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Ed Murray's essay provides a Western-oriented perspective on the opportunities and challenges in developing leaders for Eastern Europe. In this article, we also see the evolution of a non-formal model of ministry development—from a schooling orientation that is re-packaged and administered in a non-standard way (in response to the environmental challenges) to a non-formal learning orientation that is a re-forming of the fundamental assumptions of what it means to teach and learn. [ABSTRACT FROM AUTHOR]

Abstract Background The BALB/c mouse is commonly used to study RSV infection and disease. However, despite the many advantages of this well-characterised model, the inoculum is large, viral replication is restricted and only a very small amount of virus can be recovered from infected animals. A key question in this model is the fate of the administered virus. Is replication really being measured or is the model measuring the survival of the virus over time? To answer these questions we developed a highly sensitive strand-specific quantitative PCR (QPCR) able to accurately quantify the amount of RSV replication in the BALB/c mouse lung, allowing characterisation of RSV negative and positive strand RNA dynamics. Results In the mouse lung, no increase in RSV genome was seen above the background of the original inoculum whilst only a limited transient increase (< 1 log) in positive strand, replicative intermediate (RI) RNA occurred. This RNA did however persist at detectable levels for 59 days post infection. As expected, ribavirin therapy reduced levels of infectious virus and RI RNA in the mouse lung. However, whilst Palivizumab therapy was also able to reduce levels of infectious virus, it failed to prevent production of intracellular RI RNA. A comparison of RSV RNA kinetics in human (A549) and mouse (KLN205) cell lines demonstrated that RSV replication was also severely delayed and impaired in vitro in the mouse cells. Conclusions This is the first time that such a sensitive strand-specific QPCR technique has been to the RSV mouse system. We have accurately quantified the restricted and abortive nature of RSV replication in the mouse. Further in vitro studies in human and mouse cells suggest this restricted replication is due at least in part to species-specific host cell-viral interactions.

During the last decade, intellectual humility has gone from a topic of philosophical inquiry to one of serious scientific investigation. It has been variously described as a remedy for political polarization, a tool for advancing scientific credibility, and a disposition that promotes learning. However, less attention has been paid to how intellectual humility has been defined and measured or how well psychologists' definitions and measures align with one another or with philosophers' accounts. Through a systematic review of empirical intellectual humility research, we identified 18 separate definitions and 20 measures including16 unique questionnaires. We then synthesized this research to advance a new framework of intellectual humility. Implications of this framework for measurement and future research on intellectual humility are discussed.

The projected expansion of the nation's elderly population necessitates the revision of health care and policy strategies for safeguarding the health and assets of this community. The elderly are at greatly increased risk for developing mild cognitive impairment and Alzheimer's disease. These conditions are associated with diminished complex decision-making abilities that adversely affect patients, their families, and society, even during early stages of Alzheimer's disease. We present three composite patient histories that demonstrate problems routinely encountered by families, health care providers, and legal professionals during the course of early AD and MCI. We review the prevalence of cognitive and behavioral symptoms associated with MCI and early AD. Obstacles to early detection of cognitive decline, limitations of current testing modalities and benefits of earlier detection are discussed. Central themes common to medical and judicial approaches toward capacity assessment are discussed. We argue that an emphasis on earlier detection will result in benefits for patient health and result in financial savings to patients and the country as a whole. Finally, we recommend national guidelines for the evaluation of task-specific decision-making capacities to reduce the variability of outcome and improve quality of evaluations found among medical professionals, forensic evaluators, and legal actors., (© 2017 American Academy of Psychiatry and the Law.)

Pre-ECT neurology consultations are often requested to determine the relative risk of the procedure in patients with neurological comorbidities, but there is limited data to guide clinicians. The authors performed a retrospective chart review of all consecutive inpatients at McLean Hospital who underwent a pre-ECT neurological evaluation between January 2012 and June 2014 (N=68). ECT was safe and effective in patients with a wide variety of neurological diseases. Only one minor event was related to a neurological comorbidity, and there were no serious neurological complications. Based on the latest evidence, the authors provide guidance on the pre-ECT evaluation with respect to neurologic status.

