Intravenous Use of Prescription Psychostimulants; A Comparison of the Pattern and Subjective Experience between Different Methylphenidate Preparations, Amphetamine and Cocaine.

BACKGROUND/AIMS: Methylphenidate (MPH) has been the most commonly used intravenous (i.v.) substance in Iceland in recent years. In Iceland, MPH is available in 3 forms: immediate-release (IR) tablets (MPH IR, short-acting), sustainable-release (SR) capsules (MPH SR, long-acting) and osmotic-release (OROS) tablets (MPH OROS, long-acting). The aims of the study were to compare the pattern and subjective effects of i.v. MPH use to other i.v. psychostimulants and examine whether the pattern of use differs among MPH preparations. METHODS: This is a nationwide descriptive study. Information was collected from 95 i.v. substance users undergoing inpatient detoxification and reporting i.v. MPH use in the last 30 days using a semi-structured interview. RESULTS: MPH SR was both the most commonly used (96%) and preferred i.v. psychostimulant (57%). The intensity and duration of 'euphoria' did not differ between cocaine and MPH SR. No participant reported MPH OROS as their preferred substance even though a third had used it in the past month. CONCLUSIONS: The pattern of i.v. MPH use is similar to other psychostimulants among treatment seeking patients. MPH OROS was the least preferred i.v. psychostimulant, despite having the largest market share in Iceland. The results indicate that MPH OROS has less abuse potential than other MPH preparations.

Multimorbidity and use of hypnotic and anxiolytic drugs: cross-sectional and follow-up study in primary healthcare in Iceland.

BACKGROUND: The prevalence of multimorbidity is increasing worldwide, presumably leading to an increased use of medicines. During the last decades the use of hypnotic and anxiolytic benzodiazepine derivatives and related drugs has increased dramatically. These drugs are frequently prescribed for people with a sleep disorder often merely designated as "insomnia" in the medical records and lacking a clear connection with the roots of the patients' problems. Our aim was to analyse the prevalence of multimorbidity in primary healthcare in Iceland, while concurrently investigating a possible association with the prevalence and incidence of hypnotic/anxiolytic prescriptions, short-term versus chronic use. METHODS: Data were retrieved from a comprehensive database of medical records from primary healthcare in Iceland to find multimorbid patients and prescriptions for hypnotics and anxiolytics, linking diagnoses (ICD-10) and prescriptions (2009-2012) to examine a possible association. Nearly 222,000 patients, 83 % being local residents in the capital area, who contacted 16 healthcare centres served in total by 140 general practitioners, were set as a reference to find the prevalence of multimorbidity as well as the prevalence and incidence of hypnotic/anxiolytic prescriptions. RESULTS: The prevalence of multimorbidity in the primary care population was 35 %, lowest in the young, increasing with age up to the 80+ group where it dropped somewhat. The prevalence of hypnotic/anxiolytic prescriptions was 13.9 %. The incidence rate was 19.4 per 1000 persons per year in 2011, and 85 % of the patients prescribed hypnotics/anxiolytics were multimorbid. Compared to patients without multimorbidity, multimorbid patients were far more likely to be prescribed a hypnotic and/or an anxiolytic, OR = 14.9 (95 % CI = 14.4-15.4). CONCLUSIONS: Patients with multiple chronic conditions are common in the primary care setting, and prevalence and incidence of hypnotic/anxiolytic prescriptions are high. Solely explaining use of these drugs by linear thinking, i.e. that "insomnia" leads to their prescription is probably simplistic, since the majority of patients prescribed these drugs are multimorbid having several chronic conditions which could lead to sleeping problems. However, multimorbidity as such is not an indication for hypnotics, and doctors should be urged to greater caution in their prescribing, bearing in mind non-pharmacological therapy options.

The acetylcholine index: an electroencephalographic marker of cholinergic activity in the living human brain applied to Alzheimer's disease and other dementias.

