The origin of the local 1/4-keV X-ray flux in both charge exchange and a hot bubble.

The solar neighbourhood is the closest and most easily studied sample of the Galactic interstellar medium, an understanding of which is essential for models of star formation and galaxy evolution. Observations of an unexpectedly intense diffuse flux of easily absorbed 1/4-kiloelectronvolt X-rays, coupled with the discovery that interstellar space within about a hundred parsecs of the Sun is almost completely devoid of cool absorbing gas, led to a picture of a 'local cavity' filled with X-ray-emitting hot gas, dubbed the local hot bubble. This model was recently challenged by suggestions that the emission could instead be readily produced within the Solar System by heavy solar-wind ions exchanging electrons with neutral H and He in interplanetary space, potentially removing the major piece of evidence for the local existence of million-degree gas within the Galactic disk. Here we report observations showing that the total solar-wind charge-exchange contribution is approximately 40 per cent of the 1/4-keV flux in the Galactic plane. The fact that the measured flux is not dominated by charge exchange supports the notion of a million-degree hot bubble extending about a hundred parsecs from the Sun.

The Lunar Environment Heliophysics X-ray Imager (LEXI) Mission.

The Lunar Environment heliospheric X-ray Imager (LEXI) is a wide field-of-view soft X-ray telescope developed to study solar wind-magnetosphere coupling. LEXI is part of the Blue Ghost 1 mission comprised of 10 payloads to be deployed on the lunar surface. LEXI monitors the dayside magnetopause position and shape as a function of time by observing soft X-rays (0.1-2 keV) emitted from solar wind charge-exchange between exospheric neutrals and high charge-state solar wind plasma in the dayside magnetosheath. Measurements of the shape and position of the magnetopause are used to test temporal models of meso- and macro-scale magnetic reconnection. To image the boundary, LEXI employs lobster-eye optics to focus X-rays to a microchannel plate detector with a 9.1×∘9.1∘ field of view.

The Effects of Subjective Cognitive Decline on APOE Genotype Disclosure in the Butler Hospital Alzheimer's Prevention Registry.

BACKGROUND: Subjective cognitive decline (SCD) and APOE genotyping are both instrumental in identifying high-risk individuals for Alzheimer's disease (AD) prevention trials. OBJECTIVE: This study examined the relationship between SCD and the impact of APOE disclosure on the psychological and behavioral health of cognitively unimpaired individuals. Design/Setting/Participant: We recruited 189 trial volunteers (mean age 66, 65% female, 96% White), from the Butler Hospital Alzheimer's Prevention Registry. Participants completed screening for cognitive impairment and a psychological readiness assessment before learning their APOE genotype, and were followed for 6 months after. RESULTS: SCD had a modest, temporary impact on mood and event-related distress following APOE disclosure, specifically on those who were ε4 carriers. The presence of SCD (SCD+) did not compound the AD genetic test-specific distress related to learning that one was an ε4 carrier. SCD also did not moderate changes in perceived AD risk, with all non-carriers showing a more rapid decrease in perceived risk over time than carriers. Counterintuitively, those without SCD (SCD-) reported taking more steps in future-directives than the SCD+ group at baseline and after disclosure, potentially suggesting that those with SCD may have subtle executive declines that limit future-oriented actions or fear-avoidance behaviors. Further, the SCD- group was more accurate in recalling their APOE status and the recall accuracy correlated with their broad knowledge about APOE as a risk gene for AD. CONCLUSION: Our findings support the safety and tolerability of APOE disclosure in research volunteers regardless of their SCD statuses, but further studies are warranted to include diverse individuals and those pursuing testing through direct-to-consumer services outside of traditional research settings.

Soft X-ray and ENA Imaging of the Earth's Dayside Magnetosphere.

