Metabolism of phenolics in coffee and plant-based foods by canonical pathways: an assessment of the role of fatty acid ß-oxidation to generate biologically-active and -inactive intermediates.

ω-Phenyl-alkenoic acids are abundant in coffee, fruits, and vegetables. Along with ω-phenyl-alkanoic acids, they are produced from numerous dietary (poly)phenols and aromatic amino acids in vivo. This review addresses how phenyl-ring substitution and flux modulates their gut microbiota and endogenous ß-oxidation. 3',5'-Dihydroxy-derivatives (from alkyl-resorcinols, flavanols, proanthocyanidins), and 4'-hydroxy-phenolic acids (from tyrosine, p-coumaric acid, naringenin) are ß-oxidation substrates yielding benzoic acids. In contrast, 3',4',5'-tri-substituted-derivatives, 3',4'-dihydroxy-derivatives and 3'-methoxy-4'-hydroxy-derivatives (from coffee, tea, cereals, many fruits and vegetables) are poor ß-oxidation substrates with metabolism diverted via gut microbiota dehydroxylation, phenylvalerolactone formation and phase-2 conjugation, possibly a strategy to conserve limited pools of coenzyme A. 4'-Methoxy-derivatives (citrus fruits) or 3',4'-dimethoxy-derivatives (coffee) are susceptible to hepatic "reverse" hydrogenation suggesting incompatibility with enoyl-CoA-hydratase. Gut microbiota-produced 3'-hydroxy-4'-methoxy-derivatives (citrus fruits) and 3'-hydroxy-derivatives (numerous (poly)phenols) are excreted as the phenyl-hydracrylic acid ß-oxidation intermediate suggesting incompatibility with hydroxy-acyl-CoA dehydrogenase, albeit with considerable inter-individual variation. Further investigation is required to explain inter-individual variation, factors determining the amino acid to which C6-C3 and C6-C1 metabolites are conjugated, the precise role(s) of l-carnitine, whether glycine might be limiting, and whether phenolic acid-modulation of ß-oxidation explains how phenolic acids affect key metabolic conditions, such as fatty liver, carbohydrate metabolism and insulin resistance.

Impact of an ultra-low dose unenhanced planning scan on CT coronary angiography scan length and effective radiation dose.

Objective: Imaged scan length (z-axis coverage) is a simple parameter that can reduce CT dose without compromising image quality. In CT coronary angiography (CTCA), z-axis coverage may be planned using non-contrast calcium score scan (CaCS) to identify the relevant coronary anatomy. However, standardised Agatston CaCS is acquired at 120 kV which adds a relatively high contribution to total study dose and CaCS is no longer routinely recommended in UK guidelines. We evaluate an ultra-low dose unenhanced planning scan on CTCA scan length and effective radiation dose. Methods: An ultra-low dose tin filter (Sn-filter) planning scan (100 kVp, maximum iterative reconstruction) was performed and used to plan the z-axis coverage on 48 consecutive CTCAs (62% men, 62 ± 13 years) compared with 47 CTCA planned using a localiser alone (46% men, 59 ± 12 years) between May and June 2019. Excess scanning beyond the ideal scan length was calculated for both groups. Estimations of radiation dose were also compared between the two groups. Results: Addition of an ultra-low dose unenhanced planning scan to CTCA protocol was associated with reduction in overscanning with no impact on image quality. There was no significant difference in total study effective dose with the addition of the planning scan, which had an average dose-length product of 3 mGy.cm. (total study dose: Protocol A 2.1 mSv vs Protocol B 2.2 mSv, p = 0.92). Conclusion: An ultra-low dose unenhanced planning scan facilitates optimal scan length for the diagnostic CTCA, reducing overscanning and preventing incomplete cardiac imaging with no significant dose penalty or impact on image quality. Advances in knowledge: An ultra-low dose CTCA planning is feasible and effective at optimising scan length.

High-pitch versus conventional cardiovascular CT in patients being assessed for transcatheter aortic valve implantation: a real-world appraisal.

OBJECTIVE: High-pitch protocols are increasingly used in cardiovascular CT assessment for transcatheter aortic valve implantation (TAVI), but the impact on diagnostic image quality is not known. METHODS: We reviewed 95 consecutive TAVI studies: 44 (46%) high-pitch and 51 (54%) standard-pitch. Single high-pitch scans were performed regardless of heart rate. For standard-pitch acquisitions, a separate CT-aortogram and CT-coronary angiogram were performed with prospective gating, unless heart rate was ≥70 beats/min, when retrospective gating was used. The aortic root and coronary arteries were assessed for artefact (significant artefact=1; artefact not limiting diagnosis=2; no artefact=3). Aortic scans were considered diagnostic if the score was >1; the coronaries, if all three epicardial arteries scored >1. RESULTS: There was no significant difference in diagnostic image quality for either the aorta (artefact-free high-pitch: 31 (73%) scans vs standard-pitch: 40 (79%), p=0.340) or the coronary tree as a whole (10 (23%) vs 15 (29%), p=0.493). However, proximal coronary arteries were less well visualised using high-pitch acquisitions (16 (36%) vs 30 (59%), p=0.04). The median (IQR) radiation dose was significantly lower in the high-pitch cohort (dose-length product: 347 (318-476) vs 1227 (1150-1474) mGy cm, respectively, p<0.001), and the protocol required almost half the amount of contrast. CONCLUSIONS: The high-pitch protocol significantly reduces radiation and contrast doses and is non-inferior to standard-pitch acquisitions for aortic assessment. For aortic root assessment, the high-pitch protocol is recommended. However, if coronary assessment is critical, this should be followed by a conventional standard-pitch, low-dose, prospectively gated CT-coronary angiogram if the high-pitch scan is non-diagnostic.

Safety management and public spaces: restoring balance.

Since 2000, the reputation of health and safety in the United Kingdom has been tarnished, so much so that it has become the subject of both a media circus and a government inquiry. This not only threatens the worthy goals of health and safety, but also impacts upon the associated tool of risk assessment itself such that "risk assessment" is increasingly seen by the public at large as a term inviting ridicule, even abuse. The main thrust of the government's examination of health and safety has been its concern that safety requirements were placing a disproportionate burden on business. However, there is another source of discontent, which is public chagrin over the impact of injury control measures upon life beyond the conventional workplace, in particular upon the public spaces that people frequent in their leisure time and on the activities they engage in there. This article provides a perspective on this second dimension of the crisis in confidence. It describes how many U.K. agencies with responsibilities for a wide portfolio of public amenities ranging from the provision of play spaces for the young to the management of publicly accessible countryside, the maintenance of urban and rural trees, the stewardship of sites of cultural heritage, and the pursuit of outdoor educational activities have responded to some conflicts posed to their services by the new safety culture. It concludes with a discussion of implications for the management of public space and for risk assessment itself.

The rise and fall of a regulator: adventure sports in the United kingdom.

Following a tragic accident in 1993 involving the deaths of teenagers while kayaking a new regulatory regime was imposed upon some adventure sports providers in the United Kingdom. In particular, a new regulatory body, the Adventure Activities Licensing Authority (AALA), was established to oversee the sector. Yet in 2010, a government-sponsored review recommended that AALA be abolished and this recommendation has been quickly accepted by government. This article explores the background to these developments through documentation, interviews with those affected by the AALA regime, and court cases. Evidence reported here, perhaps surprising, is that AALA itself is seen in a very positive light by many, even those it regulates. What may have happened is that AALA became caught up in a wider debate about the place and management of risk in life beyond the workplace, which has been simmering in the United Kingdom for a decade or more, and of which it fell foul. It may also be that adventure sports, because they entail voluntary engagement with high consequence hazards, starkly expose serious questions about the application of conventional, factory-originated risk assessment approaches to life in general.

