Formal concept analysis for the identification of molecular fragment combinations specific for active and highly potent compounds

We introduce fragment formal concept analysis (FragFCA) to study complex relationships between fragments in active compounds taking potency information into account. Fragment combinations that are unique to active or highly potent compounds or that are shared by molecules having different or overlapping activity profiles are systematically identified using chemically intuitive queries of varying complexity. The methodology is applied to analyze fragment distributions in antagonists of seven G protein coupled receptor targets and identify signature fragments. Pairs or triplets of molecular fragments are found to be most specific for different activity profiles and compound potency levels. In addition, we demonstrate the ability of FragFCA to identify selective hits in high-throughput screening data sets.     

Associations of in Utero Exposure to Perfluorinated Alkyl Acids with Human Semen Quality and Reproductive Hormones in Adult Men

Background: Perfluorinated alkyl acids (PFAAs), persistent chemicals with unique water-, dirt-, and oil-repellent properties, are suspected of having endocrine-disrupting activity. The PFAA compounds perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are found globally in humans; because they readily cross the placental barrier, in utero exposure may be a cause for concern.Objectives: We investigated whether in utero exposure to PFOA and PFOS affects semen quality, testicular volume, and reproductive hormone levels.Methods: We recruited 169 male offspring (19–21 years of age) from a pregnancy cohort established in Aarhus, Denmark, in 1988–1989, corresponding to 37.6% of the eligible sons. Each man provided a semen sample and a blood sample. Semen samples were analyzed for sperm concentration, total sperm count, motility, and morphology, and blood samples were used to measure reproductive hormones. As a proxy for in utero exposure, PFOA and PFOS were measured in maternal blood samples from pregnancy week 30.Results: Multivariable linear regression analysis suggested that in utero exposure to PFOA was associated with lower adjusted sperm concentration (p_trend = 0.01) and total sperm count (p_trend = 0.001) and with higher adjusted levels of luteinizing hormone (p_trend = 0.03) and follicle-stimulating hormone (p_trend = 0.01). PFOS did not appear to be associated with any of the outcomes assessed, before or after adjustment.Conclusions: The results suggest that in utero exposure to PFOA may affect adult human male semen quality and reproductive hormone levels.     

Increase In Some B Vitamins,Including B12, During Fermentation Of Tempeh,Produced From Cowpeas Or Soy Beans

Tempeh samples produced from cowpeas and soy beans were analysed forvitamin B₂ (riboflavin), B₆ (pyridoxine), B₁₂ (cyanocobalamin), niacin, andpantothenic acid. Vitamin contents increased significantly during fermentation,both in cowpea tempeh and soybean tempeh. Special attention is given to theB₁₂ content during fermentation, because of its importance for people eating food primarily of vegetable origin.     

A low glycemic index diet does not affect postprandial energy metabolism but decreases postprandial insulinemia and increases fullness ratings in healthy women

At present, it is difficult to determine whether glycemic index (GI) is an important tool in the prevention of lifestyle diseases, and long-term studies investigating GI with diets matched in macronutrient composition, fiber content, energy content, and energy density are still scarce. We investigated the effects of 2 high-carbohydrate (55%) diets with low GI (LGI; 79) or high GI (HGI; 103) on postprandial blood profile, subjective appetite sensations, energy expenditure (EE), substrate oxidation rates, and ad libitum energy intake (EI) from a corresponding test meal (LGI or HGI) after consuming the diets ad libitum for 10 wk. Two groups of a total of 29 healthy, overweight women (age: 30.5 ± 6.6 y; BMI: 27.6 ± 1.5 kg/m(2)) participated in the 10-wk intervention and a subsequent 4-h meal test. The breakfast test meals differed in GI but were equal in total energy, macronutrient composition, fiber content, and energy density. The LGI meal resulted in lower plasma glucose, serum insulin, and plasma glucagon-like peptide (GLP)-1 and higher plasma glucose-dependent insulinotropic polypeptide concentrations than the HGI meal (P ≤ 0.05). Ratings of fullness were slightly higher and the desire to eat something fatty was lower after the test meal in the LGI group (P < 0.05). Postprandial plasma GLP-2, plasma glucagon, serum leptin, plasma ghrelin, EE, substrate oxidation rates, and ad libitum EI at lunch did not differ between groups. In conclusion, postprandial glycemia, insulinemia, and subjective appetite ratings after a test meal were better after 10-wk ad libitum intake of a LGI compared to a HGI diet. EE and substrate oxidation rates were, however, not affected. These findings give some support to recommendations to consume a LGI diet.     

Does socioeconomic status affect the association of social relationships and health? A moderator analysis

Background  

Social relations have repeatedly been found to be an important determinant of health. However, it is unclear whether the association between social relations and health is consistent throughout different status groups. It is likely that health effects of social relations vary in different status groups, as stated in the hypothesis of differential vulnerability. In this analysis we explore whether socioeconomic status (SES) moderates the association between social relations and health.     

