Urinary estrogen metabolites during a randomized soy trial

One of the hypothesized protective mechanisms of soy against breast cancer involves changes in estrogen metabolism to 2-hydroxy (OH) and 16α-OH estrogens. The current analysis examined the effect of soy foods on the 2:16α-OH E(1) ratio among premenopausal women during a randomized, crossover intervention study; women were stratified by equol producer status, a characteristic thought to enhance the protective effects of soy isoflavones. The study consisted of a high-soy diet with 2 soy food servings/day and a low-soy diet with <3 servings of soy/wk for 6 mo each; estrogen metabolites were measured in 3 overnight urines (baseline and at the end of the low- and high-soy diet) using gas chromatography mass spectrometry for the 82 women who completed the study. Urinary isoflavonoids were assessed by liquid chromatography mass spectrometry. When applying mixed models, the 2:16α-OH E(1) ratio increased (P = 0.05) because of a nonsignificant decrease in 16α-OH E(1) (P = 0.21) at the end of the high-soy diet. Similar nonsignificant increases in the 2:16α-OH E(1) ratio were observed in equol producers (P = 0.13) and nonproducers (P = 0.23). These findings suggest a beneficial influence of soy foods on estrogen metabolism regardless of equol producer status.     

Identification of a new antinociceptive alkaloid isopropyl N-methylanthranilate from the essential oil of Choisya ternata Kunth

Ethnopharmacological relevance

Mexican people employed infusion of leaves of Choisya ternata Kunth for their antispasmodic and “simulative properties”.

Aim of the study

In the present study the detailed GC and GC-MS analyses of the essential oil of Choisya ternata Kunth (Rutaceae) were performed. The presence of a minor constituent isopropyl N-methylanthranilate (1) was revealed among other identified volatiles. A synthesis of 1 was undertaken in order to corroborate this find and obtain gram quantities that would allow the testing of its biological activity (peripheral and central antinociceptive activity).

Materials and methods

The oils were investigated by GC and GC-MS. Synthesized compounds were spectrally characterized (UV-Vis, IR, 1D and 2D NMR, MS). The obtained synthetic samples of compounds were assayed for peripheral and central antinociceptive activity in two models (effects on acetic acid induced writhing in mice and the hot plate test for nociception).

Results

Detailed GC and GC-MS analyses of the essential oil of Choisya ternata Kunth (Rutaceae) among 157 other identified volatiles revealed the presence of a minor constituent isopropyl N-methylanthranilate (1). Compound 1, named ternanthranin, is therefore detected as a natural product for the first time with a very restricted occurrence (samples of several citrus oils were screened for the presence of 1). The antinociceptive activities were assayed for ternanthranin, the two other synthetic analogs, methyl and propyl N-methylanthranilate, as well as the essential oil and the crude ethanol extract of the leaves. The results clearly demonstrate a very high (even significant at 0.3 mg/kg) dose dependent activity for the anthranilates (and the extracts). Isopropyl N-methylanthranilate showed the highest, while methyl N-methylanthranilate showed the lowest activity (with the methyl ester at 3 mg/kg still better than acetylsalicylic acid, at 200 mg/kg, in the first, or comparable with morphine, at 5 mg/kg, in the second test).

Conclusion

This study once again revealed that detailed investigations of plant species with ethnopharmacologically documented activity may yield new natural compounds—a new alkaloid (ternanthranin), a volatile simple anthranilate that can be considered responsible for the antinociceptive activity of the crude plant extracts.     

In vivo and in vitro antimalarial activity of 4-nerolidylcatechol

4‐Nerolidylcatechol (4‐NC) isolated from Piper peltatum L. (Piperaceae) was evaluated for in vitro antiplasmodial activity against Plasmodium falciparum (cultures of both standard CQR (K1) and CQS (3D7) strains and two Amazonian field isolates) and for in vivo antimalarial activity using the Plasmodium berghei‐murine model. 4‐NC exhibits significant in vitro and moderate in vivo antiplasmodial activity. 4‐NC administered orally and subcutaneously at doses of 200, 400 and 600 mg/kg/day suppressed the growth of P. berghei by up to 63% after four daily treatments (days 1–4). Also, 4‐NC exhibited important in vitro antiplasmodial activity against both standard and field P. falciparum strains in which 50% inhibition of parasite growth (IC₅₀) was produced at concentrations of 0.05–2.11 μg/mL and depended upon the parasite strain. Interestingly, healthy (non‐infected) mice that received 4‐NC orally presented (denatured) blood plasma which exhibited significant in vitro activity against P. falciparum. This is evidence that mouse metabolism allows 4‐NC or active metabolites to enter the blood. Further chemical and pharmacological studies are necessary to confirm the potential of 4‐NC as a new antimalarial prototype. Copyright © 2011 John Wiley & Sons, Ltd.     

