Unexpected sensitivity of sst2 antagonists to N-terminal radiometal modifications

Chelated somatostatin agonists have been shown to be sensitive to N-terminal radiometal modifications, with Ga-DOTA agonists having significantly higher binding affinity than their Lu-, In-, and Y-DOTA correlates. Recently, somatostatin antagonists have been successfully developed as alternative tracers to agonists. The aim of this study was to evaluate whether chelated somatostatin antagonists are also sensitive to radiometal modifications and how. We have synthesized 3 different somatostatin antagonists, DOTA-p-NO(2)-Phe-c[D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH(2), DOTA-Cpa-c[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH(2) (DOTA-JR11), and DOTA-p-Cl-Phe-c[D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH(2), and added various radiometals including In(III), Y(III), Lu(III), Cu(II), and Ga(III). We also replaced DOTA with 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) and added Ga(III). The binding affinity of somatostatin receptors 1 through 5 was evaluated in all cases. In all 3 resulting antagonists, the Ga-DOTA analogs were the lowest-affinity radioligands, with a somatostatin receptor 2 binding affinity up to 60 times lower than the respective Y-DOTA, Lu-DOTA, or In-DOTA compounds. Interestingly, however, substitution of DOTA by the NODAGA chelator was able to increase massively its binding affinity in contrast to the Ga-DOTA analog. The 3 NODAGA analogs are antagonists in functional tests. In vivo biodistribution studies comparing (68)Ga-DOTATATE agonist with (68)Ga-DOTA-JR11 and (68)Ga-NODAGA-JR11 showed not only that the JR11 antagonist radioligands were superior to the agonist ligands but also that (68)Ga-NODAGA-JR11 was the tracer of choice and preferable to (68)Ga-DOTA-JR11 in transplantable HEK293-hsst(2) tumors in mice. One may therefore generalize that somatostatin receptor 2 antagonists are sensitive to radiometal modifications and may preferably be coupled with a (68)Ga-NODAGA chelator-radiometal complex.

Simulation-based cost-utility analysis of population screening-based alendronate use in Switzerland

A simulation model adopting a health system perspective showed population-based screening with DXA, followed by alendronate treatment of persons with osteoporosis, or with anamnestic fracture and osteopenia, to be cost-effective in Swiss postmenopausal women from age 70, but not in men. INTRODUCTION: We assessed the cost-effectiveness of a population-based screen-and-treat strategy for osteoporosis (DXA followed by alendronate treatment if osteoporotic, or osteopenic in the presence of fracture), compared to no intervention, from the perspective of the Swiss health care system. METHODS: A published Markov model assessed by first-order Monte Carlo simulation was refined to reflect the diagnostic process and treatment effects. Women and men entered the model at age 50. Main screening ages were 65, 75, and 85 years. Age at bone densitometry was flexible for persons fracturing before the main screening age. Realistic assumptions were made with respect to persistence with intended 5 years of alendronate treatment. The main outcome was cost per quality-adjusted life year (QALY) gained. RESULTS: In women, costs per QALY were Swiss francs (CHF) 71,000, CHF 35,000, and CHF 28,000 for the main screening ages of 65, 75, and 85 years. The threshold of CHF 50,000 per QALY was reached between main screening ages 65 and 75 years. Population-based screening was not cost-effective in men. CONCLUSION: Population-based DXA screening, followed by alendronate treatment in the presence of osteoporosis, or of fracture and osteopenia, is a cost-effective option in Swiss postmenopausal women after age 70.

A social network-based approach to assess de facto independence of regulatory agencies

This article uses a policy network perspective to assess the independence of regulatory agencies (RAs) in liberalized public utility sectors. We focus on the de facto independence of RAs from elected politicians, regulatees and other co-regulators. We go further than previous studies, which only undertook a general analysis of the de jure independence of RAs from political authorities. Specifically, we apply a social network analysis (SNA), which concentrates on the attributes and relational profiles of all actors involved in new regulatory arrangements. The concept of de facto independence is applied to the Swiss telecommunications sector in order to provide initial empirical insights. Results clearly show that SNA indicators are an appropriate tool to identify the de facto independence of RAs and can improve knowledge about the issues arising from the emergence of the ‘regulatory State’.

Ms. Praed. 56 - Summulae logicales

Vorbesitzer: Petrus Scriptoris de Seligenstadt; Dominikanerkloster Frankfurt am Main

Ms. Praed. 178 - Speculum virtutum

Vorbesitzer: Arnold Genepaeus; Dominikanerkloster Frankfurt am Main

Flugschr. G. Fr. 4102 - Epistola in defensione Plinii et Domitii Calderini contra Georgium Merulam ad Hermolaum Barbarum

Vorbesitzer: Bibliothek der Waldauffschen Stiftung Hall/Tirol; Gustav Freytag

Is sexual intimacy among older adults positively associated with mental well-being?

Background. The elderly population aged 60 and above is increasing rapidly throughout the world. The aging process affects physical health of individuals, which in turn affects sexuality and sexual activity. However, many elderly adults continue to engage in one or more forms of sexual activities well into their 70s, 80s, and even in 90s. Despite the widespread stereotypes, misconceptions, and negative attitudes surrounding sexuality in elderly adults, it has been found to be an important aspect of the health of the elderly. However, association between the frequency of sexual activity and mental well being among older adults has not been documented in the literature. ^ Methods. To test the hypotheses that mental well being indicators such as depression, anxiety, and stress were inversely associated with greater frequency of sexual intimacy, a secondary data analysis was conducted using the National Social Life Health and Aging Project (NSHAP) using multivariate logistic regression. The NSHAP was a population-based study that was conducted on a national scale including 1455 men and 1550 women aged 57-85.^ Results. Approximately 1430 (54.1%) of the total population reported being sexually intimate in the past 12 months whereas 1481 (45.9%) participants reported that they did not perform any sexual activity in the past 12 months. In addition, approximately 895(31.1%) participants reported engaging in sexual activity ≥ 2-3 times per month with 665 (78.9%) of these participants reported performing vaginal intercourse only, 14(2.0%) oral sex only, and 89(10.5%) reported performing both vaginal intercourse and oral sex. Controlling for socio-demographic characteristics, frequently (≥2-3 times per month) sexually active participants showed lower odds ratio of depression (OR= 0.60; 95%CI = 0.46, 0.78), anxiety (OR= 0.67; 95% CI= 0.53, 0.86), and stress (OR=0.73; 95% CI = 0.6, 0.88) compared to those who had less frequent sexual activity or who had no sexual activity in the past 12 months.^ Conclusion. Lower levels of depression, anxiety, and stress appear to be associated with greater frequency of sexual activity. Public health interventions should focus on educating elderly adults about their sexual health and how to seek medical help for their sexual problems. Public health professionals should also be educated on how to best assess sexual needs of the elderly adults.^