Common mental disorder and suicidality among doctors: differences by specialty.

BACKGROUND: Common mental disorders (CMDs) and suicidal ideation (SI) are prevalent among doctors, yet limited evidence exists investigating the relationship of specialty area to these outcomes. AIMS: This study aimed to determine the prevalence of likely CMD and SI among doctors and to investigate whether likelihood of these outcomes varied by area of medical specialty. METHODS: A secondary analysis of a representative national survey of 12,252 Australian doctors was conducted. Demographic and work-related variables, SI and CMD (GHQ-28), were assessed among doctors (n = 7037; 57%) working in a range of specialty areas. Logistic regression was used to examine the association between specialty and mental health outcomes in unadjusted and adjusted models. RESULTS: Almost one-quarter of doctors (n = 1560; 23%) reported symptom levels indicating likely CMD whilst 9% (n = 667) reported SI in the last year. Doctors in surgery (adjusted odds ratio [OR] = 0.73, 95% confidence interval [CI] 0.54-0.97, P = 0.03) were at significantly lower risk of CMD than General Practitioners (GPs), whilst doctors in anaesthetics (adjusted OR = 1.45; 95% CI 1.09-1.93, P = 0.01) and paediatrics (adjusted OR = 1.88; 95% CI 1.02-3.47, P = 0.04) were at significantly higher risk of experiencing SI compared to GPs after accounting for confounders. CONCLUSIONS: Results demonstrated that doctors in Australia working in certain specialties, specifically anaesthetics and paediatrics, were at significantly greater risk of suicidal ideation compared to GPs after accounting for confounders. Interventions to address CMD and SI among doctors in all specialties remain urgently needed.

Dual inhibition of EZH2 and G9A/GLP histone methyltransferases by HKMTI-1-005 promotes differentiation of acute myeloid leukemia cells.

All-trans-retinoic acid (ATRA)-based differentiation therapy of acute promyelocytic leukemia (APL) represents one of the most clinically effective examples of precision medicine and the first example of targeted oncoprotein degradation. The success of ATRA in APL, however, remains to be translated to non-APL acute myeloid leukemia (AML). We previously showed that aberrant histone modifications, including histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) methylation, were associated with this lack of response and that epigenetic therapy with small molecule inhibitors of the H3K4 demethylase LSD1/KDM1A could reprogram AML cells to respond to ATRA. Serving as the enzymatic component of Polycomb Repressive Complex 2, EZH2/KMT6A methyltransferase plays a critical role in normal hematopoiesis by affecting the balance between self-renewal and differentiation. The canonical function of EZH2 is methylation of H3K27, although important non-canonical roles have recently been described. EZH2 mutation or deregulated expression has been conclusively demonstrated in the pathogenesis of AML and response to treatment, thus making it an attractive therapeutic target. In this study, we therefore investigated whether inhibition of EZH2 might also improve the response of non-APL AML cells to ATRA-based therapy. We focused on GSK-343, a pyridone-containing S-adenosyl-L-methionine cofactor-competitive EZH2 inhibitor that is representative of its class, and HKMTI-1-005, a substrate-competitive dual inhibitor targeting EZH2 and the closely related G9A/GLP H3K9 methyltransferases. We found that treatment with HKMTI-1-005 phenocopied EZH2 knockdown and was more effective in inducing differentiation than GSK-343, despite the efficacy of GSK-343 in terms of abolishing H3K27 trimethylation. Furthermore, transcriptomic analysis revealed that in contrast to treatment with GSK-343, HKMTI-1-005 upregulated the expression of differentiation pathway genes with and without ATRA, while downregulating genes associated with a hematopoietic stem cell phenotype. These results pointed to a non-canonical role for EZH2, which was supported by the finding that EZH2 associates with the master regulator of myeloid differentiation, RARα, in an ATRA-dependent manner that was enhanced by HKMTI-1-005, possibly playing a role in co-regulator complex exchange during transcriptional activation. In summary, our results strongly suggest that addition of HKMTI-1-005 to ATRA is a new therapeutic approach against AML that warrants further investigation.

