Experimental and initial clinical studies suggest that transplantation of circulating blood- (CPC) or bone marrow-derived (BMC) progenitor cells may beneficially affect postinfarction remodeling ...processes after acute myocardial infarction (AMI). To relate functional characteristics of the infused cells to quantitative measures of outcome at 4-month follow-up, we performed serial contrast-enhanced MRI and assessed the migratory capacity of the transplanted progenitor cells immediately before intracoronary infusion.
In 28 patients with reperfused AMI receiving either BMCs or CPCs into the infarct artery 4.7+/-1.7 days after AMI, serial contrast-enhanced MRI performed initially and after 4 months revealed a significant increase in global ejection fraction (from 44+/-10% to 49+/-10%; P=0.003), a decrease in end-systolic volume (from 69+/-26 to 60+/-28 mL; P=0.003), and unchanged end-diastolic volumes (122+/-34 versus 117+/-37 mL; P=NS). Infarct size, measured as late enhancement (LE) volume, decreased significantly, from 46+/-32 to 37+/-28 mL (P<0.05). There was a significant correlation between the reduction in LE volume and global ejection fraction improvement. The migratory capacity of transplanted cells as assessed ex vivo toward a gradient of vascular endothelial growth factor for CPCs and stromal cell derived factor-1 for BMCs was closely correlated with the reduction of LE volume. By multivariate analysis, migratory capacity remained the most important independent predictor of infarct remodeling.
Analysis of serial contrast-enhanced MRI suggests that intracoronary infusion of adult progenitor cells in patients with AMI beneficially affects postinfarction remodeling processes. The migratory capacity of the infused cells is a major determinant of infarct remodeling, disclosing a causal effect of progenitor cell therapy on regeneration enhancement.
Hypersecretion of central corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of affective disorders. Both, basic and clinical studies suggested that disrupting CRH ...signaling through CRH type 1 receptors (CRH-R1) can ameliorate stress-related clinical conditions. To study the effects of CRH-R1 blockade upon CRH-elicited behavioral and neurochemical changes we created different mouse lines overexpressing CRH in distinct spatially restricted patterns. CRH overexpression in the entire central nervous system, but not when overexpressed in specific forebrain regions, resulted in stress-induced hypersecretion of stress hormones and increased active stress-coping behavior reflected by reduced immobility in the forced swim test and tail suspension test. These changes were related to acute effects of overexpressed CRH as they were normalized by CRH-R1 antagonist treatment and recapitulated the effect of stress-induced activation of the endogenous CRH system. Moreover, we identified enhanced noradrenergic activity as potential molecular mechanism underlying increased active stress-coping behavior observed in these animals. Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system.
Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) ...and overall survival (OS), we carried out a meta-analysis using individual patient level trial data.
Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated.
OS data were available for 912 patients. The median PFS was 3.3months (95% CI 2.9–3.6) and 6-month PFS rate was 27% (95% CI 24–30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3cm versus <3cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2months (95% CI 9.5–11.0) and 1year OS was 43% (95% CI 40–47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS.
Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.
DECT offers additional image datasets with potential benefits, but its use for H&N imaging is not justified unless image quality is preserved without increased radiation dose. The aim of this work ...was to compare image quality and radiation dose between a DE-derived WA image dataset and a standard SECT acquisition of the H&N.
Thirty-two patients underwent DECT of the H&N (tube voltages 80 and Sn140 kVp) and were compared with the last 32 patients who underwent standard SECT (120 kVp) on the same dual-source scanner. WA images from the 2 DE tubes were compared with images obtained with an SE mode. Radiation doses and attenuation measurements of the internal jugular vein, submandibular gland, and sternomastoid and tongue muscles were compared. Objective image noise was compared at 5 anatomic levels. Two blinded readers compared subjective image quality by using 5-point grading scales.
CTDI(vol) was 12% lower with DE than with SECT, a difference of 1.5 mGy, (P < .0001). Objective noise was not significantly different between DE and SECT at any of the anatomic levels (P > .05). No significant differences in attenuation measurements were observed between DE and SECT (P > .05). No significant differences in subjective image quality scores were observed between DE and SECT at any of the 5 anatomic levels (P > .05).
DE-derived WA images of the H&N are equivalent to standard SE acquisitions and thus can be used for routine diagnostic purposes. Multiple additional image datasets can be obtained with no radiation dose penalty.
Cetaceans have massive vascular plexuses (retia mirabilia) whose function is unknown. All cerebral blood flow passes through these retia, and we hypothesize that they protect cetacean brains from ...locomotion-generated pulsatile blood pressures. We propose that cetaceans have evolved a pulse-transfer mechanism that minimizes pulsatility in cerebral arterial-to-venous pressure differentials without dampening the pressure pulses themselves. We tested this hypothesis using a computational model based on morphology from 11 species and found that the large arterial capacitance in the retia, coupled with the small extravascular capacitance in the cranium and vertebral canal, could protect the cerebral vasculature from 97% of systemic pulsatility. Evolution of the retial complex in cetaceans—likely linked to the development of dorsoventral fluking—offers a distinctive solution to adverse locomotion-generated vascular pulsatility.
Protected from pressure
Marine mammals are highly adapted to living underwater. One of the most challenging aspects of this environment is the extreme pressure that animals experience at increasing depth. This condition increases the need for protection of the brain from pulsatile blood flow, something experienced by all mammals. Furthermore, the movement of marine mammal flukes during dives exerts even greater pulsatility. Lillie
et al
. modeled the extensive array of blood vessels, or retia mirabilia, found in cetacean brains across 11 species and concluded that this array minimizes blood pressure differentials, thus protecting the brain without reducing the pressure pulses and facilitating fluking locomotion (see the Perspective by Williams). —SNV
Retia reduce pulsatility in cerebral vasculature by minimizing blood pressure differentials without dampening pressure pulses themselves.
