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Lindsey A George,1,2 Rodney M Camire1–3 1Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; 2Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; 3Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Abstract: Hemophilia care has improved dramatically over the past 50 years, evolving from plasma concentrates, to purified plasma proteins, to recombinant clotting factors. These collective developments allowed for home delivery of on-demand and prophylactic treatment, resulting in the reduction of hemophilia morbidity and mortality and improved quality of life. Although efficacious in treating bleeding, conventional factor products' half-lives require frequent venipuncture, which remains a significant burden to patients. Despite the remarkable advances in hemophilia care, no improvements have, until now, been made to the pharmacokinetic properties of factor products. Multiple strategies have more recently been employed to generate novel bioengineered products that, with great hope, represent the next wave of progress in hemophilia care. The use of these products will undoubtedly raise important discussion about choosing conventional factor over new long-acting factor products. Incorporation of these therapies into clinical care is accompanied by unanswered safety questions that will likely be evaluated only in postmarketing surveillance analysis. Further, these products may change current treatment paradigms with unclear cost repercussions and feasibility. This paper will review efraloctocog alfa (FVIII-Fc) and its role in the treatment of hemophilia A. Keywords: hemophilia A, factor VIII, Fc fusion, bioengineered products, efraloctocog alfa

Insulin sensitivity decreases during pregnancy, presumably an adaptation ensuring sufficient glucose supply to feto-placental tissues. Feeds high in non-structural carbohydrates are also linked to diminished insulin sensitivity in horses. Because the equine fetus is highly glucose reliant, maternal glucose and insulin dynamics during pregnancy may have implications for optimal fetal development in horses. Mismanagement of maternal nutrition during gestation could predispose the offspring to metabolic disorders (e.g. insulin resistance) later in life. In horses, insulin resistance is associated with increased risk for development of laminitis. These studies measured insulin sensitivity and glucose dynamics in pregnant and non-pregnant mares fed high sugar and starch (SS) or high fat and fiber (FF) feeds, as well as neonatal foals born from pregnant mares fed SS and FF feed. Insulin modified frequently sampled intravenous glucose tolerance tests (FSIGT) were applied to pregnant Thoroughbred mares (n = 22) at 28 ± 3 wks (Period 1) and 47 wks (Period 2) gestation, as well as non-pregnant mares (n=10) measured simultaneously. Following the first FSIGT mares were fed SS or FF feed for the remainder of the study. After 11 wks adaptation to feeding, a subset of mares were evaluated with hourly blood samples for 24 h to assess glycemic and insulinemic response to three times daily feeding while on pasture. Neonatal foal FSIGTs (n=20) were conducted at 5 ± 1 d of age. The minimal model of glucose and insulin dynamics was used to determine insulin sensitivity (SI), glucose effectiveness (Sg), acute insulin response to glucose (AIRg) and disposition index (DI). Pregnant mares during Period 1 exhibited lowered SI, Sg and elevated AIRg relative to non-pregnant mares. Pregnant mares demonstrated greater glycemic and insulinemic responses to feeding of both SS and FF meals than non-pregnant mares consuming the same feeds. Also, SS feed elicited greater glycemic and insulinemic areas under the curve following feeding than FF feed in pregnant mares. These data support that pregnancy in mares in associated with lowered SI by 28 wks gestation and that altered SI, Sg and AIRg are associated with different responses to consuming SS and FF feeds. Foals exhibited high basal glucose, basal insulin, SI and Sg relative to mature horses, indicating a large capacity for glucose uptake with or without insulin. Basal glucose concentrations were higher and basal insulin concentrations tended to be higher in SS than FF foals (P = 0.016 and P = 0.071, respectively). Glucose and insulin dynamics in late gestation mares and neonatal foals exemplify the adaptive nature of energy metabolism in horses. Furthermore, dietary energy composition affects glucose and insulin responses to feeding in late gestation mares, which in turn was associated with different basal blood concentrations of these variables in the resulting neonatal foals. Master of Science