Extending logistic regression to model diffuse interactions

In an observational study focussed on association between a health outcome and numerous explanatory variables, the question of interactions can be problematic. Commonly, logistic regression of the outcome on the explanatory variables might be employed. Such modelling often includes an attempt to select some pairwise product interaction terms, from amongst the many such possible pairs. For several reasons, however, this can be unsatisfying. Here we consider a different approach based on a parsimonious extension of a logistic regression model without interaction terms. This extension permits an overall synergism or antagonism in how the explanatory variables combine to associate with the outcome, without any attempt to identify specific variables which give rise to interactive behaviour. We call this diffuse interaction. We elucidate some simple properties of the diffuse interaction model, and give an example of its application to epidemiological data. We also consider asymptotic behaviour in a restricted case of the model, to gain some insight into how well this kind of interaction can be detected from data.     

Lung cancer and indoor pollution from heating and cooking with solid fuels: the IARC international multicentre case-control study in Eastern/Central Europe and the United Kingdom

Exposure to fuel from cooking and heating has not been studied in Europe, where lung cancer rates are high and many residents have had a long tradition of burning coal and unprocessed biomass. Study subjects included 2,861 cases and 3,118 controls recruited during 1998-2002 in the Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, and the United Kingdom. The odds ratio of lung cancer associated with solid fuel use was 1.22 (95% confidence interval (CI): 1.04, 1.44) for cooking or heating, 1.37 (95% CI: 0.90, 2.09) for solid fuel only for cooking, and 1.24 (95% CI: 1.05, 1.47) for solid fuels used for both cooking and heating. Risk increased relative to the percentage of time that solid fuel was used for cooking (p(trend) < 0.0001), while no risk increase was detected for solid fuel used for heating. The odds ratio of lung cancer in whole-life users of solid cooking fuel was 1.80 (95% CI: 1.35, 2.40). Switching to nonsolid fuels resulted in a decrease in risk. The odds ratio for the longest duration of time since switching was 0.76 (95% CI: 0.63, 0.92). The data suggest a modest increased risk of lung cancer related to solid-fuel use for cooking rather than heating.     

Validation of a brief screen for cognitive impairment (BSCI) administered by telephone for use in the medicare population.

The aim of this research was to examine the validity of a brief screen for cognitive impairment (BSCI) consisting of three questions administered by telephone (delayed recall, frequency of help with planning trips for errands, and frequency of help remembering to take medications). The study design was an age and gender matched case-control study. Seventy managed care members, 35 with dementia (cases) and 35 without dementia (controls), were assessed using BSCI embedded within a longer health assessment questionnaire commonly used in Medicare-managed care. A number of measures were used to examine validity of BSCI, including comparisons of the differences between cases and controls in BSCI scores, comparisons of the correlations between patient scores on BSCI and the Mini Mental Status Exam (MMSE, a common screening test for dementia) and the Alzheimer's Disease Assessment Scale (ADAS, a common dementia assessment test), and comparisons of the areas under the receiver operating characteristic (ROC) curves for the three instruments. BSCI scores for cases and controls were significantly different, as were their scores for the MMSE and ADAS. Scores on BSCI were significantly correlated with scores for the MMSE and ADAS using both the Kendall's tau-b and Spearman rank-order correlation; correlations ranged from 0.654 between BSCI and ADAS to -0.83 for the correlation between BSCI and the MMSE (p < 0.001 for both). The areas under the ROC curves ranged from 0.94 to 0.96 for the three tests, meaning that they were equally accurate in discriminating between demented and nondemented patients. BSCI, a brief telephone screen for cognitive impairment due to dementia, discriminates between demented patients and normal controls as well as two standard tests of dementia, and may be considered a valid screen for dementia. Compared to existing screening tests, it has the additional advantages of extreme brevity, and ease of administration and scoring by lay interviewers via telephone. The use of brief screening instruments for dementia, such as the one validated here, will be increasingly important for the effective management of dementia and other chronic diseases where dementia is a coexisting condition.     

Insulin-like growth factor-1 and binding protein-3 in a 2-year soya intervention among premenopausal women

Soya foods may protect against the development of breast cancer. Insulin-like growth factor (IGF)-1 is under investigation as a possible link between nutrition and cancer. We examined the effect of soya foods on circulating IGF-1 and IGF binding protein (BP)-3 levels among 196 healthy premenopausal women in a 2-year randomised nutritional trial. The intervention group consumed two daily servings of soya foods including tofu, soya milk, soya nuts and soya protein powder (equivalent to 50 mg isoflavones and 5-22 g soya protein per serving); the controls maintained their regular diet. Five serum samples at baseline, 3, 6, 12, and 24 months were collected in the morning during the luteal phase and analysed for IGF-1 and IGFBP-3 by double-antibody ELISA. We applied mixed models to investigate the intervention effect and predictors of serum levels while considering the repeated measurement design. Adherence with the study regimen was high and dropout rates were acceptable. Randomisation resulted in similar mean IGF-1 and IGFBP-3 levels by group. We did not observe a significant intervention effect on IGF-1, IGFBP-3, and their molar ratio during the entire study period. However, urinary isoflavone excretion during the study period was positively associated with IGF-1 (P=0.04) and the IGF-1:IGFBP-3 ratio (P=0.06). The effect was consistent over time. Adding soya foods to the diet of premenopausal women does not appear to lower serum levels of IGF-1 and IGFBP-3; if anything, the greater protein intake from soya may lead to a small increase in IGF-1 serum levels.     

