IL-6 transsignalling modulates the early effector phase of EAE and targets the blood-brain barrier

Interleukin-6 (IL-6) plays a crucial role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). It exerts its cellular effects by a membrane-bound IL-6 receptor (IL-6R), or, alternatively, by forming a complex with the soluble IL-6R (sIL-6R), a process named IL-6 transsignalling. Here we investigate the role of IL-6 transsignalling in myelin basic protein (MBP)-induced EAE in the Lewis rat. In vivo blockade of IL-6 transsignalling by the injection of a specifically designed gp130-Fc fusion protein significantly delayed the onset of adoptively transferred EAE in comparison to control rats injected with PBS or isotype IgG. Histological evaluation on day 3 after immunization revealed reduced numbers of T cells and macrophages in the lumbar spinal cord of gp130-Fc treated rats. At the same time, blockade of IL-6 transsignalling resulted in a reduced expression of vascular cell adhesion molecule-1 on spinal cord microvessels while experiments in cell culture failed to show a direct effect on the regulation of endothelial adhesion molecules. In experiments including active EAE and T cell culture, inhibition of IL-6 transsignalling mildly increased T cell proliferation, but did not change severity of active MBP-EAE or regulate Th1/Th17 responses. We conclude that IL-6 transsignalling may play a role in autoimmune inflammation of the CNS mainly by regulating early expression of adhesion molecules, possibly via cellular networks at the blood-brain barrier.

Expression of adenosine A2a receptors gene in the olfactory bulb and spinal cord of rat and mouse

The expression of adenosine A2a receptors (A2aR) in the mammalian striatum is well known. In contrast the exact distribution of A2aR in other regions of the central nervous system remains unclear. The aim of this study was to investigate the A2aR gene expression in the rat olfactory bulb and spinal cord, two regions which are seldom included in mapping studies. Secondly, we compared the A2aR expression in the rat and in the mouse brain. Hybridization histochemistry was performed with an S35-labelled radioactive oligonucleotide probe. The results show strong expression of A2aR in the mouse and rat striatum in accordance with previous reports. In the olfactory bulb a weak but specific expression of A2aR was found in the granular cell layer in both species. In contrast, no significant expression of the A2aR gene was observed in other parts of the brain or the rat spinal cord. The presence of the A2aR in the mammalian olfactory bulb suggests a functional role for this receptor in olfaction.

Long-term outcome of acute spinal cord ischemia syndrome

BACKGROUND AND PURPOSE: Current knowledge of long-term outcome in patients with acute spinal cord ischemia syndrome (ASCIS) is based on few studies with small sample sizes and <2 years' follow-up. Therefore, we analyzed clinical features and outcome of all types of ASCIS to define predictors of recovery. METHODS: From January 1990 through October 2002, 57 patients with ASCIS were admitted to our center. Follow-up data were available for 54. Neurological syndrome and initial degree of impairment were defined according to American Spinal Injury Association (ASIA)/International Medical Society of Paraplegia criteria. Functional outcome was assessed by walking ability and bladder control. RESULTS: Mean age was 59.4 years; 29 were women; and mean follow-up was 4.5 years. The origin was atherosclerosis in 33.3%, aortic pathology in 15.8%, degenerative spine disease in 15.8%, cardiac embolism in 3.5%, systemic hypotension in 1.8%, epidural anesthesia in 1.8%, and cryptogenic in 28%. The initial motor deficit was severe in 30% (ASIA grades A and B), moderate in 28% (ASIA C), and mild in 42% (ASIA D). At follow-up, 41% had regained full walking ability, 30% were able to walk with aids, 20% were wheelchair bound, and 9% had died. Severe initial impairment (ASIA A and B) and female sex were independent predictors of unfavorable outcome (P=0.012 and P=0.043). CONCLUSIONS: Considering a broad spectrum of clinical presentations and origins, the outcome in our study was more favorable than in previous studies reporting on ASCIS subgroups with more severe initial deficits.