BACKGROUND: The cholinergic hypothesis is well established and has led to the development of pharmacological treatments for Alzheimer's disease (AD). However, there has previously been no physiological means of monitoring cholinergic activity in vivo. METHODS: An electroencephalography (EEG)-based acetylcholine (Ach) index reflecting the cholinergic activity in the brain was developed using data from a scopolamine challenge study. The applicability of the Ach index was examined in an elderly population of healthy controls and patients suffering from various causes of cognitive decline. RESULTS: The Ach index showed a strong reduction in the severe stages of AD dementia. A high correlation was demonstrated between the Ach index and cognitive function. The index was reduced in patients with mild cognitive impairment and prodromal AD, indicating a decreased cholinergic activity. When considering the distribution of the Ach index in a population of healthy elderly subjects, an age-related threshold was revealed, beyond which there is a general decline in cholinergic activity. CONCLUSIONS: The EEG-based Ach index provides, for the first time, a physiological means of monitoring the cholinergic activity in the human brain in vivo. This has great potential for aiding diagnosis and patient stratification as well as for monitoring disease progression and treatment response.

Saliva testosterone and cortisol in male depressive syndrome, a community study. The Sudurnesjamenn Study.

INTRODUCTION: The association between testosterone levels and depression is unclear. The relationship has been described as complex, i.e. more U (J)-shaped than linear in some previous studies. AIM: The primary aim of this study was to examine the relationship between saliva testosterone level variations and different levels of male depressive symptoms in a community sample. The secondary aim was to investigate whether simultaneous testing of evening cortisol and testosterone improved the detection of depression. METHODS: In a community study, 534 males were screened, using the Beck Depression Inventory (BDI), the Gotland Male Depression Scale (GMDS) and the Montgomery-Åsberg Depression Rating Scale (MADRS). Those with signs of depression (n = 65) and randomly selected controls (n = 69) had psychiatric evaluation for depressive disorder. In a sub-sample (n = 51) saliva testosterone was measured twice on a single day. RESULTS: Testosterone morning values were significantly higher than evening values (236 vs. 145 pg/ml, P = 0.009). Evening testosterone was significantly higher in depressive males, according to both MADRS (P = 0.028) and BDI (P = 0.036). Having depression increased the likelihood of being in the highest third of testosterone levels (BDI P = 0.021; MADRS P = 0.018). Positive correlation was between total BDI score and elevated evening testosterone with and without psychotropics (P = 0.017; P = 0.002). Correlation was between elevated evening cortisol and evening testosterone levels (P = 0.021) though simultaneous testing did not increase specificity of detecting depression. CONCLUSION: Evening saliva testosterone measurements seem the most informative, as they correlate with male depressive syndrome. Simultaneous testing for evening cortisol and evening testosterone levels did not increase specificity for clinical diagnosis of depressive disorder.

Saliva cortisol and male depressive syndrome in a community study. The Sudurnesjamenn study.

BACKGROUND: The degree and direction of hypothalamic-pituitary-adrenal (HPA) dysfunction to male mental health is unclear. AIMS: The aim of the study was to investigate the relationship between cortisol and male mental health. METHODS: In this community study, 534 males were screened, using the Beck Depression Inventory (BDI), Gotland Male Depression Scale (GMDS) and a general health questionnaire. Those with signs of depression (n = 65) and controls (n = 69) were evaluated in a psychiatric examination according to the DSM-IV criteria for depressive disorder (DD). In a sub-sample (n = 51) saliva cortisol was measured five times on a single day. RESULTS: Evening cortisol was significantly higher in untreated individuals with DD. Significantly higher evening cortisol (at 22 h) correlated also with a history of physical disorder, a history of any mental disorder and MADRS score ≥ 20 (Montgomery-Åsberg Depression Rating Scale). High cortisol, measured as AUC (area under curve), correlated with a high MADRS score but not with any other health variable tested. Morning cortisol did not correlate with any health variable; however, cortisol awakening response (CAR) could not be investigated. The BDI and GMDS scores did not correlate with cortisol measurements. CONCLUSION: Evening saliva cortisol measurement seems most informative, as it correlates with male depressive syndrome in our study but replications with larger studies are needed.

Genetic structure and relatedness of brown trout (Salmo trutta) populations in the drainage basin of the Ölfusá river, South-Western Iceland.

Background: Lake Þingvallavatn in Iceland, a part of the river Ölfusá drainage basin, was presumably populated by brown trout soon after it formed at the end of the last Ice Age. The genetic relatedness of the brown trout in Þingvallavatn to other populations in the Ölfusá drainage basin is unknown. After the building of a dam at the outlet of the lake in 1959 brown trout catches declined, though numbers have now increased. The aim of this study was to assess effects of geographic isolation and potential downstream gene flow on the genetic structure and diversity in brown trout sampled in several locations in the western side of the watershed of River Ölfusá. We hypothesized that brown trout in Lake Þingvallavatn constituted several local spawning populations connected by occasional gene flow before the damming of the lake. We also estimated the effective population size (NE) of some of these populations and tested for signs of a recent population bottleneck in Lake Þingvallavatn. Methods: We sampled brown trout inhabiting four lakes and 12 rivers within and near the watershed of River Ölfusá by means of electro- and net- fishing. After stringent data filtering, 2,597 polymorphic loci obtained from ddRADseq data from 317 individuals were ascertained as putative neutral markers. Results: Overall, the genetic relatedness of brown trout in the Ölfusá watershed reflected the connectivity and topography of the waterways. Ancestry proportion analyses and a phylogenetic tree revealed seven distinct clusters, some of which corresponded to small populations with reduced genetic diversity. There was no evidence of downstream gene flow from Lake Þingvallavatn, although gene flow was observed from much smaller mountain populations. Most locations showed low NE values (i.e., ~14.6 on average) while the putative anadromous trout from River Sog and the spawning population from River Öxará, that flows into Lake Þingvallavatn, showed notably higher NE values (i.e., 71.2 and 56.5, respectively). No signals of recent population bottlenecks were detected in the brown trout of Lake Þingvallavatn. Discussion: This is the first time that the genetic structure and diversity of brown trout in the watershed of River Ölfusá have been assessed. Our results point towards the presence of a metapopulation in the watershed of Lake Þingvallavatn, which has been influenced by restoration efforts and is now dominated by a genetic component originated in River Öxará. Many of the locations studied represent different populations. Those that are isolated in headwater streams and lakes are genetically distinct presenting low genetic diversity, yet they can be important in increasing the genetic variation in downstream populations. These populations should be considered for conservation and direct management.

Rofecoxib, but not celecoxib, increases the risk of thromboembolic cardiovascular events in young adults-a nationwide registry-based study.

PURPOSE: To examine the risk of thromboembolic cardiovascular events in users of coxibs and NSAIDs in a nationwide cohort. METHODS: Data were synchronised from three nationwide databases, the Icelandic Medicines Registry (IMR), The Icelandic National Patient Registry (INPR) and the Registry for Causes of Death at Statistics Iceland (RCD), for prescriptions for NSAIDs or coxibs with respect to hospitalisation for unstable angina pectoris, myocardial infarction and cerebral infarction over a 3-year period. The Cox proportional hazards model and Poisson regression were used to analyse the data. RESULTS: A total of 108,700 individuals received prescriptions for NSAIDs or coxibs (ATC code M01A), of whom 78,539 received one drug only (163,406 person-years). Among those receiving only one drug 426 individuals were discharged from hospital with endpoint diagnoses. In comparison to diclofenac, the incidence ratios, adjusted for age and gender, were significantly higher for cerebral infarction (2.13; 95% CI 1.54-2.97; P < 0.001), for myocardial infarction (1.77; 95% CI 1.34-2.32; P < 0.001) and for unstable angina pectoris (1.52; 95% CI 1.01-2.30; P = 0.047) for patients who used rofecoxib. For naproxen users, the incidence ratio was 1.46 for myocardial infarction (95% CI 1.03-2.07; P = 0.03), but was reduced in ibuprofen users (0.63; 95% CI 0.40-1.00; P = 0.05). The youngest users of rofecoxib (< or =39 years) had the highest hazard ratio (HR) for cardiovascular events (8.34; P < 0.001), while those > or =60 years had a lower but still significantly elevated HR (1.35; P = 0.001). CONCLUSION: This Icelandic nationwide registry-based study amounting to 163,406 patient-years showed increased risk of cardiovascular events, i.e. cerebral infarction, myocardial infarction and unstable angina pectoris, among rofecoxib and naproxen users in comparison to diclofenac users. The added risk was most pronounced in young adults using rofecoxib.

What electrophysiology tells us about Alzheimer's disease: a window into the synchronization and connectivity of brain neurons.

Electrophysiology provides a real-time readout of neural functions and network capability in different brain states, on temporal (fractions of milliseconds) and spatial (micro, meso, and macro) scales unmet by other methodologies. However, current international guidelines do not endorse the use of electroencephalographic (EEG)/magnetoencephalographic (MEG) biomarkers in clinical trials performed in patients with Alzheimer's disease (AD), despite a surge in recent validated evidence. This position paper of the ISTAART Electrophysiology Professional Interest Area endorses consolidated and translational electrophysiological techniques applied to both experimental animal models of AD and patients, to probe the effects of AD neuropathology (i.e., brain amyloidosis, tauopathy, and neurodegeneration) on neurophysiological mechanisms underpinning neural excitation/inhibition and neurotransmission as well as brain network dynamics, synchronization, and functional connectivity, reflecting thalamocortical and corticocortical residual capacity. Converging evidence shows relationships between abnormalities in EEG/MEG markers and cognitive deficits in groups of AD patients at different disease stages. The supporting evidence for the application of electrophysiology in AD clinical research as well as drug discovery pathways warrants an international initiative to include the use of EEG/MEG biomarkers in the main multicentric projects planned in AD patients, to produce conclusive findings challenging the present regulatory requirements and guidelines for AD studies.

[Loperamide abuse - constipation or heart attack?]

Loperamide is a µ-opioid receptor agonist with antidiarrhoeal effects. It is considered to have a low abuse potential because of substantial first-pass metabolism and P-glycoprotein-mediated efflux at the level of the blood-brain barrier. Previous case reports have described that high dosage of loperamide can induce an opioid-like effect on the central nervous system. The most common presentation of loperamide intoxication is syncope which is caused by serious cardiac dysrhythmia and can lead to death. Therefore, it was decided to analyze whether drug prescriptions in the prescription drug database from The Directorate of Health would indicate loperamide misuse in Iceland from 2006-2017. In total 94 individuals used more than one DDD (10 mg) and 17 individuals used more than two DDD (20 mg), if taken daily over one year. These results indicate that loperamide is being used excessively but the reason for each prescription and the total amount sold over the counter is unknown. Increased surveillance and decreased availability of prescription opioids might possibly boost the usage of drugs with similar function such as loperamide. Loperamide overdose can result in serious adverse effects and thus, it is important to inform healthcare employees about such severe consequences.

[Icelanders' beliefs about medicines. Use of BMQ].

OBJECTIVE: To study beliefs held by the general public in Iceland about medicines. METHODS: The Beliefs about Medicines Questionnaire was used to explore Icelanders' beliefs about medicines. A sample of 1500 Icelandic citizens, aged 18-75, obtained from the Social Science Research Insti-tute was given The Beliefs about Medicines Questionnaire. RESULTS: The response rate was 61.6%. Most Icelanders have positive beliefs about their medication as well as general trust. Those who suffer from chronic diseases are more positive towards medicines than others and less inclined to view them as excessively used and harmful. Higher level of education predicts more positive beliefs towards medication - and vice versa. Gender and age do not seem to affect such beliefs. CONCLUSION: Gaining a better understanding of people´s beliefs about medicines and what determines these beliefs can be of considerable value in the search for ways to improve therapy and adherence, espe-cially for those suffering from chronic diseases. Promoting education for the general public about medicines might result in less mis-understanding among patients and subsequently better grounded -beliefs and more adequate therapeutic adherence. Key words: beliefs, medicines, Icelanders, BMQ, survey. Correspondence: Hlif Vilhelmsdottir, hlif84@gmail.com.

[Do opioids, sedatives and proton-pump inhibitors increase the risk of fractures?]

