A Danish register-based study on involuntary treatment in anorexia nervosa.

OBJECTIVE: Involuntary treatment is controversial and widely debated, but remains a significant component of treatment for severe anorexia nervosa. Given how little is known about this topic, we describe the frequency of various involuntary measures in a national cohort of all patients diagnosed with anorexia nervosa. In a subsample of patients, we explored predictors of the first involuntary measure recorded. METHOD: Descriptive statistics and Cox proportional hazard analyses were conducted using the national registers of Denmark covering the total population. Data from the National Patient Register and the Psychiatric Central Research Register including all psychiatric visits from 1969 onwards were merged with data from the National Register on Coercion covering 1999 onward. Involuntary measures registered between 2000 and 2013 were analyzed. RESULTS: A total of 4,727 patients with a diagnosis of anorexia nervosa representing 16,592 admissions were included. Eighteen percent experienced at least one involuntary measure. A variety of measures were used with tube feeding being the most frequent followed by mechanical restraint, involuntary medication, physical restraint, constant observation, and sedative medication. A subsample of 2% of AN patients had more than 100 involuntary measures recorded. The first recorded involuntary measure was predicted by most but not all psychiatric comorbidities, especially schizophrenia, autism spectrum, and personality disorders, older age at first diagnosis, and previous admissions. DISCUSSION: It is important to develop a more granular understanding of patients at risk of requiring involuntary treatment and to determine how best to treat them effectively with minimal use of involuntary measures.

Impact of severe mental illness on cancer stage at diagnosis and subsequent mortality: A population-based register study.

BACKGROUND: Excess mortality in individuals with severe mental illness (SMI) is often explained by physical comorbidity and suboptimal healthcare. Cancer is a prevalent cause of death, and tumour stage at diagnosis is a strong predictor of mortality. We aimed to study cancer incidence, disease stage at diagnosis and subsequent mortality in individuals with SMI compared to individuals without SMI. METHODS: The entire Danish population was followed in 1978-2013 using nationwide registries. Cancer incidence and subsequent mortality stratified by disease stage were compared in individuals with and without SMI. Cox regression was used to estimate incidence rate ratios (IRR) and mortality rate ratios (MRR). Cancer was examined overall and grouped by major aetiological factors. RESULTS: The overall cancer incidence rate was lower in males with SMI than in males without SMI; IRR = 0.89 (95% CI: 0.85-0.94), but rates were similar in females with SMI and without SMI; IRR = 1.03 (95% CI: 0.99-1.07). The overall mortality rate was higher in individuals with SMI than those without; MRR = 1.56 (95% CI: 1.48-1.64) for males and MRR = 1.49 (95% CI: 1.43-1.56) for females. Incidence rates and mortality rates showed similar estimates when stratified by tumour stage and aetiology. CONCLUSIONS: We found lower cancer incidence in males with SMI compared to males without SMI and similar incidence in the two groups of women. Higher subsequent mortality was found in both sexes with SMI. The excess mortality was not explained by more advanced stages of cancer; future studies should evaluate the effect of cancer treatment and rehabilitation.

Adverse life events increase risk for postpartum psychiatric episodes: A population-based epidemiologic study.

BACKGROUND: Trauma histories may increase risk of perinatal psychiatric episodes. We designed an epidemiological population-based cohort study to explore if adverse childhood experiences (ACE) in girls increases risk of later postpartum psychiatric episodes. METHODS: Using Danish registers, we identified women born in Denmark between January 1980 and December 1998 (129,439 childbirths). Exposure variables were ACE between ages 0 and 15 including: (1) family disruption, (2) parental somatic illness, (3) parental labor market exclusion, (4) parental criminality, (5) parental death, (6) placement in out-of-home care, (7) parental psychopathology excluding substance use, and (8) parental substance use disorder. Primary outcome was first occurrence of in- or outpatient contact 0-6 months postpartum at a psychiatric treatment facility with any psychiatric diagnoses, ICD-10, F00-F99 (N = 651). We conducted survival analyses using Cox proportional hazard regressions of postpartum psychiatric episodes. RESULTS: Approximately 52% of the sample experienced ACE, significantly increasing risk of any postpartum psychiatric diagnosis. Highest risks were observed among women who experienced out-of-home placement, hazard ratio (HR) 2.57 (95% CI: 1.90-3.48). Women experiencing two adverse life events had higher risks of postpartum psychiatric diagnosis HR: 1.88 (95% CI: 1.51-2.36), compared to those with one ACE, HR: 1.24 (95% CI: 1.03-49) and no ACE, HR: 1.00 (reference group). CONCLUSIONS: ACE primarily due to parental psychopathology and disability contributes to increased risk of postpartum psychiatric episodes; and greater numbers of ACE increases risk for postpartum psychiatric illness with an observed dose-response effect. Future work should explore genetic and environmental factors that increase risk and/or confer resilience.

