Radiolabeling of the cannabinoid receptor agonist AZD1940 with carbon-11 and PET microdosing in non-human primate

IntroductionN-(2-tert-butyl-1-((4,4-difluorocyclohexyl)methyl)-1 H-benzo[d]imidazol-5-yl)ethanesulfonamide (AZD1940) is a candidate drug for treatment of neuropathic pain. As part of the preclinical evaluation of AZD1940, a microdosing study with positron emission tomography (PET) was conducted to assess brain exposure.MethodsAZD1940 was radiolabeled with carbon-11 in the benzimidazole moiety. The radioactive precursor, lithium [¹¹C]pivalate was obtained via ¹¹C-carboxylation of tert-butyl lithium. The target compound, [¹¹C]AZD1940, was in turn obtained by the microwave assisted reaction between lithium [¹¹C]pivalate and the o-phenylene diamine analog of AZD1940 (N-(3-amino-4-((4,4-difluorocyclohexyl)methylamino)phenyl)ethanesulfonamide) in neat phosphorous oxychloride. A brain PET measurement was performed in cynomolgus monkey.ResultsThe overall radiochemical yield of final formulated radiochemically pure (> 99%) [¹¹C]AZD1940 was 0.4% (uncorrected for decay) and the specific radioactivity was 13 GBq/μmol at time of administration (58 min after end of bombardment). After intravenous injection to cynomolgus monkey, the maximum concentration of radioactivity detected in the brain region of interest was 0.7% of the total injected radioactivity. The regional distribution of radioactivity within brain was homogenous.ConclusionsAZD1940 was radiolabelled with carbon-11 and its brain exposure, assessed using PET, was relatively low in comparison to peripheral organ exposure.     

Frequency and distribution pattern of melanocytic naevi in Swedish 8-9-year-old children

The naevus profile was examined in a Swedish cohort of 8-9-year-old children; 524/545 individuals (96%) were examined (279 boys and 245 girls). There was a wide variation in the total number of naevi (0-79) and boys had more naevi than girls (median 9 and 7, respectively, p<0.01). No dysplastic naevi were found. Overall, 15/ 524 (3%) had at least one lesion clinically diagnosed as a congenital melanocytic naevus. Boys had more naevi on the face (median 1) and trunk (median 5) than girls (median 0 and 3, respectively, p<0.001). There was no difference in the number of naevi on the legs between the two sexes. The highest counts per unit surface area for both sexes were found on the back, chest and the lateral aspect of the arms, areas intermittently sun-exposed. Children with fair skin and light eye colours had significantly more naevi than those with darker colours but children with red hair had very few naevi. Children with one or more naevi on the buttocks (25%), dorsal surfaces of the feet (11%) or on the scalp (7%) had twice as many naevi in total compared with those without naevi in these regions. Children with naevi in all three regions (0.8%) had four times as many naevi in total. A relationship between total counts and counts on the back or lateral aspect of the arms was found (r2 = 0.59). Either of these two areas might be suitable for predicting total naevus counts.     

Oxidised fish oil does not influence established markers of oxidative stress in healthy human subjects: a randomised controlled trial

Intake of fish oil reduces the risk of CHD and CHD deaths. Marine n-3 fatty acids (FA) are susceptible to oxidation, but to our knowledge, the health effects of intake of oxidised fish oil have not previously been investigated in human subjects. The aim of the present study was to investigate markers of oxidative stress, lipid peroxidation and inflammation, and the level of plasma n-3 FA after intake of oxidised fish oil. In a double-blinded randomised controlled study, healthy subjects (aged 18-50 years, n 54) were assigned into one of three groups receiving capsules containing either 8 g/d of fish oil (1.6 g/d EPA+DHA; n 17), 8 g/d of oxidised fish oil (1.6 g/d EPA+DHA; n 18) or 8 g/d of high-oleic sunflower oil (n 19). Fasting blood and morning spot urine samples were collected at weeks 0, 3 and 7. No significant changes between the different groups were observed with regard to urinary 8-iso-PGF2α; plasma levels of 4-hydroxy-2-hexenal, 4-hydroxy-2-nonenal and α-tocopherol; serum high sensitive C-reactive protein; or activity of antioxidant enzymes in erythrocytes. A significant increase in plasma level of EPA+DHA was observed in both fish oil groups, but no significant difference was observed between the fish oil groups. No changes in a variety of in vivo markers of oxidative stress, lipid peroxidation or inflammation were observed after daily intake of oxidised fish oil for 3 or 7 weeks, indicating that intake of oxidised fish oil may not have unfavourable short-term effects in healthy human subjects.     