The OH stretching vibrational spectrum of water was measured in a wide range of temperatures across the triple point, 269 K OH, were determined for the first time within the framework of a harmonic description of the proton dynamics. We found that in the liquid the value of OH is nearly constant as a function of T, indicating that quantum effects on the OH stretching frequency are weakly dependent on temperature. In the case of ice, ab initio electronic structure calculations, using non-local van der Waals functionals, provided OH values in agreement with INS experiments. We also found that the ratio of the stretching (OH) to the total (exp) kinetic energy, obtained from the present measurements, increases in going from ice, where hydrogen bonding is the strongest, to the liquid at ambient conditions and then to the vapour phase, where hydrogen bonding is the weakest. The same ratio was also derived from the combination of previous deep inelastic neutron scattering data, which does not rely upon the harmonic approximation, and the present measurements. We found that the ratio of stretching to the total kinetic energy shows a minimum in the metastable liquid phase. This finding suggests that the strength of intermolecular interactions increases in the supercooled phase, with respect to that in ice, contrary to the accepted view that supercooled water exhibits weaker hydrogen bonding than ice.

Introduction: The 'amyloid cascade hypothesis' remains the leading hypothesis to explain the pathophysiology of Alzheimer's disease (AD). Immunotherapeutic agents have been developed to remove the neurotoxic amyloid β42 protein and prevent the hypothesized amyloid β42-induced neurotoxicity and neurodegeneration. The most notable of these immunotherapies are bapineuzumab and solanezumab., Areas Covered: This article briefly reviews the experimental agents in development for treatment of AD and then discusses the results of bapineuzumab and solanezumab in AD patients, as reported in preclinical studies, clinical trials and press releases., Expert Opinion: Phase III trials showed that bapineuzumab failed to improve cognitive and functional performances in AD patients, and was associated with a high incidence of amyloid-related imaging abnormalities (ARIA). Solanezumab's two Phase III trials in AD patients failed to meet endpoints when analyzed independently. However, analysis of pooled data from both trials showed a significant reduction in cognitive decline in mild AD patients. The improvement was associated with an increase in plasma amyloid-β (Aβ) levels and a low incidence of ARIA in solanezumab-treated patients. The marginal benefits of solanezumab are encouraging to support continued evaluation in future studies, and offer small support in favor of the ongoing viability of the 'amyloid cascade hypothesis' of AD.

The authors have analyzed the religious figures Abraham, Moses, Jesus, and St. Paul from a behavioral, neurologic, and neuropsychiatric perspective to determine whether new insights can be achieved about the nature of their revelations. Analysis reveals that these individuals had experiences that resemble those now defined as psychotic symptoms, suggesting that their experiences may have been manifestations of primary or mood disorder-associated psychotic disorders. The rationale for this proposal is discussed in each case with a differential diagnosis. Limitations inherent to a retrospective diagnostic examination are assessed. Social models of psychopathology and group dynamics are proposed as explanations for how followers were attracted and new belief systems emerged and were perpetuated. The authors suggest a new DSM diagnostic subcategory as a way to distinguish this type of psychiatric presentation. These findings support the possibility that persons with primary and mood disorder-associated psychotic symptoms have had a monumental influence on the shaping of Western civilization. It is hoped that these findings will translate into increased compassion and understanding for persons living with mental illness.

The timescales for structural changes in a single crystal of bismuth after excitation with an intense near-infrared laser pulse are studied with femtosecond pump-probe X-ray diffraction. Changes in the intensity and reciprocal-lattice vector of several reflections give quantitative information on the structure factor and lattice strain as a function of time, with a resolution of 200 fs. The results indicate that the majority of excess carrier energy that remains near the surface is transferred to vibrational modes on a timescale of about 10 ps, and that the resultant increase in the variance of the atomic positions at these times is consistent with the overall magnitude of lattice strain that develops.

