Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Population and Harvest Dynamics of Midcontinent Sandhill Cranes

Sandhill cranes (Antigone canadensis) inhabiting the midcontinent of North America have been hunted since the 1960s under management goals of maintaining abundance, retaining geographic distribution, and maximizing sustainable harvest. Some biologists have raised concerns regarding harvest sustainability because sandhill cranes have lower reproductive rates than other game birds. We summarized demographic information in an age‐structured matrix model to better understand population dynamics and harvest. Population indices and recovered harvest since the early 1980s suggest midcontinent sandhill cranes have experienced an average long‐term annual growth of 0.9%; meanwhile, harvest has increased 1.8% annually. Adult survival and recruitment rates estimated from field data required modest adjustments (1–3%) so that model‐derived growth rates matched growth estimated from a long‐term survey (0.887 adult survival and 0.199 females/breeding female). Considering 0.9% long‐term annual growth, sandhill cranes could be harvested at a rate of 6.6% if harvest was additive to natural mortality (assumed to be 0.05) or 11.3% if harvest mortality compensated for natural mortality. Life‐history characteristics for long‐lived organisms and demographic evidence suggested that hunter harvest was primarily additive. Differential harvest rates of segments of sandhill cranes in the midcontinent population derived from differential exposure to hunting suggested potentially unsustainable harvest for greater sandhill cranes (A. c. tabida) from 2 breeding segments. Overall, demographic evidence suggests that the harvest of sandhill cranes in the midcontinent population has been managed sustainably. Monitoring activities that reduce nuisance variation and estimate vital and harvest rates by subspecies would support continued management of sandhill cranes that are of interest to hunters and bird watchers. Published 2020. This article is a U.S. Government work and is in the public domain in the USA

Timing of Spring Surveys for Midcontinent Sandhill Cranes

The U.S. Fish and Wildlife Service has used spring aerial surveys to estimate numbers of migrating sandhill cranes (Grus canadensis) staging in the Platte River Valley of Nebraska, USA. Resulting estimates index the abundance of the midcontinent sandhill crane population and inform harvest management decisions. However, annual changes in the index have exceeded biologically plausible changes in population size (\u3e50% of surveys between 1982 and 2013 indicate \u3e20% change), raising questions about nuisance variation due to factors such as migration chronology. We used locations of cranes marked with very-highfrequency transmitters to estimate migration chronology (i.e., proportions of cranes present within the Platte River Valley).We also used roadside surveys to determine the percentage of cranes staging at the Platte River Valley but outside of the survey area when surveys occur. During March 2001–2007, an average of 86% (71– 94%; SD=7%) of marked cranes were present along the Platte River during scheduled survey dates, and 0– 11% of cranes that were present along the Platte River were not within the survey boundaries. Timing of the annual survey generally corresponded with presence of the greatest proportion of marked cranes and with least inter-annual variation; consequently, accuracy of estimates could not have been improved by surveying on different dates. Conducting the survey earlier would miss birds not yet arriving at the staging site; whereas, a later date would occur at a time when a larger portion of birds may have already departed the staging site and when a greater proportion of birds occurred outside of the surveyed area. Index values used to monitor midcontinent sandhill crane abundance vary annually, in part, due to annual variation in migration chronology and to spatial distribution of cranes in the Platte River Valley; therefore, managers should interpret survey results cautiously, with awareness of a continuing need to identify and understand components of variation

epHero – a tandem-fluorescent probe to track the fate of apoptotic cells during efferocytosis

Abstract The efficient removal of apoptotic cells via efferocytosis is critical for maintaining optimal tissue function. This involves the binding and engulfment of apoptotic cells by phagocytes and the subsequent maturation of the phagosome, culminating in lysosomal fusion and cargo destruction. However, current approaches to measure efferocytosis rely on labelling apoptotic targets with fluorescent dyes, which do not sufficiently distinguish between changes to the engulfment and acidification of apoptotic material. To address this limitation, we have developed a genetically coded ratiometric probe epHero which when expressed in the cytoplasm of target cells, bypasses the need for additional labelling steps. We demonstrate that epHero is a pH-sensitive reporter for efferocytosis and can be used to simultaneously track changes to apoptotic cell uptake and acidification, both in vitro and in mice. As proof-of-principle, we modify extracellular nutrition to show how epHero can distinguish between changes to cargo engulfment and acidification. Thus, tracking efferocytosis with epHero is a simple, cost-effective improvement on conventional techniques

T315 Decreases Acute Myeloid Leukemia Cell Viability through a Combination of Apoptosis Induction and Autophagic Cell Death

T315, an integrin-linked kinase (ILK) inhibitor, has been shown to suppress the proliferation of breast cancer, stomach cancer and chronic lymphocytic leukemia cells. Here we demonstrate that T315 decreases cell viability of acute myeloid leukemia (AML) cell lines (HL-60 and THP-1) and primary leukemia cells from AML patients in a dose-responsive manner. Normal human bone marrow cells are less sensitive than leukemia cells to T315. T315 down regulates protein kinase B (Akt) and p-Akt and induces caspase activation, poly-ADP-ribose polymerase (PARP) cleavage, apoptosis and autophagy through an ILK-independent manner. Interestingly, pretreatment with autophagy inhibitors rescues cells from apoptosis and concomitant PARP cleavage, which implicates a key role of autophagic cell death in T315-mediated cytotoxicity. T315 also demonstrates efficacy in vivo, suppressing the growth of THP-1 xenograft tumors in athymic nude mice when administered intraperitoneally. This study shows that autophagic cell death and apoptosis cooperatively contribute to the anticancer activity of T315 in AML cells. In conclusion, the complementary roles of apoptotic and autophagic cell death should be considered in the future assessment of the translational value of T315 in AML therapy