Analysis of free cisplatin in microdialysates and plasma ultrafiltrate by liquid chromatography-tandem mass spectrometry.

Cisplatin is a potent cytotoxic agent used in the treatment of various malignancies and exerts its antitumor effect through malignant cell DNA damage and apoptosis induction. Evaluation of systemic delivery of cisplatin is important in optimization of cisplatin treatment. However, accurate quantification of systemic cisplatin is challenging due to its various forms in circulation. This study aimed to develop a sensitive (LOQ < 0.1 µg/mL) and precise Ultra Performance Liquid Chromatography (UPLC) - Tandem Mass Spectrometry (MS/MS) method for quantifying free cisplatin in microdialysates and plasma. Furthermore the aim was to compare free cisplatin concentrations measured in standard plasma samples with those obtained from intravenous microdialysis catheters in a porcine model. The method developed utilizes dichloro(ethylenediamine)platinum(II) as an internal standard that co-elutes with cisplatin, ensuring precise correction for ion suppression/enhancement effects. The method was validated, demonstrating linearity up to 100 µg/mL and good intermediate precision (CV% < 6 %) in the range of 1.0-100 µg/mL, with an LOQ of 0.03 µg/mL. The pharmacokinetic parameters (AUC0-last, Cmax, T1/2, and Tmax) showed no significant differences between the two sampling methods. This validated LC-MS/MS method provides a reliable tool for quantifying systemic free cisplatin concentrations, facilitating future systemic and local pharmacokinetic evaluations for optimization of cisplatin-based cancer treatments.

Dynamic changes in renal sodium handling during sympathetic stimulation in healthy human males.

The temporal response of changes in renal sodium reabsorption during increased renal sympathetic nerve activity has not been investigated. Central hypovolemia by application of lower-body negative-pressure (LBNP) elicits baroreceptor mediated sympathetic reflexes to maintain arterial blood pressure. We hypothesized, that during 90 min LBNP, the renal sodium retention would increase rapidly, remain increased during intervention, and return to baseline immediately after end of intervention. METHODS: 30 young, healthy, sodium loaded, non-obese males were exposed to -15 mmHg LBNP, -30 mmHg LBNP, -15 mmHg LBNP + renin blockade or time-control (0 mmHg LBNP) for 90 min. Urine was collected every 15 min during 90 min of intervention and 60 min of recovery to identify a possible relation between time of intervention and renal response. RESULTS: All intervention groups exhibited a comparable reduction in distal sodium excretion at the end of the intervention (P = 0.46 between groups; -15 mmHg: -3.1 ± 0.9 %, -30 mmHg: -2.9 ± 0.6 %, -15 mmHg + aslikiren: -1.8 ± 0.6 %). -15 mmHg+Aliskiren resulted in a slower onset, but all groups exhibited a continued reduction in sodium excretion after 1 h of recovery despite return to baseline of renin, aldosterone, diuresis and cardiovascular parameters. CONCLUSION: Sympathetic stimulation for 90 min via LBNP at -30 mmHg LBNP compared to -15 mmHg did not result in a greater response in fractional Na+ excretion, suggesting that additional baroreceptor unloading did not cause further increases in renal sodium reabsorption. Changes in distal Na+ excretion were linear with respect to time (dose) of intervention, but seem to exhibit a saturation-like effect at a level around 4 %. The lack of recovery after 1 h is also a new finding that warrants further investigation.

Differential gene expression indicates modulated responses to chronic and intermittent hypoxia in corallivorous fireworms (Hermodice carunculata).

Climate models predict an increase in extent, frequency, and duration of marine hypoxia events in the twenty first century. A better understanding of organismal responses to hypoxia in individual species is a crucial step for predicting ecosystem responses. We experimentally subjected a common invertebrate, the bearded fireworm (Hermodice carunculata) to two levels of chronic hypoxia and, in a separate experiment, to intermittent hypoxia. We found components of the conserved hypoxia-inducible factor (HIF) pathway and show a modulated response to hypoxia depending on the severity of hypoxic stress: under mild hypoxia, only the HIF-1α subunit is upregulated, while expression of the other subunit, aryl hydrocarbon nuclear translator, only increases significantly at more severe hypoxia levels. The chronic trials revealed down-regulation of genes related to cell adhesion, transport, development and heme-binding, and up-regulation of genes related to glycolysis, oxygen binding, cell differentiation, digestive and reproductive function. The intermittent hypoxia trials revealed an upregulation of heme transporter activity during hypoxia, and our time series analysis characterized nine clusters of genes with similar expression patterns. Our findings suggest that H. carunculata is likely to tolerate, and be resilient to, predicted future hypoxia conditions.

