The CYP1A2 genotype modifies the association between coffee consumption and breast cancer risk among BRCA1 mutation carriers.

We have recently reported that, among BRCA1 mutation carriers, the consumption of caffeinated coffee was associated with a significant reduction in breast cancer risk. Because the metabolism of caffeine is primarily by CYP1A2, we examined whether or not the CYP1A2 genotype modifies the association between a history of coffee consumption and the risk of breast cancer. A common A to C polymorphism in the CYP1A2 gene is associated with decreased enzyme inducibility and impaired caffeine metabolism. Information regarding coffee consumption habits and the CYP1A2 genotype was available for 411 BRCA1 mutation carriers (170 cases and 241 controls). We estimated the odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer associated with the CYP1A2 genotype and a history of coffee consumption before age 35, adjusting for potential confounders. The CYP1A2 genotype did not affect breast cancer risk. Among women with at least one variant C allele (AC or CC), those who consumed coffee had a 64% reduction in breast cancer risk, compared with women who never consumed coffee (OR, 0.36; 95% CI, 0.18-0.73). A significant protective effect of coffee consumption was not observed among women with the CYP1A2 AA genotype (OR, 0.93; 95% CI, 0.49-1.77). Similar results were obtained when the analysis was restricted to caffeinated coffee. This study suggests that caffeine protects against breast cancer in women with a BRCA1 mutation and illustrates the importance of integrating individual genetic variability when assessing diet-disease associations.     

Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy.

BACKGROUND: Radiation dose distributions created by two dimensional (2D) treatment planning are responsible for partial volumes receiving >107% of the prescribed dose in a proportion of patients prescribed whole breast radiotherapy after tumour excision of early breast cancer. These may contribute to clinically significant late radiation adverse effects. AIM: To test three dimensional (3D) intensity modulated radiotherapy (IMRT) against 2D dosimetry using standard wedge compensators in terms of late adverse effects after whole breast radiotherapy. METHODS: Three hundred and six women prescribed whole breast radiotherapy after tumour excision for early stage cancer were randomised to 3D IMRT (test arm) or 2D radiotherapy delivered using standard wedge compensators (control arm). All patients were treated with 6 or 10MV photons to a dose of 50Gy in 25 fractions to 100% in 5 weeks followed by an electron boost to the tumour bed of 11.1Gy in 5 fractions to 100%. The primary endpoint was change in breast appearance scored from serial photographs taken before radiotherapy and at 1, 2 and 5 years follow up. Secondary endpoints included patient self-assessments of breast discomfort, breast hardness, quality of life and physician assessments of breast induration. Analysis was by intention to treat. RESULTS: 240 (79%) patients with 5-year photographs were available for analysis. Change in breast appearance was identified in 71/122 (58%) allocated standard 2D treatment compared to only 47/118 (40%) patients allocated 3D IMRT. The control arm patients were 1.7 times more likely to have a change in breast appearance than the IMRT arm patients after adjustment for year of photographic assessment (95% confidence interval 1.2-2.5, p=0.008). Significantly fewer patients in the 3D IMRT group developed palpable induration assessed clinically in the centre of the breast, pectoral fold, infra-mammary fold and at the boost site. No significant differences between treatment groups were found in patient reported breast discomfort, breast hardness or quality of life. CONCLUSION: This analysis suggests that minimisation of unwanted radiation dose inhomogeneity in the breast reduces late adverse effects. Incidence of change in breast appearance was statistically significantly higher in patients in the standard 2D treatment arm compared with the IMRT arm. A beneficial effect on quality of life remains to be demonstrated.     

