The Mare Reproductive Loss Syndrome and the Eastern Tent Caterpillar II: A Toxicokinetic/Clinical Evaluation and a Proposed Pathogenesis: Septic Penetrating Setae

Reviewing the mare reproductive loss syndrome (MRLS), it is proposed that the fundamental mechanism of this syndrome, which includes early fetal loss, late fetal loss, uveitis, pericarditis, and encephalitis, is tissue penetration by septic barbed setal fragments (septic penetrating setae) from Eastern tent caterpillars (Malacosoma americanum). Once ingested, these barbed setal fragments migrate through moving tissues, followed by rapid hematogenous spread of bacteria, bacterial emboli, and/or septic fragments of setae (septic penetrating setal emboli), collectively referred to as septic materials. Pathogenic bacteria, therefore, enter the horse as hitchhikers on or in the caterpillar setal fragments, and MRLS is caused by 1) the barbed setal fragments’ ability to penetrate moving tissues, including blood vessels, releasing septic materials, which rapidly distribute hematogenously; 2) the high sensitivity of the pregnant mare to bacteria from such septic materials introduced into the uterus, fetal membranes, or fetal fluids; 3) the unusually broad spectrum of bacterial pathogens carried on or in the setal fragments; and 4) the less effective antibacterial responses in certain susceptible extracellular fluids (e.g., fetal, ocular, pericardial, and cerebrospinal fluids). The driving force for MRLS pathology, including abortions, is septic material- induced bacterial proliferation, which provides a critical amplification step, enabling approximately 1-gram caterpillars to rapidly (32 hours) cause abortions in 680-kg (1,500- lb) mares. Calculations based on the unique eye data suggest that the actual number of distributing effective septic material quanta in field cases may be small—on the order of 10/horse/day—accounting for the lack of systemic clinical signs in affected horses. Therefore, it is proposed that MRLS starts with ingestion of Eastern tent caterpillars, followed by barbed setal fragments randomly penetrating intestinal tissues, including thinwalled venules and other blood vessels, with release of septic material that distributes hematogenously to all points in the body. Identification of abortigenic activity with the integument of the caterpillar and recent findings of large numbers of granulomatous lesions containing setal fragments in the intestines of pigs and rats directly supports the septic penetrating setal portion of the hypothesis. Analysis of the clinical syndromes and a toxicokinetic/ statistical analysis of MRLS suggest that setally-mediated introduction of septic material into blood vessels and other tissues may be key to understanding the very unusual toxicokinetics and pathogenesis of the unique group of syndromes that constitute MRLS. Like MRLS itself, this hypothesis is unique. The septic penetrating setal emboli portion is without precedent, is based on the unique clinical characteristics of MRLS, and appears well supported by ongoing experimental approaches

Gravitational Radiation Characteristics of Nonspinning Black-Hole Binaries

We present a detailed descriptive analysis of the gravitational radiation from binary mergers of non-spinning black holes, based on numerical relativity simulations of systems varying from equal-mass to a 6:1 mass ratio. Our analysis covers amplitude and phase characteristics of the radiation, suggesting a unified picture of the waveforms' dominant features in terms of an implicit rotating source, applying uniformly to the full wavetrain, from inspiral through ringdown. We construct a model of the late-stage frequency evolution that fits the l = m modes, and identify late-time relationships between waveform frequency and amplitude. These relationships allow us to construct a predictive model for the late-time waveforms, an alternative to the common practice of modelling by a sum of quasinormal mode overtones. We demonstrate an application of this in a new effective-one-body-based analytic waveform model

Performance of the Spacecraft Propulsion Research Facility During Altitude Firing Tests of the Delta 3 Upper Stage

The Spacecraft Propulsion Research Facility at the NASA Lewis Research Center's Plum Brook Station was reactivated in order to conduct flight simulation ground tests of the Delta 3 cryogenic upper stage. The tests were a cooperative effort between The Boeing Company, Pratt and Whitney, and NASA. They included demonstration of tanking and detanking of liquid hydrogen, liquid oxygen and helium pressurant gas as well as 12 engine firings simulating first, second, and third burns at altitude conditions. A key to the success of these tests was the performance of the primary facility systems and their interfaces with the vehicle. These systems included the structural support of the vehicle, propellant supplies, data acquisition, facility control systems, and the altitude exhaust system. While the facility connections to the vehicle umbilical panel simulated the performance of the launch pad systems, additional purge and electrical connections were also required which were unique to ground testing of the vehicle. The altitude exhaust system permitted an approximate simulation of the boost-phase pressure profile by rapidly pumping the test chamber from 13 psia to 0.5 psia as well as maintaining altitude conditions during extended steady-state firings. The performance of the steam driven ejector exhaust system has been correlated with variations in cooling water temperature during these tests. This correlation and comparisons to limited data available from Centaur tests conducted in the facility from 1969-1971 provided insight into optimizing the operation of the exhaust system for future tests. Overall, the facility proved to be robust and flexible for vehicle space simulation engine firings and enabled all test objectives to be successfully completed within the planned schedule