Economic evaluations of Internet interventions for mental health: a systematic review.

BACKGROUND: Internet interventions are assumed to be cost-effective. However, it is unclear how strong this evidence is, and what the quality of this evidence is. METHOD: A comprehensive literature search (1990-2014) in Medline, EMBASE, the Cochrane Central Register of Controlled Trials, NHS Economic Evaluations Database, NHS Health Technology Assessment Database, Office of Health Economics Evaluations Database, Compendex and Inspec was conducted. We included economic evaluations alongside randomized controlled trials of Internet interventions for a range of mental health symptoms compared to a control group, consisting of a psychological or pharmaceutical intervention, treatment-as-usual (TAU), wait-list or an attention control group. RESULTS: Of the 6587 abstracts identified, 16 papers met the inclusion criteria. Nine studies featured a societal perspective. Results demonstrated that guided Internet interventions for depression, anxiety, smoking cessation and alcohol consumption had favourable probabilities of being more cost-effective when compared to wait-list, TAU, group cognitive behaviour therapy (CBGT), attention control, telephone counselling or unguided Internet CBT. Unguided Internet interventions for suicide prevention, depression and smoking cessation demonstrated cost-effectiveness compared to TAU or attention control. In general, results from cost-utility analyses using more generic health outcomes (quality of life) were less favourable for unguided Internet interventions. Most studies adhered reasonably to economic guidelines. CONCLUSIONS: Results of guided Internet interventions being cost-effective are promising with most studies adhering to publication standards, but more economic evaluations are needed in order to determine cost-effectiveness of Internet interventions compared to the most cost-effective treatment currently available.

Ovarian hyperstimulation syndrome on the acute medical unit: a problem-based review.

Ovarian Hyperstimulation Syndrome (OHSS) is a spectrum of clinical features typically resulting from assisted conception techniques. With 2.35% of all live births in the UK resulting from in-vitro fertilisation (IVF), OHSS is on the rise. Moreover, there has been an increase in the presentation of its complications to GP surgeries and unscheduled acute care services nationwide. This review will discuss signs and symptoms of the increasingly common and potentially fatal complications of OHSS, namely pleural effusion, ascites and thromboembolic events. With such propensity toward critical, life-threatening events it is not only prudent to recognise the population at risk, but also to be aware of the signs, symptoms and complications to expedite treatment and ensure optimum outcome.

Are illness perceptions related to future healthcare expenditure in patients with somatoform disorders?

BACKGROUND: Somatoform disorders are costly for society in terms of increased healthcare expenditure. Patients' illness perceptions have been found to play a role in somatoform disorders. However, it is unclear whether illness perceptions predict higher health costs in these patients. METHOD: A total of 1785 primary care patients presenting a new health complaint completed a questionnaire on their illness perceptions and emotional distress before the consultation. The physicians completed a questionnaire for each patient on diagnostics after the consultation. In a stratified subsample, physician interviewers established diagnoses of DSM-IV somatization and undifferentiated somatoform disorders (n = 144) using the Schedules for Clinical Assessment in Neuropsychiatry. Healthcare expenditure was obtained from Danish health registers for a 2-year follow-up period. RESULTS: Patients had more negative perceptions of their well-defined physical health problems when they had a co-morbid somatoform disorder. A strong illness identity [ß = 0.120, 95% confidence interval (CI) 0.029-0.212, p = 0.012], perceived negative consequences (ß = 0.010, 95% CI 0.001-0.019, p = 0.024), a long timeline perspective (ß = 0.013, 95% CI 0.005-0.021, p = 0.001), low personal control (ß = - 0.009, 95% CI -0.015 to -0.002, p = 0.011) and negative emotional representations (ß = 0.009, 95% CI 0.002-0.017, p = 0.020) predicted healthcare expenditure in somatoform disorders. CONCLUSIONS: The results suggest that illness perceptions play a role in the perpetuation of symptoms in somatoform disorders and predict higher future healthcare expenditure among a subgroup of these patients.

