Michael J. Rieder

Hair cortisol as a biological marker of chronic stress: current status, future directions and unanswered questions.

The detrimental effects of stress on human health are being increasingly recognized. There is a critical need for the establishment of a biomarker that accurately measures its intensity and course over time. Such a biomarker would allow monitoring of stress, increase understanding of its pathophysiology and may help identify appropriate and successful management strategies. Whereas saliva and urine cortisol capture real-time levels, hair cortisol analysis presents a complementary means of monitoring stress, capturing systemic cortisol exposure over longer periods of time. This novel approach for cortisol quantification is being increasingly used to identify the effects of stress in a variety of pathological situations, from chronic pain to acute myocardial infarctions. Because of its ability to provide a long-term, month-by-month measure of systemic cortisol exposure, hair cortisol analysis is becoming a useful tool, capable of answering clinical questions that could previously not be answered by other tests. In this paper we review the development, current status, limitations and outstanding questions regarding the use of hair cortisol as a biomarker of chronic stress.

Regulation of cytokine and cytokine receptor expression by glucocorticoids.

Glucocorticoids (GCS) profoundly inhibit several aspects of T cell immunity largely through inhibition of cytokine expression at the transcriptional and posttranscriptional levels. GCS were also reported to act indirectly by inducing transforming growth factor‐β expression, which in turn blocks T cell immunity. In exerting their antiproliferative effects, GCS diffuse into target cells where they bind their cytoplasmic receptor, which in turn translocates to the nucleus where it inhibits transcription of cytokine genes through direct binding to the glucocorticoid response elements (GRE), which are located in the promoter region of cytokine genes or, alternatively, through antagonism of the action of transcription factors required for optimal transcriptional activation. In contrast to their inhibitory effects on cytokine expression, GCS upregulate cytokine receptor expression that correlates with enhanced cytokine effects on target cells. In this review, we summarize the current state of knowledge of the mechanism of action of GCS, including the phenomenon of steroid‐induced rebound, which ensues upon GCS withdrawal. J. Leukoc. Biol. 60: 563–572; 1996.

More Codeine Fatalities After Tonsillectomy in North American Children

In 2009 we reported the fatal case of a toddler who had received codeine after adenotonsillectomy for obstructive sleep apnea syndrome. The child was an ultra-rapid metabolizer of cytochrome P4502D6 (CYP2D6). We now report 3 additional fatal or life-threatening cases from North America. In the 2 fatal cases, functional gene duplications encoding for CYP2D6 caused a significantly greater production of potent morphine from its parent drug, codeine. A severe case of respiratory depression in an extensive metabolizer is also noted. These cases demonstrate that analgesia with codeine or other opioids that use the CYP2D6 pathway after adenotonsillectomy may not be safe in young children with obstructive sleep apnea syndrome.

Pharmacogenomic Prediction of Anthracycline-Induced Cardiotoxicity in Children

PURPOSE Anthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants associated with ACT in patients treated for childhood cancer. PATIENTS AND METHODS We carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands. RESULTS We identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 × 10(-5) for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate-binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT. CONCLUSION We have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.

An assessment of cortisol analysis in hair and its clinical applications

Hair analyses for exogenous compounds, specifically drugs of abuse, have been a useful tool in detecting long-term drug exposure. More recently, studies have delved into the exposure of endogenous compounds in hair. Cortisol is synthesized in the adrenal cortex in response to stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. While catecholamines generally indicate acute stress, cortisol can be used as an indicator for sub-acute and chronic stress. Studies on the effects of chronic stress are most often subjective in nature, relying on questionnaires asking the participant to recall on past stressors. This can lead to the issue of recall and reporting bias. A new objective measure of chronic stress is needed for a more accurate understanding of the effects of chronic stress on the body. This review uses emerging evidence to describe the usefulness of hair analysis for cortisol and discusses the current methods used.

Hair analysis provides a historical record of cortisol levels in Cushing's syndrome.

The severity of Cushings Syndrome (CS) depends on the duration and extent of the exposure to excess glucocorticoids. Current measurements of cortisol in serum, saliva and urine reflect systemic cortisol levels at the time of sample collection, but cannot assess past cortisol levels. Hair cortisol levels may be increased in patients with CS, and, as hair grows about 1 cm/month, measurement of hair cortisol may provide historical information on the development of hypercortisolism. We attempted to measure cortisol in hair in relation to clinical course in six female patients with CS and in 32 healthy volunteers in 1 cm hair sections. Hair cortisol content was measured using a commercially available salivary cortisol immune assay with a protocol modified for use with hair. Hair cortisol levels were higher in patients with CS than in controls, the medians (ranges) were 679 (279-2500) and 116 (26-204) ng/g respectively (P<0.001). Segmental hair analysis provided information for up to 18 months before time of sampling. Hair cortisol concentrations appeared to vary in accordance with the clinical course. Based on these data, we suggest that hair cortisol measurement is a novel method for assessing dynamic systemic cortisol exposure and provides unique historical information on variation in cortisol, and that more research is required to fully understand the utility and limits of this technique.

