Effect of the peripherally selective κ-opioid agonist,asimadoline, on adjuvant arthritis

1. Opioids, though widely used as analgesics, have not been seriously considered as therapy for rheumatoid arthritis. The present study evaluated the dose-effect and time-dependence relationships of a new peripherally selective κ agonist, asimadoline, in rats with adjuvant arthritis.
2. The arthritis was assessed by a pooled severity index combining the comprehensive criteria of oedema, radiography and histological changes, in the hind limbs. Asimadoline was extremely effective in attenuating joint damage (by up to 80%) when administered parenterally (0.5 to 10 mg kg⁻¹ day⁻¹, i.p.) throughout the disease or during its early phase; treatment was less successful if confined to the latter stages. Ten fold higher doses were effective orally.
3. Equimolar doses of a peripherally-selective antagonist, naloxone methiodide, and the κ-selective antagonist, MR2266, fully reversed the peripheral anti-arthritic effects of asimadoline (5 mg kg⁻¹ day⁻¹), indicating that asimadoline acts through peripheral κ-opioid receptors. However, an equivalent dose of MR2266 did not fully reverse the anti-arthritic effects of the highest dose of asimadoline (40 mg kg⁻¹ day⁻¹), suggesting a loss of κ-selectivity at this dose.
4. Asimadoline also exhibited analgesic effects (mechanical nociceptive thresholds) in arthritic but not non-arthritic rats, indicating that inflammation is necessary for asimadoline-induced analgesia.
5. These data confirm our previous findings that κ-opioids possess anti-arthritic properties and that these effects are mediated via peripheral κ-receptors. The present results are new in showing that the peripherally acting κ-opioid agonist, asimadoline, is a potent anti-arthritic agent. Such novel drugs, essentially lacking central side effects, herald new treatments for rheumatoid arthritis.

     

Regulation of L-lysine biosynthesis in prototrophic revertants of Corynebacterium glutamicum

The regulation pattern of L-lysine biosynthesis has been investigated in protrophic revertant derived from an initially homoserine-auxotrophic strain of Corynebacterium glutamicum and, additionally, in antimetabolite-resitant mutants. The influence of regulatory important amino acids of the aspartate family on growth and L-lysine biosynthesis and especially on the activity of aspartate kinase was studied. Furthermore the activity of homoserine dehydrogenase in dependence on the growth phase was estimated. From a total number of ninety nine L-lysine forming, homoserine-prototrophic, and S-(2-aminoethyl)-L-cysteine-resistant (AEC) strains the best lysine producers were selected by an emerse cultivation assay as a preselection. Strain No. 132 forming 10 g · 1^?1 lysine was selected for the derivation of α-amino-β-hydroxyvaleric acid (AHV)- and lysine-resistant strains. From 121 double resistant mutants (hse^?rev, AEC^r, AHV^r) sixty two strains (=51.2%) were isolated producing lysine. The best producer, strain 132-IV-37, reached 19.8 g · 1^?1 after 8 optimization steps of the growth medium in comparison to 9.2 g · 1^?1 as the initial value. This higher potential for lysine synthesis in the mutant 132-IV-37 could be attributed to changed regulation of the homoserine dehydrogenase and aspartate kinase. As was shown by the action of threonine or threonine + lysine on the activity of aspartate kinase, a general desensibilization of this key enzyme exists in the mutant strain 132-IV-37, but not in the AEC-resistant parent strain. In addition to isoleucine none of several amino acids tested showed any significant influence on the aspartate kinase. This agrees with the increased lysine formation by this strain in comparison to the parent strain 132.     

