Peroxisome proliferator-activated receptor ligands regulate lipid content, metabolism, and composition in fetal lungs of diabetic rats.

Maternal diabetes impairs fetal lung development. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors relevant in lipid homeostasis and lung development. This study aims to evaluate the effect of in vivo activation of PPARs on lipid homeostasis in fetal lungs of diabetic rats. To this end, we studied lipid concentrations, expression of lipid metabolizing enzymes and fatty acid composition in fetal lungs of control and diabetic rats i) after injections of the fetuses with Leukotriene B4 (LTB4, PPARα ligand) or 15deoxyΔ(12,14)prostaglandin J2 (15dPGJ2, PPARγ ligand) and ii) fed during pregnancy with 6% olive oil- or 6% safflower oil-supplemented diets, enriched with PPAR ligands were studied. Maternal diabetes increased triglyceride concentrations and decreased expression of lipid-oxidizing enzymes in fetal lungs of diabetic rats, an expression further decreased by LTB4 and partially restored by 15dPGJ2 in lungs of male fetuses in the diabetic group. In lungs of female fetuses in the diabetic group, maternal diets enriched with olive oil increased triglyceride concentrations and fatty acid synthase expression, while those enriched with safflower oil increased triglyceride concentrations and fatty acid transporter expression. Both olive oil- and safflower oil-supplemented diets decreased cholesterol and cholesteryl ester concentrations and increased the expression of the reverse cholesterol transporter ATP-binding cassette A1 in fetal lungs of female fetuses of diabetic rats. In fetal lungs of control and diabetic rats, the proportion of polyunsaturated fatty acids increased with the maternal diets enriched with olive and safflower oils. Our results revealed important changes in lipid metabolism in fetal lungs of diabetic rats, and in the ability of PPAR ligands to modulate the composition of lipid species relevant in the lung during the perinatal period.

Folic acid and safflower oil supplementation interacts and protects embryos from maternal diabetes-induced damage.

Maternal diabetes increases the risk of embryo malformations. Folic acid and safflower oil supplementations have been shown to reduce embryo malformations in experimental models of diabetes. In this study we here tested whether folic acid and safflower oil supplementations interact to prevent embryo malformations in diabetic rats, and analyzed whether they act through the regulation of matrix metalloproteinases (MMPs), their endogenous inhibitors (TIMPs), and nitric oxide (NO) and reactive oxygen species production. Diabetes was induced by streptozotocin administration prior to mating. From Day 0.5 of pregnancy, rats did or did not receive folic acid (15 mg/kg) and/or a 6% safflower oil-supplemented diet. Embryos and decidua were explanted on Day 10.5 of gestation for further analysis of embryo resorptions and malformations, MMP-2 and MMP-9 activities, TIMP-1 and TIMP-2 levels, NO production and lipid peroxidation. Maternal diabetes induced resorptions and malformations that were prevented by folic acid and safflower oil supplementation. MMP-2 and MMP-9 activities were increased in embryos and decidua from diabetic rats and decreased with safflower oil and folic acid supplementations. In diabetic animals, the embryonic and decidual TIMPs were increased mainly with safflower oil supplementation in decidua and with folic acid in embryos. NO overproduction was decreased in decidua from diabetic rats treated with folic acid alone and in combination with safflower oil. These treatments also prevented increases in embryonic and decidual lipid peroxidation. In conclusion, folic acid and safflower oil supplementations interact and protect the embryos from diabetes-induced damage through several pathways related to a decrease in pro-inflammatory mediators.

Safflower and olive oil dietary treatments rescue aberrant embryonic arachidonic acid and nitric oxide metabolism and prevent diabetic embryopathy in rats.

Aberrant arachidonic acid and nitric oxide (NO) metabolic pathways are involved in diabetic embryopathy. Previous works have found diminished concentrations of PGE(2) and PGI(2) in embryos from diabetic rats, and that PGI(2) is capable of increasing embryonic PGE(2) concentrations through the activation of the nuclear receptor PPARdelta. PPARdelta activators are lipid molecules such as oleic and linoleic acids, present in high concentrations in olive and safflower oils, respectively. The aim of this study was to analyze the capability of dietary supplementation with either 6% olive or 6% safflower oils to regulate PGE(2), PGI(2) and NO concentrations in embryos and deciduas from control and diabetic rats during early organogenesis. Diabetes was induced by a single injection of streptozotocin (55 mg/kg) 1 week before mating. Animals were fed with the oil-supplemented diets from Days 0.5 to 10.5 of gestation. PGI(2) and PGE(2) were measured by EIA and NO through the evaluation of its stable metabolites nitrates-nitrites in 10.5 day embryos and deciduas. We found that the olive and safflower oil-supplemented treatments highly reduced resorption and malformation rates in diabetic animals, and that they were able to prevent maternal diabetes-induced alterations in embryonic and decidual PGI(2) and PGE(2) concentrations. Moreover, these dietary treatments prevented NO overproduction in embryos and deciduas from diabetic rats. These data indicate that in maternal diabetes both the embryo and the decidua benefit from the olive and safflower oil supplementation probably through mechanisms that involve the rescue of aberrant prostaglandin and NO generation and that prevent developmental damage during early organogenesis.