The LEXI and SMILE missions will provide soft X-ray images of the Earth's magnetosheath and cusps after their anticipated launch in 2023 and 2024, respectively. The IBEX mission showed the potential of an Energetic Neutral Atom (ENA) instrument to image dayside magnetosheath and cusps, albeit over the long hours required to raster an image with a single pixel imager. Thus, it is timely to discuss the two imaging techniques and relevant science topics. We simulate soft X-ray and low-ENA images that might be observed by a virtual spacecraft during two interesting solar wind scenarios: a southward turning of the interplanetary magnetic field and a sudden enhancement of the solar wind dynamic pressure. We employ the OpenGGCM global magnetohydrodynamics model and a simple exospheric neutral density model for these calculations. Both the magnetosheath and the cusps generate strong soft X-rays and ENA signals that can be used to extract the locations and motions of the bow shock and magnetopause. Magnetopause erosion corresponds closely to the enhancement of dayside reconnection rate obtained from the OpenGGCM model, indicating that images can be used to understand global-scale magnetopause reconnection. When dayside imagers are installed with high-ENA inner-magnetosphere and FUV/UV aurora imagers, we can trace the solar wind energy flow from the bow shock to the magnetosphere and then to the ionosphere in a self-standing manner without relying upon other observatories. Soft X-ray and/or ENA imagers can also unveil the dayside exosphere density structure and its response to space weather.

Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes.

Cellular immune hyporesponsiveness can be induced by the presentation of soluble protein antigens to mucosal surfaces. Most studies of mucosa-mediated tolerance have used the oral route of antigen delivery and few have examined autoantigens in natural models of autoimmune disease. Insulin is an autoantigen in humans and nonobese diabetic (NOD) mice with insulin-dependent diabetes mellitus (IDDM). When we administered insulin aerosol to NOD mice after the onset of subclinical disease, pancreatic islet pathology and diabetes incidence were both significantly reduced. Insulin-treated mice had increased circulating antibodies to insulin, absent splenocyte proliferation to the major epitope, insulin B chain amino acids 9-23, which was associated with increased IL-4 and particularly IL-10 secretion, and reduced proliferation to glutamic acid decarboxylase, another islet autoantigen. The ability of splenocytes from insulin-treated mice to suppress the adoptive transfer of diabetes to nondiabetic mice by T cells of diabetic mice was shown to be caused by small numbers of CD8 gamma delta T cells. These findings reveal a novel mechanism for suppressing cell-mediated autoimmune disease. Induction of regulatory CD8 gamma delta T cells by aerosol insulin is a therapeutic strategy with implications for the prevention of human IDDM.

An exploratory study of sunitinib plus paclitaxel as first-line treatment for patients with advanced breast cancer.

BACKGROUND: Sunitinib has shown single-agent activity in patients with previously treated metastatic breast cancer (MBC). We investigated the safety of the combination of sunitinib and paclitaxel in an exploratory study of patients with locally advanced or MBC. METHODS: Patients received oral sunitinib 25 mg/day (with escalation to 37.5 mg/day as tolerated) on a continuous daily dosing schedule and paclitaxel 90 mg/m(2) on days 1, 8, and 15 of each 28-day cycle. Study endpoints included safety (primary endpoint), pharmacokinetics, and antitumor activity. RESULTS: Twenty-two patients were enrolled. The most frequent adverse events (AEs) were fatigue/asthenia (77%), dysgeusia (68%), and diarrhea (64%). Grade 3 AEs included neutropenia (43%), fatigue/asthenia (27%), neuropathy (18%), and diarrhea (14%). No drug-drug interaction was observed on the basis of pharmacokinetic analysis. Of 18 patients with measurable disease at baseline, 7 (38.9%) achieved objective responses (including 2 complete and 5 partial responses). Clinical responses were observed in three of nine patients with triple-negative receptor status (estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor-2 negative). CONCLUSIONS: These data indicate that sunitinib and paclitaxel in combination are well tolerated in patients with locally advanced or MBC. No drug-drug interaction was detected and there was preliminary evidence of antitumor activity.

Bidentate ligation of magnesium by 1,2-dimethoxyethane in the gas phase.

The 1:1 Mg...1,2-dimethoxyethane (Mg-DXE) complexes are studied experimentally and theoretically. They are generated by a laser ablation source in a supersonic expansion. They are studied spectroscopically by resonance two-photon ionization. Density functional theory/Becke three-dimensional Lee, Yang, and Parr and ab initio calculations using the MOLPRO quantum chemistry package are performed to document their ground and excited states in a series of geometry ranging from monodentate to bidentate ligation of Mg by the O atoms of DXE. An absorption band is observed in the 27 800-30 500 cm(-1) range, which, thanks to the calculations, is attributed to the bidentate complex. The structure of the band is discussed in terms of the excitation of electronic states of the complex correlating adiabatically to the 3s3p (1)P and 3s4s (1)S states of Mg at large separation between Mg and DXE.