Adherence, shared decision-making and patient autonomy

In recent years the formerly quite strong interest in patient compliance has been questioned for being too paternalistic and oriented towards overly narrow biomedical goals as the basis for treatment recommendations. In line with this there has been a shift towards using the notion of adherence to signal an increased weight for patients’ preferences and autonomy in decision making around treatments. This ‘adherence-paradigm’ thus encompasses shared decision-making as an ideal and patient perspective and autonomy as guiding goals of care. What this implies in terms of the importance that we have reason to attach to (non-)adherence and how has, however, not been explained. In this article, we explore the relationship between different forms of shared decision-making, patient autonomy and adherence. Distinguishing between dynamically and statically framed adherence we show how the version of shared decision-making advocated will have consequences for whether one should be interested in a dynamically or statically framed adherence and in what way patient adherence should be assessed. In contrast to the former compliance paradigm (where non-compliance was necessarily seen as a problem), using observations about (non-)adherence to assess the success of health care decision making and professional-patient interaction turns out to be a much less straightforward matter.     

Women's higher likelihood of disability pension: the role of health, family and work. A 5-7 years follow-up of the Hordaland Health Study

ABSTRACT: BACKGROUND: Women's higher risk of disability pension compared with men is found in countries with high female work participation and universal welfare schemes. The aim of the study was to examine the extent to which self-perceived health, family situation and work factors explain women's higher risk of disability pension. We also explored how these factors influenced the gender difference across educational strata. METHODS: The population-based Hordaland Health Study (HUSK) was conducted in 1997--99 and included inhabitants born in 1953--57 in Hordaland County, Norway. The current study included 5,959 men and 6,306 women in paid work with valid information on education and self-perceived health. Follow-up data on disability pension, for a period of 5--7 years, was obtained by linking the health survey to a national registry of disability pension. Cox regression analyses were employed. RESULTS: During the follow-up period 99 (1.7 %) men and 230 (3.6 %) women were awarded disability pension, giving a twofold risk of disability pension for women compared with men. Except for a moderate impact of self-perceived health, adjustment for family situation and work factors did not influence the gender difference in risk. Repeating the analyses in strata of education, the gender difference in risk of disability pension among the highly educated was fully explained by self-perceived health and work factors. In the lower strata of education there remained a substantial unexplained gender difference in risk. CONCLUSIONS: In a Norwegian cohort of middle-aged men and women, self-perceived health, family situation and work factors could not explain women's higher likelihood of disability pension. However, analyses stratified by educational level indicate that mechanisms behind the gender gap in disability pension differ by educational levels. Recognizing the heterogeneity within gender may contribute to a deeper understanding of women's higher risk of disability pension.     

Development of the Perinatal Depression Inventory (PDI)-14 using item response theory: a comparison of the BDI-II,EPDS, PDI,and PHQ-9

The objective of this study is to develop a simple, brief, self-report perinatal depression inventory that accurately measures severity in a number of populations. Our team developed 159 Likert-scale perinatal depression items using simple sentences with a fifth-grade reading level. Based on iterative cognitive interviewing (CI), an expert panel improved and winnowed the item pool based on pre-determined criteria. The resulting 67 items were administered to a sample of 628 pregnant and 251 postpartum women with different levels of depression at private and public sector obstetrics clinics, together with the Beck Depression Inventory (BDI-II), Edinburg Postpartum Depression Scale (EPDS), and the Patient Health Questionnaire (PHQ-9), as well as Module A of the Structured Clinical Interview for DSM-IV Diagnoses (SCID). Responses were evaluated using Item Response Theory (IRT). The Perinatal Depression Inventory (PDI)-14 items are highly informative regarding depression severity and function similarly and informatively across pregnant/postpartum, white/non-white, and private-clinic/public-clinic populations. PDI-14 scores correlate well with the PHQ-9, EPDS, and BDI-II, but the PDI-14 provides a more precise measure of severity using far fewer words. The PDI-14 is a brief depression assessment that excels at accurately measuring depression severity across a wide range of severity and perinatal populations.