Motivation for and adherence to growth hormone replacement therapy in adults with hypopituitarism: the patients‘ perspective

Pituitary - While reasons for non-adherence in children requiring growth hormone (GH) replacement (GH-Rx) are well researched, few studies have investigated adherence in adult GH deficient...     

AT2 Receptor and Tissue Injury: Therapeutic Implications

The converging clinical effectiveness of mineralocorticoid receptor antagonists (MRAs) Spironolactone and Eplerenone has made their safety profiles/cost-effectiveness key determinants of “agents of choice” across a broad range of clinical indications. The clinical biology of the aldosterone molecule and its range of effects in varied organ systems have been well elucidated from recent mechanistic and systematic studies. Clinical experience with Spironolactone is well established, as is its adverse effects profile. The range of adverse effects experienced with Spironolactone subsequently led to its modification and synthesis of Eplerenone. Recent published reports have confirmed lower prevalence rates of sex-related adverse effects attributable to Eplerenone compared to Spironolactone. There is, however, not much to choose between these agents in regards to other adverse effects including hyperkalemia and kidney failure. As was the experience with Spironolactone, as more robust observational data on Eplerenone accrues, it is possible that the real-life experience of its adverse profile may be discordant with that reported by randomized controlled clinical trials (RCTs). In addition, its metabolism by the vulnerable and highly polymorphic cytochrome dependent pathway also makes it susceptible to various drug interactions. The potential implication of the latter (including morbidity and mortality) may take years to evolve.     

Topical rather than intradermal application of the TLR7 ligand imiquimod leads to human dermal dendritic cell maturation and CD8+ T‐cell cross‐priming

Toll‐like receptor (TLR) ligands are attractive candidate adjuvants for therapeutic cancer vaccines, since TLR signaling stimulates and tunes both humoral and cellular immune responses induced by dendritic cells (DCs). Given that human skin contains a dense network of DCs, which are easily accessible via (intra‐)dermal delivery of vaccines, skin is actively explored as an antitumor vaccination site. Here we used a human skin explant model to explore the potential of TLR ligands as adjuvants for DC activation in their complex microenvironment. We show that topical application of Aldara skin cream, 5% of which comprises the TLR7 agonist imiquimod, significantly enhanced DC migration as compared with that resulting from intradermal injection of the TLR7/8 ligand R848 or the soluble form of imiquimod. Moreover, Aldara‐treated DCs showed highest levels of the costimulatory molecules CD86, CD83, CD40, and CD70. Topical Aldara induced the highest production of pro‐inflammatory cytokines in skin biopsies. When combined with intradermal peptide vaccination, Aldara‐stimulated DCs showed enhanced cross‐presentation of the melanoma antigen MART‐1, which resulted in increased priming and activation of MART‐1‐specific CD8⁺ T cells. These results point to advantageous effects of combining the topical application of Aldara with antitumor peptide vaccination.     

Diffusion and Interface Effects during Preparation of All-Solid Microstructured Fibers

All-solid microstructured optical fibers (MOF) allow the realization of very flexible optical waveguide designs. They are prepared by stacking of doped silica rods or canes in complex arrangements. Typical dopants in silica matrices are germanium and phosphorus to increase the refractive index (RI), or boron and fluorine to decrease the RI. However, the direct interface contact of stacking elements often causes interrelated chemical reactions or evaporation during thermal processing. The obtained fiber structures after the final drawing step thus tend to deviate from the targeted structure risking degrading their favored optical functionality. Dopant profiles and design parameters (e.g., the RI homogeneity of the cladding) are controlled by the combination of diffusion and equilibrium conditions of evaporation reactions. We show simulation results of diffusion and thermal dissociation in germanium and fluorine doped silica rod arrangements according to the monitored geometrical disturbances in stretched canes or drawn fibers. The paper indicates geometrical limits of dopant structures in sub-µm-level depending on the dopant concentration and the thermal conditions during the drawing process. The presented results thus enable an optimized planning of the preform parameters avoiding unwanted alterations in dopant concentration profiles or in design parameters encountered during the drawing process.     

The impact of periodontitis on oral health‐related quality of life: a review of the evidence from observational studies

Modern population based oral health management requires a complete understanding of the impact of disease in order to provide efficient and effective oral health care and guidance. Periodontitis is an important cause of tooth loss and has been shown to be associated with a number of systemic conditions. The impact of oral conditions and disorders on quality of life has been extensively studied. However, the impact of periodontitis on quality of life has received less attention. This review summarizes the literature on the impact of periodontitis on oral health‐related quality of life (OHRQoL). Relevant publications were identified after searching the MEDLINE and EMBASE electronic databases. Screening of titles and abstracts and data extraction was conducted. Only observational studies were included in this review. Most of the reviewed studies reported a negative impact of periodontitis on OHRQoL. However, the reporting standards varied across studies. Moreover, most of the studies were conducted in developed countries.     

Anti‐LFA‐1 or rapamycin overcome costimulation blockade‐resistant rejection in sensitized bone marrow recipients

While costimulation blockade‐based mixed chimerism protocols work well for inducing tolerance in rodents, translation to preclinical large animal/nonhuman primate models has been less successful. One recognized cause for these difficulties is the high frequency of alloreactive memory T cells (Tmem) found in the (pre)clinical setting as opposed to laboratory mice. In the present study, we therefore developed a murine bone marrow transplantation (BMT) model employing recipients harboring polyclonal donor‐reactive Tmem without concomitant humoral sensitization. This model was then used to identify strategies to overcome this additional immune barrier. We found that B6 recipients that were enriched with 3 × 10⁷ T cells isolated from B6 mice that had been previously grafted with Balb/c skin, rejected Balb/c BM despite costimulation blockade with anti‐CD40L and CTLA4Ig (while recipients not enriched developed chimerism). Adjunctive short‐term treatment of sensitized BMT recipients with rapamycin or anti‐LFA‐1 mAb was demonstrated to be effective in controlling Tmem in this model, leading to long‐term mixed chimerism and donor‐specific tolerance. Thus, rapamycin and anti‐LFA‐1 mAb are effective in overcoming the potent barrier that donor‐reactive Tmem pose to the induction of mixed chimerism and tolerance despite costimulation blockade.