Squeezed states are quantum states of a harmonic oscillator in which the variance of two conjugate variables each oscillate out of phase. Ultrafast optical excitation of crystals can create squeezed phonon states, where the variance of the atomic displacements oscillates due to a sudden change in the interatomic bonding strength. With femtosecond x-ray diffraction we measure squeezing oscillations in bismuth and conclude that they are consistent with a model in which electronic excitation softens all phonon modes by a constant scaling factor.

Intense femtosecond laser excitation can produce transient states of matter that would otherwise be inaccessible to laboratory investigation. At high excitation densities, the interatomic forces that bind solids and determine many of their properties can be substantially altered. Here, we present the detailed mapping of the carrier density-dependent interatomic potential of bismuth approaching a solid-solid phase transition. Our experiments combine stroboscopic techniques that use a high-brightness linear electron accelerator-based x-ray source with pulse-by-pulse timing reconstruction for femtosecond resolution, allowing quantitative characterization of the interatomic potential energy surface of the highly excited solid.

Low temperature decreases nerve conduction velocity (NCV). The across-elbow segment of the ulnar nerve is superficial and may be particularly susceptible to decreased temperature. We evaluated patients without clinical ulnar neuropathy at the elbow (UNE) but with isolated slowing of the across-elbow ulnar NCV (normal group), and patients with clinical and electrodiagnostic findings of UNE (UNE group). All subjects had ulnar motor nerve studies completed before and after warming. The mean across-elbow NCV was 43.4 m/s and 48.6 m/s (P < 0.0001) in the normal group, and 37.4 m/s and 37.7 m/s (P = 0.90) in the UNE group, before and after warming, respectively. There was no change in the forearm segment NCV in either group. Seventeen of 32 subjects in the normal group had completely normal studies after warming. No patients with UNE developed normal across-elbow NCV with warming. Low temperature slows across-elbow ulnar NCV in normal subjects without impact on the forearm segment. Warming of the elbow improves across-elbow ulnar NCV in normals, but does not reverse the abnormalities in patients with UNE. Elbow warming should become a routine part of ulnar nerve conduction studies, especially when there is isolated conduction slowing in the across-elbow segment.

Information about the potential and extent of bioinversion of chiral drugs in laboratory animal species and humans is critical to the interpretation of preclinical pharm-tox studies with these drugs. Unlike in the dog, guinea pig, and rabbit, in humans the 2-arylpropionic acid (APA) R-flurbiprofen (R-FB) undergoes very little bioinversion to S-flurbiprofen. The primary objective of this research was to identify laboratory animal species with an R- to S-bioinversion profile similar to humans. Detailed evaluations of the pharmacokinetics parameters of R-flurbiprofen in male and female rats and mice, and male nude rats and monkeys demonstrated R- to S-bioinversion of 30% (average) in monkeys, 15-24% in mice, and approximately 4% in rats. To date, no laboratory animal species has been identified with an R-flurbiprofen bioinversion profile identical to humans. However, the rat has a bioinversion profile sufficiently similar to humans to be useful for preclinical., (Copyright 2004 Wiley-Liss, Inc.)