The Quality-of-Life Impact of Head and Neck Cancer: Preference Values from the Canadian General Public

ObjectivesTo elicit preferences for standardized head and neck cancer (HNC) health states describing the health-related quality of life (HRQoL) impact of cancer type or stage, progression, or treatment-related toxicities; and to measure the association between an individual’s locus of control (LOC) and mean preference values for HNC health states.Study DesignWe elicited preferences from a sample of 106 members of the Canadian general public, using the standard gamble method. Eight health states representing HNC characteristics, and 10 describing treatment-related toxicities, were developed based on literature review, data analysis, and clinician interview. All participants valuated these, anchored against full health and dead, and completed the Multidimensional Health LOC scale. A mixed-regression model was used to calculate adjusted preference decrements for all states compared with a reference state (locoregional preprogression nonlaryngeal HNC).ResultsMean participant age was 47 years, and 48% were male. All health states were associated with substantially decreased preferences compared with full health. Mean preferences ranged from 0.62 (locoregional laryngeal HNC) to 0.33 (hospitalization for severe toxicity). After adjusting for age and sex, mean preference decrements were: ?0.28 (postprogression), ?0.11 (metastases), and ?0.05 (recurrent disease). There was suggestive evidence that LOC was associated with preferences overall (P = .079); those with stronger beliefs in Chance rated health states lower (P = .012).ConclusionsHealth state preferences elicited here demonstrate that members of the Canadian general public rate HNC to have a large negative impact on HRQoL. The greatest impact was for postprogression and metastatic health states. These values are useful for quantifying the devastating impact of HNC on HRQoL, and for economic modeling.     

Prevalence and correlates of participation in fall prevention exercise/physical activity by older adults

ObjectiveTo examine older people's participation in fall prevention exercise/physical activities.MethodsParticipants comprised 5,681 randomly selected older people (≥ 65 years) who took part in the 2009 New South Wales (Australia) Fall Prevention telephone survey (61% response-rate). The instrument consisted of 11 prompted activities including two separate questions on participation in strength and balance training. Tai chi, dance, team sports, golf, bowls and specific balance training were classified as balance-challenging activities. Correlates of low participation were examined using multivariable logistic regression.ResultsOne in eight older people (12.0%, 95% CI: 11.0–13.0) participated in strength training, 6.0% (95% CI: 5.2–6.7) participated in balance training and 21.8% (95% CI: 20.5–23.0) participated in balance-challenging activities. Adherence to public health recommendations (≥ 2 days/week) for strength or balance-challenging activities was reported by 21.0% (95% CI: 9.8–22.2) with 5.3% adhering to both forms. Engagements in strength or in balance-challenging activities were lower among those who had low education (< high-school), lived in disadvantaged neighbourhoods, were obese, had fair/poor self-rated health, had problems with walking or used a walking aid or had fallen in the past year.ConclusionParticipation in best practice exercise to prevent falls is low. Population-based approaches and targeted strategies for high-risk group are needed.     

EVEREST STUDY: Efficacy and Safety of Verteporfin Photodynamic Therapy in Combination with Ranibizumab or Alone Versus Ranibizumab Monotherapy in Patients with Symptomatic Macular Polypoidal Choroidal Vasculopathy

PURPOSE:: To assess the effects of verteporfin photodynamic therapy (PDT) combined with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. METHODS:: In this multicenter, double-masked, primarily indocyanine green angiography-guided trial, 61 Asian patients were randomized to verteporfin PDT (standard fluence), ranibizumab 0.5 mg, or the combination. Patients were administered with verteporfin PDT/placebo and initiated with three consecutive monthly ranibizumab/sham injections starting Day 1, and re-treated (Months 3-5) as per predefined criteria. The primary endpoint was the proportion of patients with indocyanine green angiography-assessed complete regression of polyps at Month 6. Secondary endpoints included mean change in best-corrected visual acuity at Month 6 and safety. RESULTS:: At Month 6, verteporfin combined with ranibizumab or alone was superior to ranibizumab monotherapy in achieving complete polyp regression (77.8% and 71.4% vs. 28.6%; P < 0.01); mean change ± standard deviation in best-corrected visual acuity (letters) was 10.9 ± 10.9 (verteporfin PDT + ranibizumab), 7.5 ± 10.6 (verteporfin PDT), and 9.2 ± 12.4 (ranibizumab). There were no new safety findings with either drug used alone or in combination. CONCLUSION:: Verteporfin PDT combined with ranibizumab 0.5 mg or alone was superior to ranibizumab monotherapy in achieving complete regression of polyps in this 6-month study in patients with symptomatic macular polypoidal choroidal vasculopathy. All treatments were well tolerated over 6 months.