Firing Up the Crucible with Senator Lee Metcalf & Governor Forrest Anderson -- Judge Gordon Bennett in “The Crucible of Change”

During the lead-up to Montana second progressive era, Lee Metcalf and Forrest Anderson, along with others, kept the progressive flame lit in Montana. Metcalf’s political history is replete with close electoral wins because of his commitment to progressive ideals when the times were not always politically favorable for that. As State Legislator, MT Supreme Court Justice, Congressman and eventually as US Senator, Lee won races by as little as 55 votes because he stuck to his guns as a progressive. In Forrest Anderson’s career as a County Attorney, State Legislator, MT Supreme Court Justice and 12 years as MT Attorney General he was respected as a pragmatic practitioner of politics. But during that entire career leading up to his election as Governor, Forrest Anderson was also a stalwart supporter of the progressive agenda exemplified by FDR and the New Deal, which brought folks out of the Great Depression that was brought on by the bad policies of the GOP and big business. As MT’s second progressive period began in 1965, the first important election was Senator Metcalf’s successful re-election battle in 1966 with the sitting MT Governor, Tim Babcock. And the progressive express was really ignited by the election of Forrest Anderson as Governor in 1968 after 16 years of Republican Governors in MT. Gordon Bennett played a rather unique role, being a confidant of Metcalf and Anderson, both who respected his wide and varied experience, his intellect, and his roots in progressivism beginning with his formative years in the Red Corner of NE Montana. Working with Senator Metcalf and his team, including Brit Englund, Vic Reinemer, Peggy McLaughlin, Betty Davis and Jack Condon among others, Bennett helped shape the progressive message both in Washington DC and MT. Progressive labor and farm organizations, part of the progressive coalition, benefitted from Bennett’s advice and counsel and aided the Senator in his career including the huge challenge of having a sitting popular governor run against him for the Senate in 1966. Metcalf’s noted intern program produced a cadre of progressive leaders in Montana over the years. Most notably, Ron Richards transitioned from Metcalf Intern to Executive Secretary of the Montana Democratic Party (MDP) and assisted, along with Bennett, in the 1966 Metcalf-Babcock race in a big way. As Executive Secretary Richards was critical to the success of the MDP as a platform for Forrest Anderson’s general election run and win in 1968. After Forrest’s gubernatorial election, Richards became Executive Assistant (now called Chief of Staff) for Governor Anderson and also for Governor Thomas Judge. The Metcalf progressive strain, exemplified by many including Richards and Bennett, permeated Democratic politics during the second progressive era. So, too, did the coalition that supported Metcalf and his policies. The progressivism of the period of “In the Crucible of Change” was fired up by Lee Metcalf, Forrest Anderson and their supporters and coalitions, and Gordon Bennett was in the center of all of that, helping fire up the crucible, setting the stage for many policy advancements in both Washington DC and Montana. Gordon Bennett’s important role in the 1966 re-election of Senator Lee Metcalf and the 1968 election of Governor Forrest Anderson, as well as his wide experience in government and politics of that time allows him to provide us with an insider’s personal perspective of those races and other events at the beginning of the period of progressive change being documented “In the Crucible of Change,” as well as his personal insights into the larger political/policy picture of Montana. Gordon Bennett, a major and formative player “In the Crucible of Change,” was born in the far northeast town of Scobey, MT in 1922. He attended school in Scobey through the eighth grade and graduated from Helena High School. After attending Carroll College for two years, he received his BA in economics from Carleton College in Northfield, MN. During a brief stint on the east coast, his daily reading of the New York Times (“best newspaper in the world at that time … and now”) inspired him to pursue a career in journalism. He received his MA in Journalism from the University of Missouri and entered the field. As a reporter for the Great Falls Tribune under the ownership and management of the Warden Family, he observed and competed with the rigid control of Montana’s press by the Anaconda Company (the Great Falls Tribune was the only large newspaper in Montana NOT owned by ACM). Following his intellectual curiosity and his philosophical bend, he attended a number of Farm-Labor Institutes which he credits with motivating him to pursue solutions to economic and social woes through the law. In 1956, at the age of 34, he received his Juris Doctorate degree from the Georgetown University Law Center in Washington, DC. Bennett’s varied career included eighteen years as a farmer, four years in the US Army during WWII (1942-46), two years as Assistant MT Attorney General (1957-59) with Forrest Anderson, three years in private practice in Glasgow (1959-61), two years as Associate Solicitor in the Department of Interior in Washington, DC (1961-62), and private law practice in Helena from 1962 to 1969. While in Helena he was an unsuccessful candidate for the Montana Supreme Court (1962) and cemented his previous relationships with Attorney General Forrest Anderson and US Senator Lee Metcalf. Bennett modestly refuses to accept the title of Campaign Manager for either Lee Metcalf (1966 re-election over the challenger, MT Republican Governor Tim Babcock) or Forrest Anderson (his 1968 election as Governor), saying that “they ran their campaigns … we were only there to help.” But he has been generally recognized as having filled that critical role in both of those critical elections. After Governor Anderson’s election in 1968, Bennett was appointed Director of the MT Unemployment Compensation Commission, a position from where he could be a close advisor and confidant of the new Governor. In 1971, Governor Anderson appointed him Judge in the most important jurisdiction in Montana, the 1st Judicial District in Helena, a position he held for seventeen years (1971-88). Upon stepping down from his judgeship, for twenty years (1988-2008) he was a law instructor, mediator and arbitrator. He currently resides in Helena with his wife, Norma Tirrell, former newspaper reporter and researcher/writer. Bennett has two adult children and four grandchildren.

