Investigating Europa's Habitability with the Europa Clipper.

The habitability of Europa is a property within a system, which is driven by a multitude of physical and chemical processes and is defined by many interdependent parameters, so that its full characterization requires collaborative investigation. To explore Europa as an integrated system to yield a complete picture of its habitability, the Europa Clipper mission has three primary science objectives: (1) characterize the ice shell and ocean including their heterogeneity, properties, and the nature of surface-ice-ocean exchange; (2) characterize Europa's composition including any non-ice materials on the surface and in the atmosphere, and any carbon-containing compounds; and (3) characterize Europa's geology including surface features and localities of high science interest. The mission will also address several cross-cutting science topics including the search for any current or recent activity in the form of thermal anomalies and plumes, performing geodetic and radiation measurements, and assessing high-resolution, co-located observations at select sites to provide reconnaissance for a potential future landed mission. Synthesizing the mission's science measurements, as well as incorporating remote observations by Earth-based observatories, the James Webb Space Telescope, and other space-based resources, to constrain Europa's habitability, is a complex task and is guided by the mission's Habitability Assessment Board (HAB).

LAparoscopic Versus Abdominal hysterectomy (LAVA): protocol of a randomised controlled trial.

INTRODUCTION: There is uncertainty about the advantages and disadvantages of laparoscopic hysterectomy compared with abdominal hysterectomy, particularly the relative rate of complications of the two procedures. While uptake of laparoscopic hysterectomy has been slow, the situation is changing with greater familiarity, better training, better equipment and increased proficiency in the technique. Thus, a large, robust, multicentre randomised controlled trial (RCT) is needed to compare contemporary laparoscopic hysterectomy with abdominal hysterectomy to determine the safest and most cost-effective technique. METHODS AND ANALYSIS: A parallel, open, non-inferiority, multicentre, randomised controlled, expertise-based surgery trial with integrated health economic evaluation and an internal pilot with an embedded qualitative process evaluation. A within trial-based economic evaluation will explore the cost-effectiveness of laparoscopic hysterectomy compared with open abdominal hysterectomy. We will aim to recruit 3250 women requiring a hysterectomy for a benign gynaecological condition and who were suitable for either laparoscopic or open techniques. The primary outcome is major complications up to six completed weeks postsurgery and the key secondary outcome is time from surgery to resumption of usual activities using the personalised Patient-Reported Outcomes Measurement Information System Physical Function questionnaire. The principal outcome for the economic evaluation is to be cost per QALY at 12 months' postsurgery. A secondary analysis is to be undertaken to generate costs per major surgical complication avoided and costs per return to normal activities. ETHICS AND DISSEMINATION: The study was approved by the West Midlands-Edgbaston Research Ethics Committee, 18 February 2021 (Ethics ref: 21/WM/0019). REC approval for the protocol version 2.0 dated 2 February 2021 was issued on 18 February 2021.We will present the findings in national and international conferences. We will also aim to publish the findings in high impact peer-reviewed journals. We will disseminate the completed paper to the Department of Health, the Scientific Advisory Committees of the RCOG, the Royal College of Nurses (RCN) and the BSGE. TRIAL REGISTRATION NUMBER: ISRCTN14566195.

Exploring the Interior of Europa with the Europa Clipper.

The Galileo mission to Jupiter revealed that Europa is an ocean world. The Galileo magnetometer experiment in particular provided strong evidence for a salty subsurface ocean beneath the ice shell, likely in contact with the rocky core. Within the ice shell and ocean, a number of tectonic and geodynamic processes may operate today or have operated at some point in the past, including solid ice convection, diapirism, subsumption, and interstitial lake formation. The science objectives of the Europa Clipper mission include the characterization of Europa's interior; confirmation of the presence of a subsurface ocean; identification of constraints on the depth to this ocean, and on its salinity and thickness; and determination of processes of material exchange between the surface, ice shell, and ocean. Three broad categories of investigation are planned to interrogate different aspects of the subsurface structure and properties of the ice shell and ocean: magnetic induction, subsurface radar sounding, and tidal deformation. These investigations are supplemented by several auxiliary measurements. Alone, each of these investigations will reveal unique information. Together, the synergy between these investigations will expose the secrets of the Europan interior in unprecedented detail, an essential step in evaluating the habitability of this ocean world.

Uterine artery embolisation versus myomectomy for premenopausal women with uterine fibroids wishing to avoid hysterectomy: the FEMME RCT.