Silver dressings: more evidence is needed to support their widespread clinical use.

Anecdotal and clinical evidence suggests that silver dressings have a role to play in controlling local wound infection, but there is very little high-quality evidence to inform their use. Well-designed trials are needed to fill this evidence gap.

Transition-state spectroscopy of the photoinduced Ca + CH3F reaction. 3. Reaction following the local excitation to Ca(4s3d 1D).

The Ca* + CH3F --> CaF* + CH3 reaction was studied both experimentally and theoretically. The reaction was photoinduced in Ca...CH3F complexes, which were illuminated by a tunable laser in the range 18 000-24 000 cm-1. The absorption band that leads to the reaction extends between 19 000 and 23 000 cm-1. It is formed of three broad overlapping structures corresponding to the excitation of different electronic states of the complex. The two structures of lowest energy were considered in detail. They are associated with two series of respectively 2 and 3 molecular states correlating to Ca(4s3d 1D) + CH3F at infinite separation between Ca and CH3F. The assignment of these structures to specific electronic transitions of the complex stemmed from theoretical calculations where the Ca...CH3F complex is described by a linear Ca-F-C backbone. 2D potential energy surfaces were calculated by associating a pseudopotential description of the [Ca2+] and [F7+] cores, a core polarization operator on calcium, an extensive Gaussian basis, and a treatment of the electronic problem at the CI-MRCI level. All the excited levels correlating to the 4s2 1S, 4s3d 1D, and 4s4p 1P levels of Ca in the Ca + CH3F channel were documented in a calculation that explored the rearrangement channels where either Ca + CH3F or CaF + CH3 are formed. Then, wavepacket calculations on the 2D-PES's allowed one to simulate the absorption spectrum of the complex, in an approximation where the various electronic states of the complex are not coupled together. The assignment above stemmed from this. The second outcome of the calculation was that whatever the excited level of the complex that is considered, the reaction has to proceed through energy barriers. The electronic excitation of the complex on the red side of the absorption band does not seem to deposit enough energy in the system to overcome these barriers (even the lowest one) or to stimulate tunneling reactions. An alternative reaction mechanism involving a transfer to triplet PES's is proposed.

Impact of universal infant hepatitis B vaccination in the US-affiliated Pacific Islands, 1985-2015.

The US-affiliated Pacific Island countries (USAPI) is an endemic region for hepatitis B virus (HBV) infection. Universal infant hepatitis B vaccination was introduced in the USAPI in the mid-1980s to mitigate the HBV burden. We assessed the impact of universal infant vaccination on the HBV infection prevalence over time among children born in the 1980s, 1990s, and 2000s in the USAPI. Demographic and serologic data from serial sero-surveys conducted between 1985 and 2015 were obtained. Descriptive statistics and analysis of variance were performed. From data obtained from 4827 children (2-11years), HBV prevalence decreased markedly: 8.4% in the 1980s; 2.5% in the 1990s; and 0.2% in the 2000s (P<0.0001) as vaccination coverage increased: 76.4% in the 1980s; 87.3% in the 1990s; and 97.5% in the 2000s (P<0.0001). These findings underscore the protective effect of universal infant hepatitis B vaccination over time on the HBV burden in an HBV endemic region.

Phase I trial of piritrexim capsules using prolonged, low-dose oral administration for the treatment of advanced malignancies.

A phase I trial of piritrexim was conducted by use of a prolonged, low-dose oral schedule. A number of different regimens were tested, including daily dosing for 21 days followed by 7 days of no drug therapy; continuous dosing; and daily dosing for 5 of 7 days for 3 consecutive weeks followed by a week of rest. Dose escalation was accomplished by increasing the dosing frequency from once a day to twice a day and then to three times a day and by increasing the number of days of administration. Fifty-one patients with advanced cancer were entered in the study. One hundred twenty-four (96%) of 129 courses were considered assessable. Myelosuppression proved to be the dose-limiting toxic effect. Other toxic effects included stomatitis, nausea and vomiting, anorexia, diarrhea, skin rash, fatigue, and elevation of liver transaminase levels. Antitumor activity was observed in patients with melanoma and bladder cancer, and disease stabilization occurred in those with sarcoma and pheochromocytoma. The recommended dosing schedule for phase II clinical trials is 25 mg three times a day for 5 days for 3 consecutive weeks followed by 1 week of no drug therapy.

Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles.

Leishmaniasis is a disease caused by parasites of Leishmania sp., which effects nearly 12 million people worldwide and is associated with treatment complications due to widespread parasite resistance toward pathogen-directed therapeutics. The current treatments for visceral leishmaniasis (VL), the systemic form of the disease, involve pathogen-mediated drugs and have long treatment regimens, increasing the risk of forming resistant strains. One way to limit emergence of resistant pathogens is through the use of host-mediated therapeutics. The host-mediated therapeutic AR-12, which is FDA IND-approved for cancer treatment, has shown activity against a broad spectrum of intracellular pathogens; however, due to hydrophobicity and toxicity, it is difficult to reach therapeutic doses. We have formulated AR-12 into microparticles (AR-12/MPs) using the novel biodegradable polymer acetalated dextran (Ace-DEX) and used this formulation for the systemic treatment of VL. Treatment with AR-12/MPs significantly reduced liver, spleen, and bone marrow parasite loads in infected mice, while combinatorial therapies with amphotericin B had an even more significant effect. Overall, AR-12/MPs offer a unique, host-mediated therapy that could significantly reduce the emergence of drug resistance in the treatment of VL.

Phase II trial of piritrexim in metastatic melanoma using intermittent, low-dose administration.

A phase II trial of piritrexim (2,4-diamino-6[2,5-dimethoxybenzyl]-5-methyl pyrido-[2,3d] pyrimidine, 301U74; PTX) was conducted for patients with metastatic malignant melanoma using an intermittent, low-dose oral administration schedule. PTX was administered at a starting dose of 25 mg orally three times per day for 5 days weekly for 3 weeks followed by 1 week of rest. Thirty-one patients were entered onto the study. Among 31 patients assessable for response, there were two complete responses (CRs) and five partial responses (PRs) for a response rate (CR plus PR) of 23% (95% confidence limit, 10% to 42%). Five responses occurred in soft tissue lesions, and two responses occurred in lung lesions. The initial dose schedule was well tolerated. The dose-limiting toxicity was myelosuppression. PTX administered in this schedule appears to be active against malignant melanoma. Further clinical trials to confirm these results are underway.

A randomized, double-blind trial of fluorouracil plus placebo versus fluorouracil plus oral leucovorin in patients with metastatic colorectal cancer.

PURPOSE: A prospectively randomized trial was performed to determine whether the combination of fluorouracil (FU) plus leucovorin (FU-LV) administered orally is more effective than equitoxic FU for patients with metastatic colorectal cancer. PATIENTS AND METHODS: A double-blind, placebo-controlled trial design was used to eliminate observer bias. An escalating FU dosing schedule was used to achieve equal toxicity. End points were response, time to treatment failure (TTF), and eight quality-of-life (QL) parameters. A crossover arm allowed FU-treated patients to receive FU-LV combination treatment after treatment failure. RESULTS: Response rate was 32% for FU-LV versus 23% for FU (P = .15). Median TTF was 22 versus 16 weeks (P = .27). Median survival time was 44 versus 54 weeks (P = .26). QL was the same for both treatments, except for days of hospitalization, which was greater for FU-LV (P < .001). Toxicities were similar to those previously reported for FU-LV and FU alone. CONCLUSION: Oral LV-FU produces the same efficacy and toxicity pattern as has been reported for intravenous LV-FU. When FU-LV is compared with equitoxic doses of FU, there is no difference in patient outcome. These results suggest that patients with advanced disease should receive FU at doses adequate to produce toxicity.

Transgenic expression of mouse proinsulin II prevents diabetes in nonobese diabetic mice.

IDDM in humans and in nonobese diabetic (NOD) mice is a T-cell-dependent autoimmune disease in which the beta-cells of the pancreatic islets are destroyed. Several putative beta-cell autoantigens have been identified, but insulin and its precursor, proinsulin, are the only ones that are beta-cell specific. (Pro)insulin may be a key autoantigen in IDDM. To address the role of proinsulin in the development of IDDM, we generated NOD mice transgenic for the mouse proinsulin II gene driven off a major histocompatibility complex (MHC) class II promoter to direct expression of the transgene to MHC class II bearing cells, including those in the thymus, with the aim of deleting proinsulin-reactive T-cells. The mononuclear cell infiltration of the islets (insulitis) is almost completely absent, and diabetes is prevented in these transgenic NOD mice. The mononuclear cell infiltration of the salivary glands (sialitis) and immune responses to ovalbumin (OVA) are not altered, indicating that the protective effect of the transgene is specific for islet pathology and not due to general immunosuppression. We conclude that autoimmunity to proinsulin plays a pivotal role in the development of IDDM.