Responses of anaerobic rumen fungal diversity (phylum Neocallimastigomycota) to changes in bovine diet.

AIMS: Anaerobic rumen fungi (Neocallimastigales) play important roles in the breakdown of complex, cellulose-rich material. Subsequent decomposition products are utilized by other microbes, including methanogens. The aim of this study was to determine the effects of dietary changes on anaerobic rumen fungi diversity. METHODS AND RESULTS: Altered diets through increasing concentrate/forage (50 : 50 vs 90 : 10) ratios and/or the addition of 6% soya oil were offered to steers and the Neocallimastigales community was assessed by PCR-based fingerprinting with specific primers within the barcode region. Both a decrease in fibre content and the addition of 6% soya oil affected Neocallimastigales diversity within solid and liquid rumen phases. The addition of 6% soya oil decreased species richness. Assemblages were strongly affected by the addition of 6% soya oil, whereas unexpectedly, the fibre decrease had less effect. Differences in volatile fatty acid contents (acetate, propionate and butyrate) were significantly associated with changes in Neocallimastigales assemblages between the treatments. CONCLUSIONS: Diet clearly influences Neocallimastigales assemblages. The data are interpreted in terms of interactions with other microbial groups involved in fermentation processes within the rumen. SIGNIFICANCE AND IMPACT OF THE STUDY: Knowledge on the influence of diet on anaerobic fungi is necessary to understand changes in microbial processes occurring within the rumen as this may impact on other rumen processes such as methane production.

Differing perceptions of intervention thresholds for fracture risk: a survey of patients and doctors.

UNLABELLED: This survey suggests that patients are prepared to accept higher absolute fracture risk than doctors, before considering pharmacological therapy to be justified. Patients require that drug treatments confer substantial fracture risk reductions in order to consider long-term therapy. INTRODUCTION: Absolute fracture risk estimates are now incorporated into osteoporosis treatment guidelines. At present, little is known about how patients regard fracture risk and its management. We set out to describe and compare the views of patients and doctors on the level of fracture risk at which drug treatment is justified. METHODS: A cross-sectional survey was conducted on 114 patients referred for bone density measurement and 161 doctors whose practice includes management of osteoporosis. Participants were asked about fracture risk thresholds for pharmacological intervention. RESULTS: The absolute risk of both major osteoporotic fracture and hip fracture at which drug treatment was considered by patients to be justifiable was higher than that reported by doctors [major osteoporotic fracture, median (interquartile range): patients, 50% (25 to 60); doctors, 10% (10 to 20); P < 0.0001; hip fracture: patients, 50% (25 to 60); doctors, 10% (5 to 20); P < 0.0001]. Patients required that a drug provide a median 50% reduction in relative risk of fracture in order to consider taking long-term therapy, irrespective of the treatment mode or dosing schedule. Among doctors, there was an inverse relationship between the number of osteoporosis consultations conducted each month and threshold of risk for recommending drug treatment (r = -0.22 and r = -0.29 for major osteoporotic fracture and hip fracture, respectively, P < 0.01 for both) CONCLUSIONS: Patients are prepared to accept higher absolute fracture risk than doctors, before considering pharmacological therapy to be justified. Patients require that drug treatments confer substantial fracture risk reductions in order to consider long-term therapy.

The effect of dietary concentrate and soya oil inclusion on microbial diversity in the rumen of cattle.

AIMS: Methane emissions from ruminants are a significant contributor to global greenhouse gas production. The aim of this study was to examine the effect of diet on microbial communities in the rumen of steers. METHODS AND RESULTS: The effects of dietary alteration (50 : 50 vs 90 : 10 concentrate-forage ratio, and inclusion of soya oil) on methanogenic and bacterial communities in the rumen of steers were examined using molecular fingerprinting techniques (T-RFLP and automated ribosomal intergenic spacer analysis) and real-time PCR. Bacterial diversity was greatly affected by diet, whereas methanogen diversity was not. However, methanogen abundance was significantly reduced (P = 0.009) in high concentrate-forage diets and in the presence of soya oil (6%). In a parallel study, reduced methane emissions were observed with these diets. CONCLUSIONS: The greater effect of dietary alteration on bacterial community in the rumen compared with the methanogen community may reflect the impact of substrate availability on the rumen bacterial community. This resulted in altered rumen volatile fatty acid profiles and had a downstream effect on methanogen abundance, but not diversity. SIGNIFICANCE AND IMPACT OF THE STUDY: Understanding how rumen microbial communities contribute to methane production and how these microbes are influenced by diet is essential for the rational design of methane mitigation strategies from livestock.