Measuring job satisfaction of UK pharmacists: a pilot study

Objective To review the UK published literature on pharmacy job satisfaction, in order to describe and assess the strengths of their methods and the findings and to validate an existing instrument to measure work satisfaction, with a sample of locum pharmacists. Method A literature review of relevant databases was used to identify UK studies exploring any aspect of job, role, career or work satisfaction. A search of the grey literature was also undertaken. A satisfaction scale, the Warr‐Cook‐Wall scale, previously used with general practitioners (GPs), was adapted and administered to a sample of locum pharmacists (n = 175, response rate = 75%). Validity and reliability analyses were undertaken in SPSS v13. Key findings Three articles, two reports, one thesis abstract and one conference abstract were identified through the search. The findings of the review indicate that the way in which pharmacist satisfaction has been measured to date renders it difficult to determine historical trends or make cross‐sectoral comparisons. A Cronbach alpha coefficient of 0.90 was obtained for the job satisfaction scale, indicating that the job satisfaction scale is a satisfactory and reliable tool for use with this group of pharmacists. In terms of substantive findings, these suggest that locum pharmacists in general derive high levels of job satisfaction and higher levels than those reported by GPs. Conclusion Limited evidence is available regarding pharmacists' job satisfaction in the UK. The review highlights the need for a universal, multifaceted measure of satisfaction. The findings of this study suggest that the Warr‐Cook‐Wall satisfaction scale has very high reliability and is suitable for use with pharmacists without any further amendments. Although the study suggests relatively high satisfaction scores in this group of pharmacists, it would be instructive to determine the applicability of the job satisfaction measure and to explore the satisfaction levels of pharmacists in a wide range of roles and sectors, to determine relative levels of satisfaction.     

Myectomy versus anterior transposition for inferior oblique overaction

BACKGROUND: Inferior oblique overaction can be either secondary (as a sequela of ipsilateral superior oblique palsy) or primary (commonly associated with horizontal strabismus). Superior oblique underaction often coexists with both primary and secondary inferior oblique overaction. This retrospective case series compares the efficacy of inferior oblique myectomy versus anterior transposition in improving inferior oblique overaction and superior oblique underaction in eyes with either primary or secondary inferior oblique overaction. METHODS: One hundred twenty eyes of 81 patients were included in this retrospective case series, of which 20 had anterior transposition of the inferior oblique and 100 eyes underwent myectomy. Inferior oblique myectomy was compared with inferior oblique anterior transposition in improving inferior oblique overaction and superior oblique underaction in each diagnostic subgroup. Postoperative outcome was qualitatively and quantitatively assessed. Fisher's exact test was used to compare the outcomes. The quantitative improvement of function in terms of inferior oblique overaction and superior oblique underaction was analyzed by regression analysis. RESULTS: When postoperative inferior oblique overaction was considered, there was no statistically significant difference between myectomy and anterior transposition in both primary and secondary inferior oblique overaction. Myectomy was superior to anterior transposition in improving superior oblique underaction in both primary inferior oblique overaction (OR = 0.14; 95% CI, 0.015-1.45; p = 0.056) and secondary inferior oblique overaction (OR = 0; 95% CI, 0-0.027; p < 0.001). The quantitative improvement of function showed a significant difference between procedures for superior oblique underaction (t-test; p = 0.005; 95% CI, 0.25-1.3) but not inferior oblique overaction (t-test; p = 0.8; 95% CI, -0.67-0.54). CONCLUSIONS: This study demonstrates both inferior oblique myectomy and inferior oblique anterior transposition to be effective in correcting primary and secondary inferior oblique overaction. Myectomy is more effective in improving superior oblique underaction associated with both primary and secondary inferior oblique overaction. On this basis, we feel that inferior oblique myectomy has some advantage over anterior transposition in treating combined inferior oblique overaction and superior oblique underaction and can be considered the procedure of choice.     

Presence of the Metabolic Syndrome in Obese Adolescents Predicts Impaired Glucose Tolerance and Nonalcoholic Fatty Liver Disease

