Safe use of human milk for preterms in the context of maternal polypharmacy: a framework to improve practices

Maternal pharmacotherapy during lactation is an ongoing research field, which relies on scientific evidence, pharmacological reasoning and extrapolation to support risk-to-benefit assessment. Typically, drugs are studied individually for potential effects on a nursing infant, with limited information on the preterm infant. Polypharmacy during lactation is still poorly studied, leaving healthcare professionals without any scientific guidance when consulting on human milk safety in this scenario. When focusing on a dyad of a postpartum mother on polypharmacy and a preterm infant, the benefits of mother’s own milk (MOM) should be weighed against the unknown potential risks of polypharmacy during lactation. Within this setting of limited evidence, a framework to improve clinical and research practices is provided. Possible measures to minimize the risk of maternal (poly)pharmacy to the newborn include: multi-disciplinary prenatal counseling; preferring medications with low passage rate into human milk; relative rating of medications according to safety profile; and ‘mixed feeding’ (alternating between MOM and other types of feed, preferably donor human milk). These measures can be used to support shared informed decisions on the risk-to-benefit assessment. As the topic of polypharmacy during lactation is still poorly explored, a research agenda is suggested. Impact: Polypharmacy during lactation is poorly studied, and practical, evidence-based guidelines for healthcare professionals are lacking. Various methods can be employed to reduce exposure to medications through human milk, even more so when applied concomitantly: preference of medications with low passage into human milk, relative rating of medications according to known safety profile, or ‘mixed feeding’ where mother’s own milk is alternated with other types of feed, preferably donor human milk. A framework to improve clinical and research practices on provision of human milk in the setting of maternal polypharmacy and prematurity as an added challenge is provided

Phosphorus‐Containing Dibenzonaphthanthrenes: Electronic Fine Tuning of Polycyclic Aromatic Hydrocarbons through Organophosphorus Chemistry

A concise synthetic route towards a new family of phosphorus‐containing polycyclic aromatic hydrocarbons starting from the versatile acridophosphine has been established. The structural and optoelectronic properties of these compounds were efficiently modulated through derivatization of the phosphorus center. X‐ray crystallographic analysis, UV/Vis spectroscopic, and electrochemical studies supported by DFT calculations identified the considerable potential of these scaffolds for the development of organophosphorus functional materials with tailored properties upon further functionalization

Development of real-time NASBA assays with molecular beacon detection to quantify mRNA coding for HHV-8 lytic and latent genes

BACKGROUND: Human herpesvirus-8 (HHV-8) is linked to the pathogenesis of Kaposi's sarcoma (KS), and the HHV-8 DNA load in peripheral blood mononuclear cells (PBMC) is associated with the clinical stage of KS. To examine the expression of HHV-8 in PBMC, four HHV-8 mRNA specific NASBA assays were developed METHODS: We have developed four quantitative nucleic acid sequence-based amplification assays (NASBA-QT) specifically to detect mRNA coding for ORF 73 (latency-associated nuclear antigen, LANA), vGCR (a membrane receptor), vBcl-2 (a viral inhibitor of apoptosis) and vIL-6 (a viral growth factor). The NASBA technique amplifies nucleic acids without thermocycling and mRNA can be amplified in a dsDNA background. A molecular beacon is used during amplification to enable real-time detection of the product. The assays were tested on PBMC samples of two AIDS-KS patients from the Amsterdam Cohort. RESULTS: For all four assays, the limit of detection (LOD) of 50 molecules and the limit of quantification (LOQ) of 100 molecules were determined using in vitro transcribed RNA. The linear dynamic range was 50 to 10(7) molecules of HHV-8 mRNA. We found HHV-8 mRNA expression in 9 out of the 10 tested samples. CONCLUSION: These real-time NASBA assays with beacon detection provide tools for further study of HHV-8 expression in patient material

Human Herpesvirus 8 (HHV8) Sequentially Shapes the NK Cell Repertoire during the Course of Asymptomatic Infection and Kaposi Sarcoma

The contribution of innate immunity to immunosurveillance of the oncogenic Human Herpes Virus 8 (HHV8) has not been studied in depth. We investigated NK cell phenotype and function in 70 HHV8-infected subjects, either asymptomatic carriers or having developed Kaposi's sarcoma (KS). Our results revealed substantial alterations of the NK cell receptor repertoire in healthy HHV8 carriers, with reduced expression of NKp30, NKp46 and CD161 receptors. In addition, down-modulation of the activating NKG2D receptor, associated with impaired NK-cell lytic capacity, was observed in patients with active KS. Resolution of KS after treatment was accompanied with restoration of NKG2D levels and NK cell activity. HHV8-latently infected endothelial cells overexpressed ligands of several NK cell receptors, including NKG2D ligands. The strong expression of NKG2D ligands by tumor cells was confirmed in situ by immunohistochemical staining of KS biopsies. However, no tumor-infiltrating NK cells were detected, suggesting a defect in NK cell homing or survival in the KS microenvironment. Among the known KS-derived immunoregulatory factors, we identified prostaglandin E2 (PGE2) as a critical element responsible for the down-modulation of NKG2D expression on resting NK cells. Moreover, PGE2 prevented up-regulation of the NKG2D and NKp30 receptors on IL-15-activated NK cells, and inhibited the IL-15-induced proliferation and survival of NK cells. Altogether, our observations are consistent with distinct immunoevasion mechanisms that allow HHV8 to escape NK cell responses stepwise, first at early stages of infection to facilitate the maintenance of viral latency, and later to promote tumor cell growth through suppression of NKG2D-mediated functions. Importantly, our results provide additional support to the use of PGE2 inhibitors as an attractive approach to treat aggressive KS, as they could restore activation and survival of tumoricidal NK cells

Risikobetrachtungen zur Planung von Massnahmen zum Grundwasserschutz im Einflussbereich von Strassen

Available from TIB Hannover: RO 8(25) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman