Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor.

Altered systemic levels of 6-formylindolo[3,2-b]carbazole (FICZ), an enigmatic endogenous ligand for the aryl hydrocarbon receptor (AHR), may explain adverse physiological responses evoked by small natural and anthropogenic molecules as well as by oxidative stress and light. We demonstrate here that several different chemical compounds can inhibit the metabolism of FICZ, thereby disrupting the autoregulatory feedback control of cytochrome P4501 systems and other proteins whose expression is regulated by AHR. FICZ is both the most tightly bound endogenous agonist for the AHR and an ideal substrate for cytochrome CYP1A1/1A2 and 1B1, thereby also participating in an autoregulatory loop that keeps its own steady-state concentration low. At very low concentrations FICZ influences circadian rhythms, responses to UV light, homeostasis associated with pro- and anti-inflammatory processes, and genomic stability. Here, we demonstrate that, if its metabolic clearance is compromised, femtomolar background levels of this compound in cell-culture medium are sufficient to up-regulate CYP1A1 mRNA and enzyme activity. The oxidants UVB irradiation and hydrogen peroxide and the model AHR antagonist 3'-methoxy-4'-nitroflavone all inhibited induction of CYP1A1 enzyme activity by FICZ or 2,3,7,8-tetrachlorodibenzo-p-dioxin, thereby subsequently elevating intracellular levels of FICZ and activating AHR. Taken together, these findings support an indirect mechanism of AHR activation, indicating that AHR activation by molecules with low affinity actually may reflect inhibition of FICZ metabolism and raising questions about the reported promiscuity of the AHR. Accordingly, we propose that prolonged induction of AHR activity through inhibition of CYP1 disturbs feedback regulation of FICZ levels, with potential detrimental consequences.

The experience and influence of fear after anterior cruciate ligament reconstruction: an interview study with young athletes.

BACKGROUND: Despite good physical function, many athletes do not return to sports after an anterior cruciate ligament reconstruction (ACLR). One important reason for this is fear of new injury. The aim of this study was to investigate young athletes' experiences of knee-related fear after an ACLR and how they perceive this fear to affect them in their sporting and everyday life. METHODS: A qualitative interview study was conducted, using semi-structured interviews. Athletes who were active in contact or pivoting sport before an ACL injury, with the goal of returning to the same sport and who scored highly on fear of new injury at six months post-ACLR, were asked to participate. Ten athletes (six women and four men, aged 17-25 years), were interviewed by an independent researcher, 7-9 months after ACLR. Content analysis employing an abductive approach was used. RESULTS: The analysis resulted in three categories with associated subcategories: 1. The expressions of fear; (i) reason for fear, (ii) changes in fear over time, and (iii) injury situation. 2. Reactions, consequences, and adaptations; (i) reactions, (ii) behavioural adaptation and influence on rehabilitation and daily life, (iii) present consequences, and (iv) consequences for the future. 3. Fear and adaptations related to returning to sports; (i) fear related to returning to sports and, (ii) adaptations in sports and life due to fear. Fear was described in broad and complex ways, with fear of a new injury being expressed as one of several aspects. Various reasons (e.g., seeing others getting injured in the past, previous experience of injury, failed rehabilitation, perceived knee instability) were given to explain the fear, and athletes reacted both physically and mentally to fear. Both positive and negative adaptations to fear were described, in both daily life and sports. CONCLUSION: The results contribute to an increased understanding of fear as an essential psychological factor to consider during rehabilitation and leaves the way open for research to investigate how physiotherapists can work to manage fear better among ACLR patients.

Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AHR).

Several polyphenols have been shown to activate the aryl hydrocarbon receptor (AHR) in spite of the fact that they bind to the receptor with low affinity. The aim of this study was to investigate whether quercetin (QUE), resveratrol (RES), and curcumin (CUR) interfere with the metabolic degradation of the suggested endogenous AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ) and thereby indirectly activate the AHR. Using recombinant human enzyme, we confirmed earlier reported inhibitory effects of the polyphenols on cytochrome P4501A1 (CYP1A1) activity, and inhibition of metabolic clearance of FICZ was documented in FICZ-treated immortalized human keratinocytes (HaCaT). CYP1A1 activity was induced in HaCaT cells by all three compounds, and when they were added together with FICZ, a prolonged activation was observed after a dose-dependent inhibition period. The same pattern of responses was seen at the transcriptional level as determined with a CYP1A1 reporter assay in human liver hepatoma (HepG2) cells. To test the ability of the polyphenols to activate the AHR in the absence of FICZ, the cells were treated in medium, which in contrast to commercial batches of medium did not contain background levels of FICZ. Importantly, AHR activation was only observed in the commercial medium. Taken together, these findings suggest that QUE, RES, and CUR induce CYP1A1 in an indirect manner by inhibiting the metabolic turnover of FICZ. Humans are exposed to these compounds through the diet and nutritional supplements, and we propose that altered systemic levels of FICZ caused by such compounds may have physiological consequences.

Low frequency noise enhances cortisol among noise sensitive subjects during work performance.

Salivary free cortisol concentration, rated stress and annoyance were determined in 32 subjects before, during and after carrying out a battery of performance tasks for 2 hours during exposure to ventilation noise, with dominant low frequencies (low frequency noise) or a flat frequency spectrum (reference noise). Both noises had a level of 40 dBA. All subjects were studied on two occasions and were exposed to both noises in strict rotation. Subjects were categorised as high- or low-sensitive to noise in general and low frequency noise in particular on the basis of questionnaires. Cortisol concentrations during the task were not significantly modulated by the noises or related to noise sensitivity alone. The normal circadian decline in cortisol concentration was however significantly attenuated in subjects high-sensitive to noise in general, when they were exposed to the low frequency noise. This noise was rated as more annoying and more disruptive to working capacity than the reference noise. The study showed physiological evidence of increased stress related to noise sensitivity and noise exposure during work. This is the first study to demonstrate an effect of moderate levels of noise on neuroendocrine activity. The impact of long-term exposure to moderate noise levels, and particularly low frequency noise, in the workplace deserves further investigation.

Low frequency noise "pollution" interferes with performance.

To study the possible interference of low frequency noise on performance and annoyance, subjects categorised as having a high- or low sensitivity to noise in general and low frequency noise in particular worked with different performance tasks in a noise environment with predominantly low frequency content or flat frequency content (reference noise), both at a level of 40 dBA. The effects were evaluated in terms of changes in performance and subjective reactions. The results showed that there was a larger improvement of response time over time, during work with a verbal grammatical reasoning task in the reference noise, as compared to the low frequency noise condition. The results further indicated that low frequency noise interfered with a proof-reading task by lowering the number of marks made per line read. The subjects reported a higher degree of annoyance and impaired working capacity when working under conditions of low frequency noise. The effects were more pronounced for subjects rated as high-sensitive to low frequency noise, while partly different results were obtained for subjects rated as high-sensitive to noise in general. The results suggest that the quality of work performance and perceived annoyance may be influenced by a continuous exposure to low frequency noise at commonly occurring noise levels. Subjects categorised as high-sensitive to low frequency noise may be at highest risk.

Substance abusers' motives for using anabolic androgenic steroids.

BACKGROUND: The use of anabolic androgenic steroids (AAS) has been associated with the use of illegal drugs. Earlier observations suggested that users of illegal drugs may use AAS for reasons other than increasing muscle strength or size. The aim of the present study was to investigate the motives for AAS use among outpatients at a substance abuse center in Stockholm, Sweden. METHODS: All male patients under the age of 50 were asked whether they had used AAS during a 2-month period. An AAS survey was administered to those who reported AAS experiences in the admittance interview. RESULTS: Twenty of the 175 respondents (11%) reported using AAS. The most frequently reported motives were related to anabolic effects (i.e., for a good-looking body, to become stronger, or to perform better in sports). However, some users reported other motives; for example, to conceal concomitant drug use, to alleviate insecurity or low self-esteem, to become brave, or in preparation of committing a crime. Furthermore, many respondents reported side effects that were associated with AAS; most notably, irritability and depression/suicidal ideation. CONCLUSION: Some users of illicit drugs also use AAS for reasons other than the anabolic properties of these compounds. Therefore, considering that AAS may cause or contribute to diverse morbidity, it is important to ask users of illicit drugs about AAS use, even when obvious external signs of AAS use are lacking.