BACKGROUND: Uterine fibroids are the most common tumour in women of reproductive age and are associated with heavy menstrual bleeding, abdominal discomfort, subfertility and reduced quality of life. For women wishing to retain their uterus and who do not respond to medical treatment, myomectomy and uterine artery embolisation are therapeutic options. OBJECTIVES: We examined the clinical effectiveness and cost-effectiveness of uterine artery embolisation compared with myomectomy in the treatment of symptomatic fibroids. DESIGN: A multicentre, open, randomised trial with a parallel economic evaluation. SETTING: Twenty-nine UK hospitals. PARTICIPANTS: Premenopausal women who had symptomatic uterine fibroids amenable to myomectomy or uterine artery embolisation were recruited. Women were excluded if they had significant adenomyosis, any malignancy or pelvic inflammatory disease or if they had already had a previous open myomectomy or uterine artery embolisation. INTERVENTIONS: Participants were randomised to myomectomy or embolisation in a 1 : 1 ratio using a minimisation algorithm. Myomectomy could be open abdominal, laparoscopic or hysteroscopic. Embolisation of the uterine arteries was performed under fluoroscopic guidance. MAIN OUTCOME MEASURES: The primary outcome was the Uterine Fibroid Symptom Quality of Life questionnaire (with scores ranging from 0 to 100 and a higher score indicating better quality of life) at 2 years, adjusted for baseline score. The economic evaluation estimated quality-adjusted life-years (derived from EuroQol-5 Dimensions, three-level version, and costs from the NHS perspective). RESULTS: A total of 254 women were randomised - 127 to myomectomy (105 underwent myomectomy) and 127 to uterine artery embolisation (98 underwent embolisation). Information on the primary outcome at 2 years was available for 81% (n = 206) of women. Primary outcome scores at 2 years were 84.6 (standard deviation 21.5) in the myomectomy group and 80.0 (standard deviation 22.0) in the uterine artery embolisation group (intention-to-treat complete-case analysis mean adjusted difference 8.0, 95% confidence interval 1.8 to 14.1, p = 0.01; mean adjusted difference using multiple imputation for missing responses 6.5, 95% confidence interval 1.1 to 11.9). The mean difference in the primary outcome at the 4-year follow-up time point was 5.0 (95% CI -1.4 to 11.5; p = 0.13) in favour of myomectomy. Perioperative and postoperative complications from all initial procedures occurred in similar percentages of women in both groups (29% in the myomectomy group vs. 24% in the UAE group). Twelve women in the uterine embolisation group and six women in the myomectomy group reported pregnancies over 4 years, resulting in seven and five live births, respectively (hazard ratio 0.48, 95% confidence interval 0.18 to 1.28). Over a 2-year time horizon, uterine artery embolisation was associated with higher costs than myomectomy (mean cost £7958, 95% confidence interval £6304 to £9612, vs. mean cost £7314, 95% confidence interval £5854 to £8773), but with fewer quality-adjusted life-years gained (0.74, 95% confidence interval 0.70 to 0.78, vs. 0.83, 95% confidence interval 0.79 to 0.87). The differences in costs (difference £645, 95% confidence interval -£1381 to £2580) and quality-adjusted life-years (difference -0.09, 95% confidence interval -0.11 to -0.04) were small. Similar results were observed over the 4-year time horizon. At a threshold of willingness to pay for a gain of 1 QALY of £20,000, the probability of myomectomy being cost-effective is 98% at 2 years and 96% at 4 years. LIMITATIONS: There were a substantial number of women who were not recruited because of their preference for a particular treatment option. CONCLUSIONS: Among women with symptomatic uterine fibroids, myomectomy resulted in greater improvement in quality of life than did uterine artery embolisation. The differences in costs and quality-adjusted life-years are very small. Future research should involve women who are desiring pregnancy. TRIAL REGISTRATION: This trial is registered as ISRCTN70772394. FUNDING: This study was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment; Vol. 26, No. 22. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Uterine fibroids are the most common non-cancerous tumour in women of childbearing age. Uterine fibroids are associated with heavy bleeding, lower chances of having children and reduced quality of life. Traditional surgical options were either to remove the fibroids (via myomectomy) or to completely remove the womb. A newer approach, known as uterine artery embolisation, involves blocking the blood supply to the fibroids in the womb. WHAT DID WE PLAN TO DO?: We compared myomectomy with uterine artery embolisation in women with fibroids who wanted to keep their womb. We wanted to see which treatment improved quality of life, was associated with the fewest complications and was the best value for money for the NHS. We also wanted to see if either treatment had an impact on women's ability to get pregnant and give birth. We included 254 women in a clinical trial. Women were assigned to have myomectomy or uterine artery embolisation at random to ensure a fair comparison. Women completed questionnaires about their symptoms and quality of life at intervals up to 4 years after treatment. WHAT DID WE FIND?: We found that myomectomy improved women's quality of life more than uterine artery embolisation. Complications from the treatments occurred in a similar proportion of women. There appeared to be no difference on reproductive hormone levels between treatments. Too few women in the trial got pregnant for any difference in the numbers of women having children to be seen. The differences in costs and overall disease burden were small. WHAT DOES THIS MEAN?: Both treatments improve quality of life and cost about the same to the NHS but, on average, myomectomy will provide greater benefit to women. There is no evidence to suggest that either treatment is unsuitable for women wanting to get pregnant, but more research is needed in younger women.

