Pregnancy and reproduction in autoimmune rheumatic diseases

Despite evidence for the important role of oestrogens in the aetiology and pathophysiology of chronic immune/inflammatory diseases, the previous view of an unequivocal beneficial effect of oestrogens on RA compared with a detrimental effect on SLE has to be reconsidered. Likewise, the long-held belief that RA remits in the majority of pregnant patients has been challenged, and shows that only half of the patients experience significant improvement when objective disease activity measurements are applied. Pregnancies in patients with SLE are mostly successful when well planned and monitored interdisciplinarily, whereas a small proportion of women with APS still have adverse pregnancy outcomes in spite of the standard treatment. New prospective studies indicate better outcomes for pregnancies in women with rare diseases such as SSc and vasculitis. Fertility problems are not uncommon in patients with rheumatic disease and need to be considered in both genders. Necessary therapy, shortly before or during the pregnancy, demands taking into account the health of both mother and fetus. Long-term effects of drugs on offspring exposed in utero or during lactation is a new area under study as well as late effects of maternal rheumatic disease on children.

Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy

B cell activation factor of the TNF family (BAFF) is a potent B cell survival factor. BAFF overexpressing transgenic mice (BAFF-Tg mice) exhibit features of autoimmune disease, including B cell hyperplasia and hypergammaglobulinemia, and develop fatal nephritis with age. However, basal serum IgA levels are also elevated, suggesting that the pathology in these mice may be more complex than initially appreciated. Consistent with this, we demonstrate here that BAFF-Tg mice have mesangial deposits of IgA along with high circulating levels of polymeric IgA that is aberrantly glycosylated. Renal disease in BAFF-Tg mice was associated with IgA, because serum IgA was highly elevated in nephritic mice and BAFF-Tg mice with genetic deletion of IgA exhibited less renal pathology. The presence of commensal flora was essential for the elevated serum IgA phenotype, and, unexpectedly, commensal bacteria-reactive IgA antibodies were found in the blood. These data illustrate how excess B cell survival signaling perturbs the normal balance with the microbiota, leading to a breach in the normal mucosal-peripheral compartmentalization. Such breaches may predispose the nonmucosal system to certain immune diseases. Indeed, we found that a subset of patients with IgA nephropathy had elevated serum levels of a proliferation inducing ligand (APRIL), a cytokine related to BAFF. These parallels between BAFF-Tg mice and human IgA nephropathy may provide a new framework to explore connections between mucosal environments and renal pathology.

Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation

The purpose of this document is to make the output of the International Working Group for Intravascular Optical Coherence Tomography (IWG-IVOCT) Standardization and Validation available to medical and scientific communities, through a peer-reviewed publication, in the interest of improving the diagnosis and treatment of patients with atherosclerosis, including coronary artery disease.

Hypoxic preconditioning reverses protection after neonatal hypoxia-ischemia in glutathione peroxidase transgenic murine brain

The effect of hypoxic preconditioning (PC) on hypoxic-ischemic (HI) injury was explored in glutathione peroxidase (GPx)-overexpressing mice (human GPx-transgenic [hGPx-tg]) mice. Six-day-old hGPx-tg mice and wild-type (Wt) littermates were pre-conditioned with hypoxia for 30 min and subjected to the Vannucci procedure of HI 24 h after the PC stimulus. Histopathological injury was determined 5 d later (P12). Additional animals were killed 2 h or 24 h after HI and ipsilateral cerebral cortices assayed for GPx activity, glutathione (GSH), and hydrogen peroxide (H2O2). In line with previous studies, hypoxic PC reduced injury in the Wt brain. Preconditioned Wt brain had increased GPx activity, but reduced GSH, relative to naive 24 h after HI. Hypoxic PC did not reduce injury to hGPx-tg brain and even reversed the protection previously reported in the hGPx-tg. GPx activity and GSH in hGPx-tg cortices did not change. Without PC, hGPx-tg cortex had less H2O2 accumulation than Wt at both 2 h and 24 h. With PC, H2O2 remained low in hGPx-tg compared with Wt at 2 h, but at 24 h, there was no longer a difference between hGPx-tg and Wt cortices. Accumulation of H2O2 may be a mediator of injury, but may also induce protective mechanisms.

Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense

Although eosinophils are considered useful in defense mechanisms against parasites, their exact function in innate immunity remains unclear. The aim of this study is to better understand the role of eosinophils within the gastrointestinal immune system. We show here that lipopolysaccharide from Gram-negative bacteria activates interleukin-5 (IL-5)- or interferon-gamma-primed eosinophils to release mitochondrial DNA in a reactive oxygen species-dependent manner, but independent of eosinophil death. Notably, the process of DNA release occurs rapidly in a catapult-like manner--in less than one second. In the extracellular space, the mitochondrial DNA and the granule proteins form extracellular structures able to bind and kill bacteria both in vitro and under inflammatory conditions in vivo. Moreover, after cecal ligation and puncture, Il5-transgenic but not wild-type mice show intestinal eosinophil infiltration and extracellular DNA deposition in association with protection against microbial sepsis. These data suggest a previously undescribed mechanism of eosinophil-mediated innate immune responses that might be crucial for maintaining the intestinal barrier function after inflammation-associated epithelial cell damage, preventing the host from uncontrolled invasion of bacteria.

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