E-7869 (R-flurbiprofen) is a single enantiomer of a racemic nonsteroidal anti-inflammatory drug. E-7869 does not inhibit either cyclooxygenase-1 or cyclooxygenase-2. We used the transgenic adenocarcinoma mouse prostate (TRAMP) mouse, a prostate cancer model, to evaluate the effect of this drug on prostate cancer progression. Sixty 12-week-old male TRAMP mice were placed randomly into five groups. The animals were treated by daily oral gavage with vehicle (1% carboxymethylcellulose) or E-7869 for 18-weeks. During the course of the study, two diets were used. Three groups (vehicle, 15-mg/kg, and 20-mg/kg drug treatments) received a Teklad diet containing 2.4% saturated fat [a high saturated fat (HSF) diet], and two groups (vehicle and 20 mg/kg drug treatment) received an AIN-93G diet containing 1.05% saturated fat [a low saturated fat (LSF) diet]. At necropsy, the urogenital system and periaortic lymph nodes were removed and weighed. The prostate lobes, seminal vesicles, lungs, and periaortic lymph nodes were preserved and sectioned for histological evaluation. The lung and periaortic lymph nodes were graded as to the presence (+) or absence (-) of metastasis; the urogenital tissues were graded on a 1-6 scale for degree of neoplasia/carcinoma. For both diets, the urogenital wet weights and lymph node wet weights in the 20-mg/kg treatment groups were significantly lower as compared to vehicle control groups. In addition, treatment with 20 mg/kg E-7869 in the LSF diet group resulted in a significantly lower primary tumor incidence (P < 0.05) and reduced incidence of metastasis. In this treatment group, the reduced incidence of metastasis was not statistically significant because the LSF diet itself resulted in a remarkably lower incidence of metastasis in the vehicle control group (10% LSF versus 40% HSF). Treatment with 20 mg/kg E-7869 on the HSF diet resulted in a significantly lower incidence of metastasis (P < 0.05) and a reduction in the primary tumor incidence. These results suggest that E-7869 is a promising chemopreventive and treatment for human prostate cancer.

Our previous studies with the mouse model of familial adenomatous polyposis (FAP), C57BL/6J-APC(Min)/+ or Min mouse, demonstrated the optimal dose for adenoma reduction with R-flurbiprofen was 10 mg/kg/day as an undivided dose. Divided doses exhibited no increased efficaciousness. This study examines 10 mg/kg R-flurbiprofen daily (qd) on survival as well as a second daily (q.o.d.) schedule and compares it with sulindac sulfone. The q.o.d. schedule at 10 mg/kg was equally efficacious as qd treatment at the same dose. For the q.o.d. group, tumor number decreased similarly (p<0.01); while body weight gain (p<0.01), hematocrit and average tumor area (both, p<0.05) were improved compared with qd treatment. Treatment with R-flurbiprofen (10 mg/kg/day) increased survival significantly (p=0.0004, log-rank) compared to vehicle treated animals. Major biological endpoints (hematocrit, weight gain, tumor number, average and total area [99% reduction]) were significantly improved in treated animals (p<0.01). Sulindac sulfone treatment (50 mg/kg/day) of the Min mouse produced no significant biological benefit. The dose schedule study suggests that for tumor reduction it is necessary to attain a threshold drug-level but not necessarily sustain it over 24 hrs (pharmacodynamic t1/2 >> pharmacokinetic t1/2). During the period of administration R-flurbiprofen dramatically prolongs survival for the mouse model of the human disease, FAP.

We previously observed a marked increase in gastrointestinal toxicity of rac-flurbiprofen compared to the therapeutically equivalent dose of the S enantiomer. This paper quantitates these observations and examines the mechanism by which this paradoxical toxicity occurs. We have evaluated the ulcer scores, mucosal neutrophil infiltration, by immunostaining of CD11/18 antigen, and mucosal neutrophil activity by myeloperoxidase measurement at two dose levels of (R)-, (S)-, and rac-flurbiprofen, administered over 30 days. Dose-response for intestinal ulcer production was observed for rac- and (S)-flurbiprofen; animals given (R)-flurbiprofen exhibited no ulcers. Yet rac-flurbiprofen proved to be twice as ulcerogenic as (S)-flurbiprofen. The mechanism of the exacerbation of gastrointestinal toxicity of (S)-flurbiprofen by the noncyclooxygenase inhibiting (R)-flurbiprofen is believed to be associated with its effect on ICAM-1 up-regulation. This is followed by neutrophil adhesiveness to ICAM-1 via the LFA-1 antigen on its surface and the extravasation of neutrophils into the tissue. We also examined the effect of high dose (R)-flurbiprofen vs vehicle over 15 days in animals in which ulcers had been produced by treatment with (S)-flurbiprofen for the previous 15 days. (R)-flurbiprofen did not sustain induced ulcers. The results of this study suggest that human studies be conducted to determine if enhanced gastrointestinal toxicity occurs in man. This is at issue since rac compounds of this class are available over the counter and others may be introduced.