Large-scale cryovolcanic resurfacing on Pluto.

The New Horizons spacecraft returned images and compositional data showing that terrains on Pluto span a variety of ages, ranging from relatively ancient, heavily cratered areas to very young surfaces with few-to-no impact craters. One of the regions with very few impact craters is dominated by enormous rises with hummocky flanks. Similar features do not exist anywhere else in the imaged solar system. Here we analyze the geomorphology and composition of the features and conclude this region was resurfaced by cryovolcanic processes, of a type and scale so far unique to Pluto. Creation of this terrain requires multiple eruption sites and a large volume of material (>104 km3) to form what we propose are multiple, several-km-high domes, some of which merge to form more complex planforms. The existence of these massive features suggests Pluto's interior structure and evolution allows for either enhanced retention of heat or more heat overall than was anticipated before New Horizons, which permitted mobilization of water-ice-rich materials late in Pluto's history.

Uterine artery embolization or myomectomy for women with uterine fibroids: Four-year follow-up of a randomised controlled trial.

OBJECTIVE: To examine the quality of life experienced by women with symptomatic uterine fibroids who had been treated with UAE in comparison to myomectomy. We report the four-year follow-up of the FEMME randomised trial. Two-year follow-up data has been previously reported. STUDY DESIGN: Premenopausal women who had symptomatic uterine fibroids amenable to myomectomy or uterine artery embolization were recruited from 29 UK hospitals. Women were excluded if they had significant adenomyosis, any malignancy, pelvic inflammatory disease or had had a previous open myomectomy or uterine artery embolization.Participants were randomised to myomectomy or embolization in a 1:1 ratio using a minimisation algorithm. Myomectomy could be open abdominal, laparoscopic or hysteroscopic, according to clinician preference. Embolization of the uterine arteries was performed according to local practice, under fluoroscopic guidance.The primary outcome measure was the Uterine Fibroid Symptom Quality of Life questionnaire, adjusted for baseline score and reported here at four years post-randomisation. Subsequent procedures for fibroids, pregnancy and outcome were amongst secondary outcomes.Trial registration ISRCTN70772394 https://doi.org/10.1186/ISRCTN70772394. RESULTS: 254 women were randomized, 127 to myomectomy (105 underwent myomectomy) and 127 to uterine artery embolization (98 underwent embolization). At four years, 67 (53%) and 81 (64%) completed UFS-QoL quality of life scores. Mean difference in the UFS-QoL at 4 years was 5.0 points (95% CI -1.4 to 11.5; p = 0.13) in favour of myomectomy. There were 15 pregnancies in the UAE group and 7 in the myomectomy group, with a cumulative pregnancy rate to four years of 15% and 6% respectively (hazard ratio: 0.48; 95% CI 0.18-1.28). The cumulative repeat procedure rate to four years was 24% in the UAE group and 13% in the myomectomy group (hazard ratio: 0.53; 95% CI 0.27-1.05). CONCLUSIONS: Myomectomy resulted in greater improvement in quality of life compared with uterine artery embolization, although by four years, this difference was not statistically significant. Missing data may limit the generalisability of this result. The numbers of women becoming pregnant were too small draw a conclusion on the effect of the procedures on fertility.

Uterine-Artery Embolization or Myomectomy for Uterine Fibroids.

