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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 181 records · Page 10
All sourcesNASA NTRSDOE OSTI
NASA NTRS1978

A review of the consequences of fluid and electrolyte shifts in weightlessness

This review describes the renal-endocrine mechanisms related to the early losses of fluid-electrolytes from the body during weightlessness as well as their contribution to longer term adaptation of fluid-electrolyte balance. The hypotheses presented were generated by a systematic analysis of body fluid and renal dynamics observed under conditions of actual and simulated spaceflight. These have increased our understanding of the effects of acute headward fluid shifts on renal excretion, the factors promoting excess sodium excretion and the regulation of extracellular fluid composition.

Leach, C. S.↗
NASA NTRS1993

Allowable exposure limits for carbon dioxide during extravehicular activity

The intent was to review the research pertaining to human exposure to carbon dioxide (CO2) and to recommend allowable exposure limits for extravehicular activity (EVA). Respiratory, renal, and gastrointestinal systems may be adversely affected by chronic low dose CO2 exposure. Ventilation was increased 15 percent with 1 percent CO2 and 50 percent with 2 percent CO2. Chronic exposure to less than 2 percent CO2 led to 20 day cycles of uncompensated and compensated respiratory acidosis. Acid-base changes were small. Histopathologic changes in guinea pig lungs have been noted with long term exposure to 1 percent CO2. No changes were seen with exposure to 0.5 percent CO2. Cycling of bone calcium stores with associated changes in blood and urinary calcium levels occurs with long term CO2 exposure. Histologic changes in bone have been noted in guinea pigs exposed to 1 percent CO2. Renal calcification has been noted in guinea pigs with exposure to as low as 0.5 percent CO2. An increase in gastric acidity was noted in subjects with long term exposure to 1 percent CO2. Cardiovascular and neurologic function were largely unaffected. A decrease in the incidence of respiratory, renal, and gastrointestinal disease was noted in submariners coincident with a decrease in ambient CO2 from 1.2 percent to 0.8-0.9 percent. Oxygen (O2) and CO2 stimulate respiration independently and cumulatively. The addition of CO2 to high dose O2 led to the faster onset of seizure activity in mice. Experiments evaluating the physiologic responses to intermittent, repetitive exposures to low dose CO2 and 100 percent O2 mixtures should be performed. A reduction in the current NASA standard for CO2 exposure during EVA of 1 percent (7.6 mmHg) for nominal and 2 percent (15.2 mmHg) for heavy exertion to 0.5 percent (3.8 mmHg) for nominal and 1 percent (7.6 mmHg) for heavy exertion may be prudent. At a minimum, the current NASA standard should not be liberalized.

Seter, Andrew J.↗
NASA NTRS1979

A review of the consequences of fluid and electrolyte shifts in weightlessness

This review describes the renal-endocrine mechanisms related to the early losses of fluid-electrolytes from the body during weightlessness as well as their contribution to longer term adaptation of fluid-electrolyte balance. The hypotheses presented were generated by a systematic analysis of body fluid and renal dynamics observed under conditions of actual and simulated spaceflight. These have increased our understanding of the effects of acute headward fluid shifts on renal excretion, the factors promoting excess sodium excretion and the regulation of extracellular fluid composition.

Review↗
NASA NTRS2004

Production of functional proteins: balance of shear stress and gravity

The present invention provides a method for production of functional proteins including hormones by renal cells in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel. Natural mixture of renal cells expresses the enzyme 1-a-hydroxylase which can be used to generate the active form of vitamin D: 1,25-diOH vitamin D3. The fibroblast cultures and co-culture of renal cortical cells express the gene for erythropoietin and secrete erythropoietin into the culture supernatant. Other shear stress response genes are also modulated by shear stress, such as toxin receptors megalin and cubulin (gp280). Also provided is a method of treating in-need individual with the functional proteins produced in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel.