Despite the fact that histone H2A ubiquitination affects about 10-15% of this histone in most eukaryotic cells, histone ubiquitination is among one of the less-well-characterized post-translational histone modifications. Nevertheless, some important observations have been made in recent years. Whilst several enzymes had been known to ubiquitinate histones in vitro, recent studies in yeast have led to the unequivocal identification of the enzyme responsible for this post-translational modification in this organism. A strong functional co-relation to meiosis and spermiogenesis has also now been well documented, although its participation in other functional aspects of chromatin metabolism, such as transcription or DNA repair, still remains rather speculative and controversial. Because of its nature, histone ubiquitination represents the most bulky structural change to histones and as such it would be expected to exert an important effect on chromatin structure. Past and recent structural studies, however, indicate a surprising lack of effect of (H2A/H2B) ubiquitination on nucleosome architecture and of uH2A on chromatin folding. These results suggest that this modification may serve as a signal for recognition by functionally relevant trans-acting factors and/or operate synergistically in conjunction with other post-translational modifications such as for instance acetylation.

The contents of this paper are the product of discussions held by a study group on North American Security, organized by the National Capital Branch of the Canadian Institute of International Affairs. Most of the 15 group members are retired, after long service in the Department of International Affairs and International Trade, or in the Department of National Defence. Members include (BGen) Clay Beattie, Bob Cameron, (Col) Ron Cleminson, Bob Edmonds, Ross Francis, Dwight Fulford, George Grande, (BGen) Keith Greenaway, John Hadwen, Hugh Henry, David Kirkwood, George Lindsey, Blair Seaborn, Ken Williamson and Gerry Wright.THE OBJECTIVE OF THIS PAPER is to investigate how modern technology and the geography of North America can determine the most suitable roles for the Canadian Armed Forces (CAF) in protecting the continent against terrorism in the 21st century. A useful background, however, can be assembled by considering how the geography and technology of the 20th century influenced the roles played by the CAF in the defence of North America against the threats presented during the Cold War, and how some of the experience, organizations, and equipment provided for the Cold War can be exploited for the defence against terrorism.DEFENCE OF NORTH AMERICA DURING THE COLD WARBackgroundFor more than a century before the Cold War, neither Canada nor the United States faced a serious threat of attack on their territory from outside the North American continent. This came to an end, however, with the Soviet Union's acquisition of long-range bomber aircraft, Intercontinental Ballistic Missiles (ICBMs) and Submarine-Launched Ballistic Missiles (SLBMs). All were armed with nuclear payloads.The shortest and most direct routes for the Soviet bombers and ICBMs to reach the US's central 48 states would be to travel across the Northeast Pacific, the Arctic or the Northwest Atlantic Oceans. These routes were all either close to, or directly over, Canadian territory.(1) Most of the SLBMs likely would have been launched from Soviet submarines patrolling in zones off the East Coast of the United States.To counter these three threats, a reliable early warning system was required. Its primary purpose was to enable the bombers of the US Strategic Air Command (SAC) to become airborne before their bases were destroyed, and, later, to allow American ICBMs to be launched before they were destroyed on the ground. If the SAC bombers of the 1950s and 1960s were to be launched from bases in the central US, and ordered to deliver retaliatory strikes, they would need to refuel before beginning the long flight to the Soviet Union. There were two refueling options: one was to land at one of the six Canadian bases manned partially or wholly by USAF personnel;(2) the other was to receive fuel in the air from US tanker aircraft deployed in Canada.Countermeasures against the air threat: the creation of NORAD(3)In addition to its role in preservation of the American offensive forces needed for deterrence, early warning was providing information that was essential for active defence units--both American and Canadian. Against the bomber threat, these included air defence control centres, radar stations and bases for fighter aircraft, as well as anti-aircraft missiles, and guns, deployed for the interception and destruction of the bombers before they could reach their targets in the United States or Canada.The key system installed for early warning against bomber attacks was the Distant Early Warning (DEW) Line, consisting of a chain of manned radar stations following the 70[Symbol Not Transcribed] [degree] north parallel of latitude along the northern coasts of Alaska and mainland Canada (and across Baffin Island). Until 1965, another warning system, the Mid-Canada Line, was in place. Using elementary unmanned radars, it spanned the whole of Canada, along latitude 55[Symbol Not Transcribed] [degree] north, and formed a tripwire that was able to confirm if bombers were coming south. …