[Inter-sectoral costs and benefits arising from mental health (disorders)]. / Intersectorale kosten en baten van geestelijke (on)gezondheid.

BACKGROUND: Mental health disorders may bring costs and benefits to areas and sectors lying outside the health care system. However, little is known about these inter-sectoral costs and benefits (ICBs) in spite of the increasing interest in societal cost-benefit analyses (SCBA) that attempt to quantify all costs and benefits involved.
AIM: To present a first inventory of ICBs relating to mental health care and to describe the relation between ICBs and SCBA.
METHOD: We reviewed the literature and conducted a secondary analysis of the results of a previous study.
RESULTS: We found that at least eight mental health disorders were reported to have a (financial) impact on at least three sectors outside the health care system.
CONCLUSION: Further research into ICBs is needed so that future inter-sectoral policy can be better directed and targeted more efficiently.

Methods for think-aloud interviews in health-related resource-use research: the PECUNIA RUM instrument.

BACKGROUND: The think-aloud (TA) approach is a qualitative research method that allows for gaining insight into thoughts and cognitive processes. It can be used to incorporate a respondent's perspective when developing resource-use measurement (RUM) instruments. Currently, the application of TA methods in RUM research is limited, and so is the guidance on how to use them. Transparent publication of TA methods for RUM in health economics studies, which is the aim of this paper, can contribute to reducing the aforementioned gap. METHODS: Methods for conducting TA interviews were iteratively developed by a multi-national working group of health economists and additional qualitative research expertise was sought. TA interviews were conducted in four countries to support this process. A ten-step process was outlined in three parts: Part A 'before the interview' (including translation, recruitment, training), Part B 'during the interview' (including setting, opening, completing the instrument, open-ended questions, closing), and part C 'after the interview' (including transcription and data analysis, trustworthiness). CONCLUSIONS: This manuscript describes the step-by-step approach for conducting multi-national TA interviews with potential respondents of the PECUNIA RUM instrument. It increases the methodological transparency in RUM development and reduces the knowledge gap of using qualitative research methods in health economics.

International comparability of reference unit costs of education services: when harmonizing methodology is not enough (PECUNIA project).

BACKGROUND: Health problems can lead to costs in the education sector. However, these costs are rarely incorporated in health economic evaluations due to the lack of reference unit costs (RUCs), cost per unit of service, of education services and of validated methods to obtain them. In this study, a standardized unit cost calculation tool developed in the PECUNIA project, the PECUNIA RUC Template for services, was applied to calculate the RUCs of selected education services in five European countries. METHODS: The RUCs of special education services and of educational therapy were calculated using the information collected via an exploratory gray literature search and contact with service providers. RESULTS: The RUCs of special education services ranged from €55 to €189 per school day. The RUCs of educational therapy ranged from €6 to €25 per contact and from €5 to €35 per day. Variation was observed in the type of input data and measurement unit, among other. DISCUSSION: The tool helped reduce variability in the RUCs related to costing methodology and gain insights into other aspects that contribute to the variability (e.g. data availability). Further research and efforts to generate high quality input data are required to reduce the variability of the RUCs.

Preclinical mouse models for BRCA1-associated breast cancer.

A substantial part of all hereditary breast cancer cases is caused by BRCA1 germline mutations. In this review, we will discuss the insights into BRCA1 functions that we obtained from mouse models with conventional and conditional mutations in Brca1. The most advanced models closely resemble human BRCA1-related breast cancer and may therefore be useful for addressing clinically relevant questions.

FOXA1 repression is associated with loss of BRCA1 and increased promoter methylation and chromatin silencing in breast cancer.