Childhood adverse life events and parental psychopathology as risk factors for bipolar disorder.

Childhood adverse events are risk factors for later bipolar disorder. We quantified the risks for a later diagnosis of bipolar disorder after exposure to adverse life events in children with and without parental psychopathology. This register-based population cohort study included all persons born in Denmark from 1980 to 1998 (980 554 persons). Adversities before age 15 years were: familial disruption; parental somatic illness; any parental psychopathology; parental labour market exclusion; parental imprisonment; placement in out-of-home care; and parental natural and unnatural death. We calculated risk estimates of each of these eight life events as single exposure and risk estimates for exposure to multiple life events. Main outcome variable was a diagnosis of bipolar disorder after the age of 15 years, analysed with Cox proportional hazard regression. Single exposure to most of the investigated adversities were associated with increased risk for bipolar disorder, exceptions were parental somatic illness and parental natural death. By far the strongest risk factor for bipolar disorder in our study was any mental disorder in the parent (hazard ratio 3.53; 95% confidence interval 2.73-4.53) and the additional effects of life events on bipolar risk were limited. An effect of early adverse life events on bipolar risk later in life was mainly observed in children without parental psychopathology. Our findings do not exclude early-life events as possible risk factors, but challenge the concept of adversities as important independent determinants of bipolar disorder in genetically vulnerable individuals.

Introducing the White Noise task in childhood: associations between speech illusions and psychosis vulnerability.

BACKGROUND: Auditory verbal hallucinations (AVH) are common during development and may arise due to dysregulation in top-down processing of sensory input. This study was designed to examine the frequency and correlates of speech illusions measured using the White Noise (WN) task in children from the general population. Associations between speech illusions and putative risk factors for psychotic disorder and negative affect were examined. METHOD: A total of 1486 children aged 11-12 years of the Copenhagen Child Cohort 2000 were examined with the WN task. Psychotic experiences and negative affect were determined using the Kiddie-SADS-PL. Register data described family history of mental disorders. Exaggerated Theory of Mind functioning (hyper-ToM) was measured by the ToM Storybook Frederik. RESULTS: A total of 145 (10%) children experienced speech illusions (hearing speech in the absence of speech stimuli), of which 102 (70%) experienced illusions perceived by the child as positive or negative (affectively salient). Experiencing hallucinations during the last month was associated with affectively salient speech illusions in the WN task [general cognitive ability: adjusted odds ratio (aOR) 2.01, 95% confidence interval (CI) 1.03-3.93]. Negative affect, both last month and lifetime, was also associated with affectively salient speech illusions (aOR 2.01, 95% CI 1.05-3.83 and aOR 1.79, 95% CI 1.11-2.89, respectively). Speech illusions were not associated with delusions, hyper-ToM or family history of mental disorders. CONCLUSIONS: Speech illusions were elicited in typically developing children in a WN-test paradigm, and point to an affective pathway to AVH mediated by dysregulation in top-down processing of sensory input.

Evolving changes in disease biomarkers and risk of early progression in smoldering multiple myeloma.

