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We searched for the presence of ^{26}Al in deep-sea sediments as a signature of supernova influx. Our data show an exponential dependence of ^{26}Al with the sample age that is fully compatible with radioactive decay of terrigenic ^{26}Al. The same set of samples demonstrated a clear supernova ^{60}Fe signal between 1.7 and 3.2 Myr ago. Combining our ^{26}Al data with the recently reported ^{60}Fe data results in a lower limit of 0.18_{-0.08}^{+0.15} for the local interstellar ^{60}Fe/^{26}Al isotope ratio. It compares to most of the ratios deduced from nucleosynthesis models and is within the range of the observed average galactic ^{60}Fe/^{26}Al flux ratio of (0.15±0.05).

We succeeded in obtaining the depth profile of 236 U for a sampling station in the Northeast Pacific Ocean using only one litre of seawater sample from each depth. For this purpose, a new procedure was developed that allowed for the preparation of accelerator mass spectrometry targets for trace uranium using only 100 μg of iron carrier material. The 236 U concentrations in water samples from the Northeast Pacific Ocean showed large variations from (9.26 ± 0.42) × 10 6 atoms/kg at 60 m depth to (0.08 ± 0.02) × 10 6 atoms/kg at a depth of 3000 m. The high 236 U concentrations in surface water reflect the input of 236 U by global and local fallout from nuclear weapons tests. The low 236 U concentrations in seawater from 1500 m and below are an indicator for the low vertical diffusion of surface water to deeper layers in the North Pacific Ocean. The total inventory of 236 U on the water column was (8.35 ± 0.23) × 10 12 atoms/m 2 , which is lower compared to those of other ocean regions solely affected by global fallout on comparable latitudes. This study represents the first dataset for 236 U in the Pacific Ocean and shows the possibility of downsizing sample volumes which may help in future applications of 236 U as tracer for large ocean areas., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The rate of supernovae in our local Galactic neighbourhood within a distance of about 100 parsecs from Earth is estimated to be one every 2-4 million years, based on the total rate in the Milky Way (2.0 ± 0.7 per century). Recent massive-star and supernova activity in Earth's vicinity may be traced by radionuclides with half-lives of up to 100 million years, if trapped in interstellar dust grains that penetrate the Solar System. One such radionuclide is (60)Fe (with a half-life of 2.6 million years), which is ejected in supernova explosions and winds from massive stars. Here we report that the (60)Fe signal observed previously in deep-sea crusts is global, extended in time and of interstellar origin from multiple events. We analysed deep-sea archives from all major oceans for (60)Fe deposition via the accretion of interstellar dust particles. Our results reveal (60)Fe interstellar influxes onto Earth at 1.5-3.2 million years ago and at 6.5-8.7 million years ago. The signal measured implies that a few per cent of fresh (60)Fe was captured in dust and deposited on Earth. Our findings indicate multiple supernova and massive-star events during the last ten million years at distances of up to 100 parsecs.

(236)U was analyzed in an ombrotrophic peat core representing the last 80 years of atmospheric deposition and a minerotrophic peat sample from the last interglacial period. The determination of (236)U at levels of 10(7) atoms/g was possible by using ultraclean laboratory procedures and accelerator mass spectrometry. The vertical profile of the (236)U/(238)U isotopic ratio along the ombrotrophic peat core represents the first observation of the (236)U bomb peak in a terrestrial environment. A constant level of anthropogenic (236)U with an average (236)U/(238)U isotopic ratio of (1.24 ± 0.08) × 10(-6) in the top layers of the core was observed. Comparing the abundances of the global fallout derived (236)U and (239)Pu along the peat core, the post depositional migration of plutonium clearly exceeds that of uranium. However, the cumulative (236)U/(239)Pu ratio of 0.62 ± 0.31 is in agreement with previous studies on the global fallout uranium and plutonium. In the interglacial peat samples a (236)U/(238)U isotopic ratio of (3.3 ± 0.7) × 10(-12) was detected; although this measurement is an upper limit, it constitutes a significant step forward in the experimental determination of the natural (236)U abundance and represents a true background sample for the ombrotrophic peat core.

