Optic Nerve Sheath Mechanics in VIIP Syndrome

Visual Impairment and Intracranial Pressure (VIIP) syndrome results in a loss of visual function and occurs in astronauts following long-duration spaceflight. Understanding the mechanisms that lead to the ocular changes involved in VIIP is of critical importance for space medicine research. Although the exact mechanisms of VIIP are not yet known, it is hypothesized that microgravity-induced increases in intracranial pressures (ICP) drive the remodeling of the optic nerve sheath, leading to compression of the optic nerve which in turn may reduce visual acuity. Some astronauts present with a kink in the optic nerve after return to earth, suggesting that tissue remodeling in response to ICP increases may be taking place. The goal of this work is to characterize the mechanical properties of the optic nerve sheath (dura mater) to better understand its biomechanical response to increased ICP

Finite Element Modeling of the Posterior Eye in Microgravity

Microgravity experienced during spaceflight affects astronauts in various ways, including weakened muscles and loss of bone density. Recently, visual impairment and intracranial pressure (VIIP) syndrome has become a major concern for space missions lasting longer than 30 days. Astronauts suffering from VIIP syndrome have changes in ocular anatomical and visual impairment that persist after returning to earth. It is hypothesized that a cephalad fluid shift in microgravity may increase the intracranial pressure (ICP), which leads to an altered biomechanical environment of the posterior globe and optic nerve sheath (ONS).Currently, there is a lack of knowledge of how elevated ICP may lead to vision impairment and connective tissue changes in VIIP. Our goal was to develop a finite element model to simulate the acute effects of elevated ICP on the posterior eye and optic nerve sheath. We used a finite element (FE) analysis approach to understand the response of the lamina cribrosa and optic nerve to the elevations in ICP thought to occur in microgravity and to identify which tissue components have the greatest impact on strain experienced by optic nerve head tissues

Biomechanics of the Optic Nerve Sheath in VIIP Syndrome

Long-duration space flight carries the risk of developing Visual Impairment and Intracranial Pressure (VIIP) syndrome, a spectrum of ophthalmic changes including posterior globe flattening, choroidal folds, distension of the optic nerve sheath (ONS), optic nerve kinking and potentially permanent degradation of visual function. The slow onset of VIIP, its chronic nature, and certain clinical features strongly suggest that biomechanical factors acting on the ONS play a role in VIIP. Here we measure several relevant ONS properties needed to model VIIP biomechanics. The ONS (meninges) of fresh porcine eyes (n7) was reflected, the nerve proper was truncated near the sclera, and the meninges were repositioned to create a hollow cylinder of meningeal connective tissue attached to the posterior sclera. The distal end was cannulated, sealed, and pressure clamped (mimicking cerebrospinal fluid [CSF] pressure), while the eye was also cannulated for independent control of intraocular pressure (IOP). The meninges were inflated (CSF pressure cycling 7-50 mmHg) while ONS outer diameter was imaged. In another set of experiments (n4), fluid permeation rate across the meninges was recorded by observing the drainage of an elevated fluid reservoir (30 mmHg) connected to the meninges. The ONS showed behavior typical of soft tissues: viscoelasticity, with hysteresis in early preconditioning cycles and repeatable behavior after 4 cycles, and nonlinear stiffening, particularly at CSF pressures 15 mmHg (Figure). Tangent moduli measured from the loading curve were 372 101, 1199 358, and 2050 379 kPa (mean SEM) at CSF pressures of 7, 15 and 30 mmHg, respectively. Flow rate measurements through the intact meninges at 30mmHg gave a permeability of 1.34 0.46 lmincm2mmHg (mean SEM). The ONS is a tough, strain-stiffening connective tissue that is surprisingly permeable. The latter observation suggests that there could be significant CSF drainage through the ONS into the orbit, likely important for CSF transport in the optic nerve. These experimental measurements, extended to human eyes, are informing computational models of the pathophysiology and biomechanics of the ONS in VIIP syndrome

