Hypoxia-inducible factor 1 alpha-mediated RelB/APOBEC3B down-regulation allows hepatitis B virus persistence

Background and Aims: Therapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia‐inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis‐related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization. Approach and Results: We addressed whether HIF1α interferes with immune‐mediated induction of the cytidine deaminase, apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B; A3B), and subsequent covalently closed circular DNA (cccDNA) decay. Liver biopsies of chronic HBV (CHB) patients were analyzed by immunohistochemistry and in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR‐agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analyzed by RT‐qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune‐active patients. In vitro, HIF1α stabilization strongly impaired A3B expression and anti‐HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up‐regulation and ‐mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v‐rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator. Conclusions: In conclusion, inhibiting HIF1α expression or stabilization represents an anti‐HBV strategy in the context of immune‐mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies

Successful desensitization with human insulin in a patient with an insulin allergy and hypersensitivity to protamine: a case report

<p>Abstract</p> <p>Introduction</p> <p>Insulin allergy may occur in patients treated with subcutaneous applications of insulin preparations. Besides additives in the insulin preparation such as protamine, cresol, and phenol, the insulin molecule itself may be the cause of the allergy. In the latter case, therapeutic options are rare.</p> <p>Case presentation</p> <p>A 68-year-old man with poorly controlled type 2 diabetes mellitus received different insulin preparations subcutaneously while on oral medication. Six to eight hours after each subcutaneous application, he developed pruritic plaques with a diameter of >15 cm at the injection sites that persisted for several days. Allergologic testing revealed positive reactions against every insulin preparation and against protamine. Investigation of serum samples demonstrated IgG antibodies against human and porcine insulin. We treated the patient with human insulin using an ultra-rush protocol beginning with 0.004 IU and a rapid augmentation in dose up to 5 IU. Therapy was accompanied by antihistamine therapy. Subsequent conversion to therapy with glargine insulin (6 IE twice daily) was well-tolerated.</p> <p>Conclusion</p> <p>As reported in this case, desensitization with subcutaneously administered human insulin using an ultra-rush protocol in patients with an insulin allergy may present an easy form of therapy that is successful within a few days.</p

Foot Strike in Runners: The Relationship Between Heel Length, Foot Strike, and Calf Muscle Thickness

One major way that running style varies between individuals is how their foot strikes the ground (forefoot strike or rearfoot strike). Running generates a torque about the ankle that depends on the individual’s foot strike pattern, length of their plantar flexor moment arm, and force generated from the plantar flexor muscles. The foot strike pattern during running, gastrocnemii muscle thickness, and heel length (used as an approximation for plantar flexor moment arm) were determined in 41 runners. Forefoot and rearfoot strike runners had the same thickness of the gastrocnemii muscles. However, in comparison with sedentary walkers, the runners had thicker calf muscles. These results imply a “peak” muscle thickness seems to be attained by running. Runners with longer heels were more likely to use a forefoot strike running style, possibly due to a mechanical advantage in the generation of torque