An investigation into the effects of social evaluation on cardiovascular and endocrine responses to the CO2 stress test in humans.

The present study examined whether social evaluation could heighten individuals' physiological responses to the CO(2) stress test, and the hypothalamic-pituitary-adrenal (HPA) response in particular. Twenty-five healthy volunteers undertook the CO(2) test under three conditions: (i) standard CO(2) protocol, (ii) standard CO(2) protocol conducted in front of a full-length mirror (mirror) and (iii) standard CO(2) protocol conducted in front of a video camera deemed to be transmitting live images of the procedure to investigators evaluating participant performance (video). Despite counterbalancing for task order, there were significant differences in anger and depression among the conditions. Repeated measures analysis of variances (ANOVAs), controlling for these mood indices, revealed that salivary cortisol, heart rate and systolic blood pressure responses to the CO(2) test were not affected by social evaluation (i.e. mirror or video). Although the data provide no evidence that endocrine and cardiovascular responses to the CO(2) test are affected by social evaluation, the potency of the social evaluation manipulation in this study is in question. Thus, further research is warranted which includes evidence of, or instructions suggesting negative social evaluation.

Retinoblastoma protein and the leukemia-associated PLZF transcription factor interact to repress target gene promoters.

Translocations of the retinoic acid receptor-alpha (RARalpha) locus with the promyelocytic leukemia zinc-finger (PLZF) or PML genes lead to expression of oncogenic PLZF-RARalpha or PML-RARalpha fusion proteins, respectively. These fusion oncoproteins constitutively repress RARalpha target genes, in large part through aberrant recruitment of multiprotein co-repressor complexes. PML and PML-RARalpha have previously been shown to associate with the retinoblastoma (Rb) tumour suppressor protein in its hypophosphorylated state. Here, we demonstrate that PLZF also interacts with Rb in vitro and in vivo. The interaction between PLZF and Rb is mediated through the Rb pocket and the region of PLZF that lies between its transcriptional repression (poxvirus and zinc-finger, POZ) and DNA-binding (zinc-finger) domains. In addition, Rb can simultaneously interact with PLZF and the E2F1 S phase-inducing transcription factor, suggesting that these proteins can exist in the same multiprotein complex. In contrast to the interaction of Rb with PML or E2F1, the PLZF-Rb interaction is not dependent on hypophosphorylation of Rb. These data are supported by chromatin immunoprecipitation analysis, which indicates that PLZF associates with the promoter region of CDC6, a known E2F/Rb target gene. Co-expression of PLZF and Rb results in enhancement of transcriptional repression of PLZF and E2F/Rb target genes, indicating functional co-operation between the two proteins. Both PLZF and Rb have been shown to function in stem cells and taken together these data suggest that interactions between PLZF and Rb could be important in stem cell biology.

Histone deacetylase inhibitors in APL and beyond.

In recent years the study of chemical modifications to chromatin and their effects on cellular processes has become increasingly important in the field of cancer research. Disruptions to the normal epigenetic pattern of the cell can serve as biomarkers and are important determinants of cancer progression. Accordingly, drugs that inhibit the enzymes responsible for modulating these epigenetic markers, in particular histone deacetylases, are the focus of intense research and development. In this chapter we provide an overview of class I and II histone deacetylases as well as a guide to the diverse types of histone deacetylase inhibitors and their activities in the context of APL. We also discuss the rationale for the use of histone deacetylase inhibitors in combination therapy for the treatment of cancer and the current status of clinical trials.