Reducing the pain of childhood vaccination: an evidence-based clinical practice guideline (summary)

Injections for vaccinations, the most common source of iatrogenic pain in childhood,[1][1] are administered repeatedly to almost all Canadian children throughout infancy, childhood and adolescence.[2][2] The pain associated with such injections is a source of distress for children, their parents and

Inadequate pain management during routine childhood immunizations: the nerve of it.

BACKGROUND Immunization is regarded as one of the most significant medical achievements of all time. Recently, increasing attention has been paid to the pain resulting from routine childhood immunizations. OBJECTIVE This narrative review summarizes existing knowledge about: (1) the epidemiology of childhood immunization pain; (2) the pain experience of children undergoing immunization; (3) current analgesic practices; (4) barriers to practicing pain management in children; and (5) recommendations for improvements in pain management during immunization. METHODS We conducted a search of MEDLINE, PsycINFO, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials for primary research and review articles published from inception of the databases through October 2008. Key search terms included immunization, pain, child/infant, vaccine, and intervention. Additional studies were identified through searches of the reference lists in the retrieved articles. No language restrictions were imposed regarding the type of article (eg, full article, abstract) or language. RESULTS Vaccine injections are the most common iatrogenic procedure performed in childhood and a major source of distress for children (of all ages), their parents, and the participating health care professionals, as well as a direct cause of vaccine nonadherence. In addition, lack of adequate pain management during immunization exposes children to unnecessary suffering and the potential for long-term consequences, such as fear of needles. Numerous pain management strategies are available to reduce vaccine injection pain, including: (1) physical interventions and injection techniques; (2) psychological interventions; and (3) phar-macologic and combined interventions. However, adoption of pain-relieving techniques into clinical practice has been suboptimal. The underutilization of pain management strategies can be attributed to a lack of knowledge about pain and effective pain prevention strategies, and the persistence of attitudes about pain that interfere with optimal clinical practices. Current analgesic practices could be improved substantially if all stakeholders involved in immunization (eg, policy makers, practitioners, consumers) participate in efforts to reduce pain. Treating pain during childhood immunization has the potential to reduce distress during the procedure and greatly improve satisfaction with the immunization experience through more positive experiences for children and their families. Other potential benefits include improved adherence to immunization schedules and reduced sequelae of untreated pain. CONCLUSION Immunization is a global health priority. Medical care can be improved if pain management becomes a routine aspect of the delivery of vaccine injections.

Results of inpatient pediatric resuscitation.

We retrospectively reviewed the results of 42 cardiopulmonary arrests occurring over 1 yr in the general ward of a pediatric hospital. These data were compared to those of a similar study done 10 yr previously in the same institution. Patients were divided into those having pure respiratory arrest and those who also had cardiac arrest. In the most recent series, overall 6-month survival was 17%; however, only 9% of the cardiac arrest patients survived. Ten years previously, the survival rate from cardiac arrest was 11%. In both series, pure respiratory arrest had a significantly better outcome than cardiopulmonary arrest, and predictors of nonsurvival were a duration of arrest greater than 15 min and the administration of more than one iv bolus of epinephrine. During the more recent series, sepsis and apper airway problems produced fewer arrests. There was one neurologically damaged survivor in each study period. Our study confirms that the outcome of pediatric cardiac arrest is poor when arrest occurs in the hospital.

Hair cortisol and the risk for acute myocardial infarction in adult men.

Acute stress is increasingly recognized as a precipitant of acute myocardial infarction (AMI). However, the role of chronic stress in developing AMI is less clear. We have developed a method to measure cortisol in hair, which allows longitudinal assessment of cortisol levels prior to an acute event. We aimed to evaluate the hypothesis that chronic stress, as assessed by hair cortisol content, is associated with the development of AMI. A prospective case–control study included 56 patients admitted to hospital with AMI and 56 control patients, admitted to internal medicine wards for other indications. An enzyme immunoassay technique was used to measure cortisol in the most proximal 3 cm of hair, considered to represent the most recent 3 months of exposure. Median hair cortisol contents (range) were 295.3 (105.4–809.3)ng/g in AMI patients and 224.9 (76.58–949.9)ng/g in controls (p = 0.006, Mann–Whitney U-test). After controlling for other risk factors for AMI using multiple logistic regression, log-transformed hair cortisol content remained the strongest predictor (OR 17.4, 95% CI 2.15–140.5; p = 0.007). We demonstrated elevated hair cortisol concentrations in patients with AMI. This suggests that chronic stress, as assessed by increased hair cortisol in the 3 months prior to the event, may be a contributing factor for AMI.