Low attendance by non-native women to human papillomavirus vaccination and cervical cancer screening - A Danish nationwide register-based cohort study.

BACKGROUND: Cervical cancer is preventable through human papillomavirus vaccination and cervical cancer screening. However, possibly due to systemic, individual (e.g. low socio-economic staus) and socio-cultural barriers, it is likely that non-natives, especially non-westerns, are more prone to attend neither vaccination nor screening (combined non-attendance). This is disturbing as the non-native population in Denmark is predicted to rise to 21% by 2060. We aimed to investigate differences in combined non-attendance by nativity and region of origin, and to analyse the association between country of origin and combined non-attendance adjusted for socio-economic status. SETTING: 1.6.2007-31.12.2016 Denmark. METHODS: Logistic regression was performed to estimate crude and adjusted odds ratios with 95% confidence intervals for combined non-attendance. RESULTS: 170,158 women were included. Overall combined non-attendance was 11.8% [11.7-12.0]; 10.0% [9.8-10.1] for native women and 27.1% [26.4-27.7] for non-native women, with highest degrees among Middle-Eastern and North-Africans (30.1% [29.2-30.9]). Even when adjusted for socio-economics, women from Middle-East and North-Africa had substantially higher odds of combined non-attendance than natives (adj. OR = 7.5 [6.3-8.9] for Somali women). CONCLUSION: Denmark has a relatively low degree of combined non-attendance. However, cervical cancer preventive programmes seem to be better tailored to the needs of native women and do not appear to cater sufficiently to the needs of the fast-growing non-native populations, particularly not to the needs of Middle-Eastern and North African women. In order to secure more just cervical cancer prevention, future studies are recommended to develop tailored intervention sensitive to the need of non-native women.

Validity and reliability of State-Trait Anxiety Inventory in Danish women aged 45 years and older with abnormal cervical screening results.

BACKGROUND: State Trait Anxiety Inventory (STAI) scale was developed in the 1980's and has been widely used both in clinical settings and in research. However the Danish version of STAI has not been validated. The aim of this study was to assess the validity and reliability of STAI - state anxiety scale in Danish women aged 45 years and older with abnormal cervical cancer screening results. METHODS: Women ≥45 years referred with an abnormal cervical cytology and healthy volunteers (n = 12) underwent cognitive interview after completing STAI. Further, STAI was sent out in an electronic questionnaire to women (n = 109) seen at the gynecological department with abnormal cervical cancer screening test during 2018. Validity and reliability of STAI was evaluated according to the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist by examining internal consistency, test-retest reliability, measurement error, floor and ceiling, construct validity and content validity. RESULTS: In the cognitive interviews the content validity was evaluated to be very good. The internal consistency of the scale was excellent with Cronbach's α = 0.93. Test-retest reliability was good with an intra-class correlation coefficient of 0.80 and the systematic difference between test-retest results was negligible. The construct validity was good. CONCLUSION: To our best knowledge, this is the first validation study of the Danish translation of STAI-state anxiety scale. This version of STAI demonstrates an acceptable reliability and validity when used in a gynecological setting.

Mandibular canal-related parameters interpreted in panoramic images and CBCT of mandibular third molars as risk factors to predict sensory disturbances of the inferior alveolar nerve.