Calcium-induced calcium release in smooth muscle: loose coupling between the action potential and calcium release.

Calcium-induced calcium release (CICR) has been observed in cardiac myocytes as elementary calcium release events (calcium sparks) associated with the opening of L-type Ca(2+) channels. In heart cells, a tight coupling between the gating of single L-type Ca(2+) channels and ryanodine receptors (RYRs) underlies calcium release. Here we demonstrate that L-type Ca(2+) channels activate RYRs to produce CICR in smooth muscle cells in the form of Ca(2+) sparks and propagated Ca(2+) waves. However, unlike CICR in cardiac muscle, RYR channel opening is not tightly linked to the gating of L-type Ca(2+) channels. L-type Ca(2+) channels can open without triggering Ca(2+) sparks and triggered Ca(2+) sparks are often observed after channel closure. CICR is a function of the net flux of Ca(2+) ions into the cytosol, rather than the single channel amplitude of L-type Ca(2+) channels. Moreover, unlike CICR in striated muscle, calcium release is completely eliminated by cytosolic calcium buffering. Thus, L-type Ca(2+) channels are loosely coupled to RYR through an increase in global [Ca(2+)] due to an increase in the effective distance between L-type Ca(2+) channels and RYR, resulting in an uncoupling of the obligate relationship that exists in striated muscle between the action potential and calcium release.

Pharmacokinetic and pharmacodynamic evaluation of the glycinamide ribonucleotide formyltransferase inhibitor AG2034.

Glycinamide ribonucleotide formyltransferase (GARFT) is a component of the de novo purine synthesis pathway. AG2034 is a specific inhibitor of GARFT that was designed based on the GARFT crystal structure. In conjunction with Phase I studies at four clinical centers in the United States and United Kingdom, AG2034 pharmacology was evaluated in 54 patients receiving 1-11 mg/m2 AG2034 as a 2-5 min injection. Blood samples were obtained just prior to and 5, 15, 30, and 45 min, and 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, and 96 h after bolus injection during course 1. Limited sampling was also performed on course 3. Plasma AG2034 was measured using a sensitive and reproducible ELISA assay. AG2034 demonstrated a trimodal elimination pattern over 24 h, with median half-life (t(1/2))alpha = 8.7 min, t(1/2)beta = 72.6 min, and t(1/2)gamma = 364.2 min. AG2034 systemic clearance ranged from 9.4-144.5 ml/min/m2, and volume of distribution was 1.2-7.6 liters/m2. Course 1 AG2034 area under the concentration versus time curve (AUC) had a linear relationship with dose (r(s) = 0.86). Accumulation of AG2034 was evident, because course 3 AUC was higher than course 1 in 23 of 23 evaluable patients, but was not associated with an increase in erythrocyte AG2034. AG2034 systemic exposure had an impact on toxicity, because course 1 and course 3 AG2034 AUCs were significantly higher for patients with grade III/IV toxicity than patients with less than grade II toxicity (P < 0.001 and P = 0.001 for course 1 and course 3, respectively). This study demonstrates rapid systemic clearance of AG2034 and suggests pharmacokinetic approaches that may minimize patient toxicity and aid the development of this interesting class of anticancer agents.

CFTR chloride channels in human and simian heart.