INTRODUCTION: A pharmacoepidemiological study was conducted to analyse the relationship between bone fracture and the use of certain drugs. MATERIAL/METHODS: The study includes patients 40 years and older, diagnosed with bone fractures in the Emergency Department of Landspitali University Hospital in Reykjavik, Iceland, during a 10-year period (2002-2011). Also were included those who picked up from a pharmacy 90 DDD or more per year of the drugs included in the study in the capital region of Iceland during same period. Opiates, benzodiazepines/hypnotics (sedatives) were compared with HMG-CoA reductase inhibitors (statins), non-steroid anti-inflammatory drugs (NSAID) and beta blockers. Proton-pump inhibitors (PPI) and histamine H2-antagonists were also examined. To examine the association between above drugs and fractures the data from electronic hospital database were matched to the prescription database run by the Directorate of Health. RESULTS: A total of 29,056 fractures in 22,891 individuals were identified. The females with fractures were significantly older and twice as many, compared to males. The odds ratio (OR) for fractures was not significantly different between the NSAID, statins and beta blockers. OR for opiates showed almost double increased risk of fractures, 40% increased risk for sedatives and 30% increased risk for PPIs compared to beta blockers. No increased fracture-risk was noted in patients taking H2 antagonists. CONCLUSION: This study shows a relationship between the use of opiates, sedatives and bone fractures. The incidence of fractures was also increased in patients taking PPIs which is interesting in the light of the wide-spread use of PPIs in the community. Key words: Opiates, sedatives, proton- pump inhibitors, fractures. Correspondence: Magnus Johannsson, magjoh@hi.is.

The effects of adrenocorticotrophic hormone and an equivalent dose of cortisol on the serum concentrations of lipids, lipoproteins, and apolipoproteins.

Previous studies have shown a strong lipid-lowering effect of adrenocorticotrophic hormone (ACTH) in healthy individuals and in patients with different kinds of dyslipoproteinemia. The mechanism behind this effect has not been established and its direct ACTH-specific nature has been questioned. Therefore, the present study was performed. Thirty healthy young males were randomized into 3 groups of equal size: one group received ACTH1-24 1 mg IM, daily for 4 days, another group was treated with cortisol 150 mg ID (50 mg tid) daily for 4 days, whereas a control group was observed for 4 days. Fasting blood samples were collected before and after treatment or observation. The serum concentrations of cholesterol (12%, P < .05), low-density lipoprotein cholesterol (24%, P < .01), and apolipoprotein (apo) B (31%, P < .01) decreased significantly in the ACTH group but not in the cortisol and control groups. The statistical workup confirmed that only ACTH had a lowering effect on the apo B-containing lipoproteins. In contrast, the results indicated conformity between the treatment groups with respect to increases in the serum apo E concentrations. There were inconsistent changes in the serum concentrations of the triglycerides, high-density lipoprotein cholesterol, apo A, and lipoprotein(a). The main results were clear: the lowering effect of ACTH on the serum concentration of apo B-containing lipoproteins could not be ascribed to cortisol. These, in combination with previous in vitro results, indicated an ACTH-specific effect.

Effects of different doses of adrenocorticotrophic hormone on the serum lipoprotein profile in healthy subjects.

Adrenocorticotrophic hormone (ACTH) at pharmacological dosage has marked lipid-lowering effects that may have therapeutic implications. The rationale behind the present investigation was the possible use of ACTH as a lipid-lowering replacement for steroids. Thirty-two healthy individuals were randomly divided into four groups of 8 each. Three ACTH groups received different doses of ACTH(1-24) intramuscularly (0.1 mg, 0.5 mg and 1.0 mg daily for four days) and the control group received NaCl 0.9% 1 ml intramuscularly daily for four days. Moreover, 8 healthy subjects were given ACTH(1-24) 1.0 mg intramuscularly five times at an interval of four days. Blood and urine samples were collected at regular intervals. ACTH treatment at the dose of 1.0 mg daily lowered the serum concentrations of low density lipoprotein (LDL) cholesterol and apolipoprotein B by 28% and 22%, respectively, which is similar to previous observations. ACTH treatment at the doses of 0.5 mg and 0.1 mg gave smaller reductions (17% and 12%, and 9% and 8%, respectively) resulting in near linear dose-response relationships. There were no changes in the control group. Only the ACTH dose of 1.0 mg resulted in significant changes when compared with the control group. During the ACTH administration at four-days intervals, the serum concentrations of LDL cholesterol and apolipoprotein B reached the lowest values at 48 hr after an injection, remained there at 72 hr but were rising again at 96 hr. For effective lipid reduction, an ACTH dose of about 1 mg is needed and it should be given more often than every fourth day, probably every second or third day. With regard to the cortisol exposure, the results should be viewed in the light of calculations, presented in the paper, that 1 mg of ACTH is equivalent to 90 mg of cortisol administered parenterally.

Validity of Gotland Male Depression Scale for male depression in a community study: the Sudurnesjamenn study.

BACKGROUND: Several studies suggest a "male depressive syndrome", where not only the standard symptoms of major depressive disorder (MDD) but also symptoms of anxiety, anger, irritability and antisocial behaviour are prominent. METHOD: In a community study, 534 males were screened for possible depression by the Gotland Male Depression Scale (GMDS) and Beck's Depression Inventory (BDI). For comparison psychiatrists examined a sub-sample of healthy and depressive males (n=137). The validity of the GMDS was compared both with the BDI and MDD diagnosis according to DSM-IV. RESULTS: GMDS was as good as BDI for screening males. ROC-curve analysis gave AUC 0.945 (95% CI 0.923-0.968) for GMDS when tested against BDI. Second, when both scales were tested by ROC-curves against DSM-IV, the GMDS had AUC=0.861 (95% CI 0.800-0.921) and BDI had AUC=0.822 (95% CI 0.751-0.893). The estimated prevalence was 14-15%. LIMITATIONS: Low participation rate (25%) in the screening phase. CONCLUSION: GMDS is a valid screening tool for detecting male depression (MDD). Furthermore it is a short self-rating scale, easy to use in daily practice to screen for depression. Our results support recent reports of high prevalence of depressions in the community which supports active screening of males in clinical practice.

Prevalent intravenous abuse of methylphenidate among treatment-seeking patients with substance abuse disorders: a descriptive population-based study.

OBJECTIVES: Prescription rates of methylphenidate (MPH) are sharply rising in most Western countries. Although it has been reported that MPH has abuse potential, little is known about the prevalence of intravenous (IV) abuse of MPH. The aim of the study was to investigate the prevalence of IV MPH abuse among treatment-seeking IV substance abusers in Iceland. METHODS: This is a descriptive population-based study using a semistructured interview assessing sociodemographics, substance abuse history, and the method of administration of 108 IV substance abusers. During 1 year, consecutively admitted adult inpatients with substance use disorder at any detoxification center in Iceland that reported any IV substance abuse in the past 30 days were invited to participate. Abuse was defined as nontherapeutic use of a substance to gain psychological or physiological effect. RESULTS: Prevalence of any IV MPH abuse among participants was 88% in the last 30 days (95% confidence interval [CI], 0.82-0.94) and MPH was the most commonly abused substance (65%) and the preferred substance (63%). Around one third (30%) reported MPH as the first IV substance ever abused. However, among those reporting a shorter history than 10 years of IV abuse, 42% reported MPH as the first IV substance ever abused. CONCLUSIONS: This first nationwide study on IV abuse of MPH shows that it is common among treatment-seeking IV abusers in Iceland and suggests that MPH has high abuse potential. Therefore, both the use and possible abuse of MPH in those with high abuse potential should be monitored, especially in countries where MPH prescriptions rates are on the rise.

[Research in pharmacoepidemiology in Iceland]. / Rannsóknir í lyfjafaraldsfraedi á Islandi.

Pharmacoepidemiology is a rapidly growing discipline that is useful in studies on effects and adverse effects of drugs. During past years and decades databases have been built in Iceland that are becoming powerful tools for this kind of research. The databases are, however only useful for pharmacoepidemiological research if they include personal identification and can be merged. The personal identification should be without time limits because in many cases we are interested in what happened years or decades ago. The prescriptions database was started in 2002 and has dramatically changed the possibilities for pharmacoepidemiological studies in Iceland. The main aim of this review is to give an overview of the existing databases in Iceland and to encourage research in this important field.