Cognitive effects of cancer and its treatments at the intersection of aging: what do we know; what do we need to know?

There is a fairly consistent, albeit non-universal body of research documenting cognitive declines after cancer and its treatments. While few of these studies have included subjects aged 65 years and older, it is logical to expect that older patients are at risk of cognitive decline. Here, we use breast cancer as an exemplar disease for inquiry into the intersection of aging and cognitive effects of cancer and its therapies. There are a striking number of common underlying potential biological risks and pathways for the development of cancer, cancer-related cognitive declines, and aging processes, including the development of a frail phenotype. Candidate shared pathways include changes in hormonal milieu, inflammation, oxidative stress, DNA damage and compromised DNA repair, genetic susceptibility, decreased brain blood flow or disruption of the blood-brain barrier, direct neurotoxicity, decreased telomere length, and cell senescence. There also are similar structure and functional changes seen in brain imaging studies of cancer patients and those seen with "normal" aging and Alzheimer's disease. Disentangling the role of these overlapping processes is difficult since they require aged animal models and large samples of older human subjects. From what we do know, frailty and its low cognitive reserve seem to be a clinically useful marker of risk for cognitive decline after cancer and its treatments. This and other results from this review suggest the value of geriatric assessments to identify older patients at the highest risk of cognitive decline. Further research is needed to understand the interactions between aging, genetic predisposition, lifestyle factors, and frailty phenotypes to best identify the subgroups of older patients at greatest risk for decline and to develop behavioral and pharmacological interventions targeting this group. We recommend that basic science and population trials be developed specifically for older hosts with intermediate endpoints of relevance to this group, including cognitive function and trajectories of frailty. Clinicians and their older patients can advance the field by active encouragement of and participation in research designed to improve the care and outcomes of the growing population of older cancer patients

Cancer-Related Cognitive Outcomes Among Older Breast Cancer Survivors in the Thinking and Living With Cancer Study

Purpose To determine treatment and aging-related effects on longitudinal cognitive function in older breast cancer survivors. Methods Newly diagnosed nonmetastatic breast cancer survivors (n = 344) and matched controls without cancer (n = 347) 60 years of age and older without dementia or neurologic disease were recruited between August 2010 and December 2015. Data collection occurred during presystemic treatment/control enrollment and at 12 and 24 months through biospecimens; surveys; self-reported Functional Assessment of Cancer Therapy-Cognitive Function; and neuropsychological tests that measured attention, processing speed, and executive function (APE) and learning and memory (LM). Linear mixed-effects models tested two-way interactions of treatment group (control, chemotherapy with or without hormonal therapy, and hormonal therapy) and time and explored three-way interactions of ApoE (ε4+ v not) by group by time; covariates included baseline age, frailty, race, and cognitive reserve. Results Survivors and controls were 60 to 98 years of age, were well educated, and had similar baseline cognitive scores. Treatment was related to longitudinal cognition scores, with survivors who received chemotherapy having increasingly worse APE scores (P = .05) and those initiating hormonal therapy having lower LM scores at 12 months (P = .03) than other groups. These group-by-time differences varied by ApoE genotype, where only ε4+ survivors receiving hormone therapy had short-term decreases in adjusted LM scores (three-way interaction P = .03). For APE, the three-way interaction was not significant (P = .14), but scores were significantly lower for ε4+ survivors exposed to chemotherapy (−0.40; 95% CI, −0.79 to −0.01) at 24 months than ε4+ controls (0.01; 95% CI, 0.16 to 0.18; P < .05). Increasing age was associated with lower baseline scores on all cognitive measures (P < .001); frailty was associated with baseline APE and self-reported decline (P < .001). Conclusion Breast cancer systemic treatment and aging-related phenotypes and genotypes are associated with longitudinal decreases in cognitive function scores in older survivors. These data could inform treatment decision making and survivorship care planning