Goodwin, Thomas John↗
NASA NTRS2007

Production of functional proteins: balance of shear stress and gravity

The present invention provides a method for production of functional proteins including hormones by renal cells in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel. Natural mixture of renal cells expresses the enzyme 1-a-hydroxylase which can be used to generate the active form of vitamin D: 1,25-diOH vitamin D3. The fibroblast cultures and co-culture of renal cortical cells express the gene for erythropoietin and secrete erythropoietin into the culture supernatant. Other shear stress response genes are also modulated by shear stress, such as toxin receptors megalin and cubulin (gp280). Also provided is a method of treating in-need individual with the functional proteins produced in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel.

Goodwin, Thomas John↗
NASA NTRS2009

Bisphosphonate as a Countermeasure to Space Flight-Induced Bone Loss

The purpose of this research is to determine whether anti-resorptive pharmaceuticals such as bisphosphonates, in conjunction with the routine in-flight exercise program, will protect ISS crewmembers from the regional decreases in bone mineral density and bone strength and the increased renal stone risk documented on previous long-duration space flights [1-3]. Losses averaged ~ 1 to 2 percent per month in such regions as the lumbar spine and hip. Although losses showed significant heterogeneity among individuals and between bones within a given subject, space flight-induced bone loss was a consistent finding. More than 90 percent of astronauts and cosmonauts on long-duration flights (average 171 days) aboard Mir and the ISS, had a minimum 5 percent loss in at least one skeletal site, 40 percent of them had a 10 percent or greater loss in at least one skeletal site, and 22 percent of the Mir cosmonauts experienced a 15 to 20 percent loss in at least one site. These losses occurred even though the crewmembers performed time-consuming in-flight exercise regimens. Moreover, a recent study of 16 ISS astronauts using quantitative computed tomography (QCT) demonstrated trabecular bone losses from the hip averaging 2.3 percent per month [4]. These losses were accompanied by significant losses in hip bone strength that may not be recovered quickly [5]. This rapid loss of bone mass results from a combination of increased and uncoupled remodeling, as demonstrated by increased resorption with little or no change in bone formation markers [6-7]. This elevated remodeling rate likely affects the cortical and trabecular architecture and may lead to irreversible changes. In addition to bone loss, the resulting hypercalciuria increases renal stone risk. Therefore, it is logical to attempt to attenuate this increased remodeling with anti-resorption drugs such as bisphosphonates. Success with alendronate was demonstrated in a bed rest study [8]. This work has been extended to space flight and two dosing regimens: 1) an oral dose of 70 mg of alendronate taken weekly during flight or 2) a single intravenous (IV) dose of 4 mg of zoledronic acid given several weeks before flight. Currently the study is focusing on the oral option because of NASA s safety concerns with the IV-administered drug. The protocol requests 10 male or female crewmembers on ISS flights of 90 days or longer. Controls are 16 previous ISS crewmembers with QCT scans of the hip performed by these same investigators. The primary outcome measure for this study is hip trabecular bone mineral density measured by QCT, but other measures of bone mass are performed including peripheral QCT (pQCT) and dual-energy x-ray absorptiometry. Serum and urinary bone markers and renal stone risk measured before, during, and after flight are included. Postflight data are currently being collected from 2 ISS crewmembers. Two additional crewmembers will return this spring after ~6-month missions. To date no untoward effects have been encountered.

Spector, Elisabeth↗
NASA NTRS2011

Production of functional proteins: balance of shear stress and gravity

A method for the production of functional proteins including hormones by renal cells in a three dimensional culturing process responsive to shear stress uses a rotating wall vessel. Natural mixture of renal cells expresses the enzyme 1-.alpha.-hydroxylase which can be used to generate the active form of vitamin D: 1,25-diOH vitamin D.sub.3. The fibroblast cultures and co-culture of renal cortical cells express the gene for erythropoietin and secrete erythropoietin into the culture supernatant. Other shear stress response genes are also modulated by shear stress, such as toxin receptors megalin and cubulin (gp280). Also provided is a method of treating an in-need individual with the functional proteins produced in a three dimensional co-culture process responsive to shear stress using a rotating wall vessel.