We used the C57BL/6J-APC(Min)/+ mouse (Min mouse) to evaluate the chemopreventive effects of R-flurbiprofen (R-FB), the noncyclooxygenase-inhibiting enantiomer of FB. Weanling Min mice were administered 6 weeks of oral treatment with R-FB using 2.5-25 mg/kg of R-FB once per day (q.d.), 2.5-10 mg/kg of R-FB twice per day (b.i.d.), and 5 mg/kg of R-FB b.i.d. challenged with a high saturated fat diet. At necropsy we determined tumor and ulcer numbers, tumor size, and plasma levels of R- and S-FB. A linear dose response was observed from 2.5 to 10 mg/kg of R-FB, regardless of whether the drug was administered as a single or divided dose. Reductions in tumor number were significant (P < or = 0.02) for doses of R-FB from 2.5 to 25 mg/kg/day. A dose of 5 mg/kg R-FB b.i.d. was able to overcome the doubling in tumor number associated with the high saturated fat diet. At 20 and 25 mg/kg/day R-FB, we obtained the maximum response with up to 90% inhibition of total tumor number. At these doses, however, there was toxicity and animal deaths. This toxicity was associated with ulceration, presumably resulting from the in vivo epimerization of R- to S-FB that occurs in the mouse. Thus, we evaluated the oral pharmacokinetics of R-FB and its conversion to S-FB in wild-type mice. These kinetics experiments revealed inversion rates of 7.3 and 11.0% for the 2.5 and 10 mg/kg R-FB doses, respectively. S-FB administered alone (0.5 and 2.0 mg/kg q.d.), in doses mimicking the concentrations of S-FB associated with the R to S epimerization of the doses of R-FB used in our experiments, had little or no antitumor efficacy (P > 0.05). Thus, we conclude that R-FB itself, not the S-FB resulting from epimerization in the mouse, inhibits adenoma formation in the Min mouse. In humans, where there is no R to S epimerization, it is possible that larger doses of R-FB can be used without causing cyclooxygenase inhibition and its resulting ulcerogenicity and other side effects. To assess the effect of R-FB on established adenomas, we allowed 40 Min mice to remain untreated until 70 days of age (the time of necropsy in the previous experiments) and then treated them for an additional 42 days with 10 mg/kg R-FB q.d. or 5 mg/kg R-FB b.i.d.. Both drug-treated groups demonstrated tumor numbers significantly less than that of the vehicle control (P < 0.01). Our results suggest that prophylaxis and treatment trials of R-FB should be extended to humans.

The structural elucidation and mechanism of action of a potential component, LLU-alpha, of what is possibly a multifactorial complex known as "natriuretic hormone" was recently reported [Wechter, W.J. et al. (1996a) Proc. Natl. Acad. Sci. U.S.A. 93: 6002-6007]. "Natriuretic hormone," a long-sought factor, is believed to regulate extracellular fluid volume and consequently be pathomimetic for hypertension, cirrhosis, congestive heart failure and other volume expanded states. The studies reported herein further characterize LLU-alpha. The precursor of the endogenous LLU-alpha was demonstrated to be gamma-tocopherol by radiolabeling studies. The pharmacokinetics of infused rac-LLU-alpha proved to be biphasic (half-lives: 12 min and 6 h). Specificity of the inhibition of the 70 pS potassium channel of the thick ascending limb of the loop of Henle was examined with the natural S-enantiomer being the most potent known inhibitor whereas the analogous alpha-tocopherol metabolite, rac-5-Me-LLU-alpha, showed no inhibition. Rac-LLU-alpha does not inhibit two isozymes of the Na+/K+-ATPase. LLU-alpha is natriuretic acting via inhibition of the 70 pS potassium channel and not Na+/K+-ATPase, the assumed mechanism of action of the "natriuretic hormone." LLU-alpha, a metabolite of a vitamin, if it were found to play a role in the regulation of extracellular fluid volume, would be the second example of a vitamin acting as a precursor for a hormone. Of considerable interest is the fact that this manuscript reports the first biological activity of gamma-tocopherol, a member of the vitamin E complex.