[Back to the past. Case report and review on retrograde memory loss]. / Sjúkratilfelli og yfirlit um afturvirkt minnisleysi.

Retrograde memory loss where many years disappear suddenly from memory is a known but rare form of memory disturbance among young and old subjects. For those whose brain is affected by a known organic damage such as head trauma the time lost from memory is usually not counted in years, but typically hours or sometimes days or weeks. We review in this article current knowledge on retrograde memory loss as we describe the experience of a 31 year old woman who experienced an unusually long form of retrograde amnesia. She developed the memory loss in the wake of disappointment and a life event. At the time she had major depression. Having described the case and presented the results of neuropsychological testing, we associate her story with the state of knowledge on retrograde memory loss.

[Hepatotoxicity associated with the use of Herbalife]. / Lifrarskadi tengdur notkun á Herbalife.

OBJECTIVE: Many herbal products are known to be hepatotoxic. In a recent survey in Iceland concerning adverse reactions related to herbal medicines, Herbalife products were implicated in the majority of the reported cases of hepatotoxicity. METHODS: The clinical presentations of five cases of Herbalife related liver injury during the period of 1999-2008 are analysed. Causality was assessed by using the WHO-UMC system for causality assessment and the RUCAM method. RESULTS: Of the five cases there were four females and one male; median age was 46 years (range 29-78). Herbalife had been used for 1 to 7 months prior to presentation. Four patients presented with a hepatocellular and one with a cholestatic reaction. Median values were for bilirubin 190 micromol/L (range: 26-311; ref. < 20 micromol/L), ALP 407 U/L (range: 149-712; ref. 35-105 U/L) and ALT 24 87 U/L (range: 456-2637; ref. 70 and 45 U/L for males and females, respectively). Liver biopsy was performed in 2 patients and was consistent with toxic hepatitis in both cases. Other causes of hepatitis were excluded by appropriate serological testing and ultrasound. Causality assessment according to RUCAM was probable in three cases and possible in two. Using the WHO-UMC criteria causality was certain in one case, probable in two and possible in two cases. CONCLUSIONS: Hepatotoxicity is probably associated with the use of Herbalife products. Hepatotoxicity due to herbal remedies is an important differential diagnosis in the diagnostic work-up of liver injury.

Migraine with aura and risk of cardiovascular and all cause mortality in men and women: prospective cohort study.

OBJECTIVE: To estimate whether migraine in mid-life is associated with mortality from cardiovascular disease, other causes, and all causes. DESIGN: Population based cohort study. SETTING: Reykjavik, Iceland. PARTICIPANTS: 18,725 men and women, born 1907-35 and living in Reykjavik and adjacent communities. MAIN OUTCOME MEASURES: Mortality from cardiovascular disease, non-cardiovascular disease, and all causes. Questionnaires and clinical measures were obtained in mid-life (mean age 53, range 33-81) in the Reykjavik Study (1967-91). Headache was classified as migraine without aura, migraine with aura, or non-migraine headache. Median follow-up was 25.9 years (0.1-40.2 years), with 470,990 person years and 10,358 deaths: 4323 from cardiovascular disease and 6035 from other causes. We used Cox regression to estimate risk of death in those with migraine compared with others, after adjusting for baseline risk factors. RESULTS: People with migraine with aura were at increased risk of all cause mortality (adjusted (for sex and multivariables) hazard ratio 1.21, 95% confidence interval 1.12 to 1.30) and mortality from cardiovascular disease (1.27, 1.13 to 1.43) compared with people with no headache, while those with migraine without aura and non-migraine headache were not. Further examination of mortality from cardiovascular disease shows that people with migraine with aura were at increased risk of mortality from coronary heart disease (1.28, 1.11 to 1.49) and stroke (1.40, 1.10 to 1.78). Women with migraine with aura were also at increased risk of mortality from non-cardiovascular disease (1.19, 1.06 to 1.35). CONCLUSIONS: Migraine with aura is an independent risk factor for cardiovascular and all cause mortality in men and women. The risk of mortality from coronary heart disease and stroke mortality is modestly increased in people with migraine, particularly those with aura.