Interview of Howard O. Wessbecher by Brian Shoemaker

Baker, Dave, p. 60 Bergstrum, Jim, pp. 59-60 Bowers, Dick, pp. 51-53, 58-59 Condit, Father (priest), p. 70 Dufek, Admiral George, pp. 53, 55-56, 69, 72-73 Glendyer, Jay, pp. 3, 42-43 Goodale, Edward L., pp. 3, 42-43, 62 Haglan, Mel, pp. 7-8 Harrison, Richard, p. 6 Jones, Elmo, pp. 57-58 Molton, Ken, pp. 3, 42-46 Nash, Jack, p. 49 Siple, Paul, pp. 50, 72 Wilkins, Sir Hubert, pp. 43-44 Woods, Ernest, p. 43Howard Wessbecher served at the Alert and Resolute sites in the Arctic region, as well as McMurdo in Antarctica. He wintered over in all three places. Earlier in his career, he served in WWII, completed a degree in forestry, and accepted a position with the Weather Bureau. His first major assignment (April 1952 until March 1953) was as storekeeper in Resolute Bay, in remote northern Canada. The small base had only 12 persons, six Americans and six Canadians. Four smaller satellite stations, with eight people each, were in outlaying regions. Resolute was re-supplied twice a year by the Air Force, once in the spring and once in the fall. Wessbecher adjusted well to the isolation and harsh conditions. At Resolute, and the other stations as well, there was a radiosonde program that involved launching weather balloons twice a day into the upper atmosphere. The radiosonde was a small box with a radio transmitter, and a pressure gauge. Using radio signals it gave readings for humidity, temperature, air pressure, wind speed and direction. At first the men made their own hydrogen gas for launching the balloons. Later the Weather Bureau supplied much safer helium gas. There was also a glaciological study program at Resolute which involved measuring the thickness of sea ice, and analyzing the depth, gradations, and composition of snow layers. Once a day, Wessbecher ventured out on the sea ice in the bay to measure its thickness. He always carried a rifle as a defense against polar bears. Several Eskimo families also lived at Resolute Bay. There was also a Mountie at the Canadian base; his main task at Resolute seemed to be to keep the Eskimos from raiding the garbage dumps. Twice a year the US Navy refilled the main 15,000 gallon oil tanks at Resolute. One of Wessbecher’s responsibilities was to fill from these larger tanks all of the 55 gallon oil drums that were to be flown to the satellite stations. Once there, he had to transfer the oil yet again, this time from the 55-gallon drums to 500-1000 gallon storage tanks. All of the men at the base were involved in routine maintenance, such as, cleaning, painting, clearing the airstrip of snow, etc. Their main task was weather studies. After a two-week leave at home in March 1953, Wessbecher returned to the Arctic as the Executive Officer at Camp Alert, a remote base just 400 miles from the North Pole on the northern tip of Ellesmere Island. One could see Greenland off in the distance. No natives lived on the island. Only eight people were stationed at Camp Alert, four Americans and four Canadians. All eight men were busy with various tasks most of the time. Two radiosondes were launched by balloon each day, and the surface weather had to be studied, coded, and recorded every four hours. Data was transmitted by radio. The men made their own hydrogen gas the dangerous way using caustic soda, aluminum chips, and water. The small air strip had to be plowed using tractors. Electricity was produced using three diesel generators. Fortunately, the cook was excellent and the food was delicious after all of this hard work. Despite the cold and long periods of darkness, there were certain compensations. The air was so clear it seemed one could reach out and touch the moon. They were too far north, however, to see auroras. During the summer they might get an occasional outside visitor, but basically there was nothing at Camp Alert except the weather station. After one year at Camp Alert during 1953-54, Wessbecher returned to Camp Resolute without taking any vacation. It was very difficult to go home for two weeks, and then readjust to the darkness and isolation. Some changes had occurred at the Camp since his earlier stay there. The Canadian government had resettled several volunteer Eskimo families in the area, and encouraged them to continue their traditional ways of igloos, hunting, and fishing. They killed polar bears, walrus, and seals, and according to Wessbecher, the Eskimo women and children would scoop out the raw blubber from seals and eat it quickly with both hands. “It was just like eating candy.” In January 1955, Wessbecher’s assignment at Camp Resolute ended suddenly. He was recalled to Washington D.C., to serve on the Antarctic Planning Staff, a new initiative of the U.S. Weather Bureau. Later it became the Polar Operations Project. The assignment was to advise on living and surviving in polar regions, in both the Arctic and Antarctic areas, including food, buildings, clothing, supplies, sleeping gear, etc. Wessbecher was named contracting officer, and purchased supplies that would be needed in Antarctica. When Ken Molton, already there as part of Operation Deepfreeze, declined to overwinter, Wessbecher was drafted (“volunteered”) as his replacement. Once in Antarctica, Wessbecher became one of the two civilian representatives to the US Navy, and the International Geophysical Year (IGY). Among his duties was to organize and inventory the tremendous number of boxes of scientific weather equipment intended for the upcoming South Pole project, headed by Paul Siple. Much of it had to be “palletized,” equipped with parachutes, so that it could be delivered next season. Dick Bowers handled the delivery of building materials for the South Pole base. Although Wessbecher still worked for the Weather Bureau he reported to the US National Committee of the IGY. He was the Senior Science Representative in McMurdo to IGY. In addition to taking weather observations at McMurdo, he helped plan research in other areas, including Aurora study, geomagnetism, glaciology, and geomorphology. Admiral George Dufek and his pilot made the first landing at the South Pole, but before long many others followed. Contrary to inaccurate press reports, there was no real conflict between the Navy, who provided the transportation, and the scientists who were anxious to get to the Pole as soon as possible. Dufek promised to start the flights to the Pole as soon as the weather allowed. Wessbecher, and the only other civilian at McMurdo, Elmo Jones, a photographer, spent the winter at the base. This meant that he spent almost four straight years, including four winters, in the Arctic and Antarctic. Wessbecher first arrived in Antarctica in March 1955, aboard the icebreaker, the US Glacier. The trip from Littleton, New Zealand, was quite rough, but fascinating. In order to make it all the way to McMurdo it was necessary to break some ice. All the way the Glacier was also towing a fuel tanker. Wessbecher recalls the names of several of the military personnel who wintered over, including helicopter pilots, electricians, and others. Father Condit, a Catholic priest, also wintered over. Wessbecher was asked to make a pole that could be mounted and left at the South Pole, and he designed a bamboo one 12 feet long. Evidently it is still there, buried deep in the snow. In 1959 he was honored with a “Special Award” certificate from the National Academy of Sciences honoring his various accomplishments in Antarctica. Major Themes Wessbecher’s almost continuous four years of duty in the Arctic and Antarctica The International Geophysical Year, and Deepfreeze I Challenges, tasks, and equipment used, in weather observations in polar areas Service at Camps Resolute and Alert in Arctic region, and McMurdo in Antarctica Relations between Navy and civilian personnel in polar regionsFunded by a grant from the National Science Foundation