Finite Element Modeling Techniques for Analysis of VIIP

Visual Impairment and Intracranial Pressure (VIIP) syndrome is a major health concern for long-duration space missions. Currently, it is thought that a cephalad fluid shift in microgravity causes elevated intracranial pressure (ICP) that is transmitted along the optic nerve sheath (ONS). We hypothesize that this in turn leads to alteration and remodeling of connective tissue in the posterior eye which impacts vision. Finite element (FE) analysis is a powerful tool for examining the effects of mechanical loads in complex geometries. Our goal is to build a FE analysis framework to understand the response of the lamina cribrosa and optic nerve head to elevations in ICP in VIIP

Changes in the Optic Nerve Head and Choroid Over 1 Year of Spaceflight

Importance: While 6-month data are available regarding spaceflight-associated neuro-ocular syndrome, manned missions for 1 year and beyond are planned, warranting evaluation for spaceflight-associated neuro-ocular syndrome beyond 6 months. Objective: To determine if the manifestation of spaceflight-associated neuro-ocular syndrome worsens during International Space Station missions exceeding the present 4- to 6-month duration. Design, Setting, and Participants: The One-Year Mission Study used quantitative imaging modalities to investigate changes in ocular structure in 2 crew members who completed a 1-year-long spaceflight mission. This study investigated the ocular structure of crew members before, during, and after their mission on the International Space Station. Two crew members participated in this study from March 2015 to September 2016. Analysis began in March 2015 and ended in May 2020. Exposures: Crew members were tested before, during, and up to 1 year after spaceflight. Main Outcomes and Measures: This study compares ocular changes (peripapillary retinal edema, axial length, anterior chamber depth, and refraction) in two 1-year spaceflight mission crew members with cohort crew members from a 6-month mission (n = 11). Minimum rim width (the shortest distance between Bruch membrane opening and the internal limiting membrane) and peripapillary total retinal thickness were measured using optical coherence tomography. Results: Both crew members were men. Minimum rim width and total retinal thickness increased in both participants throughout the duration of spaceflight exposure to the maximal observed change from preflight (minimum rim width: participant 1, 561 [+149 from preflight] μm at flight day 270; participant 2, 539 [+56 from preflight] μm at flight day 270; total retinal thickness: participant 1, 547 [+135 from preflight] μm at flight day 90; participant 2, 528 [+45 from preflight] μm at flight day 210). Changes in peripapillary choroid engorgement, axial length, and anterior chamber depth appeared similar between the 1-year mission participants and a 6-month mission cohort. Conclusions and Relevance: This report documents the late development of mild optic disc edema in 1 crew member and the progressive development of choroidal folds and optic disc edema in another crew member over the duration of 1 year in low Earth orbit aboard the International Space Station. Previous reports characterized the ocular risk associated with 4 to 6 months of spaceflight. As future spaceflight missions are planned to increase in duration and extend beyond low Earth orbit, further observation of astronaut ocular health on spaceflight missions longer than 6 months in duration may be warranted

VIIP: Central Nervous System (CNS) Modeling

Current long-duration missions to the International Space Station and future exploration-class missions beyond low-Earth orbit expose astronauts to increased risk of Visual Impairment and Intracranial Pressure (VIIP) syndrome. It has been hypothesized that the headward shift of cerebrospinal fluid (CSF) and blood in microgravity may cause significant elevation of intracranial pressure (ICP), which in turn may then induce VIIP syndrome through interaction with various biomechanical pathways. However, there is insufficient evidence to confirm this hypothesis. In this light, we are developing lumped-parameter models of fluid transport in the central nervous system (CNS) as a means to simulate the influence of microgravity on ICP. The CNS models will also be used in concert with the lumped parameter and finite element models of the eye described in the related IWS works submitted by Nelson et al., Feola et al. and Ethier et al