2,7,8-Trimethyl-(S)-2-(beta-carboxyethyl)-6-hydroxy chroman (S-LLU-alpha) isolated from human uremic urine is apparently an oxidative side-chain degradation product of gamma-tocopherol. This compound exhibits natriuretic activity in vivo and it appears to mediate the inhibition of the 70 pS K+ channel in the apical membrane of the thick ascending limb of the nephron. The stereochemistry at the C-2 of LLU-alpha has been unequivocally established to be S(+) by X-ray crystallographic analysis of a diastereomeric amide derivative. It was also established that the chroman ring oxidation of S-LLU-alpha proceeded without racemization at C-2. This finding can be extended to nonepimerization at C-2 of alpha-delta tocopherols (Vitamin E) during side-chain oxidation and stereospecificity (retention or inversion) of oxidative opening of the chroman ring. The resolution of the enantiomers of the parent compound and derivatives was accomplished by chiral high-performance liquid chromatography. The stereospecific enzymatic hydrolysis by an array of commercially available enzymes of the racemic methyl ester of LLU-alpha was investigated. The lipase from Humicola languinosa appears to be the best enzyme for resolution by selective hydrolysis of the racemic methyl ester.

For over three decades, renal physiology has sought a putative natriuretic hormone (third factor) that might control the body's pool of extracellular fluid, an important determinant in hypertension, congestive heart failure, and cirrhosis. In our search for this hormone, we have isolated several pure natriuretic factors from human uremic urine that would appear, alone or in combination, to mark a cluster of phenomena previously presumed to be that of a single "natriuretic hormone." This paper reports the purification, chemical structure, and total synthesis of the first of these compounds, LLU-alpha, which proved to be 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman, presumably a metabolite of gamma-tocopherol. Both natural LLU-alpha and synthetic material are identical (except for optical activity) with respect to structure and biological activity. It appears that the natriuretic activity of LLU-alpha is mediated by inhibition of the 70 pS K+ channel in the apical membrane of the thick ascending limb of the kidney.

Nonsteroidal antiinflammatory drugs (NSAIDs) are recognized for inhibiting growth of colon tumors in animal models, and for reducing the risk of colon cancer in humans. The mechanisms involved have not been established, but are thought to be related to reduced prostaglandin biosynthesis. The present study investigates the effect of COX-inhibiting and non-COX-inhibiting enantiomers of flurbiprofen on rat colonocyte proliferation. Intestinal ulceration was used as a surrogate indicator of COX inhibition. Sprague Dawley rats were treated orally with 6.3 mg/kg of R- or s-flurbiprofen or vehicle. Colonocyte labeling index and small bowel ulcer index were measured. R-flurbiprofen and S-flurbiprofen significantly reduced colonocyte labeling index, by 34% and 23% respectively, compared with vehicle. R-flurbiprofen caused minimal ulcer formation (4.48 mm2) compared with S-flurbiprofen (94.4 mm2). These findings suggest that R-flurbiprofen-mediated control of colonocyte proliferation is independent of prostaglandin biosynthesis.