2-Aryl indole NK(1) antagonists: optimisation of the amide substituent.

The in vivo properties of a series of 2-arylindole NK(1) antagonists have been improved, by modification of the amide substituent. The 1-(2-methoxyphenyl)piperazine amide was identified as a major area of metabolism in the lead compound 1. Replacement of this amine moiety by a 4-benzyl-4-hydroxypiperidine resulted in a compound 18 with reduced clearance and improved central duration of action.

Diminished use of osteopathic manipulative treatment and its impact on the uniqueness of the osteopathic profession.

PURPOSE: To determine whether osteopathic manipulative treatment (OMT), a key identifiable feature of osteopathic medicine, is becoming a "lost art" in the profession, and whether the long-term evolution of osteopathic medicine into mainstream medicine and particularly specialization has had a similar impact on the use of OMT by family practitioners and specialists. METHOD: In April 1998, a two-page questionnaire was mailed to 3,000 randomly selected osteopathic physicians in the United States to assess factors affecting their use of OMT. Descriptive statistics, linear regression analyses, and analysis of variance techniques were used to test for differences. RESULTS: The response rate was 33.2%. Over 50% of the responding osteopathic physicians used OMT on less than 5% of their patients, and analysis of variance revealed OMT use was significantly affected by practice type, graduation date, and family physicians versus specialists. For specialists, 58% of the variance regression was attributed to barriers to use, practice protocol, attitudes, and training, whereas for family physicians, 43% of the variance regression was attributed to barriers to use, practice protocol, and attitudes. More important, the eventual level of OMT use was related to whether postgraduate training had been undertaken in osteopathic, allopathic, or mixed staff facilities, particularly for osteopathic specialists. CONCLUSIONS: The evidence supports the assertion that OMT is becoming a lost art among osteopathic practitioners. Osteopathic as well as allopathic medical educators and policymakers should address the impact of the diminished use of OMT on both U.S. health care and the unique identifying practices associated with the osteopathic profession.

Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs.

The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2- phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.

Inhibition of fungal sphingolipid biosynthesis by rustmicin, galbonolide B and their new 21-hydroxy analogs.

The mode of action of the known antifungal macrolides rustmicin (1) and galbonolide B (2) has been determined to be the inhibition of sphingolipid biosynthesis. A large scale fermentation and isolation process was developed for production of large quantities of rustmicin. New 21-hydroxy derivatives of both compounds were isolated from pilot scale fermentations and were also produced by biotransformation of rustmicin and galbonolide B.

Variables influencing the use of osteopathic manipulative treatment in family practice.

A questionnaire was mailed to 2000 randomly selected osteopathic physicians to assess use of osteopathic manipulative treatment (OMT). In all, 1055 responses were summarized for the study. The contention is supported that OMT is being used less and less by practicing physicians. Only 6% of the respondents treated more than 50% of their patients with OMT, and nearly one third used OMT on less than 5% of their patients. A progressive de-emphasis of OMT use correlated with more recent graduation from osteopathic medical colleges. Thirty-eight percent of the variance regarding OMT use was attributed to two factors: barriers to use, and OMT protocol used. Perceptions by physicians of insufficient OMT training were not predictive of decreased use of OMT. Significantly more OMT was used in solo practice as opposed to other settings. The results present a wake-up call for the osteopathic medical profession. The profession must strive to remove barriers that preclude OMT use by justifying to policymakers, health professionals, and the public the cost-benefits of OMT in holistic healthcare.

Aerosol and parenteral pneumocandins are effective in a rat model of pulmonary aspergillosis.

The pneumocandins are semisynthetic analogs of echinocandin-like compounds that have shown efficacy in animal models of systemic candidiasis, disseminated aspergillosis, and pneumocystis pneumonia. However, the most common form of Aspergillus infection in susceptible patients is pulmonary aspergillosis, which was not directly tested in the mouse models used in the past. We have evaluated three pneumocandins, L-693,989, L-731,373, and L-733,560, in a rat model of pulmonary aspergillosis. Male Sprague-Dawley rats were treated for 2 weeks with cortisone and tetracycline and fed a low-protein diet before being inoculated via the trachea with 10(6) conidia of Aspergillus fumigatus H11-20. In the absence of drug treatment, the animals developed a progressive, rapidly fatal bronchopneumonia. All three pneumocandins at doses of 5 mg/kg (intraperitoneally [i.p.] every 12 h [q12h]) were effective in delaying mortality in this model. Survival at day 7 postinfection was 20% among controls (n = 10 for all groups), while it was 60, 80, and 90% in groups that were treated with L-693,989, L-731,373, and L-733,560, respectively. In another trial, survival at day 7 postinfection was 25% among controls (n = 8 for all groups); it was 87.5% in a group treated with amphotericin B (0.5 mg/kg i.p. q12h) and was 100% in a group treated with L-733,560 (0.625 mg/kg i.p. q12h). In a separate trial, aerosol L-693,989 administered 2 h before infection (5 mg/kg) delayed mortality. Eight of the 10 animals treated with aerosol L-693,989 survived for 7 days, whereas only 2 of 10 control animals survived. We conclude that the pneumocandins we tested were highly effective in an animal model of pulmonary aspergillosis.

