Different hepatobiliary effects of oral and transdermal estradiol in postmenopausal women

Estrogen-replacement therapy is important for the prevention of postmenopausal osteoporosis. However, oral synthetic and conjugated estrogens increase biliary cholesterol saturation index and risk of gallstone disease. To examine whether transdermal estrogen administration could avoid these adverse effects, 17 postmenopausal women were treated with transdermal estradiol (Estraderm TTS; Ciba-Geigy, Arnhem, The Netherlands), 100 micrograms/day for 4 weeks, and after 1 month without therapy, with oral estradiol (Progynova; Schering, Weesp, The Netherlands), 2 mg/day for 4 weeks. The increase in the serum estradiol level was much higher during transdermal than oral estradiol administration. On the contrary, the increase in the serum estrone level was much more pronounced during oral treatment. Both modes of treatment led to a similar reduction of urinary calcium excretion. A highly significant decrease in serum phosphate levels was found during transdermal therapy. Biliary cholesterol saturation index did not change during transdermal therapy (mean +/- SEM, 1.25 +/- 0.06 before and 1.22 +/- 0.07 at the end of transdermal therapy; P = NS). A slight increase in cholesterol saturation index that did not reach statistical significance was found during oral therapy (1.28 +/- 0.09 before and 1.36 +/- 0.09 during oral treatment). However, the subgroup of women with strong increases in serum estrone levels during oral estradiol therapy (greater than 0.5 pmol/mL; n = 8) generally had increased biliary cholesterol saturation index, a decrease in relative percentage chenodeoxycholic acid in bile, and increased serum sex hormone-binding globulin levels during oral treatment. Cholesterol monohydrate crystals were never found in duodenal biles during either treatment. This study indicates that transdermal estradiol does not induce lithogenic bile. On the contrary, oral estradiol leads to lithogenic bile in a subgroup of women with strong increases in serum estrone levels during oral treatment.     

Broad consent versus dynamic consent in biobank research: Is passive participation an ethical problem?

In the endeavour of biobank research there is dispute concerning what type of consent and which form of donor–biobank relationship meet high ethical standards. Up until now, a ‘broad consent'' model has been used in many present-day biobank projects. However it has been, by some scholars, deemed as a pragmatic, and not an acceptable ethical solution. Calls for change have been made on the basis of avoidance of paternalism, intentions to fulfil the principle of autonomy, wish for increased user participation, a questioning of the role of experts and ideas advocating reduction of top–down governance. Recently, an approach termed ‘dynamic consent'' has been proposed to meet such challenges. Dynamic consent uses modern communication strategies to inform, involve, offer choices and last but not the least obtain consent for every research projects based on biobank resources. At first glance dynamic consent seems appealing, and we have identified six claims of superiority of this model; claims pertaining to autonomy, information, increased engagement, control, social robustness and reciprocity. However, after closer examination, there seems to be several weaknesses with a dynamic consent approach; among others the risk of inviting people into the therapeutic misconception as well as individualizing the ethical review of research projects. When comparing the two models, broad consent still holds and can be deemed a good ethical solution for longitudinal biobank research. Nevertheless, there is potential for improvement in the broad model, and criticism can be met by adapting some of the modern communication strategies proposed in the dynamic consent approach.     

In vitro culture of human osteosarcoma cell lines: a comparison of functional characteristics for cell lines cultured in medium without and with fetal calf serum

Purpose Experimental in vitro models including well-characterised cell lines can be used to identify possible new therapeutic targets for the treatment of osteosarcoma. Culture media including inactivated serum is often recommended for in vitro culture of osteosarcoma cells, but the serum component then represents a nonstandardised parameter including a wide range of unidentified mediators. To improve the standardisation we have investigated whether serum-free culture media can be used in experimental in vitro studies of osteosarcoma cell lines.Methods The seven osteosarcoma cell lines Cal72, SJSA-1, Saos-2, SK-ES-1, U2OS, 143.98.2, and KHOS-32IH were cultured in vitro in various serum-free media and media supplemented with 10% heat-inactivated fetal calf serum (FCS).Results Although proliferation often was relatively low in serum-free media (X-vivo 10, X-vivo 15, X-vivo 20, Stem Span SFEM), some cell lines (Cal72, KHOS-32IH, Saos-2) showed proliferation comparable with the recommended FCS-containing media even when using serum-free conditions. The optimal serum-free medium then varied between cell lines. We also compared 6 different FCS-containing media (including Stem Span with 10% FCS) and the optimal FCS-containing medium varied between cell lines. However, all cell lines proliferated well in Stem Span with FCS, and this medium was regarded as optimal for four of the lines. FCS could not be replaced by fatty acids or low density lipoprotein when testing the Stem Span medium. The release of a wide range of soluble mediators showed only minor differences when using serum-free and FCS-containing media (including Stem Span with and without FCS), and serum-free Stem Span could also be used for in vitro studies of mitogen-stimulated T cell activation in the presence of accessory osteosarcoma cells. The use of Stem Span with 10% FCS allowed the release of a wide range of chemokines by osteosarcoma cell lines (Cal72, SJSA-1), and the chemokine release profile was very similar to the fibroblast lines Hs27 and HFL1.Conclusions Serum-free culture media can be used for in vitro studies of several osteosarcoma cell lines, but the optimal medium varies between cell lines and thus depends on: (i) the cell lines to be investigated/compared; (ii) the functional characteristic that is evaluated (proliferation, cytokine release); and (iii) whether coculture experiments are included.     

Evaluation of the impact of a clinical pathway on the organization of a multidisciplinary dental sleep clinic

Purpose

Clinical pathways are used to organize complex care processes by providing structure and standardization. The multidisciplinary approach of oral appliance (OA) therapy for sleep-disordered breathing (SDB) is a complex and dynamic process suitable for such a structured pathway approach.

Methods

A clinical pathway for patients referred for OA therapy was developed and implemented. The aim of this study was to evaluate the impact of this clinical pathway on the time to delivery of the OA and the organization of the multidisciplinary dental sleep clinic (MDSC). The latter was achieved using the care process self-evaluation tool (CPSET).

Results

First, development and implementation of the clinical pathway gave structure and shortened the mean time to delivery by 102 days (240?±?70 vs. 138?±?33 days) (Mann–Whitney U: P?<?0.001). Second, the CPSET scores were obtained in a cohort of 49 healthcare professionals involved in the pathway. Overall, patient-focused organization received the highest scores (80.5?±?9.0 %), whereas cooperation with primary care received the lowest score (66.7?±?12.4 %).

Conclusions

This is the first project on clinical pathways in OA therapy for SDB. The implementation of the pathway in our MDSC has created a significant shortening of the time to delivery. A first evaluation of the clinical pathway using the CPSET scores indicates that all disciplines involved should be thoroughly informed in an ongoing approach.     

Genetics of hypertrophic cardiomyopathy in Norway

Genetic testing for hypertrophic cardiomyopathy (HCM) became available in Norway in 2003. Here, we describe the results of this testing in probands with HCM referred until the end of 2012. The translated exons of MYBPC3, MYH7, TNNI3, TNNT2, MYL2 and MYL3 were analyzed in two groups of probands. In Group 1, comprising 696 probands above 1 year of age, a mutation was found in 203 patients (29.2%). Of those, 5.9% were carriers of two mutations. Mean age in double mutation carriers, single mutation carriers and mutation negative probands was 44 years (±19 years), 50 years (±15 years) and 55 years (±16 years), respectively. In Group 2, comprising 26 infants below the age of 1, a mutation was found in 15.4%. A total of 120 different mutations were found of which 51 (42.5%) were novel.