The aim of this study was to determine whether cone beam computed tomography (CBCT) before mandibular third molar removal can improve the risk assessment for neurosensory disturbances of the inferior alveolar nerve (IAN) compared to panoramic radiography (PAN). One hundred and six mandibular third molars examined by PAN and CBCT were removed. A temporary sensory disturbance of the IAN was present in 20 cases; a permanent disturbance was found in one case. Three blinded observers assessed radiographic risk factors in PAN and CBCT images. Positive (PPV) and negative (NPV) predictive values and positive (LR+) and negative (LR-) likelihood ratios were calculated for all parameters for all observers. Inter-observer reproducibility was expressed as both the percentage accordance and the kappa-statistic. Generally, the PPV and LR + were the same for PAN and CBCT, and there was good inter-observer reproducibility. The highest PPV and LR + for PAN were found when part of the roots were positioned inferior to the lower white border line of the canal, and for CBCT when the canal was positioned between the roots of the tooth. In conclusion, parameters assessed in PAN and CBCT are not reliable risk factors for neurosensory disturbances of the IAN, and CBCT appears not to improve the risk assessment.

Amplification and aural rehabilitation in resource-constrained environments.

OBJECTIVES: This article attempts to highlight the challenges and possibilities for hearing healthcare through technology and aural rehabilitation in a resource-constrained setting, using South Africa as an example.Results and conclusionThe authors argue that it is possible to enhance service delivery by using free resources and maximising the limited existing resources. In order to provide a sustainable hearing healthcare service in developing countries, it is pertinent to understand the context where the services are needed, and not just adopt an approach developed for a different context. Audiologists in such settings need to employ strategies to develop context-specific tools, and adapt existing tools to serve the needs of the local population. Some examples, although not exhaustive, are provided in the article.

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.

Local recurrence rate in a national Danish patient cohort after curative treatment for rectal cancer.

AIM: Several trials have shown that preoperative (chemo)radiotherapy (CRT) reduces local recurrence rates (LRRs) in rectal cancer (RC). The use of CRT varies greatly between countries. It is unknown whether the restrictive use of CRT in Denmark results in a higher LRR relative to other countries. The aim was to evaluate the LRR in a national Danish consecutive cohort of patients with RC. METHODS: All data from patients with RC in Denmark in 2009-2010 who were operated on with curative intent were retrieved from the Danish Colorectal Cancer Group database. Patients with metastases at the time of diagnosis, patients with synchronous colon cancer, and patients, in whom only local surgical procedures were performed, were excluded. In total, 1633 patients met the inclusion criteria. Clinical follow-up was at least five years with a cut-off date of 31 December 2015. RESULTS: Clinical follow-up was 5.4 years (median) with an interquartile range of 4.5-6.1 years. Of all included patients, 479 (29%) were treated with preoperative long-course CRT. Local recurrence was found in 68 patients, resulting in an LRR of 4.2%, and 182 (11%) patients developed distant metastases. Five-year overall survival was 74% (95% CI: 71.64-75.91). CONCLUSIONS: Five-year follow-up of curatively treated patients with RC in Denmark revealed a low LRR. This figure is identical to those reported in other Nordic countries, despite Denmark's considerably stricter guidelines for CRT. The obtained results justify the currently adopted restrictive use of preoperative CRT in Denmark.

Effects of chronic exposure to 12‰ saltwater on the endocrine physiology of juvenile American alligator (Alligator mississippiensis).

American alligator (Alligator mississippiensis) habitats are prone to saltwater intrusion following major storms, hurricanes or droughts. Anthropogenic impacts affecting hydrology of freshwater systems may exacerbate saltwater intrusion into freshwater habitats. The endocrine system of alligators is susceptible to changes in the environment but it is currently not known how the crocodilian physiological system responds to environmental stressors such as salinity. Juvenile alligators were exposed to 12‰ saltwater for 5 weeks to determine the effects of chronic exposure to saline environments. Following 5 weeks, plasma levels of hormones [e.g. progesterone, testosterone, estradiol, corticosterone, aldosterone (ALDO), angiotensin II (ANG II)] were quantified using liquid chromatography and tandem mass spectrometry. Compared with freshwater-kept subjects, saltwater-exposed alligators had significantly elevated plasma levels of corticosterone, 11-deoxycortisol, 17α-hydroxyprogesterone, testosterone, 17ß-estradiol, estrone and estriol whereas pregnenolone and ANG II were significantly depressed and ALDO levels were unchanged (slightly depressed). On the one hand, saltwater exposure did not affect gene expression of renal mineralocorticoid and glucorticoid and angiotensin type 1 (AT-1) receptors or morphology of lingual glands. On the other hand, saltwater exposure significantly reduced plasma glucose concentrations whereas parameters diagnostic of perturbed liver function (aspartate aminotransferase and alanine aminotransferase) and kidney function (creatinine and creatine kinase) were significantly elevated. Except for plasma potassium levels (K+), plasma ions Na+ and Cl- were significantly elevated in saltwater alligators. Overall, this study demonstrated significant endocrine and physiological effects in juvenile alligators chronically exposed to a saline environment. Results provide novel insights into the effects of a natural environmental stressor (salinity) on the renin-angiotensin-aldosterone system and steroidogenesis of alligators.