A low molecular weight endogenous substance believed to be responsible for extracellular fluid homeostasis in mammals has been sought for many years. Our goal is to isolate and structurally characterize this putative "natriuretic hormone." We have developed an assay using the conscious rat to measure prolonged natriuresis (Benaksas et al (1993) Life Sciences, 52, 1045-1054), the activity originally described for this putative substance. Using this assay we have identified a number of natriuretic compounds isolated from human uremic urine. The collected urine is processed by ultrafiltration (< or = 3 kDa), gel filtration chromatography (G-25) and extraction with isopropanol and diethyl ether. The organic soluble material is then subjected to sequential high-performance liquid chromatography. We report here the initial characterization of two pure isolates (LLU-alpha and LLU-gamma) obtained by this method, and the structural elucidation of a third pure compound, LLU-beta 1, a natriuretic and previously unreported metabolite of the drug diltiazem.

The route of administration of the NSAID, flurbiprofen (sq vs. po) resulted in positive and negative results respectively with regard to enhanced cancellous and cortical bone accumulation in the immature rat. This pharmacokinetic study was an effort to understand the pharmacodynamic difference between the two routes of administration observed when the same dose range of drug, given as single daily doses, had been employed in both studies. Conventional chiral pharmacokinetics were evaluated in young rats. A significant difference was observed in the Tmax of the active (S)-enantiomer by both administration routes (sq 4 h and po 1 h). The bioavailability, as evaluated by AUCs favored the sq route as expected. The plasma concentrations over 18 h, at steady state, for one po dose group (0.5 mg/kg/day) fell well within the therapeutic window described by the 0.1 and 0.5 mg/kg sq doses which had demonstrated anabolic bone activity. Oral dosing had exhibited no significant bone activity. We conclude that the pharmacodynamic difference between routes of administration cannot be simply explained on a pharmacokinetic basis. Consequently, experiments detailing the pharmacodynamics and pharmacokinetics of single and multiple dose administration of aryl-propionic acids in normal and osteopenic states need further pharmacologic study.

The most common, and sometimes life-threatening, side-effects associated with the human use of the analgesic, nonsteroidal antiinflammatory drugs (NSAIDs) are gastrointestinal. These include gastritis, ulceration, and severe bleeding. The aryl propionic acid class of NSAIDs are among the most widely used of these drugs in the world, including rac-ibuprofen, rac-flurbiprofen, and rac-ketoprofen. Marketed as racemates, it was assumed that the "inactive" (R)-enantiomers, having no cyclooxygenase inhibiting effect, also had no toxic effect. In a 30-day dose response study of (S)-, (R)-, and rac-flurbiprofen given daily over a range of doses the (R)-isomer alone proved to be without apparent gastrointestinal (GI) toxicity. On the other hand the racemate proved to be 2 to 4 times as ulcerogenic in enantiomerically equivalent doses as the (S)-enantiomer. These results have significant clinical implications.

It is our intention to isolate, purify, and characterize the putative low-molecular-weight "natriuretic hormone" responsible for extracellular fluid (ECF) homeostasis. Toward this end, we are purifying from human uremic urine, and identifying endogenous vasopressor and natriuretic compounds. Bioactive components from large volumes of pooled urine were purified by ultrafiltration (< or = 3 kDa), gel filtration chromatography, and sequential reverse-phase and normal-phase high-performance liquid chromatography (HPLC). After each HPLC step, the fractions were evaluated in vivo, were assayed for inhibition of Na+/K(+)-ATPase-mediated 86Rb+ uptake, and were checked for cross-reactivity with an anti-ouabain antibody. Fractions assayed in vivo were identified that induced natriuresis, altered mean arterial pressure, or increased plasma cyclic-GMP. Also, many fractions inhibited Na+/K(+)-ATPase and/or cross-reacted with anti-ouabain antibody. None of the in vitro assays correlates with natriuretic or pressor effects. This plethora of bioactivities, revealed only with increased sample purity, may account for much of the confusion and multiplicity of crude isolates claimed to be the putative hormone. Presently we are attempting to purify and identify these natriuretic materials. One of these, a 3-substituted indole, has been partially characterized.