Gene Regulation and Transcriptomics

Borrelia (Borreliella) burgdorferi, along with closely related species, is the etiologic agent of Lyme disease. The spirochete subsists in an enzootic cycle that encompasses acquisition from a vertebrate host to a tick vector and transmission from a tick vector to a vertebrate host. To adapt to its environment and persist in each phase of its enzootic cycle, B. burgdorferi wields three systems to regulate the expression of genes: the RpoN-RpoS alternative sigma factor cascade, the Hk1/Rrp1 two-component system and its product c-di-GMP, and the stringent response mediated by RelBbu and DksA. These regulatory systems respond to enzootic phase-specific signals and are controlled or fine- tuned by transcription factors, including BosR and BadR, as well as small RNAs, including DsrABb and Bb6S RNA. In addition, several other DNA-binding and RNA-binding proteins have been identified, although their functions have not all been defined. Global changes in gene expression revealed by high-throughput transcriptomic studies have elucidated various regulons, albeit technical obstacles have mostly limited this experimental approach to cultivated spirochetes. Regardless, we know that the spirochete, which carries a relatively small genome, regulates the expression of a considerable number of genes required for the transitions between the tick vector and the vertebrate host as well as the adaptation to each

Mutations in PIK3CA are infrequent in neuroblastoma

BACKGROUND: Neuroblastoma is a frequently lethal pediatric cancer in which MYCN genomic amplification is highly correlated with aggressive disease. Deregulated MYC genes require co-operative lesions to foster tumourigenesis and both direct and indirect evidence support activated Ras signaling for this purpose in many cancers. Yet Ras genes and Braf, while often activated in cancer cells, are infrequent targets for activation in neuroblastoma. Recently, the Ras effector PIK3CA was shown to be activated in diverse human cancers. We therefore assessed PIK3CA for mutation in human neuroblastomas, as well as in neuroblastomas arising in transgenic mice with MYCN overexpressed in neural-crest tissues. In this murine model we additionally surveyed for Ras family and Braf mutations as these have not been previously reported. METHODS: Sixty-nine human neuroblastomas (42 primary tumors and 27 cell lines) were sequenced for PIK3CA activating mutations within the C2, helical and kinase domain "hot spots" where 80% of mutations cluster. Constitutional DNA was sequenced in cases with confirmed alterations to assess for germline or somatic acquisition. Additionally, Ras family members (Hras1, Kras2 and Nras) and the downstream effectors Pik3ca and Braf, were sequenced from twenty-five neuroblastomas arising in neuroblastoma-prone transgenic mice. RESULTS: We identified mutations in the PIK3CA gene in 2 of 69 human neuroblastomas (2.9%). Neither mutation (R524M and E982D) has been studied to date for effects on lipid kinase activity. Though both occurred in tumors with MYCN amplification the overall rate of PIK3CA mutations in MYCN amplified and single-copy tumors did not differ appreciably (2 of 31 versus 0 of 38, respectively). Further, no activating mutations were identified in a survey of Ras signal transduction genes (including Hras1, Kras2, Nras, Pik3ca, or Braf genes) in twenty-five neuroblastic tumors arising in the MYCN-initiated transgenic mouse model. CONCLUSION: These data suggest that activating mutations in the Ras/Raf-MAPK/PI3K signaling cascades occur infrequently in neuroblastoma. Further, despite compelling evidence for MYC and RAS cooperation in vitro and in vivo to promote tumourigenesis, activation of RAS signal transduction does not constitute a preferred secondary pathway in neuroblastomas with MYCN deregulation in either human tumors or murine models

Haptoglobin phenotype and abnormal uterine artery Doppler in a racially diverse cohort

The anti-oxidant and proangiogenic protein haptoglobin (Hp) is believed to be important for implantation and pregnancy, although its specific role is not known. The three phenotypes (1-1, 2-1 and 2-2) differ in structure and function. Hp 2-2 is associated with increased vascular stiffness in other populations. We examined whether Hp phenotype is associated with abnormal uterine artery Doppler (UAD) in pregnancy