Symmetric dimethylarginine, high-density lipoproteins and cardiovascular disease.

AIMS: The vascular effects of high-density lipoproteins (HDL) differ under certain clinical conditions. The composition of HDL is modified in patients with chronic kidney disease (CKD). As a consequence, uremic HDL induces endothelial dysfunction. We have previously shown that accumulation of symmetric dimethylarginine (SDMA) in HDL causes these adverse effects of HDL in CKD. The aim of the study is to determine the impact of the accumulation of SDMA on the association between HDL and mortality. METHODS AND RESULTS: Mortality, renal function, serum SDMA and HDL-cholesterol (HDL-C) were assessed in the LURIC study including 3310 subjects undergoing coronary angiography. All-cause mortality was 30.0% during median follow-up of 9.9 years. Serum SDMA levels significantly predicted all-cause and cardiovascular mortality, and were significantly correlated with SDMA accumulation in HDL. Notably, higher serum SDMA was independently associated with lower cholesterol efflux (P = 0.004) as a measure of HDL functionality. In subjects with low SDMA levels, higher HDL-C was associated with significantly lower mortality. In contrast, in subjects with high SDMA, HDL-C was associated with higher mortality. These findings were confirmed in 1424 participants of the MONICA/KORA S3 cohort. Of note, we derived an algorithm allowing for calculation of biologically effective HDL-C' based on measured HDL-C and SDMA. We corroborated these clinical findings with invitro evidence showing that SDMA accumulation abolishes the anti-inflammatory and regenerative properties of HDL. CONCLUSION: The data identify SDMA as a marker of HDL dysfunction. These findings highlight on the pivotal role of SDMA accumulation in HDL as a mediator of pre-mature cardiovascular disease in patients with CKD.

RhoA determines disease progression by controlling neutrophil motility and restricting hyperresponsiveness.

Neutrophil responses are central to host protection and inflammation. Neutrophil activation follows a 2-step process in which priming amplifies responses to activating stimuli. Priming is essential for life span extension, chemotaxis, and respiratory burst activity. Here we show that the cytoskeletal organizer RhoA suppresses neutrophil priming via formins. Premature granule exocytosis in Rho-deficient neutrophils activated numerous signaling pathways and amplified superoxide generation. Deletion of Rho altered front-to-back coordination by simultaneously increasing uropod elongation, leading edge formation, and random migration. Concomitant negative and positive regulation of ß2 integrin-independent and ß2 integrin-dependent migration, respectively, reveal Rho as a key decision point in the neutrophil response to discrete chemotactic agents. Although even restricted influx of Rho-deficient hyperactive neutrophils exacerbated lipopolysaccharide-mediated lung injury, deleting Rho in innate immune cells was highly protective in influenza A virus infection. Hence, Rho is a key regulator of disease progression by maintaining neutrophil quiescence and suppressing hyperresponsiveness.

Astronaut medical selection during the shuttle era: 1981-2011.

INTRODUCTION: U.S. astronauts undergo extensive job-related screening and medical examinations prior to selection in order to identify candidates optimally suited for careers in spaceflight. Screening medical standards evolved over many years and after extensive spaceflight experience. These standards assess health-related risks for each astronaut candidate, minimizing the potential for medical impact on future mission success. This document discusses the evolution of the Shuttle-era medical selection standards and the most common reasons for medical dis-qualification of applicants. METHODS: Data for astronaut candidate finalists were compiled from medical records and NASA archives from the period of 1978 to 2004 and were retrospectively reviewed for medically disqualifying conditions. RESULTS: During Shuttle selection cycles, a total of 372 applicants were disqualified due to 425 medical concerns. The most common disqualifying conditions included visual, cardiovascular, psychiatric, and behavioral disorders. During this time period, three major expert panel reviews resulted in refinements and alterations to selection standards for future cycles. DISCUSSION: Shuttle-era screening, testing, and specialist evaluations evolved through periodic expert reviews, evidence-based medicine, and astronaut medical care experience. The Shuttle medical program contributed to the development and implementation of NASA and international standards, longitudinal data collection, improved medical care, and occupational surveillance models. The lessons learned from the Shuttle program serve as the basis for medical selection for the ISS, exploration-class missions, and for those expected to participate in commercial spaceflight.