Circulating antisperm antibodies and fertility prognosis: a prospective study

In a prospective study performed on 235 couples with long standinginfertility (median 5 years), circulating antisperm antibodies(ASA) were determined with both a standard tray-agglutinationtest (TAT) and a radloimmunoassay (RIA). Serum levels were correlatedwith results of sperm analysis (SA), postcoital testing (PCT)and in-vitro sperm-cervical mucus penetration testing (SCMIPT),performed with cervical mucus and spermatozoa of patients andin parallel with material of fertile donors. A simultaneousmicrobial screening included Chiamydia trachomatis, mycoplasmas,Herpes simplex virus, gonococci, other potentially pathogenicaerobic and anaerobic bacteria and yeasts. The pregnancy rate12 months after determination of ASA in the serum samples was27% (64/235). Between ASA-positive and -negative male and/orfemale patients (TAT as well as RIA), no significant differencewas found for any of the tested variables of SA, PCT, crossedSCMPT and colonization of genital secretions with microorganisms.Patients who later achieved pregnancy and those who did notdid not differ with regard to serum antibody status (TAT aswell as RIA). The findings suggest that the clinical significanceof circulating ASA determined with the currently available methodsis low. ASA in serum samples of infertile female andlor malepatients do not influence the fertility prognosis.     

Lern- und curriculumsteuernde Effekte von Prüfungen: Eine Standortbestimmung aus der Schweiz

Wiener Medizinische Wochenschrift - Das Eidgenössische Medizinalberufegesetz sieht für die Curricula Humanmedizin in der Schweiz zur Qualitätssicherung und -entwicklung eine...     

Human Milk Oligosaccharides in Cord Blood Are Altered in Gestational Diabetes and Stimulate Feto-Placental Angiogenesis In Vitro

(1) Background: Human milk oligosaccharides (HMOs) are present in maternal serum during pregnancy and their composition is altered in gestational diabetes (GDM). HMOs are also in fetal cord blood and in contact with the feto-placental endothelium, potentially affecting its functions, such as angiogenesis. We hypothesized that cord blood HMOs are changed in GDM and contribute to increased feto-placental angiogenesis, hallmark of GDM. (2) Methods: Using HPLC, we quantified HMOs in cord blood of women with normal glucose tolerance (NGT, n = 25) or GDM (n = 26). We investigated in vitro angiogenesis using primary feto-placental endothelial cells (fpECs) from term placentas after healthy pregnancy (n = 10), in presence or absence of HMOs (100 µg/mL) isolated from human milk, 3′-sialyllactose (3′SL, 30 µg/mL) and lactose (glycan control) and determined network formation (Matrigel assay), proliferation (MTT assays), actin organization (F-actin staining), tube formation (fibrin tube formation assay) and sprouting (spheroid sprouting assay). (3) Results: 3′SL was higher in GDM cord blood. HMOs increased network formation, HMOs and 3’SL increased proliferation and F-actin staining. In fibrin assays, HMOs and 3’SL increased total tube length by 24% and 25% (p < 0.05), in spheroid assays, by 32% (p < 0.05) and 21% (p = 0.056), respectively. Lactose had no effect. (4) Conclusions: Our study suggests a novel role of HMOs in feto-placental angiogenesis and indicates a contribution of HMO composition to altered feto-placental vascularization in GDM.     

Fifty Shades: ambivalence about birth control in an erotic bestseller and its cultural implications

Abstract

The Fifty Shades trilogy by E.L. James has taken the world by storm and become a cultural phenomenon. The lack of contraceptive use in the erotic fiction, first pointed out by bloggers, is analysed in this article and compared to medical information. James may be praised for sexualising condom use. However, her protagonist makes poor choices in terms of hormonal contraception and is negligent about its use, resulting in an unintended pregnancy and resolved in marital bliss and motherhood. What is of more interest here than a possible message about contraceptive use, is the outcome that the fiction’s negligence in birth control and responsibility affirms an ideology in which female sexuality and sexual experimentation can only be tolerated within the context of procreation and affirmation of motherhood. Subsequently, the cultural significance of the trilogy’s popularity and its tension between sexual exploration, birth control and fertility is explored. In a globally popular fantasy published more than five decades after the introduction of the pill, the protagonist’s lack of attention to reliable birth control leads to a telling dichotomy that combines adventurous exploration of female sexuality and affirmation of the nuclear family.