Evaluation Of Risk And Possible Mitigation Schemes For Previously Unidentified Hazards

This report presents the results of arc track testing conducted to determine if such a transfer of power to un-energized wires is possible and/or likely during an arcing event, and to evaluate an array of protection schemes that may significantly reduce the possibility of such a transfer. The results of these experiments may be useful for determining the level of protection necessary to guard against spurious voltage and current being applied to safety critical circuits. It was not the purpose of these experiments to determine the probability of the initiation of an arc track event only if an initiation did occur could it cause the undesired event: an inadvertent thruster firing. The primary wire insulation used in the Orbiter is aromatic polyimide, or Kapton , a construction known to arc track under certain conditions [3]. Previous Boeing testing has shown that arc tracks can initiate in aromatic polyimide insulated 28 volts direct current (VDC) power circuits using more realistic techniques such as chafing with an aluminum blade (simulating the corner of an avionics box or lip of a wire tray), or vibration of an aluminum plate against a wire bundle [4]. Therefore, an arc initiation technique was chosen that provided a reliable and consistent technique of starting the arc and not a realistic simulation of a scenario on the vehicle. Once an arc is initiated, the current, power and propagation characteristics of the arc depend on the power source, wire gauge and insulation type, circuit protection and series resistance rather than type of initiation. The initiation method employed for these tests was applying an oil and graphite mixture to the ends of a powered twisted pair wire. The flight configuration of the heater circuits, the fuel/oxider (or ox) wire, and the RCS jet solenoid were modeled in the test configuration so that the behavior of these components during an arcing event could be studied. To determine if coil activation would occur with various protection wire schemes, 145 tests were conducted using various fuel/ox wire alternatives (shielded and unshielded) and/or different combinations of polytetrafuloroethylene (PTFE), Mystik tape and convoluted wraps to prevent unwanted coil activation. Test results were evaluated along with other pertinent data and information to develop a mitigation strategy for an inadvertent RCS firing. The SSP evaluated civilian aircraft wiring failures to search for aging trends in assessing the wire-short hazard. Appendix 2 applies Weibull statistical methods to the same data with a similar purpose

Complement system in multiple sclerosis: its role in disease course and potential as a therapeutic target

Multiple sclerosis (MS) is a clinically heterogeneous neurological condition characterized by neuroinflammation and neurodegeneration. Relapsing-remitting MS, defined by inflammatory attacks, is the most common initial form of MS and there are currently 23 FDA-approved treatments for these patients. These therapies work primarily by reducing inflammation in the CNS; they do not work well in progressive disease. Therefore, an unmet medical need exists for effective therapeutic options to treat progressive MS (PMS). In MS, intrathecal immunoglobulins synthesis (IIgS) correlates with disease progression. My goals for this dissertation were to establish the pathological role of IIgS and identify new potential therapeutic targets for PMS. To investigate this, I used a mouse model of relapsing-remitting MS, rEAE, and a virally induced model of PMS, TMEV-IDD, along with a range of methodologies such as microarray, real-time PCR, immunofluorescent microscopy, immunoassays and behavior analyses. I first demonstrated that, in contrast to rEAE, TMEV-IDD has high levels of IIgS along with demyelination, axonal injury, and neuronal death. In TMEV-IDD mice, IIgS also correlated with disability. After investigating possible effector mechanisms of IIgS, I found evidence for the pathological involvement of the complement system. I demonstrated that TMEV-IDD relies more on activating the classical complement pathway while protecting from acute relapses in rEAE. Overall, my studies showed in TMEV-IDD higher levels of CNS C1q, the initiating protein of the classical complement pathway, along with more severe clinical and pathological disease. The classic complement pathway represents a link between IIgS and MS progression. Canonically, activation of C1q requires binding immune-complexes. Therefore, increased IIgS could over-activate the classical complement cascade. Using inhibitory molecules and two treatment options designed to overcome the BBB, intraventricular infusion of a murine anti-C1q antibody with an Alzet Osmotic Pump and a modified anti-C1q nanobody, I demonstrated that C1 antagonization reduces neuroaxonal damage and neuroinflammation, improving disease outcomes in TMEV-IDD but not rEAE. In conclusion, I showed that TMEV-IDD replicates IIgS as is observed in PMS, that IIgS is linked to an overactivation of the classical complement pathway, and that C1q antagonization represents a valid therapeutic strategy in progressive but not acute neuroinflammation

Divergent complement system activation in two clinically distinct murine models of multiple sclerosis