We studied 190 patients with smoldering multiple myeloma (SMM) at our institution between 1973 and 2014. Evolving change in monoclonal protein level (eMP) was defined as ⩾10% increase in serum monoclonal protein (M) and/or immunoglobulin (Ig) (M/Ig) within the first 6 months of diagnosis (only if M-protein ⩾3 g/dl) and/or ⩾25% increase in M/Ig within the first 12 months, with a minimum required increase of 0.5 g/dl in M-protein and/or 500 mg/dl in Ig. Evolving change in hemoglobin (eHb) was defined as ⩾0.5 g/dl decrease within 12 months of diagnosis. A total of 134 patients (70.5%) progressed to MM over a median follow-up of 10.4 years. On multivariable analysis adjusting for factors known to predict for progression to MM, bone marrow plasma cells ⩾20% (odds ratio (OR)=3.37 (1.30-8.77), P=0.013), eMP (OR=8.20 (3.19-21.05), P<0.001) and eHb (OR=5.86 (2.12-16.21), P=0.001) were independent predictors of progression within 2 years of SMM diagnosis. A risk model comprising these variables was constructed, with median time to progression of 12.3, 5.1, 2.0 and 1.0 years among patients with 0-3 risk factors respectively. The 2-year progression risk was 81.5% in individuals who demonstrated both eMP and eHb, and 90.5% in those with all three risk factors.

Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma.

A markedly elevated serum free light chain (FLC) ratio may serve as a biomarker for malignant transformation in high-risk smoldering multiple myeloma (SMM) and identify patients who are at imminent risk of progression. We retrospectively studied the predictive value of the serum (FLC) assay in 586 patients with SMM diagnosed between 1970 to 2010. A serum involved/uninvolved FLC ratio ≥ 100 was used to define high-risk SMM, which included 15% (n=90) of the total cohort. Receiver operating characteristics analysis determined the optimal FLC ratio cut-point to predict progression to symptomatic multiple myeloma (MM) within 2 years of diagnosis, which resulted in a specificity of 97% and sensitivity of 16%. Fifty-six percent of patients developed progressive disease during median follow-up of 52 months, but this increased to 98% in the subgroup of patients with FLC ratio ≥ 100. The median time to progression in the FLC ratio ≥ 100 group was 15 months versus 55 months in the FLC <100 group (P<0.0001). The risk of progression to MM within the first 2 years in patients with an FLC ratio ≥ 100 was 72%; the risk of progression to MM or light chain amyloidosis in 2 years was 79%. We conclude that a high FLC ratio ≥ 100 is a predictor of imminent progression in SMM, and such patients may be considered candidates for early treatment intervention.

Can people feel happy and sad at the same time?

The authors investigated whether people can feel happy and sad at the same time. J. A. Russell and J. M. Carroll's (1999) circumplex model holds that happiness and sadness are polar opposites and, thus, mutually exclusive. In contrast, the evaluative space model (J. T. Cacioppo & G. G. Berntson, 1994) proposes that positive and negative affect are separable and that mixed feelings of happiness and sadness can co-occur. The authors both replicated and extended past research by showing that whereas most participants surveyed in typical situations felt either happy or sad, many participants surveyed immediately after watching the film Life Is Beautiful, moving out of their dormitories, or graduating from college felt both happy and sad. Results suggest that although affective experience may typically be bipolar, the underlying processes, and occasionally the resulting experience of emotion, are better characterized as bivariate.

[Clozapine-induced toxic hepatitis]. / Clozapin-udløst toksisk hepatitis.

A case of clozapine-induced toxic hepatitis in a 49-year old woman with schizophrenia is described. The daily clozapine dose was clinically titrated to 300 mg. Subsequently, the patient experienced lethargy and anorexia, and fever, eosinophilia, leucocytosis and abnormal liver parameters were found. The serum concentration of clozapine was 8595 nmol/l, and treatment was discontinued. After eight days, the condition stabilised, and low-dose clozapine treatment was successfully reinstituted with serum monitoring (TDM).

Tacrine is not an ideal probe drug for measuring CYP1A2 activity in vivo.

