index >32.5 kg/m2. Whereas 5.3% of participants were hypertensive by CBP, 19.2% were hypertensive by aABP; 15.7% of those with nonelevated CBP had masked hypertension. Conclusions: Contrary to a widely held belief, based primarily on cohort studies of patients with elevated CBP, ABP is not usually lower than CBP, at least not among healthy, employed individuals. Furthermore, a substantial proportion of otherwise healthy individuals with nonelevated CBP have masked hypertension. Demonstrated CBP−aABP gradients, if confirmed in representative samples (eg, NHANES [National Health and Nutrition Examination Survey]), could provide guidance for primary care physicians as to when, for a given CBP, 24-hour ABP would be useful to identify or rule out masked hypertension

Hematopoietic Stem Cells Are the Major Source of Multilineage Hematopoiesis in Adult Animals

Hematopoietic stem cells (HSCs) sustain long-term reconstitution of hematopoiesis in transplantation recipients, yet their role in the endogenous steady-state hematopoiesis remains unclear. In particular, recent studies suggested that HSCs provide a relatively minor contribution to immune cell development in adults. We directed transgene expression in a fraction of HSCs that maintained reconstituting activity during serial transplantations. Inducible genetic labeling showed that transgene-expressing HSCs gave rise to other phenotypic HSCs, confirming their top position in the differentiation hierarchy. The labeled HSCs rapidly contributed to committed progenitors of all lineages and to mature myeloid cells and lymphocytes, but not to B-1a cells or tissue macrophages. Importantly, labeled HSCs gave rise to more than two-thirds of all myeloid cells and platelets in adult mice, and this contribution could be accelerated by an induced interferon response. Thus, classically defined HSCs maintain immune cell development in the steady state and during systemic cytokine responses

Effect of Inhibition of the Lysophosphatidic Acid Receptor 1 on Metastasis and Metastatic Dormancy in Breast Cancer

Background Previous studies identified the human nonmetastatic gene 23 (NME1, hereafter Nm23-H1) as the first metastasis suppressor gene. An inverse relationship between Nm23-H1 and expression of lysophosphatidic acid receptor 1 gene (LPAR1, also known as EDG2 or hereafter LPA1) has also been reported. However, the effects of LPA1 inhibition on primary tumor size, metastasis, and metastatic dormancy have not been investigated. Methods The LPA1 inhibitor Debio-0719 or LPA1 short hairpinned RNA (shRNA) was used. Primary tumor size and metastasis were investigated using the 4T1 spontaneous metastasis mouse model and the MDA-MB-231T experimental metastasis mouse model (n = 13 mice per group). Proliferation and p38 intracellular signaling in tumors and cell lines were determined by immunohistochemistry and western blot to investigate the effects of LPA1 inhibition on metastatic dormancy. An analysis of variance-based two-tailed t test was used to determine a statistically significant difference between treatment groups. Results In the 4T1 spontaneous metastasis mouse model, Debio-0719 inhibited the metastasis of 4T1 cells to the liver (mean = 25.2 liver metastases per histologic section for vehicle-treated mice vs 6.8 for Debio-0719-treated mice, 73.0% reduction, P < .001) and lungs (mean = 6.37 lesions per histologic section for vehicle-treated mice vs 0.73 for Debio-0719-treated mice, 88.5% reduction, P < .001), with no effect on primary tumor size. Similar results were observed using the MDA-MB-231T experimental pulmonary metastasis mouse model. LPA1 shRNA also inhibited metastasis but did not affect primary tumor size. In 4T1 metastases, but not primary tumors, expression of the proliferative markers Ki67 and pErk was reduced by Debio-0719, and phosphorylation of the p38 stress kinase was increased, indicative of metastatic dormancy. Conclusion The data identify Debio-0719 as a drug candidate with metastasis suppressor activity, inducing dormancy at secondary tumor site