PURPOSE: To evaluate whether the presence of metabolic syndrome (MS) in obese adolescents is associated with other comorbidities of obesity METHODS: A total of 85 obese teens (70% female and 30% male) with fasting insulin >25 microU/ml and family history of type 2 diabetes mellitus and/or acanthosis nigricans were studied. Mean age was 15.8 +/- 1.7 years and body mass index (BMI) was 39.3 +/- 6.6 kg/m(2). Of the subjects, 54% were Hispanic and 35% black, 5% white, 5% American Indian, and 1% Asian. Laboratory analysis included fasting lipids, glucose, gamma-glutamyl transpeptidase (GGT), and oral glucose tolerance testing. Additional liver transaminase levels were determined and liver ultrasound (US) was performed to evaluate the presence and severity of fatty liver. RESULTS: All subjects met MS criteria for children for waist circumference, 49% for blood pressure, 54% for high-density lipoprotein, 54% for triglycerides, and 20% for impaired fasting glucose (IFG) or impaired glucose tolerance [IGT]). In all, 47 subjects had three or more MS criteria. BMI was no different between groups with and without MS. Subjects with three or more MS criteria were more likely to have IGT (p = .004), elevated alanine aminotransferase (p = .039), elevated GGT (p = .036), fatty liver on US (p < .001), and more severe fatty liver (p = .001). CONCLUSIONS: Abnormal glucose regulation and evidence of nonalcoholic fatty liver disease (NAFLD) were more common in subjects meeting three criteria for MS than in those meeting fewer criteria. The identification of MS provides value to the primary care provider. Those patients meeting criteria for MS should be evaluated for glucose intolerance and NAFLD.     

Semi-synthesis of C20 3H-resiniferatoxin

There has recently been considerable interest concerning the biochemical and pharmacological mechanisms of action of resiniferatoxin (Rx). Rx is a daphnane diterpene ester, which is part of the phorbol ester family of diterpenes. We have synthesized ³H-Rx in a three-step process from the parent alcohol, resiniferonol (Ro). The tritium label is incorporated into the resiniferonol nucleus at the C₂₀ position, before esterification of ³H-Ro to ³H-Rx. This compound will be of use in the elucidation of the binding characteristics of Rx to its biochemical receptor site(s).     

PERINATAL, NEUROLOGICAL, ENVIRONMENTAL AND DEVELOPMENTAL CHARACTERISTICS OF SEVEN-YEAR-OLD CHILDREN WITH STABLE BEHAVIOUR PROBLEMS

From a large sample of 7-yr-olds in Dunedin, New Zealand, a group of 52 boys and 32 girls with stable behaviour problems was selected and compared with the remainder of the sample. The groups did not differ in terms of perinatal problems except for a higher prevalence of being small for gestational age in the problem group. The mothers of the problem children tended to be younger, to have lower mental ability and poorer health than the rest of the sample. The families of the problem children were rated as having poorer relationships, and there was more parental separation and solo parenting in this group. Finally, the children with stable problems showed cognitive delays at age 7 yr.     

Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes: differential regulation of function by specific classes of physiologic stimuli

Dendritic cells (DCs) are a family of leukocytes that initiate T- and B-cell immunity against pathogens. Migration of antigen-loaded DCs from sites of infection into draining lymphoid tissues is fundamental to the priming of T-cell immune responses. In humans, the major peripheral blood DC (PBDC) types, CD1c+ DCs and interleukin 3 receptor-positive (IL-3R+) plasmacytoid DCs, are significantly expanded in vivo with the use of Flt3 ligand (FL). DC-like cells can also be generated from monocyte precursors (MoDCs). A detailed comparison of the functional potential of these types of DCs (in an autologous setting) has yet to be reported. Here, we compared the functional capacity of FL-expanded CD1c+ PBDCs with autologous MoDCs in response to 3 different classes of stimuli: (1) proinflammatory mediators, (2) soluble CD40 ligand trimer (CD40L), and (3) intact bacteria (Escherichia coli). Significant differences in functional capacities were found with respect to changes in phenotype, migratory capacity, cytokine secretion, and T-cell stimulation. MoDCs required specific stimuli for the expression of functions. They responded vigorously to CD40L or E coli, expressing cytokines known to regulate interferon-gamma (IFN-gamma) in T cells (IL-12p70, IL-18, and IL-23), but required prostaglandin E2 (PGE2) during stimulation to migrate to chemokines. In contrast, PBDCs matured in response to minimal stimulation, rapidly acquired migratory function in the absence of PGE2-containing stimuli, and were low cytokine producers. Interestingly, both types of DCs were equivalent with respect to stimulation of allogeneic T-cell proliferation and presentation of peptides to cytotoxic T lymphocyte (CTL) lines. These distinct differences are of particular importance when considering the choice of DC types for clinical applications.