Biomedical subjects
Publications and source records attributed to M Klaus.
Zakharov-Shabat systems with single-hump and real, but not necessarily symmetric, potentials are shown to have purely imaginary eigenvalues only. Coupled with examples of double-hump potentials with nonimaginary eigenvalues, this establishes that confinement of Zakharov-Shabat eigenvalues to the imaginary axis is a characteristic of potentials whose energy is concentrated in a single region of the time axis.
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Our goal was to contrast the influence of intermittent and continuous support provided by doulas during labor and delivery on 5 childbirth outcomes. Data were aggregated across 11 clinical trials by means of meta-analytic techniques. Continuous support, when compared with no doula support, was significantly associated with shorter labors (weighted mean difference -1.64 hours, 95% confidence interval -2.3 to -.96) and decreased need for the use of any analgesia (odds ratio.64, 95% confidence interval.49 to.85), oxytocin (odds ratio.29, 95% confidence interval.20 to.40), forceps (odds ratio.43, 95% confidence interval.28 to.65), and cesarean sections (odds ratio.49, 95% confidence interval.37 to.65). Intermittent support was not significantly associated with any of the outcomes. Odds ratios differed between the 2 groups of studies for each outcome. Continuous support appears to have a greater beneficial impact on the 5 outcomes than intermittent support. Future clinical trials, however, will need to control for possible confounding influences. Implications for labor management are discussed.
The purpose of this study was to investigate the effects of retinoid analogues with different retinoid receptor specificity on the growth of human D10 and Cloudman S91 mouse melanoma cells. We compared the growth inhibitory effects with the ability of retinoids to downregulate cell surface expression of the melanocortin receptor (MC1-R). Retinoic acid receptor (RAR)-gamma-selective retinoids exerted the most prominent growth effects, with up to 68% and 69% inhibition in D10 and S91 cells, respectively. A retinoid X receptor (RXR)-selective compound inhibited cell growth by only 14% and 23% in D10 and S91 cells, respectively. Growth inhibition by RARalpha- and RARbeta-selective compounds was below 10% in both cells. In D10 cells, MC1-R downregulation was also induced most effectively by an RARgamma-selective retinoid (84% relative to controls). RARalpha-, RARbeta-and RXR-selective agonists induced only 16-24% MC1-R downregulation in these cells. The pattern for MC1-R downregulation was completely different in S91 cells. The RXR-selective compound was the most active (85%), followed by the RARalpha-selective agonist (58%), the RARgamma-selective compound (47%), and finally by the RARbeta-selective agonist (29%). We conclude that RARgamma-selective retinoids may have potential as therapeutic agents in melanoma. Different selectivity profiles for growth inhibition and MC1-R downregulation in S91 cells suggest that these two retinoid effects are not directly dependent on each other.
Recent behavioral and physiologic observations of infants and mothers have shown them ready to begin interacting in the first minutes of life. Included among these findings are the newborn infant's ability to crawl toward the breast to initiate suckling and mother-infant thermoregulation. The attachment felt between mother and infant may be biochemically modulated through oxytocin; encouraging attachment through early contact, suckling, and rooming-in has been shown to reduce abandonment.
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BACKGROUND: Rheumatoid neutrophilic dermatitis (RND) is a recently recognized, rare cutaneous manifestation of rheumatoid arthritis. It occurs in patients with severe rheumatoid arthritis and is typically asymptomatic. Rheumatoid neutrophilic dermatitis was originally described by Ackerman in 1978. Since that time, 8 patients with this disease have been described in the literature. OBSERVATIONS: We report 2 cases of RND. Findings of skin biopsy specimens from both patients revealed characteristic signs of dermal leukocytosis and leukocytoclasia without vasculitis. The pathogenesis of the neutrophilic infiltrate is unclear. Processes that may play a role in the pathogenesis of RND include immune complex activations, cell adhesion and migration, and cytokine release. CONCLUSIONS: Rheumatoid neutrophilic dermatitis falls into the spectrum of neutrophilic vascular reactions described by Jorizzo and Daniels. Although early reports suggest that prominent leukocytoclasia is not a feature of RND, our findings confirm the observations of Lowe et al that leukocytoclasia can be seen in RND and may be striking. It is important for dermatologists to be aware of this rare manifestation of rheumatoid arthritis.