Factor Xa and VIIa inhibition by tissue factor pathway inhibitor is prevented by a monoclonal antibody to its Kunitz-1 domain.

Essentials Activated FVII (FVIIa) and FX (FXa) are inhibited by tissue factor pathway inhibitor (TFPI). A monoclonal antibody, mAb2F22, was raised against the N-terminal fragment of TFPI (1-79). mAb2F22 bound exclusively to the K1 domain of TFPI (KD ∼1 nm) and not to the K2 domain. mAb2F22 interfered with inhibition of both FVIIa and FXa activities and restored clot formation. SUMMARY: Background Initiation of coagulation is induced by binding of activated factor VII (FVIIa) to tissue factor (TF) and activation of factor X (FX) in a process regulated by tissue factor pathway inhibitor (TFPI). TFPI contains three Kunitz-type protease inhibitor domains (K1-K3), of which K1 and K2 block the active sites of FVIIa and FXa, respectively. Objective To produce a monoclonal antibody (mAb) directed towards K1, to characterize the binding epitope, and to study its effect on TFPI inhibition. Methods A monoclonal antibody, mAb2F22, was raised against the N-terminal TFPI(1-79) fragment. Binding data were obtained by surface plasmon resonance analysis. The Fab-fragment of mAb2F22, Fab2F22, was expressed and the structure of its complex with TFPI(1-79) determined by X-ray crystallography. Effects of mAb2F22 on TFPI inhibition were measured in buffer- and plasma-based systems. Results mAb2F22 bound exclusively to K1 of TFPI (KD ~1 nm) and not to K2. The crystal structure of Fab2F22/TFPI (1-79) mapped an epitope on K1 including seven residues upstream of the domain. TFPI inhibition of TF/FVIIa amidolytic activity was neutralized by mAb2F22, although the binding epitope on K1 did not include the P1 residue. Binding of mAb2F22 to K1 blocked TFPI inhibition of the FXa amidolytic activity and normalized hemostasis in hemophilia human A-like plasma and whole blood. Conclusion mAb2F22 blocked TFPI inhibition of both FVIIa and FXa activities and mapped a FXa exosite for binding to K1. It reversed TFPI feedback inhibition of TF/FVIIa-induced coagulation and restored clot formation in FVIII-neutralized human plasma and blood.

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.

COMT Val158Met and MTHFR C677T moderate risk of schizophrenia in response to childhood adversity.

OBJECTIVE: Mesolimbic dopamine sensitization has been hypothesized to be a mediating factor of childhood adversity (CA) on schizophrenia risk. Activity of catechol-O-methyltransferase (COMT) Val158Met increases mesolimbic dopamine signaling and may be further regulated by methylenetetrahydrofolate reductase (MTHFR) C677T. This study investigates the three-way interaction between CA, COMT, and MTHFR. METHODS: We conducted a nested case-control study on individuals born after 1981, linking population-based registers to study the three-way interaction. We included 1699 schizophrenia cases and 1681 controls, and used conditional logistic regression to report incidence rate ratios (IRRs). RESULTS: Childhood adversity was robustly associated with schizophrenia. No main genetic effects were observed. MTHFR C677T increased schizophrenia risk in a dose-dependent manner per MTHFR T allele (P = 0.005) consequent upon CA exposure. After inclusion of the significant (P = 0.03) COMT × MTHFR × CA interaction, the risk was further increased per high-activity COMT Val allele. Hence, exposed COMT Val/Val and MTHFR T/T carriers had an IRR of 2.76 (95% CI, 1.66-4.61). Additional adjustments for ancestry and parental history of mental illness attenuated the results with the interaction being only marginally significant. CONCLUSION: MTHFR C677T and COMT Val158Met interact with CA to increase risk of schizophrenia.