Frequent premature ventricular contractions in an orbital spaceflight participant.

BACKGROUND: Commercial spaceflight participants on orbital flights typically are older than career astronauts and they often have medical conditions that have not been studied at high g or in microgravity. This is a case report of a 56-yr-old orbital spaceflight participant with essential tremor and frequent premature ventricular contractions that occurred at rates up to 7000 per day. Before training and spaceflight, he was required to complete extensive clinical investigations to demonstrate normal cardiac structures and the absence of cardiac pathology. The evaluation included signal averaged ECG, transthoracic stress echocardiography, exercise tolerance tests, electrophysiological studies, cardiac MRI, electron beam CT, Holter monitoring, and overnight oximetry. While no cardiac pathology was demonstrated, the Russian medical team required that the PVCs be treated prior to training and spaceflight. For the initial flight, a selective beta-1 receptor beta blocker was used and for the second a calcium channel blocker was used in combination with a nonselective beta blocker for tremor control. Analogue environment testing assured that this combination of medications was compatible. CONCLUSION: The spaceflight participant's PVCs were incompletely suppressed with a low-dose selective beta-1 blocker, but were well suppressed by a calcium channel blocker. He tolerated in-flight periodic use of a nonselective beta blocker in combination with a calcium channel blocker. In-flight ECG and blood pressure monitoring results were normal, and an ECG obtained midmission and on landing day showed successful PVC suppression. He did not have any cardiac difficulty with launch, on-orbit operations, entry, or recovery

The ISS flight of Richard Garriott: a template for medicine and science investigation on future spaceflight participant missions.

BACKGROUND: A total of eight commercial spaceflight participants have launched to the International Space Station (ISS) on Soyuz vehicles. Based on an older mean age compared to career astronauts and an increased prevalence of medical conditions, spaceflight participants have provided the opportunity to learn about the effect of space travel on crewmembers with medical problems. The 12-d Soyuz TMA-13/12 ISS flight of spaceflight participant Richard Garriott included medical factors that required preflight intervention, risk mitigation strategies, and provided the opportunity for medical study on-orbit. Equally important, Mr. Garriott conducted extensive medical, scientific, and educational payload operations during the flight. These included 7 medical experiments and a total of 15 scientific projects such as protein crystal growth, Earth observations/photography, educational projects with schools, and amateur radio. The medical studies included the effect of microgravity on immune function, sleep, bone loss, corneal refractive surgery, low back pain, motion perception, and intraocular pressure. CONCLUSION: The overall mission success resulted from non-bureaucratic agility in mission planning, cooperation with investigators from NASA, ISS, International Partners, and the Korean Aerospace Research Institute, in-flight support and leadership from a team with spaceflight and Capcom experience, and overall mission support from the ISS program. This article focuses on science opportunities that suborbital and orbital spaceflight participant flights offer and suggests that the science program on Richard Garriott's flight be considered a model for future orbital and suborbital missions. The medical challenges are presented in a companion article.

Giant hepatic hemangioma and cross-fused ectopic kidney in a spaceflight participant.

Commercial spaceflight participants are typically older than traditional astronauts and often have medical conditions that make medical certification for flight difficult. This case report considers a 43-yr-old spaceflight participant who planned a short-duration Soyuz flight to the International Space Station (ISS). While he participated in many hazardous activities such as parachuting, hang gliding, scuba diving, Antarctic and jungle exploration, and deep sea submersible operations, he knew that several of his medical conditions precluded serving as a career astronaut. At the time of his initial spaceflight prescreen examination, he was known to have previous bilateral photorefractive keratectomy (PRK) for myopia and a cross-fused left ectopic kidney that would be disqualifying for a career astronaut. During the evaluation for the left single cross-fused ectopic kidney, a giant hepatic hemangioma was also discovered. In order to medically qualify for flight, the giant hepatic hemangioma was surgically removed. This case summary investigat*es the implications of a single cross-fused left ectopic kidney and the decision process and treatment implications for spaceflight medical certification in an individual with an asymptomatic giant hepatic hemangioma.

