Despite its potent biologic effect on human sebocytes, 13-cis retinoic acid exhibits low binding affinity for cellular retinoic acid binding proteins and nuclear retinoid receptors. Hence, 13-cis retinoic acid may represent a pro-drug possibly acting through all-trans isomerization. In this study, marked isomerization of 13-cis retinoic acid has been confirmed in cultured SZ95 sebocytes showing 2- to 15-fold higher levels of all-trans retinoic acid at 12-72 h, as measured by high performance liquid chromatography. In contrast, only low amounts of all-trans retinoic acid were converted intracellularly to its 13-cis isoform. 9-cis retinoic acid was not detected after either 13-cis retinoic acid or all-trans retinoic acid treatment. The rapid isomerization of 13-cis retinoic acid to high levels of all-trans retinoic acid was a sebocyte-specific event, as no significant isomerization of 13-cis retinoic acid to all-trans retinoic acid occurred in HaCaT keratinocytes. De novo mRNA expression of cytochrome P450 1A1, a major xenobiotic metabolizing enzyme, in SZ95 sebocytes was induced by all-trans retinoic acid, but not by 13-cis retinoic acid. In addition, mRNA levels of cellular retinoic acid-binding protein II, which is supposed to regulate the concentration of intracellular all-trans retinoic acid, rapidly increased under all-trans retinoic acid treatment (30 min-6 h), whereas the 13-cis retinoic acid effect was markedly weaker and delayed. Both 13-cis retinoic acid and all-trans retinoic acid suppressed mRNA expression of cytochrome P450 1A2. In parallel experiments, 13-cis retinoic acid significantly reduced SZ95 sebocyte proliferation at 10-7 M, show- ing 30-40% inhibition after 9 d. All-trans retinoic acid and 9-cis retinoic acid exhibited similar anti-proliferative effects. AGN 193109, a pan-antagonist of the retinoic acid receptors, antagonized the anti-proliferative activity of all retinoic acid isomers tested in a concentration-dependent manner with complete abolishment at ratios of 1:10 13-cis retinoic acid and 1:1 all-trans retinoic acid. Coincubation of SZ95 sebocytes with 13-cis retinoic acid and AGN 193109 did not alter the intracellular concentration of 13-cis retinoic acid and its isomerization profile. In contrast, the retinoid X receptor antagonist CD 3507 did not affect the inhibition of SZ95 sebocyte proliferation induced by retinoic acids. Our findings indicate: (i) a selective 13-cis retinoic acid isomerization to all-trans retinoic acid in the intracellular compartment of SZ95 sebocytes; (ii) a reduced all-trans retinoic acid inactivation process after 13-cis retinoic acid treatment as compared with treatment with all-trans retinoic acid; and (iii) a retinoic acid receptor-mediated inhibition of SZ95 sebocyte proliferation. These data explain the sebocyte-specific activity of 13-cis retinoic acid and support a pro-drug/drug relation between 13-cis retinoic acid and all-trans retinoic acid.

13-cis Retinoic acid is rapidly absorbed into cells and exerts its anti-proliferative effect on human sebocytes by specific isomerization to high levels of all-trans retinoic acid and binding the retinoic acid receptors. In this study, we have shown that bovine serum albumin, an extracellular binding protein for 13-cis retinoic acid, plays an important part in the uptake of 13-cis retinoic acid in human sebocytes, its intracellular isomerization to all-trans retinoic acid, and the induction of its anti-proliferative effect. The addition of highly concentrated bovine serum albumin (20 mg per ml) to the serum-free maintenance medium resulted in a rather controlled uptake of constant levels of 13-cis and all-trans retinoic acid into the cells over the 72 h of treatment. As a consequence, significantly reduced and delayed isomerization of 13-cis retinoic acid to all-trans retinoic acid was detected. In parallel experiments, the anti-proliferative activity of 13-cis retinoic acid on SZ95 sebocytes was abrogated by adding 20 mg bovine serum albumin per ml into the serum-free medium. These results indicate a critical function of serum albumin as retinoid-binding protein in reducing the concentration of active retinoids and restricting their biologic effects on human sebocytes.

Dependence of left heart opacification on ventricular function was evaluated for the new transpulmonary echo enhancing agent (SH U 508-A). The contrast agent was injected intravenously in 5 patients with normal cardiac function (ejection fraction [EF] greater than 60% and echocardiographic left ventricular end-diastolic diameter [LVED] less than 56 mm) and in five patients with pathological ventricular function (EF less than 40%, LVED greater than 65 mm). A concentration of 400 mg/mL with dosages of 5, 9, and 16 mL was used in all patients. The visually assessed signal enhancement as well as the videodensitometrically determined peak intensity and duration of signal enhancement did not differ significantly between the two patient groups, while the transit times were markedly prolonged in patients with impaired ventricular function. No significant alteration was found for systemic blood pressure and heart rate. Side effects were transitory and dose related. The noninvasive nature of the procedure and the absence of hemodynamic effects make repeated studies of left ventricular performance with SH U 508-A in patients with varied hemodynamic status possible.

The number of identified listeriosis outbreaks has increased since the sequence typing of Listeria monocytogenes isolates was established in Germany. Due to the nature of the disease, listeriosis outbreaks are difficult to solve. We present investigational tracing as a simple and rapid method to conduct outbreak investigations. The method was applied in 2019 to stop a prolonged listeriosis outbreak in Germany. The starting point for the investigational tracing was nine health care facilities (HCF). Single cases developed listeriosis while they were staying at the nine facilities. Data were collected from companies that delivered foods to HCF and from ready-to-eat (RTE) foods that were consumed there. Following a step-wise approach, data analysis identified similarities in the food supply of the HCF. Food data were heterogeneous and needed to be standardised. Own brands and changing article numbers were challenging aspects during the identification of manufacturers. The analysis of the delivering companies revealed no similarities. Detailed information about the consumed risk foods for Listeria contamination became available for six HCF. All facilities served a wide variety of cold cut meat products to their in-patients. Investigational tracing revealed that only meat products from one out of 29 food business operators had been consumed in all six HCF. Further activities of the authorities enabled the identification of the outbreak strain on food products and in the processing environment of this company. A product recall and the measures taken stopped the listeriosis outbreak. Thus, investigational tracing can be crucial for the clarification of listeriosis outbreaks.