The isotopic composition of plutonium ((239)Pu, (240)Pu, (241)Pu and (242)Pu) was investigated in a ∼0.5 m long peat core from an ombrotrophic bog (Black Forest, Germany) using clean room procedures and accelerator mass spectrometry (AMS). This sophisticated analytical approach was ultimately needed to detect reliably the Pu concentrations present in the peat samples at femtogram (fg) and attogram (ag) levels. The mean (240)Pu/(239)Pu isotopic ratio of 0.19 ± 0.02 (N = 32) in the peat layers, representing approximately the last 80 years, was in good agreement with the accepted value of 0.18 for the global fallout in the Northern Hemisphere. This finding is largely supported by the corresponding and rather constant (241)Pu/(239)Pu (0.0012 ± 0.0005) and (242)Pu/(239)Pu (0.004 ± 0.001) ratios. Since the Pu isotopic composition characteristic of the global fallout was also identified in peat samples pre-dating the period of atmospheric atom bomb testing (AD 1956-AD 1980), migration of Pu within the peat profile is clearly indicated. These results highlight, for the first time, the mobility of Pu in a peat bog with implications for the migration of Pu in other acidic, organic rich environments such as forest soils and other wetland types. These findings constitute a direct observation of the behaviour of Pu at fg and ag levels in the environment. The AMS measurements of Pu concentrations (referring to a corresponding activity of (240+239)Pu from 0.07 mBq g(-1) to 5 mBq g(-1)) essentially confirm our a priori estimates based on existing (241)Am and (137)Cs data in the investigated peat core and agree well with the global fallout levels from the literature. Exclusively employing the Pu isotope ratios established for the peat samples, the date of the Pu irradiation (AD 1956, correctable to AD 1964) was calculated and subsequently compared to the (210)Pb age of the peat layers; this comparison provided an additional hint that global fallout derived Pu is not fixed in the peat column, but has migrated downwards along the peat profile to layers preceding the nuclear age.

Anthropogenic 236 U ( t ½ =23.4 My) is an emerging isotopic ocean tracer with interesting oceanographic properties, but only with recent advances in accelerator mass spectrometry techniques is it now possible to detect the levels from global fall-out of nuclear weapons testing across the water column. To make full use of this tracer, an assessment of its input into the ocean over the past decades is required. We captured the bomb-pulse of 236 U in an annually resolved coral core record from the Caribbean Sea. We thereby establish a concept which gives 236 U great advantage - the presence of reliable, well-resolved chronological archives. This allows studies of not only the present distribution pattern, but gives access to the temporal evolution of 236 U in ocean waters over the past decades.

Objective: To identify the benefits and consequences of having part-time faculty members in departments of pharmacy practice from the department chair's perspective., Methods: A stratified purposive sample of 12 pharmacy practice department chairs was selected. Eleven telephone interviews were conducted. Two investigators independently read interview notes and categorized and enumerated responses to determine major themes using content analysis. The investigators jointly reviewed the data and came to consensus on major themes., Results: Benefits of allowing full-time faculty members to reduce their position to part-time included faculty retention and improved individual faculty work/life balance. Consequences of allowing part-time faculty positions included the challenges of managing individual and departmental workloads, the risk of marginalizing part-time faculty members, and the challenges of promotion and tenure issues. All requests to switch to part-time status were faculty-driven and most were approved., Conclusions: There are a variety of benefits and consequences of having part-time faculty in pharmacy practice departments from the chair's perspective. Clear faculty and departmental expectations of part-time faculty members need to be established to ensure optimal success of this working arrangement.