The effects of racemic D,L-methadone and L-methadone in substituted patients--a randomized controlled study

AIMS: To test the hypothesis that switching from L-methadone to D,L-methadone is associated with more frequent withdrawal symptoms and side-effects than switching from D,L-methadone to L-methadone. DESIGN: Stratified, randomized 2 x 2 crossover study design over a time-period of 8 weeks. At study entry, every second patient was switched from the pre-study substance to the other medication, after 4 weeks all patients were subject to a (re-)switch. SETTING: The study was conducted as a multi-centre trial in three methadone maintenance therapy (MMT) clinics. PARTICIPANTS: Seventy-five patients previously treated with either D,L-methadone or L-methadone for at least 1 year took part in the study. MEASUREMENTS: Intra-individual changes in withdrawal symptoms (Short Opiate Withdrawal Scale, SOWS) and side-effects were defined as primary outcome criteria. Secondary outcome measures included necessity for methadone dose adjustment. FINDINGS: Complete data were available for 68 patients (91%). Sample strata were unbalanced at baseline: 15 patients (22%) were treated with L-methadone and 43 with D,L-methadone (78%). Thirty-five patients were randomized into the group treated with L-methadone and 33 into the group treated with D,L-methadone during the first 4 weeks. There were no significant differences in intra-individual change of withdrawal symptoms and side-effects between groups after crossover. However, patients treated with levomethadone tended to feel less withdrawal symptoms than patients treated with d,l-methadone. CONCLUSIONS: D,L-methadone and L-methadone can safely be replaced by each other on a 2:1 ratio. Withdrawal symptoms or side-effects due to conversion are of transient nature only.     

Pharmacokinetics of alpha-lipoic acid in subjects with severe kidney damage and end-stage renal disease

In an open-label, parallel-group study involving 16 patients (8 with severely reduced renal function, 8 with end-stage renal disease needing hemodialysis), the effect of renal function on the pharmacokinetics, metabolism, and safety and of alpha-lipoic acid (thioctic acid) was evaluated by comparing the pharmacokinetic parameters with those of a reference group of 8 healthy subjects. Alpha-lipoic acid 600 mg was administered orally once daily for 4 days, and the pharmacokinetic parameters were measured on days 1 and 4. The mean percentage of the administered dose excreted in urine as parent compound was 0.2 and 0.05 in healthy subjects and subjects with severely reduced renal function, respectively. Assuming a bioavailability of 30%, this represents 0.67% and 0.17% of the bioavailable amount of alpha-lipoic acid, respectively. The percentage of total urinary recovered amounts of alpha-lipoic acid and 5 of its metabolites was 12.0 on both days. The respective values for patients with severe kidney damage were 5.2% (day 1) and 6.4% (day 4). The total percentage of the administered dose removed by hemodialysis was 4.0 in patients with end-stage renal disease. Renal clearance of alpha-lipoic acid and its major metabolites, 6,8-bismethylthio-octanoic acid, 4,6-bismethylthio-hexanoic acid and 2,4-bismethylthio-butanoic acid, were significantly decreased in subjects with kidney damage compared to the reference group. Apparent total clearance of alpha-lipoic acid was poorly correlated with creatinine clearance. There is strong evidence that alpha-lipoic acid is mainly excreted by nonrenal mechanism or further degraded to smaller units in the catabolic process. The significantly increased area under the curve values of 4,6-bismethylthio-hexanoic acid and half-lives of 2,4-bismethylthio-butanoic acid on both days in patients with severely reduced function and end-stage renal disease were not considered to be clinically relevant. Although trough levels of both metabolites tend to increase slightly in these subjects, no accumulation effects were detected. We conclude that the pharmacokinetics of alpha-lipoic acid are not influenced by creatinine clearance and are unaffected in subjects with severely reduced kidney function or end-stage renal disease. Hemodialysis did not significantly contribute to the clearance of alpha-lipoic acid. Hence, dose adjustment of alpha-lipoic acid is not necessary in patients with renal dysfunction.     

Is mixture toxicity measured on a biomarker indicative of what happens on a population level? A study with Lemna minor

For plants, pigment content has shown to be a remarkably consistent biomarker across chemicals with different modes of action. In this study, we evaluated the use of pigment content as endpoint in binary mixture toxicity studies compared to three growth endpoints on the floating plant Lemna minor. Six binary combinations of six herbicides with different mode of action were used. Data were tested against both the concentration addition (CA) and independent action (IA) reference models. For CA, two statistical approaches were used. The study showed that for some herbicide combinations the mixture toxicity measured on pigment content did not reflect the results measured on plant population growth, emphasizing the importance of measuring growth in parallel with biomarkers. CA explained the data just as well as IA, and the two different statistical models used to test the data in relation to CA showed very similar results.