Apolipoprotein D (apoD) is a human plasma protein, belonging to the lipocalin superfamily, that is produced by a specific subtype of highly differentiated breast carcinomas and that is strongly up-regulated by retinoic acid (RA) in breast cancer cells. In this work, we have examined the molecular mechanisms mediating the induction of apoD gene expression by retinoids in T-47D human breast cancer cells. Northern blot analysis revealed that Ro40-6055, a synthetic retinoid that selectively binds and activates the retinoic acid receptor RARalpha, induced the accumulation of apoD mRNA in breast cancer cells in a time- and dose-dependent manner. The time course analysis demonstrated that apoD mRNA was induced 14-fold over control cells after 48 h of incubation with 10(-8) M Ro40-6055. As little as 10(-11) M of this retinoid induced apoD mRNA 5-fold over the control, whereas incubation with 10(-7) M Ro40-6055 induced maximally 15-fold over control cells. RARalpha-selective antagonists counteracted the inductive effects of all-trans-RA, 9-cis-RA, and Ro40-6055 on the expression of apoD, when present at the same concentration as the retinoid agonists. By contrast, RARbeta-, RARgamma-, and RXR-selective retinoids did not affect apoD gene expression. The retinoid agonist Ro40-6055 had an antiproliferative effect on T-47D cells, with maximal growth inhibition of approximately 60% obtained after 7 days of incubation with 10(-7) M. This antiproliferative effect could be counteracted by a 100-fold excess of the antagonist Ro41-5253. Treatment of the cells with retinoids that do not bind the nuclear retinoic acid receptors did not affect apoD expression, despite the fact that they did have a strong antiproliferative effect on T-47D cells. On the basis of these results, a role for RARalpha on apoD gene expression induction by retinoids in breast cancer cells is proposed.
Retinoids are known to inhibit the growth of hormone-dependent but not that of hormone-independent breast cancer cells. We investigated the involvement of retinoic acid (RA) receptors (RARs) in the differential growth-inhibitory effects of retinoids and the underlying mechanism. Our data demonstrate that induction of RAR beta by RA correlates with the growth-inhibitory effect of retinoids. The hormone-independent cells acquired RA sensitivity when the RAR beta expression vector was introduced and expressed in the cells. In addition, RA sensitivity of hormone-dependent cells was inhibited by a RAR beta-selective antagonist and the expression of RAR beta antisense RNA. Introduction of RAR alpha also restored RA sensitivity in hormone-independent cells, but this restoration was accomplished by the induction of endogenous RAR beta expression. Furthermore, we show that induction of apoptosis contributes to the growth-inhibitory effect of RAR beta. Thus, RAR beta can mediate retinoid action in breast cancer cells by promoting apoptosis. Loss of RAR beta, therefore, may contribute to the tumorigenicity of human mammary epithelial cells.
Cellular responsiveness to retinoic acid and its metabolites is conferred through two distinct families of receptors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Herein, we report on the identification and characterization of several conformationally restricted retinoids, which selectively bind and activate RX receptors. Under the influence of retinoids, HL-60 myelocytic leukemia cells differentiate into granulocytes. This effect is mediated by RAR alpha, as has been demonstrated through the use of a selective RAR alpha antagonist (Apfel, C., Bauer, F., Crettaz, M., Forni, L., Kamber, M., Kaufmann, F., LeMotte, P., Pirson, W., and Klaus, M. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 7129-7133). Here, we show that conformationally restricted RXR-specific retinoids, at doses that are per se inactive, are able to potentiate by up to one order of magnitude the pro-differentiating effects of all-trans retinoic acid and an RAR alpha-selective synthetic retinoid. We also present evidence that these RXR-selective ligands are able to bind to a DNA RXR.RAR heterodimer complex. This finding demonstrates that agonists for RARs and RXRs can synergistically promote HL-60 differentiation, which could be mediated through a heterodimer of these receptors.
A novel arotinoid, 4-((2-(p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthyl)propenyl]phenoxy))ethyl))-morpholine, was tested in rats bearing established chemically induced mammary tumors. At a dose of 0.35 mmol/kg/day of 4-((2-(p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthyl)propenyl]phenoxy)ethyl))-morpholine, decreased tumor growth was seen after 2 weeks. By weeks 4 and 5, tumor burdens were decreased to 10-30% of initial values and 50-70% of the animals became free of palpable tumors. Stabilization of tumor size through 15 weeks of treatment was seen in rats given 0.23 mmol/kg/day of the arotinoid. The predominate adverse effects of this compound were dose-dependent weight loss during the first 1-3 weeks, attributed to poor palatability of the food admix as well as flaking of the skin and alopecia at later times. Bone toxicity, a characteristic side effect of retinoids in rodents, was rare with this arotinoid, mainly confined to young rats treated for more than 12 weeks with high doses. In a comparative study, neither all-trans-retinoic acid nor 13-cis-retinoic acid had significant antitumor effects at doses that were tolerated by the animals. When all-trans-retinoic acid was administered at 0.08 mmol/kg/day, tumor reduction was seen during weeks 4-6, but treatment was terminated after week 6 due to severe skeletal toxicity and general deterioration in all the animals. Such marked toxicity was not evident with the arotinoid at doses having high antitumor activity. The high efficacy and relatively low toxicity of 4-((2-(p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthyl)propenyl]phenoxy)ethyl))-morpholine suggest that it may be a promising new anticancer agent.