Adjuvant FOLFOX +/- cetuximab in full RAS and BRAF wildtype stage III colon cancer patients.

Background: RAS mutations have been shown to confer resistance to anti- epidermal growth factor receptor (EGFR) treatment. We analysed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer. Patients and methods: Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumours harbouring RAS and BRAF WT, and RAS mutations. The prognostic value of each individual mutation was also tested. Results: Among the 2559 pts analysed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAF V600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2, 3, 4 or NRAS exon 2, 3, 4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS and BRAF WT tumours (HR 0.77-1.03, all P > 0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAF V600E mutations. Conclusion: Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favour of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancer pts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting. Clinical trial number: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.

Incidence of West Nile virus infection in the Dallas-Fort Worth metropolitan area during the 2012 epidemic.

The 2012 West Nile virus (WNV) epidemic was the largest since 2003 and the North Texas region was the most heavily impacted. We conducted a serosurvey of blood donors from four counties in the Dallas-Fort Worth area to characterize the epidemic. Blood donor specimens collected in November 2012 were tested for WNV-specific antibodies. Donors positive for WNV-specific IgG, IgM, and neutralizing antibodies were considered to have been infected in 2012. This number was adjusted using a multi-step process that accounted for timing of IgM seroreversion determined from previous longitudinal studies of WNV-infected donors. Of 4971 donations screened, 139 (2·8%) were confirmed WNV IgG positive, and 69 (1·4%) had IgM indicating infection in 2012. After adjusting for timing of sampling and potential seroreversion, we estimated that 1·8% [95% confidence interval (CI) 1·5-2·2] of the adult population in the Dallas-Fort Worth area were infected during 2012. The resulting overall estimate for the ratio of infections to reported WNV neuroinvasive disease (WNND) cases was 238:1 (95% CI 192-290), with significantly increased risk of WNND in older age groups. These findings were very similar to previous estimates of infections per WNND case, indicating no change in virulence as WNV evolved into an endemic infection in the United States.

Infections and exposure to anti-infective agents and the risk of severe mental disorders: a nationwide study.

OBJECTIVE: Severe infections are associated with increased risks of mental disorders; however, this is the first large-scale study investigating whether infections treated with anti-infective agents in the primary care setting increase the risks of schizophrenia and affective disorders. METHOD: We identified all individuals born in Denmark 1985-2002 (N = 1 015 447) and studied the association between infections treated with anti-infective agents and the subsequent risk of schizophrenia and affective disorders during 1995-2013. Cox regression analyses were adjusted for important confounders. RESULTS: Infections treated with anti-infective agents were associated with increased risks of schizophrenia by a hazard rate ratio (HRR) of 1.37 (95%-CI = 1.20-1.57) and affective disorders by a HRR of 1.64 (95%-CI = 1.48-1.82), fitting a dose-response and temporal relationship (P < 0.001). The excess risk was primarily driven by infections treated with antibiotics, whereas infections treated with antivirals, antimycotics, and antiparasitic agents were not significant after mutual adjustment. Individuals with infections requiring hospitalization had the highest risks for schizophrenia (HRR = 2.05; 95%-CI = 1.77-2.38) and affective disorders (HRR = 2.59; 95%-CI = 2.31-2.89). CONCLUSION: Infections treated with anti-infective agents and particularly infections requiring hospitalizations were associated with increased risks of schizophrenia and affective disorders, which may be mediated by effects of infections/inflammation on the brain, alterations of the microbiome, genetics, or other environmental factors.

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.

Respiratory rates measured by a standardised clinical approach, ward staff, and a wireless device.