Remembering Lee Metcalf - Natural Resources, Environmental and Conservation Excerpts (done for 75th Anniversary of Montana State Parks System - 2014)

Montana's Lee Metcalf was an extraordinary Montana leader with an unbelievable record of accomplishment fighting for the little people against the forces of economic and political power. The public memory is so short that this film will serve to help reacquaint Lee & Donna Metcalf to most of those who were around during their time. But it will also provide an opportunity for new generations to receive a perspective of an important leader from an important time. (Language from YouTube version of the film, written and provided by Executive Producer Evan Barrett) Lee Warren Metcalf (January 28, 1911 – January 12, 1978) was an American lawyer, judge, and politician. A member of the Democratic Party, he served as a U.S. Representative (1953–1961) and a U.S. Senator (1961–1978) from Montana. He was permanent acting President pro tempore of the Senate, the only person to hold that position, from 1963 until his death in 1978. Excerpts from main film for 75th Anniversary of Montana State Parks System

Remembering Lee Metcalf

Abstract Montana's Lee Metcalf was an extraordinary Montana leader with an unbelievable record of accomplishment fighting for the little people against the forces of economic and political power. The public memory is so short that this film will serve to help reacquaint Lee & Donna Metcalf to most of those who were around during their time. But it will also provide an opportunity for new generations to receive a perspective of an important leader from an important time. (Language from YouTube version of the film, written and provided by Executive Producer Evan Barrett) Lee Warren Metcalf (January 28, 1911 – January 12, 1978) was an American lawyer, judge, and politician. A member of the Democratic Party, he served as a U.S. Representative (1953–1961) and a U.S. Senator (1961–1978) from Montana. He was permanent acting President pro tempore of the Senate, the only person to hold that position, from 1963 until his death in 1978. U.S. House of Representatives During his tenure in the House, Metcalf served on the Education and Labor Committee (1953–1959), Interior and Insular Affairs Committee (1955–1959), Select Astronautics and Space Exploration Committee (1958), and Ways and Means Committee (1959–1960). He became known as one of Congress's "Young Turks" who promoted liberal domestic social legislation and reform of congressional procedures. He introduced legislation to provide health care to the elderly ten years before the creation of Medicare. He earned the nickname "Mr. Education" after sponsoring a comprehensive bill providing for federal aid to education. He also voted against legislation that would have raised grazing permits on federal lands, and led the opposition to a bill that would have swapped forested public lands for cutover private lands. He was elected chairman of the Democratic Study Group in 1959. U. S. Senate Regarded as "a pioneer of the conservation movement", Metcalf worked to protect the natural environment and regulate utilities. He helped pass the Wilderness Act of 1964, and supported the creation of the Great Bear Wilderness and the Absaroka-Beartooth Wilderness. In 1962, he introduced a "Save Our Streams" bill to preserve natural recreation facilities and protect fish and wildlife from being destroyed by highway construction. He was a longtime member of the Migratory Bird Conservation Commission. He was also active on the issue of education. He was a leading supporter of the Elementary and Secondary Education Act, the effort to extend the G.I. Bill's educational benefits to a new generation of veterans, and the development of legislation to improve federally-aided vocational education.[1] The Peace Corps was established under leadership of Metcalf and Senator Mansfield. In 1983, by act of Congress, the Lee Metcalf Wilderness area was created in southwestern Montana in honor of the late Congressman. The Great Bear Wilderness and Absaroka-Beartooth Wilderness areas were also created as a result of Metcalf's efforts in Congress, in addition to the Lee Metcalf National Wildlife Refuge in Montana. Metcalf was ranked number 15 on a list of the 100 Most Influential Montanans of the Century by the Missoulian newspaper. This text is courtesy of Wikipedia®, a registered trademark of the Wikimedia Foundation, Inc., a non-profit organization, and is available under the Creative Commons Attribution-ShareAlike License.