AIMS: The aim of the present study was to examine the CYP1A2 substrate tacrine as a possible alternative to caffeine for assessing CYP1A2 activity in vivo. METHODS: Eighteen, healthy, nonsmoking men participated. Each volunteer was tested by caffeine (200 mg orally), and caffeine metabolic ratios were calculated. Subsequently, on two occasions, separated by at least 4 weeks, each volunteer was tested with tacrine (40 mg orally). The apparent oral clearance, partial clearances and different metabolic ratios of tacrine were determined. RESULTS: The median oral clearances of tacrine in the two study periods were 1893 l h-1 (range: 736-3098) and 1890 l h-1 (range: 438-4175), respectively. The interindividual coefficient of variation was 42% and 49%, respectively. The intraindividual coefficients of variation ranged from 0.28% to 64% (median: 13%). In both study periods, the oral clearance of tacrine correlated with the caffeine urinary metabolic ratio. However, only modest magnitudes of correlation were observed (rs: 0.64-0.66, P<0. 01). No tacrine metabolic ratio correlating with the oral clearance of tacrine was found. Conclusion The applicability of tacrine as a probe drug for measuring CYP1A2 activity in vivo appears limited.

Fluvoxamine is a potent inhibitor of tacrine metabolism in vivo.

OBJECTIVE: In vitro studies have shown that tacrine is metabolized by cytochrome P4501A2 (CYP1A2). One of the monohydroxy-metabolites has been incriminated with tacrine-induced hepatotoxicity. The aim of this study was to establish whether the potent CYP1A2 inhibitor fluvoxamine in clinically relevant doses could inhibit tacrine metabolism. METHODS: Eighteen healthy young men were enrolled in an open, randomized crossover study. In the first study period a single oral dose of tacrine 40 mg was given. In the second period the volunteers were randomized to maintenance doses of fluvoxamine 50 or 100 mg per day, and a single oral dose of tacrine 20 mg was given. RESULTS: Fluvoxamine was found to be a very potent inhibitor of tacrine metabolism. A fractional decrement in tacrine clearance of approximately 85% was found with both fluvoxamine doses, which was in good agreement with a prediction based on in vitro data. The medians of the steady-state concentration of fluvoxamine were 43 nM (range 25-49) and 70 nM (range 44-124) in the 50 mg per day and 100 mg per day groups, respectively. The steady-state concentration of fluvoxamine correlated with the fractional decrement in tacrine clearance (Spearman Rs = 0.53, P < 0.05). Modest, but statistically significant, reductions in the formation of the metabolites 1- and 2-hydroxytacrine were found during concomitant fluvoxamine treatment. CONCLUSION: Fluvoxamine at clinically relevant doses is a potent inhibitor of tacrine metabolism. This interaction is very likely to have clinical relevance. Whether concomitant fluvoxamine treatment reduces tacrine-induced hepatotoxicity needs further study.

Negative information weighs more heavily on the brain: the negativity bias in evaluative categorizations.

Negative information tends to influence evaluations more strongly than comparably extreme positive information. To test whether this negativity bias operates at the evaluative categorization stage, the authors recorded event-related brain potentials (ERPs), which are more sensitive to the evaluative categorization than the response output stage, as participants viewed positive, negative, and neutral pictures. Results revealed larger amplitude late positive brain potentials during the evaluative categorization of (a) positive and negative stimuli as compared with neutral stimuli and (b) negative as compared with positive stimuli, even though both were equally probable, evaluatively extreme, and arousing. These results provide support for the hypothesis that the negativity bias in affective processing occurs as early as the initial categorization into valence classes.

Determination of tacrine and its metabolites in human plasma and urine by high-performance liquid chromatography and fluorescence detection.

A new method for the simultaneous quantitation of tacrine and the three metabolites, 1-hydroxytacrine (velnacrine, maleate), 2-hydroxytacrine and 4-hydroxytacrine, in human plasma and urine has been developed. The method was based on simple one-step liquid-liquid extraction with ethyl acetate followed by isocratic, reversed-phase high-performance liquid chromatography and fluorescence detection (excitation: 330 nm and emission: 365 nm). The limit of detection in plasma was 0.5 nM for 2-hydroxytacrine and 4-hydroxytacrine, 2 nM for 1-hydroxytacrine and tacrine. In urine it was 60 nM for 2-hydroxytacrine and 4-hydroxytacrine, 30 nM for 1-hydroxytacrine and 80 nM for tacrine. The limit of quantification in plasma was 2.5 nM for 2-hydroxytacrine and 4-hydroxytacrine, 10 nM for 1-hydroxytacrine and 2 nM for tacrine. In urine it was 120 nM for all components. The overall mean recoveries ranged from 84 to 105% in plasma and from 64 to 100% in urine for all four compounds.