In vivo bioavailability, absorption, excretion, and pharmacokinetics of [14C]procyanidin B2 in male rats.

Procyanidins are important biologically active compounds, but the pathway and extent of absorption and metabolism are controversial. We conducted a mass balance study to evaluate the total radioactivity excreted in urine and feces after oral administration of [(14)C]procyanidin B2 to male rats (n = 5). Urine and feces were collected daily from 0 to 96 h. Absolute bioavailability of (14)C from [(14)C]procyanidin B2 was calculated as approximately 82% using the values for total urinary (14)C. A pharmacokinetic study measured total radioactivity in the blood (n = 9). Blood samples were collected at designated time intervals (0.5-24 h) after administration. Three treatments were used: 1) intravenous, 2) oral higher dose (21 mg/kg b.wt.), and 3) oral lower dose (10.5 mg/kg). Blood concentration of total (14)C reached a maximum at approximately 6 h after ingestion of [(14)C]procyanidin B2 (groups II and III), and area under the curve (AUC) was dependent on oral dose. After intravenous or oral administration the terminal half-lives were similar, whereas 8-fold larger values were obtained after oral dosing for total clearance and the apparent volumes of distribution. These pharmacokinetic differences explain the apparently lower (14)C bioavailability (8-11%) for [(14)C]procyanidin calculated from blood [AUC((0-24))] values. After oral administration of [(14)C]procyanidin B2, 63% was excreted via urine within 4 days. The data suggest that much of the parent compound administered orally is degraded by the gut microflora before absorption and that these microbial metabolites have a different distribution from the compounds circulating after the intravenous dose.

Factors affecting the bioavailability of soy isoflavones in humans after ingestion of physiologically relevant levels from different soy foods.

The precise role that isoflavones play in the health-related effects of soy foods, and their potential for adverse effects are controversial. This may be due in part to a lack of basic knowledge regarding their bioavailability and metabolism, particularly as it relates to the soy source. To date, there is little information concerning possible differences in the bioavailability of isoflavones derived from natural soy foods consumed at physiologically relevant intakes and whether age- or gender-related differences influence that bioavailability. In the current study of healthy adults [premenopausal (n = 21) and postmenopausal (n = 17) women and a group of men (n = 21)], we examined the effect of age, gender, and the food matrix on the bioavailability of isoflavones for both the aglycon and glucoside forms that are naturally present in 3 different soy foods, soy milk, textured vegetable protein, and tempeh. The study was designed as a random crossover trial so that all individuals received each of the 3 foods. The dose of isoflavones administered to each individual as a single bolus dose was 0.44 mg/kg body weight. Pharmacokinetic parameters were normalized to mg of each isoflavone ingested per kilogram body weight to account for differences in daidzein and genistein content between the diets. Serum isoflavone concentrations in all individuals and groups increased rapidly after the ingestion of each soy food; as expected, genistein concentrations exceeded daidzein concentrations in serum. In this small study, gender differences in peak concentrations of daidzein were observed, with higher levels attained in women. Consumption of tempeh (mainly isoflavone aglycon) resulted in higher serum peak levels of both daidzein (P < 0.001) and genistein (P < 0.01) and the associated area under the curve (P < 0.001 and P < 0.03, respectively) compared with textured vegetable protein (predominantly isoflavone glucosides). However, soy milk was absorbed faster and peak levels of isoflavones were attained earlier than with the other soy foods. Only 30% of the subjects were equol producers and no differences in equol production with age or gender were observed.

Evidence against trigger point injection technique for the treatment of cervicothoracic myofascial pain with botulinum toxin type A.