BACKGROUND: Uterine fibroids, the most common type of tumor among women of reproductive age, are associated with heavy menstrual bleeding, abdominal discomfort, subfertility, and a reduced quality of life. For women who wish to preserve their uterus and who have not had a response to medical treatment, myomectomy and uterine-artery embolization are therapeutic options. METHODS: We conducted a multicenter, randomized, open-label trial to evaluate myomectomy, as compared with uterine-artery embolization, in women who had symptomatic uterine fibroids and did not want to undergo hysterectomy. Procedural options included open abdominal, laparoscopic, or hysteroscopic myomectomy. The primary outcome was fibroid-related quality of life, as assessed by the score on the health-related quality-of-life domain of the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire (scores range from 0 to 100, with higher scores indicating a better quality of life) at 2 years; adjustment was made for the baseline score. RESULTS: A total of 254 women, recruited at 29 hospitals in the United Kingdom, were randomly assigned: 127 to the myomectomy group (of whom 105 underwent myomectomy) and 127 to the uterine-artery embolization group (of whom 98 underwent embolization). Data on the primary outcome were available for 206 women (81%). In the intention-to-treat analysis, the mean (±SD) score on the health-related quality-of-life domain of the UFS-QOL questionnaire at 2 years was 84.6±21.5 in the myomectomy group and 80.0±22.0 in the uterine-artery embolization group (mean adjusted difference with complete case analysis, 8.0 points; 95% confidence interval [CI], 1.8 to 14.1; P = 0.01; mean adjusted difference with missing responses imputed, 6.5 points; 95% CI, 1.1 to 11.9). Perioperative and postoperative complications from all initial procedures, irrespective of adherence to the assigned procedure, occurred in 29% of the women in the myomectomy group and in 24% of the women in the uterine-artery embolization group. CONCLUSIONS: Among women with symptomatic uterine fibroids, those who underwent myomectomy had a better fibroid-related quality of life at 2 years than those who underwent uterine-artery embolization. (Funded by the National Institute for Health Research Health Technology Assessment program; FEMME Current Controlled Trials number, ISRCTN70772394.).

Dunes on Pluto.

The surface of Pluto is more geologically diverse and dynamic than had been expected, but the role of its tenuous atmosphere in shaping the landscape remains unclear. We describe observations from the New Horizons spacecraft of regularly spaced, linear ridges whose morphology, distribution, and orientation are consistent with being transverse dunes. These are located close to mountainous regions and are orthogonal to nearby wind streaks. We demonstrate that the wavelength of the dunes (~0.4 to 1 kilometer) is best explained by the deposition of sand-sized (~200 to ~300 micrometer) particles of methane ice in moderate winds (<10 meters per second). The undisturbed morphology of the dunes, and relationships with the underlying convective glacial ice, imply that the dunes have formed in the very recent geological past.

Charon tectonics.

New Horizons images of Pluto's companion Charon show a variety of terrains that display extensional tectonic features, with relief surprising for this relatively small world. These features suggest a global extensional areal strain of order 1% early in Charon's history. Such extension is consistent with the presence of an ancient global ocean, now frozen.

Convection in a volatile nitrogen-ice-rich layer drives Pluto's geological vigour.

The vast, deep, volatile-ice-filled basin informally named Sputnik Planum is central to Pluto's vigorous geological activity. Composed of molecular nitrogen, methane, and carbon monoxide ices, but dominated by nitrogen ice, this layer is organized into cells or polygons, typically about 10 to 40 kilometres across, that resemble the surface manifestation of solid-state convection. Here we report, on the basis of available rheological measurements, that solid layers of nitrogen ice with a thickness in excess of about one kilometre should undergo convection for estimated present-day heat-flow conditions on Pluto. More importantly, we show numerically that convective overturn in a several-kilometre-thick layer of solid nitrogen can explain the great lateral width of the cells. The temperature dependence of nitrogen-ice viscosity implies that the ice layer convects in the so-called sluggish lid regime, a unique convective mode not previously definitively observed in the Solar System. Average surface horizontal velocities of a few centimetres a year imply surface transport or renewal times of about 500,000 years, well under the ten-million-year upper-limit crater retention age for Sputnik Planum. Similar convective surface renewal may also occur on other dwarf planets in the Kuiper belt, which may help to explain the high albedos shown by some of these bodies.

The geology of Pluto and Charon through the eyes of New Horizons.