Knowledge; Attitudes and Practices of Women Regarding the Prevention of Mother-To-Child Transmission (PMTCT) Programme at the Vanguard Community Health Centre; Western Cape - A Pilot Study

Objective.The aim of the study was to determine the knowledge; attitudes and practices of women regarding the prevention of mother-to-child transmission (PMTCT) programme at a community health centre (CHC). Method. A descriptive study was conducted using an administered; structured questionnaire.Subjects and setting. Thirty-six educated women aged 18 - 39 years and attending the clinic took part.Participants were from informal settlements and mostly unemployed; receiving government grants.Results. The majority (88.9) scored 80or more with regard to general HIV knowledge. Although the majority (78) were formula feeding; primarily owing to their HIV status and convenience while working; 24would not be able to sustain this feeding method after the initial 6 months' free supply provided by the provincial health services. The majority could not define the terms exclusive breastfeeding (89); mixed feeding (81) or cup feeding (94) correctly. Attitudes were found to be positive with regard to both breastfeeding and formula feeding; but HIV status influenced it significantly ( p 0.1). Conclusion. In conclusion; certain aspects of the PMTCT programme appear to have been effective at the CHC included in this study. The women were knowledgeable about HIV transmission and mother-to-child transmission (MTCT); but they were uninformed about certain essential aspects; i.e. prevention; cure and infant feeding.Attitudes were similar towards breastmilk or formula milk as a feeding choice but were influenced by HIV status. It was indicated that an informed decision-making process was not followed; rather that the women were advised to formula feed. Sustainability of formula feeding after 6 months and training of health workers specifically regarding feeding options need to be addresse

Patients with acute myocardial infarction have an inaccurate understanding of their risk of a future cardiac event.

BACKGROUND: Accurate perceptions of future cardiac risk are important to ensure informed treatment choices and lifestyle adaptation in patients following myocardial infarction (MI). The aim of this study was to investigate whether risk perceptions of patients with MI were accurate compared with an established clinical risk model. METHODS: Seventy-nine consecutive patients with acute MI admitted to the Coronary Care Unit, Auckland Hospital, completed a questionnaire assessing risk perceptions. Clinical data were used to calculate patients' Thrombolysis In Myocardial Infarction (TIMI) risk scores, a validated predictive model of prognosis. The main outcome measures were the associations between perceived risk, TIMI risk scores and troponin T. RESULTS: Patients' risk perceptions showed no correlation with thrombolysis in myocardial infarction risk scores (r = -0.06; P = 0.61) or with troponin T (r = -0.07; P = 0.53). Patients' risk perceptions were not significantly associated with age or sex, and were not significantly higher in those who had experienced a previous MI, a family history of coronary heart disease, diabetes or smokers. Higher perceived risk was significantly associated with a number of illness perceptions, including worse consequences of the MI and lower beliefs in the benefit of treatment. Patients who overestimated their risk were more anxious than other patients (F(2, 73) = 22.97; P = 0.0001). CONCLUSION: Patients with MI ideas about their personal risk of future MI are not congruent with their clinical risk assessments. Inpatient hospital care appears to be unsuccessful in communicating prognosis effectively to patients. Improving the accuracy of risk perceptions may help decrease unnecessary cardiac anxiety and invalidism in some patients and prompt risk-reducing behaviours in others.

Modern health worries in medical students.

OBJECTIVE: The aim of this study was to investigate the association between modern health worries (MHW), subjective health complaints, and use of health care services in first-year Dutch medical students, and to compare MHW in Dutch and New Zealand cohorts. METHODS: Two hundred and twenty-seven Dutch first-year medical students completed questionnaires assessing MHW, subjective health complaints, positive and negative affect (PA and NA, respectively), and use of health care services. RESULTS: Dutch medical students were most concerned about drug resistant bacteria and least concerned about vaccination programmes. Overall, female students were more concerned about modern health issues than were male students. Students' scores on the MHW scale were significantly associated with subjective health complaints. Subjective health complaints were also significantly related to the use of health care services. The factor structure of the MHW scale was replicated. Respondents reported significantly lower scores on all MHW items than did New Zealand students. CONCLUSIONS: Worries about modernity are reliably associated with subjective health complaints and use of health care services in Dutch medical students.