Retinoic acid (RA) exerts its pleiotropic effects on cell growth and differentiation through the activation of a family of transcription factors-the RA receptors (RARs). Three subtypes of these receptors exist, RAR alpha, RAR beta, and RAR gamma. The receptors are differentially expressed in different cell types and stages of development, suggesting that they may regulate different sets of genes. We have identified a synthetic retinoid with the characteristics of a selective RAR alpha antagonist. This antagonist counteracts RA effects on HL-60 cell differentiation and on B-lymphocyte polyclonal activation. Beyond its potential practical relevance, this and other specific antagonists will be useful to dissect the RAR system and to assign to one given receptor each of the many RA-regulated functions.
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The continuous presence of a supportive companion (doula) during labor and delivery in two studies in Guatemala shortened labor and reduced the need for cesarean section and other interventions. In a US hospital with modern obstetric practices, 412 healthy nulliparous women in labor were randomly assigned to a supported group (n = 212) that received the continuous support of a doula or an observed group (n = 200) that was monitored by an inconspicuous observer. Two hundred four women were assigned to a control group after delivery. Continuous labor support significantly reduced the rate of cesarean section deliveries (supported group, 8%; observed group, 13%; and control group, 18%) and forceps deliveries. Epidural anesthesia for spontaneous vaginal deliveries varied across the three groups (supported group, 7.8%; observed group, 22.6%; and control group, 55.3%). Oxytocin use, duration of labor, prolonged infant hospitalization, and maternal fever followed a similar pattern. The beneficial effects of labor support underscore the need for a review of current obstetric practices.
The effect of structural modifications on the arotinoid molecule, a new class of retinoids, on their teratogenicity in mice was studied. Animals were treated on days 8 and 9 of gestation, the most susceptible stages to retinoid-induced malformations in rodents. The teratogenic potency of the 13 arotinoids tested varied over a dose range of more than five orders of magnitude. Next, we tested whether the quantitative differences in the teratogenicity of these arotinoids correlates with their activity in high density (micromass) cultures of rat embryonic limb bud and midbrain cells. There was a good quantitative correlation between the in vivo teratogenicity and the in vitro activity in limb bud cells but no correlation was found in midbrain cells. Thus, the limb bud cell culture system may be useful for a preliminary testing to select non-teratogenic retinoids. For the risk assessment in humans, however, the in vitro results should be verified in animals studies.
PURPOSE, PATIENTS, AND METHODS: Blood coagulation abnormalities are common in patients with cancer, particularly after treatment with chemotherapeutic agents. Chemotherapy has been associated with an increased incidence of thromboembolic events, and patients treated with chemotherapy often develop evidence of local phlebitis, which may lead to loss of venous access. We have utilized the radioimmunoassay for plasma fibrinopeptide A (FPA) and in vitro FPA generation to assess the rate of in vivo blood coagulation and the level of plasma thrombin activity in 16 cancer patients treated with chemotherapy. Eight patients were treated twice, once with chemotherapy alone and once with chemotherapy after an intravenous infusion of heparin (5,000 U). RESULTS: Our results confirm that FPA levels are elevated in most cancer patients. Following chemotherapy, FPA levels were further increased within 45 minutes (mean FPA = 5.2 ng/mL before chemotherapy versus 8.3 ng/mL after chemotherapy, p less than 0.01) and were accompanied by an increase in the FPA generation rate. Infusion of heparin prior to chemotherapy significantly lowered plasma FPA levels and abolished post-chemotherapy FPA generation. CONCLUSION: These data suggest that patients receiving chemotherapy express thrombin-like activity in plasma and, therefore, may be at risk for clinically significant intravascular activation of coagulation. Heparin diminished the laboratory evidence of this chemotherapy-related coagulopathy and may have a role in the prevention of thromboembolic disorders in some cancer patients undergoing cytotoxic therapy.
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A highly sensitive and specific method for the determination of the aromatic retinoic acid Ro 13-7410 in plasma at the picogram per millilitre level is described. The method involves extraction of plasma using Extrelut-1 columns, purification of the extract with Bond Elut-NH2 cartridges, derivatization with pentafluorobenzyl bromide, and subsequent analysis by two-dimensional capillary gas chromatography using the zone-cutting technique, stable isotope dilution and selective negative ion monitoring chemical ionization mass spectrometry. A tetradeuterated analogue is used as internal standard. Quantification is possible down to 25 pg/ml using 1 ml of plasma. The coefficients of variation of the method as calculated from quality control samples are 8.5 and 4.2% at the 100 and 400 pg/ml levels. The method has been applied to the analysis of plasma of volunteers following an oral dose of 40 micrograms Ro 13-7410 and plasma of dogs following an intravenous and oral dose of 25 and 50 micrograms, respectively.