NASA's New Horizons spacecraft has revealed the complex geology of Pluto and Charon. Pluto's encounter hemisphere shows ongoing surface geological activity centered on a vast basin containing a thick layer of volatile ices that appears to be involved in convection and advection, with a crater retention age no greater than ~10 million years. Surrounding terrains show active glacial flow, apparent transport and rotation of large buoyant water-ice crustal blocks, and pitting, the latter likely caused by sublimation erosion and/or collapse. More enigmatic features include tall mounds with central depressions that are conceivably cryovolcanic and ridges with complex bladed textures. Pluto also has ancient cratered terrains up to ~4 billion years old that are extensionally faulted and extensively mantled and perhaps eroded by glacial or other processes. Charon does not appear to be currently active, but experienced major extensional tectonism and resurfacing (probably cryovolcanic) nearly 4 billion years ago. Impact crater populations on Pluto and Charon are not consistent with the steepest impactor size-frequency distributions proposed for the Kuiper belt.

Very high-dose cholecalciferol and arteriovenous fistula maturation in ESRD: a randomized, double-blind, placebo-controlled pilot study.

PURPOSE: While vitamin D is critical for optimal skeletal health, it also appears to play a significant role in vascular homeostasis. This pilot study compared arteriovenous (AV) access outcomes following cholecalciferol supplementation compared to placebo in end-stage renal disease patients preparing to undergo AV access creation. METHODS: A total of 52 adult hemodialysis patients preparing for arteriovenous fistula (AVF) creation were randomized to receive perioperative high-dose cholecalciferol versus placebo in this double-blind, randomized, placebo-controlled pilot study. The primary outcome was mean response to high-dose oral cholecalciferol versus placebo, and secondary outcome AV access maturation at 6 months. Logistic regression was used to assess the association between AV access maturation and baseline, posttreatment and overall change in vitamin D concentration. RESULTS: A total of 45% of cholecalciferol-treated and 54% of placebo-treated patients were successfully using their AVF or arteriovenous graft (AVG) at 6 months (p=0.8). Baseline serum concentrations of 25(OH)D and 1,25(OH)2D did not differ between those who experienced AVF or AVG maturation and those who did not (p=0.22 and 0.59, respectively). Similarly, there was no relationship between AVF or AVG maturation and posttreatment serum 25(OH)D and 1,25(OH)2D concentration (p=0.24 and 0.51, respectively). CONCLUSIONS: Perioperative high-dose vitamin D3 therapy does correct 25(OH)D level but does not appear to have an association with AV access maturation rates. Future research may include extended preoperative vitamin D3 therapy in a larger population or in certain subpopulations at high risk for AVF failure.

Histomorphologic changes of the long head of the biceps tendon in common shoulder pathologies.

PURPOSE: To assess molecular and histologic differences between the proximal (intra-articular) and distal (extra-articular) portions of the long head of the biceps (LHB) tendon in 3 different disease states (biceps instability, tendinosis, and degenerative joint disease [DJD]) compared with a healthy tendon (fresh frozen). METHODS: We used 32 LHB tendons of patients undergoing tenodesis (mean age, 54.7 ± 10.1 years) and 9 harvested tissue donors. Tendons were divided according to 4 diagnostic groups: (1) biceps instability, (2) tendinosis, (3) DJD, and (4) normal control. After sectioning, tendons were fixed in formalin and stained with H&E and alcian blue for histologic analysis. Measurements of collagen organization by use of polarized light microscopy was then performed, and protein expression for type I and type III collagen, tenascin C, and decorin was determined. RESULTS: There were no statistical differences found for protein expression of type I or type III collagen, tenascin C, or decorin. The proximal and distal regions of the tendons had statistically significant differences in alcian blue staining, with the proximal portion containing a higher amount of proteoglycan (instability, P = .001; tendinosis, P = .005; DJD, P = .008; control, P = .011). When compared with the nonpathologic control tendons, a significant increase in alcian blue staining for the proximal region was seen in all 3 groups. Total polarized light analysis showed that the distal tendon had a significantly higher intensity (organization) compared with the proximal tendon (P < .001); this was also seen in all of the diagnostic groups (instability, P = .010; tendinosis, P = .013; DJD, P = .07; control, P = .028). CONCLUSIONS: This study showed a greater degree of degeneration of the proximal (intra-articular) regions of the LHB tendon when compared with the distal regions in all pathologic groups. However, no major differences at the cellular level were found among groups. CLINICAL RELEVANCE: The pathomechanisms of the various forms of known LHB diagnoses are not yet fully understood and basic science studies may help in understanding their etiology and therefore optimizing treatment options.

In vitro changes in human tenocyte cultures obtained from proximal biceps tendon: multiple passages result in changes in routine cell markers.