Who is not reassured following benign diagnosis of breast symptoms?

UNLABELLED: Many women fail to be reassured about their breast symptom following benign diagnosis. Identification of the factors contributing to this continued anxiety is important in order that appropriate intervention can be incorporated into the care of women undergoing diagnosis. In this study, we measured levels of anxiety, depression, stress, perceived personal risk of breast cancer, fear of breast cancer treatment and general health anxiety along with clinical and demographic variables in women undergoing investigation of breast symptoms. We then assessed if these factors were associated with reassurance about the breast symptom immediately following benign diagnosis. METHODS: Women attending a specialist 'one-stop' breast clinic completed a questionnaire in the clinic prior to diagnosis and a reassurance measure post-benign breast symptom diagnosis. RESULTS: Post-diagnosis, 67% of women were reassured however, 33% were not reassured about their breast symptom despite a benign diagnosis. Women who were not reassured were more likely to be educated only to high school level and have presenting symptoms of a change in breast shape/dimpling of the breast. There was a trend for women who were not reassured to have breast pain and be diagnosed with a benign breast cyst. Examination of the psychological variables showed that women who were not reassured compared to reassured women had higher levels of health anxiety, perceived stress, fear of breast cancer treatment and general anxiety. Logistic regression analysis entering all the predictors suggests that level of education was the strongest predictor of lack of reassurance following benign diagnosis. CONCLUSION: This study found that a significant proportion of women who undergo investigation and receive a benign diagnosis of their breast symptom experience uncertainty. Our finding that women who were not reassured were more likely to be educated only to high school level suggests that this group may benefit from additional information about breast symptoms and benign diagnosis. Additionally, our results indicate that women with high levels of anxiety, perceived stress and general worry about their health may need further reassurance in the immediate diagnosis phase. Further research focussing on how reassurance is interpreted in the context of women's perceptions about breast symptoms and breast disease is important so that appropriate support can be offered for women undergoing diagnosis of breast symptoms.

Stereotyping the smoker: adolescents' appraisals of smokers in film.

OBJECTIVE: To assess the relation between demographic factors and film smoking stereotypes in adolescents and the potential influence of smoker stereotypes on smoking susceptibility. DESIGN: A cross sectional questionnaire survey of school students (n = 3041) aged 12-13 and 16-17 years who were asked to describe the personal characteristics of female and male smokers in films. SETTING: 15 primary or intermediate schools and 10 secondary schools in Auckland, New Zealand. RESULTS: Appraisals of smokers in film were strongly influenced by age and sex with younger adolescents and males more likely to see female smokers as sexy, intelligent and healthy whereas older students and females more often appraised female smokers as stressed bored and depressed. Overall, image stereotypes (sexy, stylish) were more likely to be significantly associated with smoking susceptibility than emotional sensitivity stereotypes (stressed, depressed etc). CONCLUSIONS: Adolescents differ significantly in their appraisal of smokers in films; however, image based stereotypes, rather than emotional sensitivity stereotypes, are significantly associated with smoking susceptibility.

Melatonin for the prevention and treatment of jet lag.