Paradoxical autonomic responses to aversive stimuli in the developing rat.

The goals of this research were to determine (a) the change in heart rate elicited by aversive auditory stimuli in the laboratory rat at different ages and (b) the autonomic origins of those changes at each age. The results of the first 2 experiments showed that aversive white noise stimuli elicited cardiac deceleration in preweanling (16-day-old) rats and cardiac acceleration in weanling (23-day-old), periadolescent (30-day-old), and adult (60-day-old) rats. Subsequent experiments showed that (a) the decrease in heart rate elicited by the noise stimulus in preweanling rats was mediated by parasympathetic activation of the heart, (b) the stimulus-elicited increase in heart rate elicited by the noise in periadolescent rats was mediated by parasympathetic withdrawal of the heart, and (c) the noise-induced increase in heart rate in adult rats was primarily mediated by sympathetic activation of the heart.

Teaching the process of obtaining informed consent to medical students.

This paper describes a unit on the informed consent process taught to 119 first-year students at the Michigan State University College of Osteopathic Medicine in 1988-89. The unit consisted of a pretest and a posttest, a lecture, readings, small-group discussions, a model videotaped interview, and the students' videotaped interviews with one of two simulated patients. In the interviews, the students were most successful in establishing rapport and engaging the patients in discussions of treatment alternatives, and were less successful in perceiving the patients as unique individuals and in dealing with situations that involved conflict or confrontation. The authors suggest that curricula can be enhanced by focusing on the importance of patients' participation in the informed consent process.

How effectively are osteopathic medical students coping with a stressful life-style?

Medical education has been described as an extremely intense and stressful experience. First- and second-year osteopathic medical students (N = 225) were surveyed to assess their perceptions of their own physical and psychological well-being, mechanisms they use to combat daily stress, their leisure activities, and the health-promoting behaviors in which they engage. This study found perceived physical and psychological well-being to be quite good, with more than 82% of respondents reporting "good" or "excellent" in both areas. Only 11% of students reported using tobacco, and the mean number of alcoholic drinks consumed per day was less than one. Most of the students reported that they exercised regularly and that they did not view sleep deprivation as a significant problem; however, the students did perceive the stress attributed to the demands of medical school as quite high. The primary coping behaviors they used in response to stress included humor, leisure, exercise, and social activity. Smoking, using medication, and using illicit drugs were infrequently indicated as coping strategies. From a comprehensive perspective, student perceptions indicate that they are effectively coping with the stresses of medical education.

An integrated osteopathic treatment approach in acute otitis media.

Ear pain is a common patient complaint in the practice of the primary care physician. Acute otitis media can affect a person of any age, although it is more often seen in children than in adults. The disease is usually caused by Streptococcus pneumoniae (Diplococcus pneumoniae) or Haemophilus influenzae. The differential diagnosis and subsequent treatment of otitis media is approximately the same for children and adults. First-line therapy usually consists of an antibiotic regimen of amoxicillin in combination with autoinflation exercises. In the case presented, a pharmacologic regimen was combined with osteopathic manipulation.

Students' stereotypes of patients as barriers to clinical decision-making.

The ability to formulate quick, accurate clinical judgments is stressed in medical training. Speed is usually an asset when a physician sorts through his biomedical knowledge, but it is often a liability when the physician assesses the sociocultural context of a clinical encounter. At the Michigan State University College of Osteopathic Medicine, a study was designed which graphically illustrated to beginning students that unconscious sociocultural stereotypes may influence clinical decision-making. Three entering classes of students were shown a videotape depicting five simulated patients (attractive black woman, attractive white woman, professional man, middle-aged housewife, and elderly man), each presenting with the same physical complaint. Elements of positive and negative stereotypes were incorporated into each of the portrayals, and the students rated these patients on positive and negative characteristics. The results suggested that the students attributed both positive and negative characteristics to patients on the basis of irrelevant characteristics, such as attractiveness, and with little further justification for their attributions. Such stereotypic generalizations held by students may become barriers to the students' objective clinical decision-making.

Developmental defects resulting from arginine auxotrophy in Aspergillus nidulans.

A mutant of Aspergillus nidulans, isolated for inability to form asexual spores (conidia) on complete medium, was found to regain the ability to conidiate if the medium was supplemented with arginine. On minimal medium the mutant required arginine for growth but at a much lower concentration than that required for conidiation. This mutant, designated argB12, thus defines a phase-critical gene, i.e. a gene whose function is in greater demand for development than for growth. In addition to its aconidial phenotype, the mutant also exhibited (depending on the medium) aberrant sexual development and a low efficiency of conidial germination. In crosses, each of these developmental phenotypes segregated with arginine auxotrophy. Genetic and biochemical analyses showed the argB12 mutation to be an allele of the previously described argB locus, mutants of which lack ornithine transcarbamylase. Arginine-requiring mutants at at least two other loci were also found to be defective in asexual sporulation, but the germination defect appears to be specific to argB mutants.