Objective: To determine trends among departments of pharmacy practice regarding use of adjunct faculty members for classroom-based teaching and to assess departmental support provided to these faculty members., Methods: Chairs of pharmacy practice departments in US colleges and school of pharmacy were contacted by e-mail and asked to complete an 11-item electronic survey instrument., Results: Chair respondents reported an average of 5.7 adjunct faculty members hired to teach required courses and 1.8 adjunct faculty members hired to teach elective courses. Compensation averaged $108 per lecture hour and $1,257 per 1-credit-hour course. Twenty-five percent of the respondents expected to hire more adjunct faculty members to teach required courses in the upcoming year due to curricular changes, faculty hiring freezes, and the shortage of full-time faculty members. Only 7% of respondents reported that they provided a teaching mentor and 14% offered no support to their adjunct faculty members., Conclusions: Departments of pharmacy practice commonly use adjunct faculty members to teach required and elective courses. Given the pharmacy faculty shortage, this trend is expected to increase and may be an area for future faculty development.

Objective: To review the literature regarding the safety and efficacy of epidural corticosteroid injections in the treatment of low back pain (LBP) of various etiologies., Data Sources: A MEDLINE search (1966-February 1999) of English-language literature pertaining to the use of epidural corticosteroids in LBP was performed. Additional literature was obtained from reference lists of pertinent articles identified through the search., Study Selection and Data Extraction: All articles were considered for the review. The clinical trials included are those that enrolled a larger patient population and were primarily controlled clinical trials. The authors selected pertinent information for further discussion., Data Synthesis: Nerve root compression and inflammation are thought to be factors contributing to LBP. Corticosteroids act to decrease inflammation and may be of benefit in relieving LBP, especially if administered directly to the affected area via the epidural route. However, data on the efficacy of various corticosteroid agents administered via this route are limited. In addition, there have been reports of significant adverse reactions, thought to be due primarily to the preservative components in the corticosteroid preparations. Therefore, the role of these agents in the therapy of LBP remains to be determined., Conclusions: Based on the studies reviewed, epidural corticosteroids may be an effective treatment for LBP. Their use is warranted in patients who have failed conservative therapy. Although they contain preservatives, it appears that these agents are relatively safe and do not cause significant neurotoxicities.

The objective of this study was to evaluate the economic outcomes of drug options for stress ulcer prophylaxis in critically ill and/or intensive care unit patients. Decision analytic modelling was used to compare the costs of stress ulcer prophylaxis and possible clinical outcomes [acute upper gastrointestinal bleeding (AUGB) and nosocomial pneumonia]. The regimens evaluated were: antacids, histamine H2 receptor antagonists (H2RAs), sucralfate and no prophylaxis. The results of published studies were pooled to determine the expected probability of AUGB and nosocomial pneumonia following stress ulcer prophylaxis with each of the agents under study. The costs of stress ulcer prophylaxis, treatment of AUGB and treatment of nosocomial pneumonia were identified from various sources. Sucralfate was the least costly agent for stress ulcer prophylaxis. The average net costs per patient for sucralfate, antacids, no prophylaxis and H2RAs were $US1457, $US1737, $US2268, and $US2638 to $US2712, respectively (1994 dollars). No prophylaxis was found to be less costly than giving H2RAs. Sucralfate and antacids, which induced net savings of $US7373 and $US4321 per case of AUGB averted, respectively, were more cost effective than H2RAs. Sensitivity and threshold analyses revealed that the results were constant over a wide range of cost and probability values. Break-even analysis suggested that sucralfate was the optimal agent for stress ulcer prophylaxis unless the acquisition cost of a prophylactic course of sucralfate was > $US304.05 per patient. At that point, antacids become the optimal agent. Based on this analysis, sucralfate may be the most cost-effective agent for stress ulcer prophylaxis in critically ill or intensive care patients.