BACKGROUND: Traditional strategies for myofascial pain relief provide transient, incomplete, variable, or unpredictable outcomes. Botulinum toxin is itself an analgesic but can also cause sustained muscular relaxation, thereby possibly affording even greater relief than traditional therapies. METHODS: The study goal was to determine whether direct injection of botulinum toxin type A (BoNT-A) into trigger points was efficacious for cervicothoracic myofascial pain, and if so, to determine the presence or absence of a dose-response relation. One hundred thirty-two patients with cervical or shoulder myofascial pain or both and active trigger points were enrolled in a 12-week, randomized, double-blind, placebo-controlled trial. After a 2-week washout period for all medications, patients were injected with either saline or 10, 25, or 50 U BoNT-A into up to five active trigger points. The maximum doses in each experimental group were 0, 50, 125, and 250 U per patient, respectively. Patients subsequently received myofascial release physical therapy and amitriptyline, ibuprofen, and propoxyphene-acetaminophen napsylate. Follow-up visits occurred at 1, 2, 4, 6, 8, and 12 weeks. Outcome measures included visual analog pain scores, pain threshold as measured by pressure algometry, and rescue dose use of propoxyphene-acetaminophen napsylate. RESULTS: No significant differences occurred between placebo and BoNT-A groups with respect to visual analog pain scores, pressure algometry, and rescue medication. CONCLUSIONS: Injection of BoNT-A directly into trigger points did not improve cervicothoracic myofascial pain. The role of direct injection of trigger points with BoNT-A is discussed in comparison to other injection methodologies in the potential genesis of pain relief.

Inflammation, reactive oxygen species and cytochrome P450.

Inflammation may ultimately result from damage to membrane lipids by reactive oxygen species (ROS) such as peroxide, superoxide anion, hydroxyl radical and singlet oxygen. This study compares some of the methods used to determine ROS-ethane exhalation, malondialdehyde quantified as thiobarbituric acid-reacting materials, and luminol-activated chemiluminescence (LAC)-and explores possible relationships with oedema formation in the rat foot-pad model. Iron nitrilotriacetate was the most effective of the model compounds tested in producing lipid peroxidation and ethane exhalation in mice. In the mouse and the rat, iron nitrilotriacetate caused increased ethane exhalation and concomitant increases in liver and kidney malondialdehyde. In the rat foot-pad oedema model, the challenge with Freund's complete adjuvant produced maximum malondialdehyde and maximum LAC in the inflamed paw 8 h after dosing, at which time oedema had also reached a high level. These effects were attributed mainly to hydroxyl radical and singlet oxygen. The inhibition of oedema by four anti-inflammatory drugs correlated well with LAC but less well with inhibition of malondialdehyde production. This study shows good agreement between different methods of determining ROS formation, and that inhibition of ROS formation in vivo is paralleled by a decrease in inflammation.

Abnormal iron parameters in the pregnancy syndrome preeclampsia.

OBJECTIVE: Our purpose was to investigate iron status parameters in preeclampsia with a view to exploring their possible contribution to the etiology. STUDY DESIGN: In prepared serum samples from 40 preeclamptic women and matched pregnant control subjects at the John Radcliffe Hospital, Oxford, a number of iron status parameters were measured. Statistical analysis was by the Wilcoxon signed rank test and linear regression. RESULTS: Serum iron concentration, ferritin, and percent saturation of transferrin were significantly higher in the preeclamptic patients than in control subjects, whereas unsaturated iron-binding capacity and apotransferrin levels were significantly lower. No difference was found in hemopexin concentrations in the two groups. Gestational age at the time of sampling was correlated (positively) with only two parameters, total and unsaturated iron-binding capacity, but only in the preeclampsia group. Eighteen percent of preeclamptic subjects had percent transferrin saturation levels in the region associated with iron overload. CONCLUSION: Released iron species in preeclampsia may contribute to the etiology and will exacerbate lipid peroxidation and endothelial cell injury. Given the high prevalence of heterozygosity for hemochromatosis with the associated reduced ability to exclude ingested iron, it would seem inadvisable, in the absence of evidence of iron deficiency, to give iron supplements to pregnant women at high risk for preeclampsia.