Remembering Lee Metcalf

A Montana Public Radio Commentary from Evan Barrett. Published newspaper columns written by Evan Barrett on this topic, which vary somewhat in content from this commentary, appeared in the following publications: Havre Daily News, February 27, 2013 Ravalli Republic, February 28, 2013 Bozeman Daily Chronicle, March 4, 2013 Helena Independent Record, March 4, 2013 Montana Standard, March 13, 2013 Missoulian, March 22, 2013

Effect of detraining on bone and muscle tissue in subjects with chronic spinal cord injury after a period of electrically-stimulated cycling: a small cohort study

OBJECTIVE: To investigate adaptive changes in bone and muscle parameters in the paralysed limbs after detraining or reduced functional electrical stimulation (FES) induced cycling following high-volume FES-cycling in chronic spinal cord injury. SUBJECTS: Five subjects with motor-sensory complete spinal cord injury (age 38.6 years, lesion duration 11.4 years) were included. Four subjects stopped FES-cycling completely after the training phase whereas one continued reduced FES-cycling (2-3 times/week, for 30 min). METHODS: Bone and muscle parameters were assessed in the legs using peripheral quantitative computed tomography at 6 and 12 months after cessation of high-volume FES-cycling. RESULTS: Gains achieved in the distal femur by high-volume FES-cycling were partly maintained at one year of detraining: 73.0% in trabecular bone mineral density, 63.8% in total bone mineral density, 59.4% in bone mineral content and 22.1% in muscle cross-sectional area in the thigh. The subject who continued reduced FES-cycling maintained 96.2% and 95.0% of the previous gain in total and trabecular bone mineral density, and 98.5% in muscle cross-sectional area. CONCLUSION: Bone and muscle benefits achieved by one year of high-volume FES-cycling are partly preserved after 12 months of detraining, whereas reduced cycling maintains bone and muscle mass gained. This suggests that high-volume FES-cycling has clinical relevance for at least one year after detraining.

Cellular and network mechanisms of rhythm generation in spinal cord circuits

The generation of rhythmic electrical activity is a prominent feature of spinal cord circuits that is used for locomotion and also for circuit refinement during development. The mechanisms involved in rhythm generation in spinal cord networks are not fully understood. It is for example not known whether spinal cord rhythms are driven by pacemaker neurons and if yes, which neurons are involved in this function. We studied the mechanisms involved in rhythm generation in slice cultures from fetal rats that were grown on multielectrode arrays (MEAs). We combined multisite extracellular recordings from the MEA electrodes with intracellular patch clamp recordings from single neurons. We found that spatially restricted oscillations of activity appeared in most of the cultures spontaneously. Such activity was based on intrinsic activity in a percentage of the neurons that could activate the spinal networks through recurrent excitation. The local oscillator networks critically involved NMDA, AMPA and GABA / glycine receptors at subsequent phases of the oscillation cycle. Intrinsic spiking in individual neurons (in the absence of functional synaptic coupling) was based on persistent sodium currents. Intrinsic firing as well as persistent sodium currents were increased by 5-HT through 5-HT2 receptors. Comparing neuronal activity to muscle activity in co-cultures of spinal cord slices with muscle fibers we found that a percentage of the intrinsically spiking neurons were motoneurons. These motoneurons were electrically coupled among each other and they could drive the spinal networks through cholinergic recurrent excitation. These findings open the possibility that during development rhythmic activity in motoneurons is not only involved in circuit refinement downstream at the neuromuscular endplates but also upstream at the level of spinal cord circuits.