Background and Purpose: The ex vivo effect of aspirin (ASA) on platelet aggregation, the platelet component of thrombosis, was studied at repeated intervals in a cohort of patients taking aspirin for recurrent ischemic stroke prevention to define the maintenance of efficacy over time., Methods: We administered increasing doses of aspirin (from 325 to 1300 mg/d) to patients with previous ischemic stroke and determined the extent of inhibition of platelet aggregation after 2 weeks and thereafter at approximately 6-month intervals., Results: Over 33 months, 306 patients had platelet aggregation studies performed to define their initial response to ASA therapy. Of these, 228 had complete and 78 had partial inhibition of platelet aggregation at initial testing. To date, 119 of those who had complete inhibition and 52 who had partial inhibition have undergone repeat testing at least once. At repeat testing 39 of the 119 (32.7%) with complete inhibition at initial testing had lost part of the antiplatelet effect of ASA and converted from complete to partial inhibition without change in ASA dosage. Of the 52 with partial inhibition at initial testing, 35 achieved complete inhibition either by ASA dosage escalation (in 325 mg/d increments) or fluctuation of response at the same dosage, but 8 of those 35 (22.8%) had reverted to partial inhibition when tested again. Overall, 8.2% of patients ultimately exhibited ASA resistance to 1300 mg/d-8 of 52 (15.4%) with partial inhibition and 6 of 119 (5.0%) with complete inhibition at initial testing., Conclusions: The antiplatelet (and presumably the antithrombotic) effect of a fixed dose of ASA is not constant over time in all individuals. The mechanisms by which increased dosage requirement or ASA resistance develops and the clinical significance of this development are currently undefined.

Background and Purpose: The purpose of this study was to assess the biological effect of aspirin as measured by the inhibition of platelet aggregation in patients taking aspirin for stroke prevention and in patients with acute stroke., Methods: We administered increasing doses of aspirin (325, 650, 975, and 1,300 mg daily) to 113 patients for stroke prevention and measured the inhibition of platelet aggregation in these patients and in 33 patients with acute stroke taking aspirin before stroke onset., Results: Eighty-five patients on < or = 325 and six on > or = 650 mg aspirin had complete inhibition of platelet aggregation. Increase of the dose by 325 mg in nine of the 22 patients with partial inhibition of platelet aggregation produced complete inhibition in five patients at 650 mg and in one at 975 mg. At 1,300 mg, three patients still had only partial inhibition of platelet aggregation (aspirin resistance). Of the 33 inpatients with acute stroke, 24 had platelet aggregation studies done before further administration of aspirin. Of these, 19 had complete inhibition of platelet aggregation and three had partial inhibition, with production of complete inhibition of platelet aggregation at dose escalation; one patient was aspirin-resistant and the other noncompliant., Conclusions: How the inhibition of platelet aggregation relates to stroke prevention remains unclear. The ability of aspirin and the dose required to inhibit platelet aggregation may depend upon the individual.

Tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO) derivatives (e.g., R82150) are potent, human immunodeficiency virus-1 (HIV-1)-specific, inhibitors of reverse transcriptase (RT) that are undergoing initial evaluation in clinical trials. Because HIV-1 has become resistant to other RT inhibitors, we investigated the potential for viral resistance to TIBO R82150 by serial in vitro passage of HIV-1IIIB in the presence of drug. R82150-resistant variants (> 100-fold increase in IC50) dominated the replicating virus population after only three or four passages. R82150-resistant virus was partially cross-resistant to other HIV-1-specific RT inhibitors, including nevirapine (approximately 10-fold increase in IC50) and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (approximately 3.5-fold increase) but remained susceptible to 2',3'-dideoxynucleosides and phosphonoformate. DNA sequencing of cloned resistant RT, combined with site-specific mutational analyses and construction of mutant recombinant proviruses, demonstrated that a single, conservative amino acid substitution (Leu100 to Ile) in HIV-1 RT is responsible for high level R82150 resistance and partial nevirapine resistance. These studies indicate that a subtle mutation in HIV-1 RT can dramatically affect viral susceptibility to an HIV-1-specific RT inhibitor. The clinical efficacy of TIBO derivatives and other HIV-1-specific RT inhibitors may be limited by the emergence of drug-resistant viral strains.