Utilization of glutathione (L-gamma-glutamyl-L-cysteinylglycine) by Fusobacterium nucleatum subspecies nucleatum.

Although fusobacteria use amino acids and peptides as energy source, it is not known whether they are able to actively transport peptides into the cell. In the present study the tripeptide glutathione was used as a model substance to investigate peptide uptake in Fusobacterium nucleatum subsp. nucleatum. Cells harvested after 2 days of growth on blood agar or in their exponential growth phase in broth were suspended in buffer with glutathione, L-cysteinylglycine and L-cysteine. As a measure of cell uptake, the formation of hydrogen sulfide was followed. Cells from blood agar had a low capacity to form hydrogen sulfide from the tripeptide glutathione and the dipeptide L-cysteinylglycine. However, hydrogen sulfide was formed from L-cysteinylglycine, but not from glutathione or from L-cysteine, by cells grown in broth in such a way that it strongly indicated an active transport of L-cysteinylglycine with a Km of 18 microM. Hydrogen sulfide was efficiently formed from glutathione by cells grown in broth in the presence 1 mM glutathione. In these cells a glycylglycine-dependent L-gamma-glutamyl peptidase activity was induced. It is probable that the efficient utilization of glutathione for hydrogen sulfide formation mirrored the uptake of L-cysteinylglycine after an L-gamma-glutamyl peptidase had split L-glutamate off from glutathione.

Peptostreptococcus micros has a uniquely high capacity to form hydrogen sulfide from glutathione.

There are high amounts of hydrogen sulfide in deep periodontal pockets. This volatile sulfur compound may be formed from L-cysteine, but only low levels of this amino acid can be expected to be present in periodontal pockets. Glutathione, L-gamma-glutamyl-L-cysteinylglycine, is in high concentration in most tissue cells, and this tripeptide may be more readily available as a source of hydrogen sulfide formation in the pockets. The ability of 37 different species of oral bacteria to utilize glutathione in hydrogen sulfide formation was studied. Of these species, only 2 species of Peptostreptococcus and 5 species of Fusobacterium formed high amounts of hydrogen sulfide from glutathione within 24 h. Since the initial rate of hydrogen sulfide formation was more than 5 times higher in Peptostreptococcus micros than in any of the other bacterial species, the kinetics of sulfide formation from glutathione by P. micros was further elucidated. The formation of sulfide followed quite closely hyperbolic Michaelis-Menten kinetics. The maximal initial rate of sulfide formation (Vmax) was 163 +/- 2 nmol sulfide per minute per milligram of cellular protein. Half maximal initial rate (Km) was obtained at 7.4 +/- 0.8 microM glutathione. The initial rate of sulfide formation from L-cysteine was much slower and was almost proportional to L-cysteine concentration. This difference in kinetics of sulfide formation between glutathione and L-cysteine strongly suggested that glutathione was actively transported into the cell, whereas the transport of L-cysteine was more or less controlled by diffusion. The sulfide formation from the dipeptide L-cysteinylglycine also followed quite closely hyperbolic Michaelis-Menten kinetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Four major transcriptional responses in the methionine/threonine biosynthetic pathway of Saccharomyces cerevisiae.

Genes encoding enzymes in the threonine/methionine biosynthetic pathway were cloned and used to investigate their transcriptional response to signals known to affect gene expression on the basis of enzyme specific-activities. Four major responses were evident: strong repression by methionine of MET3, MET5 and MET14, as previously described for MET3, MET2 and MET25; weak repression by methionine of MET6; weak stimulation by methionine but no response to threonine was seen for THR1, HOM2 and HOM3; no response to any of the signals tested, for HOM6 and MES1. In a BOR3 mutant, THR1, HOM2 and HOM3 mRNA levels were increased slightly. The stimulation of transcription by methionine for HOM2, HOM3 and THR1 is mediated by the GCN4 gene product and hence these genes are under the general amino acid control. In addition to the strong repression by methionine, MET5 is also regulated by the general control.