Gynecologic Risk Mitigation Considerations for Long-Duration Spaceflight.

INTRODUCTION: As NASA and its international partners, as well as the commercial spaceflight industry, prepare for missions of increasing duration and venturing outside of low-Earth orbit, mitigation of medical risk is of high priority. Gynecologic considerations constitute one facet of medical risk for female astronauts. This manuscript will review the preflight, in-flight, and postflight clinical evaluation, management, and prevention considerations for reducing gynecologic and reproductive risks in female astronauts.METHODS: Relevant gynecological articles from databases including Ovid, Medline, Web of Science, various medical libraries, and NASA archives were evaluated for this review. In particular, articles addressing preventive measures or management of conditions in resource-limited environments were evaluated for applicability to future long-duration exploration spaceflight.RESULTS: Topics including abnormal uterine bleeding, anemia, bone mineral density, ovarian cysts, venous thromboembolism, contraception, fertility, and health maintenance were reviewed. Prevention and treatment strategies are discussed with a focus on management options that consider limitations of onboard medical capabilities.DISCUSSION: Long-duration exploration spaceflight will introduce new challenges for maintenance of gynecological and reproductive health. The impact of the space environment outside of low-Earth orbit on gynecological concerns remains unknown, with factors such as increased particle radiation exposure adding complexity and potential risk. While the most effective means of minimizing the impact of gynecologic or reproductive pathology for female astronauts is screening and prevention, gynecological concerns can arise unpredictably as they do on Earth. Careful consideration of gynecological risks and potential adverse events during spaceflight is a critical component to risk analysis and preventive medicine for future exploration missions.Steller JG, Blue RS, Burns R, Bayuse TM, Antonsen EL, Jain V, Blackwell MM, Jennings RT. Gynecologic risk mitigation considerations for long-duration spaceflight. Aerosp Med Hum Perform. 2020; 91(7):543-564.

Human health and performance for long-duration spaceflight.

Future long-duration spaceflights are now being planned to the Moon and Mars as a part of the "Vision for Space Exploration" program initiated by NASA in 2004. This report describes the design reference missions for the International Space Station, Lunar Base, and eventually a Mars Expedition. There is a need to develop more stringent preflight medical screening for crewmembers to minimize risk factors for diseases which cannot be effectively treated in flight. Since funding for space life sciences research and development has been eliminated to fund program development, these missions will be enabled by countermeasures much like those currently in use aboard the International Space Station. Artificial gravity using centrifugation in a rotating spacecraft has been suggested repeatedly as a "universal countermeasure" against deconditioning in microgravity and could be an option if other countermeasures are found to be ineffective. However, the greatest medical unknown in interplanetary flight may be the effects of radiation exposure. In addition, a Mars expedition would lead to a far greater level of isolation and psychological stress than any space mission attempted previously; because of this, psychiatric decompensation remains a risk. Historically, mortality and morbidity related to illness and injury have accounted for more failures and delays in new exploration than have defective transportation systems. The medical care system on a future Mars expedition will need to be autonomous and self-sufficient due to the extremely long separation from definitive medical care. This capability could be expanded by the presence of a physician in the crew and including simple, low-technology surgical capability.

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.

BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. FINDINGS: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies. INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

Medical qualification of a commercial spaceflight participant: not your average astronaut.