Goodwin, Thomas John↗
NASA NTRS1993

Alkali absorption and citrate excretion in calcium nephrolithiasis

The role of net gastrointestinal (GI) alkali absorption in the development of hypocitraturia was investigated. The net GI absorption of alkali was estimated from the difference between simple urinary cations (Ca, Mg, Na, and K) and anions (Cl and P). In 131 normal subjects, the 24 h urinary citrate was positively correlated with the net GI absorption of alkali (r = 0.49, p < 0.001). In 11 patients with distal renal tubular acidosis (RTA), urinary citrate excretion was subnormal relative to net GI alkali absorption, with data from most patients residing outside the 95% confidence ellipse described for normal subjects. However, the normal relationship between urinary citrate and net absorbed alkali was maintained in 11 patients with chronic diarrheal syndrome (CDS) and in 124 stone-forming patients devoid of RTA or CDS, half of whom had "idiopathic" hypocitraturia. The 18 stone-forming patients without RTA or CDS received potassium citrate (30-60 mEq/day). Both urinary citrate and net GI alkali absorption increased, yielding a significantly positive correlation (r = 0.62, p < 0.0001), with the slope indistinguishable from that of normal subjects. Thus, urinary citrate was normally dependent on the net GI absorption of alkali. This dependence was less marked in RTA, confirming the renal origin of hypocitraturia. However, the normal dependence was maintained in CDS and in idiopathic hypocitraturia, suggesting that reduced citrate excretion was largely dietary in origin as a result of low net alkali absorption (from a probable relative deficiency of vegetables and fruits or a relative excess of animal proteins).

Non-NASA Center↗
NASA NTRS2015

Delineating the Impact of Weightlessness on Human Physiology Using Computational Models

Microgravity environment has profound effects on several important human physiological systems. The impact of weightlessness is usually indirect as mediated by changes in the biological fluid flow and transport and alterations in the deformation and stress fields of the compliant tissues. In this context, Fluid-Structural and Fluid-Solid Interaction models provide a valuable tool in delineating the physical origins of the physiological changes so that systematic countermeasures can be devised to reduce their adverse effects. In this presentation, impact of gravity on three human physiological systems will be considered. The first case involves prediction of cardiac shape change and altered stress distributions in weightlessness. The second, presents a fluid-structural-interaction (FSI) analysis and assessment of the vestibular system and explores the reasons behind the unexpected microgravity caloric stimulation test results performed aboard the Skylab. The last case investigates renal stone development in microgravity and the possible impact of re-entry into partial gravity on the development and transport of nucleating, growing, and agglomerating renal calculi in the nephron. Finally, the need for model validation and verification and application of the FSI models to assess the effects of Artificial Gravity (AG) are also briefly discussed.

Computational Models↗
DOE OSTI2021

PTEN protects kidney against acute kidney injury by alleviating apoptosis and promoting autophagy via regulating HIF1-α and mTOR through PI3K/Akt pathway

Highlights: • PTEN protects kidney against acute kidney injury. • The effect of PTEN works by alleviating apoptosis and promoting autophagy via regulating HIF1-α and mTOR by PI3K/Akt pathway. Phosphatase and tensin homolog (PTEN) deleted on human chromosome 10 is a tumor suppressor with bispecific phosphatase activity, which is often involved in the study of energy metabolism and tumorigenesis. PTEN is recently reported to participate in the process of acute injury. However, the mechanism of PTEN in Ischemia-Reperfusion Injury (IRI) has not yet been clearly elucidated. In this study, mice with bilateral renal artery ischemia-reperfusion and HK-2 cells with hypoxia/reoxygenation (H/R) were used as acute kidney injury models. We demonstrated that PTEN was downregulated in IRI-induced kidney as well as in H/R-induced HK-2 cells. By silencing and overexpressing PTEN with si-PTEN RNA and PHBLV-CMV-PTEN-flag lentivirus before H/R, we found that PTEN protected HK-2 cells against H/R-induced injury reflected by the change in cell activity and the release of LDH. Furthermore, we inhibited HIF1-α with PX-478 and inactivated mTOR with Rapamycin before the silence of PTEN in H/R model. Our data indicated that the renoprotective effect of PTEN worked via PI3K/Akt/mTOR pathway and PI3K/Akt/HIF1-α pathway, hence alleviating apoptosis and improving autophagy respectively. Our findings provide valuable insights into the molecular mechanism underlying renoprotection of PTEN on autophagy and apoptosis induced by renal IRI, which offers a novel therapeutic target for the treatment of AKI.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Moving Beyond Mortality: Development and Application of a Desirability of Outcome Ranking (DOOR) Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia

Abstract Background Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are frequently caused by multidrug-resistant organisms. Patient-centered endpoints in clinical trials are needed to develop new antibiotics for HABP/VABP. Desirability of outcome ranking (DOOR) is a paradigm for the design, analysis, and interpretation of clinical trials based on a patient-centered, benefit-risk evaluation. Methods A multidisciplinary committee created an infectious diseases DOOR endpoint customized for HABP/VABP, incorporating infectious complications, serious adverse events, and mortality. We applied this to 2 previously completed, large randomized controlled trials for HABP/VABP. ZEPHyR compared vancomycin to linezolid and VITAL compared linezolid to tedizolid. For each trial, we evaluated the DOOR distribution and probability, including DOOR component and partial credit analyses. We also applied DOOR in subgroup analyses. Results In both trials, the HABP/VABP DOOR demonstrated similar overall clinical outcomes between treatment groups. In ZEPHyR, the probability that a participant treated with linezolid would have a more desirable outcome than a participant treated with vancomycin was 50.2% (95% confidence interval [CI], 45.1%­−55.3%). In VITAL, the probability that a participant treated with tedizolid would have a more desirable outcome than a participant treated with linezolid was 48.7% (95% CI, 44.8%–52.6%). The DOOR component analysis revealed that participants treated with tedizolid had a less desirable outcome than those treated with linezolid when considering clinical response alone. However, participants with decreased renal function had improved overall outcomes with tedizolid. Conclusions The HABP/VABP DOOR provided more granular information about clinical outcomes than is typically presented in clinical trials. HABP/VABP trials would benefit from prospectively using DOOR.

Immunology↗
DOE OSTI2020

Irradiation of the kidneys causes pathologic remodeling in the nontargeted heart: A role for the immune system

Cardiac disease is a frequent and significant adverse event associated with radiotherapy for cancer. Identifying the underlying mechanism responsible for radiation injury to the heart will allow interventions to be developed. In the present study, we tested if local kidney irradiation results in remodeling of the shielded, nontargeted heart. One kidney, two kidneys, or the total body of male WAG and Dahl SS rats were irradiated with 10 Gy of X-rays. Local kidney irradiation resulted in systemic hypertension, increased BUN, infiltration of T lymphocytes, natural killer cells, and macrophages into the renal cortex and medulla, and renal fibrosis. Local irradiation of kidneys in WAG rats resulted in remodeling in the nontargeted heart after 120 days, manifested by perivascular fibrosis and increased interventricular septal thickness, but was not seen in Dahl SS rats due to a high baseline level of fibrosis in the sham-irradiated animals. Genetic depletion of T cells mitigated the nephropathy after local kidney irradiation, indicating a role for the immune system in mediating this outcome. Local kidney irradiation resulted in a cascade of pro-inflammatory cytokines and low-molecular weight metabolites into the circulation associated with transmission of signals resulting in pathologic remodeling in the nontargeted heart. A new model is proposed whereby radiation-induced cardiac remodeling in susceptible animals is indirect, with lower hemi body organs such as the kidney exporting factors into the circulation that cause remodeling outside of the irradiated field in the shielded, nontargeted heart. This nontargeted effect appears to be mediated, in part, by the immune system.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Generalizability of heat-related health risk associations observed in a large healthcare claims database of patients with commercial health insurance