BACKGROUND: Respiratory rate is among the first vital signs to change in deteriorating patients. The aim was to investigate the agreement between respiratory rate measurements by three different methods. METHODS: This prospective observational study included acutely admitted adult patients in a medical ward. Respiratory rate was measured by three methods: a standardised approach over 60 s while patients lay still and refrained from talking, by ward staff and by a wireless electronic patch (SensiumVitals). The Bland-Altman method was used to compare measurements and three breaths per minute (BPM) was considered a clinically relevant difference. RESULTS: We included 50 patients. The mean difference between the standardised approach and the electronic measurement was 0.3 (95% CI: -1.4 to 2.0) BPM; 95% limits of agreement were -11.5 (95% CI: -14.5 to -8.6) and 12.1 (95% CI: 9.2 to 15.1) BPM. Removal of three outliers with huge differences lead to a mean difference of -0.1 (95% CI: -0.7 to 0.5) BPM and 95% limits of agreement of -4.2 (95% CI: -5.3 to -3.2) BPM and 4.0 (95% CI: 2.9 to 5.0) BPM. The mean difference between staff and electronic measurements was 1.7 (95% CI: -0.5 to 3.9) BPM; 95% limits of agreement were -13.3 (95% CI: -17.2 to -9.5) BPM and 16.8 (95% CI: 13.0 to 20.6) BPM. CONCLUSION: A concerning lack of agreement was found between a wireless monitoring system and a standardised clinical approach. Ward staff's measurements also seemed to be inaccurate.

Functional characterization of the ectopically expressed olfactory receptor 2AT4 in human myelogenous leukemia.

The olfactory receptor (OR) family was found to be expressed mainly in the nasal epithelium. In the last two decades members of the OR family were detected to be functional expressed in different parts of the human body such as in liver, prostate or intestine cancer cells. Here, we detected the expression of several ORs in the human chronic myelogenous leukemia (CML) cell line K562 and in white blood cells of clinically diagnosed acute myeloid leukemia (AML) patients by RT-PCR and next-generation sequencing. With calcium-imaging, we characterized in greater detail the cell biological role of one OR (OR2AT4) in leukemia. In both cell systems, the OR2AT4 agonist Sandalore-evoked strong Ca(2+) influx via the adenylate cyclase-cAMP-mediated pathway. The OR2AT4 antagonist Phenirat prevented the Sandalore-induced intracellular Ca(2+) increase. Western blot and flow cytometric experiments revealed that stimulation of OR2AT4 reduced the proliferation by decreasing p38-MAPK phosphorylation and induced apoptosis via phosphorylation of p44/42-MAPK. Furthermore, Sandalore increased the number of hemoglobin-containing cells in culture. We described for the first time an OR-mediated pathway in CML and AML that can regulate proliferation, apoptosis and differentiation after activation. This mechanism offers novel therapeutic options for the treatment of AML.

Postural influence on intracranial and cerebral perfusion pressure in ambulatory neurosurgical patients.

We evaluated postural effects on intracranial pressure (ICP) and cerebral perfusion pressure [CPP: mean arterial pressure (MAP) - ICP] in neurosurgical patients undergoing 24-h ICP monitoring as part of their diagnostic workup. We identified nine patients (5 women, age 44 ± 20 yr; means ± SD), who were "as normal as possible," i.e., without indication for neurosurgical intervention (e.g., focal lesions, global edema, abnormalities in ICP-profile, or cerebrospinal fluid dynamics). ICP (tip-transducer probe; Raumedic) in the brain parenchyma (n = 7) or in the lateral ventricles (n = 2) and cardiovascular variables (Nexfin) were determined from 20° head-down tilt to standing up. Compared with the supine position, ICP increased during 10° and 20° of head-down tilt (from 9.4 ± 3.8 to 14.3 ± 4.7 and 19 ± 4.7 mmHg; P < 0.001). Conversely, 10° and 20° head-up tilt reduced ICP to 4.8 ± 3.6 and 1.3 ± 3.6 mmHg and ICP reached -2.4 ± 4.2 mmHg in the standing position (P < 0.05). Concordant changes in MAP maintained CPP at 77 ± 7 mmHg regardless of body position (P = 0.95). During head-down tilt, the increase in ICP corresponded to a hydrostatic pressure gradient with reference just below the heart, likely reflecting the venous hydrostatic indifference point. When upright, the decrease in ICP was attenuated, corresponding to formation of a separate hydrostatic gradient with reference to the base of the skull, likely reflecting the site of venous collapse. ICP therefore seems to be governed by pressure in the draining veins and collapse of neck veins may protect the brain from being exposed to a large negative pressure when upright. Despite positional changes in ICP, MAP keeps CPP tightly regulated.