Several newly discovered potent and selective non-nucleoside inhibitors of human immunodeficiency virus-1 reverse transcriptase (RT) are undergoing evaluation in clinical trials. We studied the potential for development of viral resistance to one of the prototype compounds, BI-RG-587, a dipyridodiazepinone derivative. Human immunodeficiency virus-1 resistant to BI-RG-587 emerged after only one cycle of in vitro infection in the presence of the drug. Resistant virus was cross-resistant to the non-nucleoside tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione derivative R82150 but remained susceptible to 2',3'-dideoxynucleosides and phosphonoformate. Both native (virion-associated) and recombinant RT derived from resistant virus were insensitive to BI-RG-587 and R82150. Nucleotide sequence analysis of multiple drug-resistant and -sensitive recombinant RT clones identified a single predicted amino acid change common to all resistant clones (tyrosine-181----cysteine). These studies suggest that the viral resistance to non-nucleoside RT inhibitors may develop in vivo. This possibility should be carefully monitored in clinical trials of these compounds.

A guinea pig model was used to determine the mechanisms of injury to the central nervous system by cytomegalovirus. Focal, well-contained, histopathologic responses included the microglial nodule without residua, and the ependymitis with focal residual glial scarring. Higher virus dose infection in the brain resulted in inflammatory necrosis with an astrocytic response to injury. However, monocytes and microglia were the predominant responding cells of host defense. A vasogenic pathogenesis was suggested by the involvement of the vascular endothelium, and separately by central nervous system vasculitis, demonstrated here for the first time in this model. Hence, our studies suggest four potential mechanisms of injury to the central nervous system by cytomegalovirus: viral cytopathology, inflammatory mediators from cells of the monocyte series, two separate types of vascular impairment, and astroglial scarring.

We previously demonstrated the transmission of murine cytomegalovirus to syngeneic mice and preformed monolayers of mouse embryo fibroblasts with plastic-adherent peritoneal exudate cells from infected mice as a source of macrophages. In the present studies we compared this standard feeder layer method with a reverse feeder layer method in which the adhering peritoneal exudate cells remained attached to plastic and to which were added mouse embryo fibroblasts. Recovery of virus from the adherent peritoneal exudate cells of infected mice was achieved with both methods. Whereas the standard method achieved greater accuracy and usually recovered more virus, the reverse method appeared to recover virus more frequently and required fewer cells to perform the assay. Furthermore, the reverse method demonstrated the survival of murine cytomegalovirus in adhering cells after culture periods of up to 2 weeks.

Despite the importance of cytomegalovirus (CMV) infection of the central nervous system in acquired immune deficiency syndrome, a well characterized laboratory model of glial nodule encephalitis after systemic CMV infection is not available. We now report that after intraperitoneal infection of young guinea pigs with CMV, infection of the brain was routinely found in the 2nd week. Recovery of virus from the brain was achieved at the time of viremia. Histopathologic changes in the brain followed the recovery of virus and continued beyond the point that virus was cleared from the brain. Microglial nodules, which were sometimes observed in association with intranuclear inclusion bearing cells, were the predominant feature. Other histopathology included perivascular infiltrates, vascular endothelial swelling, subependymal infiltrates, and sporadic focal leptomeningitis. In comparison to our previous studies after intracerebral inoculation, parenchymal changes dominated and leptomeningitis was found infrequently. The present studies suggest that focal central nervous system infection by CMV may be relatively common, though clinically silent, in the course of systemic infection. Relevant to acquired immune deficiency syndrome, the model should facilitate studies of the mechanism of brain infection, local central nervous system host defense, and mechanisms of injury to the brain.