PURPOSE: Results of in vitro cell models are commonly used to promote new therapies (e.g., platelet-rich plasma), and clinicians have to be aware of the specific limitations of such models. To gain a sufficient and effective cell load, many current in vitro models use cells multiplied through various passages. This is especially important in tendon-like cell (TLC) models, since native tendon tissue is not available unlimited and contains limited amount of tenocytes. The purpose was to determine the occurrence of phenotypic changes following extended monolayer culture of TLCs, according to cell-passage number. METHODS: Tendon samples were obtained from 15 healthy patients undergoing biceps tenodesis. Tendons were digested and cultured (monolayer) for six passages. Tendon-specific markers (collagens I and III, decorin, tenascin-C, and tenomodulin) and their histology were analyzed using gene expression and protein content assays. Native cells, the cells cultured and cells passaged one to six times were analyzed at each passage. RESULTS: Gene expression of types I and III collagen of cultured TLCs significantly decreased after two passages. Gene expression of decorin, tenascin-C, and tenomodulin exhibited a trend of decreased gene expression with increased passage. Protein levels of types I and III collagen and decorin decreased after four passages. CONCLUSIONS: The significant findings let conclude that tenocyte-like cells obtained from human LHB can be maintained in monolayer culture at low passages, before the signs of phenotypic drift are present. But researchers must be aware of rapid phenotypic drift at higher passage numbers. Therefore, only cells within the first 3 passages should be used as a precaution for in vitro monolayer cell models, and one has to be aware of the phenotypic changes if TLCs passaged multiple times are used. The clinical relevance of this data is that understanding of in vitro TLC models, and their limitations may finally help the clinician to judge the potential of experimental data of new biologic treatment options.

Increased plasma chymase concentration and mast cell chymase expression in venous neointimal lesions of patients with CKD and ESRD.

The underlying inflammatory component of chronic kidney disease may predispose blood vessels to intimal hyperplasia (IH), which is the primary cause of dialysis access failure. We hypothesize that vascular pathology and markers of IH formation are antecedent to arteriovenous (AV) fistula creation. Blood, cephalic, and basilic vein segments were collected from predialysis chronic kidney disease (CKD) patients with no previous AV access and patients with end-stage renal disease (ESRD). Immunohistochemistry was performed with antibodies against mast cell chymase, transforming growth factor-beta (TGF-ß) and interleukin-6 (IL-6), which cause IH. Plasma chymase was measured by ELISA. IH was present in 91% of CKD and 75% of ESRD vein segments. Chymase was abundant in vessels with IH, with the greatest expression in intima and medial layers, and virtually absent in the controls. Chymase colocalized with TGF-ß1 and IL-6. Plasma chymase concentration was elevated up to 33-fold in patients with CKD versus controls and was associated with increased chymase in vessels with IH. We show that chymase expression in vessels with IH corresponds with plasma chymase concentrations. As chymase inhibition attenuates IH in animal models, and we find chymase is highly expressed in IH lesions of patients with CKD and ESRD, we speculate that chymase inhibition could have therapeutic value in humans.

Selective inhibition of the cellular sodium pump by emicymarin and 14ß anhydroxy bufadienolides.

Partial inhibition of the sodium pump (Na/K-ATP-ase) by a circulating inhibitor is known to occur in humans. The objectives of this study were to determine the effects of novel bufadienolides lacking an oxygen at C14 on sodium pumps in human erythrocytes and leucocytes, dog kidney and pig brain and to document the importance of the stereochemistry at C17 on the ability to inhibit these sodium pumps. 14α bufadienolides were weak inhibitors of all preparations studied. 3ß-OH,5ß,14ß bufadienolide produced near-total inhibition of dog kidney and pig brain Na/K-ATP-ase. Over the same concentration range, it maximally inhibited the sodium pump of erythrocytes by 70% and leucocytes by 47%. The inhibition profile induced in the leucocyte sodium pump deviated significantly from the simple sigmoidal relationship present in the other preparations over the 3×10(-5) to 1×10(-7) mol/l concentration range. Allo-emicymarin (17α) was confirmed to be a weak inhibitor of the sodium pump/ATP-ase compared with emicymarin (17ß) but both were weaker inhibitors of the leucocyte sodium pump than that of the other preparations. Molecules with the C14 in the ß configuration are more efficacious than in the α configuration. In the case of emicymarin, the attachment of the furone at C17 in the α configuration results in substantially weaker inhibitory activity than in the beta configuration, seen in most cardenolides and bufadienolides. Unlike ouabain and bufalin that show no specificity of action in these preparations, 3ß- OH,5ß,14ß bufadienolide selectively inhibits the activity of at least one low-prevalence subset of the leucocyte Na/K-ATP-ase.