Extreme ambient heat is unambiguously associated with higher risk of illness and death. The Optum Labs Data Warehouse (OLDW), a database of medical claims from US-based patients with commercial or Medicare Advantage health insurance, has been used to quantify heat-related health impacts. Whether results for the insured sub-population are generalizable to the broader population has to our knowledge not been documented. We sought to address this question, for the US population in California from 2012 to 2019. We examined changes in daily rates of emergency department (ED) encounters and in-patient hospitalization encounters for all-causes, heat-related outcomes, renal disease, mental/behavioral disorders, cardiovascular disease, and respiratory disease. OLDW was the source for health data for insured individuals in California, and health data for the broader population were gathered from the California Department of Health Care Access and Information (HCAI). We defined extreme heat exposure as any day in a group of 2 or more days with maximum temperatures exceeding the county-specific 97.5 th percentile and used a space-time-stratified case–crossover design to assess and compare the impacts of heat on health. Average incidence rates of medical encounters differed by dataset. However, rate ratios for ED encounters were similar across datasets for all causes (ratio of incidence rate ratios (rIRR) = 0.989; 95% confidence interval (CI) = 0.973, 1.011), heat-related causes (rIRR = 1.080; 95% CI = 0.999, 1.168), renal disease (rIRR = 0.963; 95% CI = 0.718, 1.292), and mental health disorders (rIRR = 1.098; 95% CI = 1.004, 1.201). Rate ratios for inpatient encounters were also similar. This work presents evidence that OLDW can continue to be a resource for estimating the health impacts of extreme heat.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2024

The Connected We St@nd programme: A feasibility pilot study of an online self‐management intervention for adults on in‐centre haemodialysis and family caregivers

Abstract Objective The ‘Connected We St@nd’ is an online self‐management intervention programme for people receiving in‐centre haemodialysis and family caregivers that combines an educational and psychosocial support component. This study aimed to evaluate its feasibility and acceptability before proceeding to a large‐scale trial. Design This was a pre‐post single‐arm feasibility pilot study conducted with adults undergoing in‐centre haemodialysis and family caregivers. Methods Feasibility was based on eligibility, consent, retention, completion and intervention adherence rates, while acceptability was assessed in post‐intervention focus group interviews. Results Twenty‐six people (16 adults on haemodialysis and 10 family caregivers) recruited through social networks completed the intervention. Consent, retention and completion rates were excellent (>90%) and eligibility (77.5%) and intervention adherence were satisfactory (69% for the psychosocial support sessions). Qualitative findings revealed that participants shared positive feelings regarding their participation in the programme. The valuable interactions with group peers and health psychologists during the support sessions, the perception of the adequacy and coherence of the programme's contents and materials and the participants' confidence in using the platform developed to deliver the intervention were some of the aspects highlighted as facilitators of intervention acceptability. Additionally, people on haemodialysis and caregivers reported that participation in the programme brought several educational and emotional benefits (e.g., additional disease‐related knowledge, improved communication and coping skills, greater confidence in managing dialysis complications or caregiving demands) that helped increase their self‐management skills and psychosocial adjustment to the demands of kidney failure and renal therapies. Conclusions The results suggested that the ‘Connected We St@nd’ programme is likely to be feasible and acceptable for adults on haemodialysis and family caregivers, thus representing a promising resource for the future of interdisciplinary renal rehabilitation. Suggestions were made to fine‐tune the intervention design to proceed with a large‐scale trial.