Abstract The mechanical properties of aortic elastin vary regionally, but the microstructural basis for this variation is unknown. This study was designed to identify the relative contributions of ...lamellar and interlamellar elastin to circumferential load bearing in the mouse thoracic and abdominal aortas. Forces developed in uniaxial tests of samples of fresh and autoclaved aorta were correlated with elastin content and morphology obtained from histology and multiphoton laser scanning microscopy. Autoclaving should render much of the interlamellar elastin mechanically incompetent. In autoclaved tissue force per unit sample width correlated with lamellar elastin content ( P ≪0.001) but not total elastin content. In fresh tissue at low strain where elastin dominates the mechanical response, forces were higher than in the autoclaved tissue, but force did not correlate with total elastin content. Therefore although interlamellar elastin likely contributed to the stiffness in the fresh aorta, its contribution appeared not in proportion to its quantity. In both fresh and autoclaved tissue, elastin stiffness consistently decreased along the abdominal aorta, a key area for aneurysm development, and this difference could not be fully accounted for on the basis of either lamellar or total elastin content. These findings are relevant to the development of mathematical models of arterial mechanics, particularly for mouse models of arterial diseases involving elastic tissue. In microstructural based models the quantity of each mural constituent determines its contribution to the total response. This study shows elastin's mechanical response cannot necessarily be accounted for on the basis of fibre quantity, orientation, and modulus.
Urocortin 3 (UCN3) is strongly expressed in specific nuclei of the rodent brain, at sites distinct from those expressing urocortin 1 and urocortin 2, the other endogenous ligands of ...corticotropin-releasing hormone receptor type 2 (CRH-R2). To determine the physiological role of UCN3, we generated UCN3-deficient mice, in which the UCN3 open reading frame was replaced by a tau-lacZ reporter gene. By means of this reporter gene, the nucleus parabrachialis and the premammillary nucleus were identified as previously unknown sites of UCN3 expression. Additionally, the introduced reporter gene enabled the visualization of axonal projections of UCN3-expressing neurons from the superior paraolivary nucleus to the inferior colliculus and from the posterodorsal part of the medial amygdala to the principal nucleus of the bed nucleus of the stria terminalis, respectively. The examination of tau-lacZ reporter gene activity throughout the brain underscored a predominant expression of UCN3 in nuclei functionally connected to the accessory olfactory system. Male and female mice were comprehensively phenotyped but none of the applied tests provided indications for a role of UCN3 in the context of hypothalamic-pituitary-adrenocortical axis regulation, anxiety- or depression-related behavior. However, inspired by the prevalent expression throughout the accessory olfactory system, we identified alterations in social discrimination abilities of male and female UCN3 knock-out mice that were also present in male CRH-R2 knock-out mice. In conclusion, our results suggest a novel role for UCN3 and CRH-R2 related to the processing of social cues and to the establishment of social memories.
We review recent work on low-frequency Floquet engineering and its application to quantum materials driven by light, focusing on van der Waals systems hosting Moiré superlattices. These ...non-equilibrium systems combine the twist-angle sensitivity of the band structure with the flexibility of light drives. The frequency, amplitude, and polarization of light can be tuned in experimental setups, leading to platforms with on-demand properties. First, we review recent theoretical developments to derive effective Floquet Hamiltonians, emphasizing the low-frequency regime. We then review applications of some of these theories to study twisted graphene and transition metal dichalcogenide systems irradiated by light in free space and inside a waveguide. We study the changes induced in the quasienergies and steady-states, which can lead to topological transitions. Next, we consider van der Waals magnetic materials driven by low-frequency light pulses in resonance with the phonons. We discuss the phonon dynamics induced by the light and the resulting magnetic transitions from a Floquet perspective. We finish by outlining new directions for Moiré–Floquet engineering in the low-frequency regime and their relevance for technological applications.
•Review of theoretical and experimental advances in Floquet engineering.•Review of theories to derive effective Floquet Hamiltonians, with a focus on the low-frequency regime.•Review of the theoretical effects of light in Moiré materials.
While EBV PCR is used in the management of PTLD, the optimal primer set, relative importance of intracellular versus free plasma EBV, and the baseline profile in an organ transplant population ...remains unclear. We performed a prospective 2‐arm trial utilizing an EBV PCR panel measuring LMP‐1, EBER‐1 and EBNA‐1 in both free plasma as well as intracellular whole blood. Control Arm A consisted of 31 lung transplant patients and Arm B consisted of 35 transplant patients being evaluated for possible PTLD. In Arm A, 1/31 (3%) patients developed a transient plasma EBV load. Thirteen of 31 (42%) had detectable intracellular EBV. In Arm B, 17 (49%) patients were diagnosed with PTLD. Thirteen (76%) had EBV‐positive PTLD with 12/13 (92%) having detectable EBV by PCR. The EBV PCR panel had a high sensitivity (92%), specificity (72%), positive predictive value (PPV) (71%) and negative predictive value (NPV) (93%) for diagnosing EBV‐positive PTLD and followed patients' clinical course well (p < 0.001). Comparing the individual PCR assays, plasma EBNA PCR was superior with high sensitivity (77%), specificity (100%), PPV (100%) and NPV (86%). We conclude that EBV PCR is a useful test for managing PTLD patients. While plasma EBNA PCR is the best single assay for diagnosing and monitoring PTLD, the complete PCR panel is superior for ruling out its presence.
This study determined that utilizing plasma as a specimen source and gene targets EBNA and EBER in EBV quantitative real‐time PCR assays provided the highest sensitivity and specificity for diagnosing and monitoring PTLD. Therefore an assay that incorporates both gene targets would be the most successful in the management of PTLD patients.
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