BACKGROUND: : Jet-lag commonly affects air travellers who cross several time zones. It results from the body's internal rhythms being out of step with the day-night cycle at the destination. Melatonin is a pineal hormone that plays a central part in regulating bodily rhythms and has been used as a drug to re-align them with the outside world. OBJECTIVES: : To assess the effectiveness of oral melatonin taken in different dosage regimens for alleviating jet-lag after air travel across several time zones. SEARCH STRATEGY: : We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE, PsychLit and Science Citation Index electronically, and the journals 'Aviation, Space and Environmental Medicine' and 'Sleep' by hand. We searched citation lists of relevant studies for other relevant trials. We asked principal authors of relevant studies to tell us about unpublished trials. Reports of adverse events linked to melatonin use outside randomised trials were searched for systematically in 'Side Effects of Drugs' (SED) and SED Annuals, 'Reactions Weekly', MEDLINE, and the adverse drug reactions databases of the WHO Uppsala Monitoring Centre (UMC) and the US Food & Drug Administration. SELECTION CRITERIA: : Randomised trials in airline passengers, airline staff or military personnel given oral melatonin, compared with placebo or other medication. Outcome measures should consist of subjective rating of jet-lag or related components, such as subjective wellbeing, daytime tiredness, onset and quality of sleep, psychological functioning, duration of return to normal, or indicators of circadian rhythms. DATA COLLECTION AND ANALYSIS: : Ten trials met the inclusion criteria. All compared melatonin with placebo; one in addition compared it with a hypnotic, zolpidem. Nine of the trials were of adequate quality to contribute to the assessment, one had a design fault and could not be used in the assessment. Reports of adverse events outside trials were found through MEDLINE, 'Reactions Weekly', and in the WHO UMC database. MAIN RESULTS: : Nine of the ten trials found that melatonin, taken close to the target bedtime at the destination (10pm to midnight), decreased jet-lag from flights crossing five or more time zones. Daily doses of melatonin between 0.5 and 5mg are similarly effective, except that people fall asleep faster and sleep better after 5mg than 0.5mg. Doses above 5mg appear to be no more effective. The relative ineffectiveness of 2mg slow-release melatonin suggests that a short-lived higher peak concentration of melatonin works better. Based on the review, the number needed to treat (NNT) is 2. The benefit is likely to be greater the more time zones are crossed, and less for westward flights. The timing of the melatonin dose is important: if it is taken at the wrong time, early in the day, it is liable to cause sleepiness and delay adaptation to local time. The incidence of other side effects is low. Case reports suggest that people with epilepsy, and patients taking warfarin may come to harm from melatonin. REVIEWER'S CONCLUSIONS: : Melatonin is remarkably effective in preventing or reducing jet-lag, and occasional short-term use appears to be safe. It should be recommended to adult travellers flying across five or more time zones, particularly in an easterly direction, and especially if they have experienced jet-lag on previous journeys. Travellers crossing 2-4 time zones can also use it if need be. The pharmacology and toxicology of melatonin needs systematic study, and routine pharmaceutical quality control of melatonin products must be established. The effects of melatonin in people with epilepsy, and a possible interaction with warfarin, need investigation.

Lineage restriction of the RARalpha gene expression in myeloid differentiation.

To better understand the role of retinoids in myelopoiesis, expression of the retinoid receptor genes (retinoic acid receptors [RARs] and retinoid X receptors [RXRs]) were examined during differentiation of factor-dependent cell-Paterson (FDCP)-mixA4 murine progenitor cells. The major receptor expressed in undifferentiated A4 cells was RARalpha (primarily the RARalpha1 isoform). Following induction of myelomonocytic differentiation with granulocyte and granulocyte-macrophage colony-stimulating factors, a dramatic increase in RARalpha expression (particularly the RARalpha2 isoform) was seen. In contrast, expression of both RARalpha isoforms was rapidly extinguished upon induction of erythroid differentiation with erythropoeitin (EPO). A modest induction of RXRalpha expression was seen, particularly during differentiation in the myelomonocytic lineage. Low expression levels of RARgamma2 and RXRbeta remained unchanged, irrespective of differentiation pathway. Consistent with the gene expression patterns, RARalpha agonists and antagonists stimulated myelomonocytic and erythroid differentiation of FDCP-mixA4 cells, respectively. Taken together, these results suggest that erythropoiesis and granulopoiesis require diminished and enhanced RARalpha activities, respectively, which at physiological all-trans-retinoic acid (RA) concentrations may be accomplished by reciprocal effects of EPO and myelomonocytic growth factors on its expression. This hypothesis is corroborated by data showing that RA, which positively regulates RARalpha2 expression, can exert inhibitory effects on erythroid differentiation.