OBJECTIVES: The cAMP-dependent Cl- conductance in heart is believed to be due to cardiac expression of the cystic fibrosis transmembrane conductance regulator (CFTR). While CFTR expressed in rabbit and guinea-pig heart (CFTRcardiac) is an alternatively spliced isoform of the epithelial gene product, little information is known regarding possible expression of CFTR in primate heart. In this study, we examined molecular expression of CFTR in human and simian atrium and ventricle and functional expression of cAMP-dependent Cl- currents in isolated human atrial and simian ventricular cells. METHODS: The reverse transcription polymerase chain reaction (RT-PCR) was performed on human and simian atrial and ventricular mRNA using primers designed to border regions of the CFTR gene product corresponding to transmembrane segments I-VI (TSI-VI), the first nucleotide binding domain (NBD1), transmembrane segments VII-XII (TSVII-XII), and the large cytoplasmic domain which includes the regulatory (R) domain and NBD1. Functional expression of CFTR Cl- channels in human atrial and simian ventricular myocytes was determined using whole-cell and giant inside-out patch-clamp techniques. RESULTS: Southern blot analysis of these RT-PCR products demonstrated expression of CFTR transcripts in human and simian atrial and ventricular tissue and revealed a novel pattern of expression compared to most animal species studies: both the exon 5 plus (unspliced) and exon 5 minus (spliced) CFTR transcripts are co-expressed in human and simian atrium and ventricle. Whole-cell experiments demonstrated a Cl- sensitive time-independent background conductance in both human atrial and simian ventricular myocytes that was activated by forskolin (FSK) and insensitive to 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS). In inside-out patches utilizing the giant patch technique on human atrial myocytes, unitary Cl- sensitive channels resembling CFTR Cl- channels (approximately 14 pS conductance) were activated by the catalytic subunit of protein kinase A (PKA) in 3/12 patches examined. CONCLUSIONS: These results clearly demonstrate the molecular expression of CFTR Cl- channels and provide electrophysiological evidence consistent with functional expression of these channels in human atrial and simian ventricular myocardium.

Accumulation of tissue factor in endothelial cells induces cell apoptosis, mediated through p38 and p53 activation.

We previously reported that high levels of tissue factor (TF) can induce cellular apoptosis in endothelial cells. In this study, TF-mediated mechanisms of induction of apoptosis were explored. Endothelial cells were transfected to express wild-type TF. Additionally, cells were transfected to express Asp253-substituted, or Ala253-substitued TF to enhance or prevent TF release, respectively. Alternatively, cells were pre-incubated with TF-rich and TF-poor microvesicles. Cell proliferation, apoptosis and the expression of cyclin D1, p53, bax and p21 were measured following activation of cells with PAR2-agonist peptide. Greatest levels of cell proliferation and cyclin D1 expression were observed in cells expressing wild-type or Asp253-substituted TF. In contrast, increased cellular apoptosis was observed in cells expressing Ala253-substituted TF, or cells pre-incubated with TF-rich microvesicles. The level of p53 protein, p53-phosphorylation at ser33, p53 nuclear localisation and transcriptional activity, but not p53 mRNA, were increased in cells expressing wild-type and Ala253-substituted TF, or in cells pre-incubated with TF-rich microvesicles. However, the expression of bax and p21 mRNA, and Bax protein were only increased in cells pre-incubated with TF-rich microvesicle and in cells expressing Ala253-substituted TF. Inhibition of the transcriptional activity of p53 using pifithrin-α suppressed the expression of Bax. Finally, siRNA-mediated suppression of p38α, or inhibition using SB202190 significantly reduced the p53 protein levels, p53 nuclear localisation and transcriptional activity, suppressed Bax expression and prevented cellular apoptosis. In conclusion, accumulation of TF within endothelial cells, or sequestered from the surrounding can induce cellular apoptosis through mechanisms mediated by p38, and involves the stabilisation of p53.

Intranuclear binding of [3H]dihydrotestosterone by cultured human fibroblasts.

The uptake of [1,2,4,5,6,7-3H]dihydrotestosterone into whole cells and nuclei has been assessed in fibroblasts grown from genital skin of 10 controls and 9 subjects with hereditary male pseudohermaphroditism due to androgen resistance. The cells were exposed to hypotonic buffer and ruptured by passage through a 25-gauge needle, and the nuclei were purified by sedimentation through 2.1 M sucrose. Uptake of the hormone into nuclei reached an apparent plateau in 45 min, was saturable at 1 nM dihydrotestosterone, and was not detectable in the presence of excess nonradioactive hormones. Over a wide range of uptake by intact cells from control subjects and from subjects with androgen resistance due to 5alpha-reductase deficiency or receptor deficiency, nuclear uptake averaged about half of the total cell uptake. Furthermore, in cells from two unrelated 46,XY phenotypic females with androgen resistance but normal 5alpha-reductase activity and normal whole cell dihydrotestosterone binding, uptake into the nucleus was also normal. In these subjects, the defect in androgen action must be at some terminal phase of androgen action.