BACKGROUND: Candidates for commercial spaceflight may be older than the typical astronaut and more likely to have medical problems that place them at risk during flight. Since the effects of microgravity on many medical conditions are unknown, physicians have little guidance when evaluating and certifying commercial spaceflight participants. This dynamic new era in space exploration may provide important data for evaluating medical conditions, creating appropriate medical standards, and optimizing treatment alternatives for long-duration spaceflight. CASE: A 57-yr-old spaceflight participant for an ISS mission presented with medical conditions that included moderately severe bullous emphysema, previous spontaneous pneumothorax with talc pleurodesis, a lung parenchymal mass, and ventricular and atrial ectopy. The medical evaluation required for certification was extensive and included medical studies and monitoring conducted in analogue spaceflight environments including altitude chambers, high altitude mixed-gas simulation, zero-G aircraft, and high-G centrifuge. To prevent recurrence of pneumothorax, we performed video-assisted thoracoscopic pleurodesis, and to assess lung masses, several percutaneous or direct biopsies. The candidate's 10-d mission was without incident. CONCLUSION: Non-career astronauts applying for commercial suborbital and orbital spaceflight will, at least in the near future, challenge aerospace physicians with unknowns regarding safety during training and flight, and highlight important ethical and risk-assessment problems. The information obtained from this new group of space travelers will provide important data for the evaluation and in-flight treatment of medical problems that space programs have not yet addressed systematically, and may improve the medical preparedness of exploration-class missions.

Rho family and Rap GTPase activation assays.

The detection of Ras superfamily GTPase activity in innate immune cells is important when studying signaling events elicited by various ligands and cellular processes. The development of high-affinity probes detecting the activated, GTP-bound form of small GTPases has significantly enhanced our understanding of initiation and termination of GTPase-regulated signaling pathways. These probes are created by fusing a high-affinity GTPase-binding domain derived from a specific downstream effector protein to glutathione S-transferase (GST). Such domains bind preferentially to the GTP-bound form of the upstream Rho or Ras GTPase. Coupling these probes to beads enables extraction of the complex and subsequent quantification of the active GTP-binding protein by immunoblotting. Although effector domains that discriminate efficiently between GDP- and GTP-bound states and highly specific antibodies are not yet available for every small GTPase, analysis of certain members of the Rho and Ras GTPase family is now routinely performed. Here, we describe affinity-based pulldown assays for detection of Rho GTPase (Rac1/2, Cdc42, RhoA/B) and Rap1/2 activity in stimulated neutrophils or macrophages.

Neutrophil migration through extracellular matrix.

Neutrophil migration from the bloodstream to sites of infection or injury is a multistep process that requires, dependent on the tissue structures being encountered, different modes of movement. Neutrophil locomotion can range from mesenchymal to amoeboid movement and may include multiple shape changes, contractile squeezing through gaps, and adhesion/de-adhesion cycles. In vitro migration assays reflect only some aspects of the complex in vivo neutrophil recruitment. For two-dimensional in vitro migration chemotaxis chambers, microscopic analysis of movement towards a pipette gradient or Boyden chambers is used. To analyze three-dimensional in vitro migration neutrophils can be embedded into matrices of diverse biophysical properties or can be placed onto matrices that are layered on a wide-pore filter, enabling migration through the matrix and the filter of a transwell plate towards a gradient of chemoattractant. We utilize here a commercially available setup for migration of murine neutrophils from the top of a loose collagen type I matrix, which determines the ability of neutrophils to attach to the matrix, sense the chemoattractant, polarize, digest the matrix, and move through the matrix into the lower transwell chamber. While the mode of migration inside the matrix cannot be studied in detail, this assay permits quantitative assessment of migrated neutrophils during a defined period of time.

Visual stability of laser vision correction in an astronaut on a Soyuz mission to the International Space Station.

UNLABELLED: This report documents the effects of photorefractive keratectomy (PRK) in an astronaut during a 12-day Russian Soyuz mission to the International Space Station in 2008. Changing environmental conditions of launch, microgravity exposure, and reentry create an extremely dynamic ocular environment. Although many normal eyes have repeatedly been subject to such stresses, the effect on an eye with a relatively thin cornea as a result of PRK has not been reported. This report suggests that PRK is a safe, effective, and well-tolerated procedure in astronauts during space flight. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.