Sousa, Helena↗
DOE OSTI2022

Clinical pharmacology information in regulatory submissions and labeling: A comparative analysis of orphan and non-orphan drugs approved by the FDA

Clinical pharmacology is an integral discipline supporting the development, regulatory evaluation, and clinical use of drugs for the treatment of both common and rare diseases. Here, we evaluated the recommendations and information available from select clinical pharmacology studies in the therapeutic product labeling of new molecular entities (NMEs) approved from 2017 to 2019 for both common and rare diseases. A total of 151 NMEs, including 72 orphan and 79 non-orphan drugs, were analyzed for recommendations and information available related to food–drug interaction, drug–drug interaction, renal impairment, hepatic impairment, QT assessment, and human radiolabeled mass balance studies using data collected from the original labeling and other regulatory documents. The analysis showed no statistically significant difference in the recommendations between orphan and non-orphan drugs except for renal impairment related recommendations in section 8 of the labeling. Although not significant, fewer hepatic impairment labeling recommendations were available for orphan drugs when compared with non-orphan drugs. At the time of initial approval, 79 postmarketing requirements (PMRs) and postmarketing commitments (PMCs) for 33 orphan drugs and 39 PMRs and PMCs for 19 non-orphan drugs were established; with most difference observed for drug–drug interaction, hepatic impairment, and QT assessment. Overall, although there was a trend for more labeling recommendations and fewer postmarketing studies and clinical trials for non-orphan drugs, there appeared to be no substantial differences in how these select clinical pharmacology studies are leveraged during the development and approval of orphan and non-orphan drugs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Sel1-like proteins and peptides are the major Oxalobacter formigenes -derived factors stimulating oxalate transport by human intestinal epithelial cells

Kidney stones (KSs) are very common, excruciating, and associated with tremendous healthcare cost, chronic kidney disease (CKD), and kidney failure (KF). Most KSs are composed of calcium oxalate and small increases in urinary oxalate concentration significantly enhance the stone risk. Oxalate also potentially contributes to CKD progression, kidney disease-associated cardiovascular diseases, and poor renal allograft survival. This emphasizes the urgent need for plasma and urinary oxalate lowering therapies, which can be achieved by enhancing enteric oxalate secretion. We previously identified Oxalobacter formigenes (O. formigenes)-derived factors secreted in its culture-conditioned medium (CM), which stimulate oxalate transport by human intestinal Caco2-BBE (C2) cells and reduce urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion. Given their remarkable therapeutic potential, we now identified Sel1-like proteins as the major O. formigenes-derived secreted factors using mass spectrometry and functional assays. Crystal structures for six proteins were determined to confirm structures and better understand functions. OxBSel1-14-derived small peptides P8 and P9 were identified as the major factors, with P8 + 9 closely recapitulating the CM’s effects, acting through the oxalate transporters SLC26A2 and SLC26A6 and PKA activation. Besides C2 cells, P8 + 9 also stimulate oxalate transport by human ileal and colonic organoids, confirming that they work in human tissues. Finally, P8 and P9 peptides are identified as the major O. formigenes-derived secreted factors and they have significant therapeutic potential for hyperoxalemia, hyperoxaluria, and related disorders, impacting the outcomes of patients suffering from KSs, enteric hyperoxaluria, primary hyperoxaluria, CKD, KF, and renal transplant recipients.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Near-Single-Cell Proteomics Profiling of the Proximal Tubular and Glomerulus of the Normal Human Kidney

Molecular assessments at the single-cell level can accelerate biological research by providing detailed assessments of cellular organization and tissue heterogeneity in both disease and health. The human kidney has complex multi-cellular states with varying functionality, much of which can now be completely harnessed with recent technological advances in tissue proteomics at a near single-cell level. We discuss the foundational steps in the first application of this mass spectrometry (MS) based proteomics method for analysis of sub-sections of the normal human kidney, as part of the Kidney Precision Medicine Project (KPMP). Using approximately 30-40 laser captured micro-dissected kidney cells, we identified more than 2500 human proteins, with specificity to the proximal tubular (PT; n=25 proteins) and glomerular (Glom; n=67 proteins) regions of the kidney and their unique metabolic functions. This pilot study provides the roadmap for application of our near-single-cell proteomics workflow for the analysis of other renal micro-compartments, on a larger scale, to unravel perturbations of renal sub-cellular function in the normal kidney as well as different etiologies of acute and chronic kidney disease.

60 APPLIED LIFE SCIENCES↗