One-Step Preservation of Phosphoproteins and Tissue Morphology at Room Temperature for Diagnostic and Research Specimens

BACKGROUND: There is an urgent need to measure phosphorylated cell signaling proteins in cancer tissue for the individualization of molecular targeted kinase inhibitor therapy. However, phosphoproteins fluctuate rapidly following tissue procurement. Snap-freezing preserves phosphoproteins, but is unavailable in most clinics and compromises diagnostic morphology. Formalin fixation preserves tissue histomorphology, but penetrates tissue slowly, and is unsuitable for stabilizing phosphoproteins. We originated and evaluated a novel one-step biomarker and histology preservative (BHP) chemistry that stabilizes signaling protein phosphorylation and retains formalin-like tissue histomorphology with equivalent immunohistochemistry in a single paraffin block. RESULTS: Total protein yield extracted from BHP-fixed, routine paraffin-embedded mouse liver was 100% compared to snap-frozen tissue. The abundance of 14 phosphorylated proteins was found to be stable over extended fixation times in BHP fixed paraffin embedded human colon mucosa. Compared to matched snap-frozen tissue, 8 phosphoproteins were equally preserved in mouse liver, while AMPKβ1 Ser108 was slightly elevated after BHP fixation. More than 25 tissues from mouse, cat and human specimens were evaluated for preservation of histomorphology. Selected tissues were evaluated in a multi-site, independent pathology review. Tissue fixed with BHP showed equivalent preservation of cytoplasmic and membrane cytomorphology, with significantly better nuclear chromatin preservation by BHP compared to formalin. Immunohistochemical staining of 13 non-phosphorylated proteins, including estrogen receptor alpha, progesterone receptor, Ki-67 and Her2, was equal to or stronger in BHP compared to formalin. BHP demonstrated significantly improved immunohistochemical detection of phosphorylated proteins ERK Thr202/Tyr204, GSK3-α/β Ser21/Ser9, p38-MAPK Thr180/Tyr182, eIF4G Ser1108 and Acetyl-CoA Carboxylase Ser79. CONCLUSION: In a single paraffin block BHP preserved the phosphorylation state of several signaling proteins at a level comparable to snap-freezing, while maintaining the full diagnostic immunohistochemical and histomorphologic detail of formalin fixation. This new tissue fixative has the potential to greatly facilitate personalized medicine, biobanking, and phospho-proteomic research

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

Tumour growth is tightly related to new blood vessel formation, tissue remodelling and invasiveness capacity. A number of tissular factors fuel the growth of glioblastoma multiforme, the most aggressive brain neoplasm. In fact, gene array analyses demonstrated that the proapoptotic cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibited mRNA expression of VEGF, along with those of matrix metalloproteinase-2 (MMP-2), its inhibitor tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), as well as the tumour invasiveness-related gene secreted protein acid rich in cysteine (SPARC) in different human glioblastoma cell lines. Particularly, VEGF mRNA and protein expression and release from glioblastoma cells were also inhibited by TRAIL. The latter also exerted antimitogenic effects on human umbilical vein endothelial cells (HUVECs). With the same cells, TRAIL inhibited new vessel formation in the in vitro matrigel model, as well as it exerted powerful inhibition of blood vessel formation induced by an angiogenic cocktail administered in subcutaneous pellets in vivo in the C57 mouse. Moreover, the expression of MMP-2, its inhibitor TIMP-2 and the tumour invasiveness-related protein SPARC were effectively inhibited by TRAIL in glioblastoma cell lines. In conclusion, our data indicate that TRAIL inhibits the orchestra of factors contributing to glioblastoma biological aggressiveness. Thus, the TRAIL system could be regarded as a molecular target to exploit for innovative therapy of this type of tumour

Multimodality Bayesian algorithm for image reconstruction in positron emission tomography

The use of anatomical information to improve the quality of reconstructed images in Positron Emission Tomography (PET) has been extensively studied. A common strategy has been to include spatial smoothing within boundaries defined from the anatomical data. The authors present an alternate method for the incorporation of anatomical information into PET image reconstruction, wherein they use segmented Magnetic Resonance (MR) images to assign tissue composition to PET image pixels. The authors model the image as a sum of activities for each tissue type, weighted by the assigned tissue composition. The reconstruction is performed as a maximum a posteriori (MAP) estimation of the activities of each tissue type. Two prior functions, defined for tissue type activities, are considered. The algorithm is tested in realistic simulations employing a full physical model of the PET scanner