Multiple sclerosis (MS) is a neurological disease featuring neuroinflammation and neurodegeneration in young adults. So far, most research has focused on the peripheral immune system, which appears to be the driver of acute relapses. Concurrently, the mechanisms underlying neurodegeneration in the progressive forms of the disease remain unclear. The complement system, a molecular component of the innate immunity, has been recently implicated in several neurological disorders, including MS. However, it is still unknown if the complement proteins detected in the central nervous system (CNS) are actively involved in perpetuating chronic inflammation and neurodegeneration. To address this knowledge gap, we compared two clinically distinct mouse models of MS: 1) proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (rEAE) resembling a relapsing-remitting disease course, and 2) Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) resembling a progressive disease. Real-time PCR was performed in the spinal cord of rEAE mice, TMEV-IDD mice and age-matched sham controls to quantify gene expression for a broad range of complement components. In both experimental models, we found significantly increased expression of complement factors, such as C1q, C3, CfB, and C3aR. We showed that the complement system, specifically the classical complement pathway, was associated with TMEV-IDD pathogenesis, as the expression of C1q, C3 and C3aR1 were all significantly correlated to a worse disease outcome (all P≤0.0168). In line with this finding, C1q and C3 deposition was observed in the spinal cord of TMEV-IDD mice. Furthermore, C1q deposition was detected in spinal cord regions characterized by inflammation, demyelination, and axonal damage. Conversely, activation of the classical complement cascade seemed to result in protection from rEAE (C1q: P=0.0307). Interestingly, the alternative pathway related to a worse disease outcome in rEAE (CFb: P=0.0006). Overall, these results indicate potential divergent roles for the complement system in MS. The chronic-progressive disease form is more reliant on the activation of the classic complement pathway, while protecting from acute relapses. Conversely, relapsing MS appears more likely affected by the alternative pathway. Understanding the functions of the complement system in MS is critical and can lead to better, more targeted therapies in the future

Maternal Fish Consumption and Infant Birth Size and Gestation: New York State Angler Cohort Study

BACKGROUND: The scientific literature poses a perplexing dilemma for pregnant women with respect to the consumption of fish from natural bodies of water. On one hand, fish is a good source of protein, low in fat and a rich source of other nutrients all of which have presumably beneficial effects on developing embryos and fetuses. On the other hand, consumption of fish contaminated with environmental toxicants such as polychlorinated biphenyls (PCBs) has been associated with decrements in gestation and birth size. METHODS: 2,716 infants born between 1986–1991 to participants of the New York State Angler Cohort Study were studied with respect to duration of maternal consumption of contaminated fish from Lake Ontario and its tributaries and gestation and birth size. Hospital delivery records (maternal and newborn) were obtained for 92% of infants for the ascertainment of gestation (weeks), birth size (weight, length, chest, and head circumference) and other known determinants of fetal growth (i.e., maternal parity, history of placental infarction, uterine bleeding, pregnancy loss or cigarette smoking and infant's race, sex and presence of birth defect). Duration of maternal fish consumption prior to the index infant's birth was categorized as: none; 1–2, 3–7, 8+ years, while birth weight (in grams), birth length (in centimeters), and head and chest circumference (in centimeters) were left as continuous variables in multiple linear regression models. Birth size percentiles, ponderal indices and head to chest circumference ratios were computed to further assess proportionality and birth size in relation to gestational age. RESULTS: Analysis of variance failed to identify significant mean differences in gestation or any measure of birth size in relation to duration of maternal lifetime fish consumption. Multiple linear regressions identified gestational age, male sex, number of daily cigarettes, parity and placental infarction, as significant determinants of birth size. CONCLUSIONS: The results support the absence of an adverse relation between Lake Ontario fish consumption and reduced birth size as measured by weight, length and head circumference. Biological determinants and maternal cigarette smoking during pregnancy remain important determinants of birth size

In Memoriam: A Memoir for Our Fallen "Heroes"

This article is made available for unrestricted research re-use and secondary analysis in any form or be any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Even though neurosurgeons exercise these enormous and versatile skills, the COVID-19 pandemic has shaken the fabrics of the global neurosurgical family, jeopardizing human lives, and forcing the entire world to be locked down. We stand on the shoulders of the giants and will not forget their examples and their teachings. We will work to the best of our ability to honor their memory. Professor Harvey Cushing said: “When to take great risks; when to withdraw in the face of unexpected difficulties; whether to force an attempted enucleation of a pathologically favorable tumor to its completion with the prospect of an operative fatality, or to abandon the procedure short of completeness with the certainty that after months or years even greater risks may have to be faced at a subsequent session—all these require surgical judgment which is a matter of long experience.” It is up to us, therefore, to keep on the noble path that we have decided to undertake, to accumulate the surgical experience that these icons have shown us, the fruit of sacrifice and obstinacy. Our tribute goes to them; we will always remember their excellent work and their brilliant careers that will continue to enlighten all of us. This memorial is intended to commemorate our colleagues who succumbed during the first 4 months

An Architectural Metaphor: the Destining of Imhotep Stone

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