FOXA1 expression correlates with the breast cancer luminal subtype and patient survival. RNA and protein analysis of a panel of breast cancer cell lines revealed that BRCA1 deficiency is associated with the downregulation of FOXA1 expression. Knockdown of BRCA1 resulted in the downregulation of FOXA1 expression and enhancement of FOXA1 promoter methylation in MCF-7 breast cancer cells, whereas the reconstitution of BRCA1 in Brca1-deficent mouse mammary epithelial cells (MMECs) promoted Foxa1 expression and methylation. These data suggest that BRCA1 suppresses FOXA1 hypermethylation and silencing. Consistently, the treatment of MMECs with the DNA methylation inhibitor 5-aza-2'-deoxycitydine induced Foxa1 mRNA expression. Furthermore, treatment with GSK126, an inhibitor of EZH2 methyltransferase activity, induced FOXA1 expression in BRCA1-deficient but not in BRCA1-reconstituted MMECs. Likewise, the depletion of EZH2 by small interfering RNA enhanced FOXA1 mRNA expression. Chromatin immunoprecipitation (ChIP) analysis demonstrated that BRCA1, EZH2, DNA methyltransferases (DNMT)1/3a/3b and H3K27me3 are recruited to the endogenous FOXA1 promoter, further supporting the hypothesis that these proteins interact to modulate FOXA1 methylation and repression. Further co-immunoprecipitation and ChIP analysis showed that both BRCA1 and DNMT3b form complexes with EZH2 but not with each other, consistent with the notion that BRCA1 binds to EZH2 and negatively regulates its methyltransferase activity. We also found that EZH2 promotes and BRCA1 impairs the deposit of the gene silencing histone mark H3K27me3 on the FOXA1 promoter. These associations were validated in a familial breast cancer patient cohort. Integrated analysis of the global gene methylation and expression profiles of a set of 33 familial breast tumours revealed that FOXA1 promoter methylation is inversely correlated with the transcriptional expression of FOXA1 and that BRCA1 mutation breast cancer is significantly associated with FOXA1 methylation and downregulation of FOXA1 expression, providing physiological evidence to our findings that FOXA1 expression is regulated by methylation and chromatin silencing and that BRCA1 maintains FOXA1 expression through suppressing FOXA1 gene methylation in breast cancer.

The pharmacokinetics of intradural morphine in major abdominal surgery.

The pharmacokinetics of intradural morphine used for major abdominal surgery were evaluated. Lumbar spinal fluid and plasma concentrations were measured at intervals after morphine 0.05 mg/kg had been injected intradurally in 21 patients scheduled for elective abdominal aortic surgery. The CSF morphine concentrations were fitted by a biexponential function. A non-compartmental model based on statistical moment theory was used for calculating the intradural morphine disposition. Mean residence time was 137 +/- 54.9 minutes, mean initial volume of distribution 15 +/- 5.49 ml, mean volume of distribution at steady-state 42 +/- 18.25 ml and mean clearance 0.34 +/- 0.18 ml/min (0.02 +/- 0.01 L/h). The moments of the morphine concentration-time curves and the pharmacokinetic parameters varied between the patients. They were not significantly different with regard to morphine dosage, or patient sex or age. Free morphine could not be detected in plasma. Morphine-3-glucuronide appeared in plasma at 5 minutes, increased to a maximum at 240 minutes and fell below the detection limit at about 16 hours after morphine administration. Possible clinical causes of interindividual variations in the CSF morphine concentrations and the pharmacokinetics of intradural morphine are discussed.

Visualization of flow patterns from stents and stent-grafts in an in vitro flow-model.

RATIONALE AND OBJECTIVES: The authors determine flow characteristics and pressure gradients of different stents and stent grafts in an in vitro flow-model. METHODS: Five vascular stents (Memotherm, Cragg, two Palmaz P308, Strecker, and Wall) and one stent graft (Cragg EndoPro System 1), equal in length (60 mm) and diameter (10 mm), were deployed in a closed flow-model. The inner diameter of the tube measured 9 mm. Flow at 1.5 L/min, 6 L/min, and 10 L/min was simulated. Flow patterns were visualized by anionic particles illuminated with two Helium-Neon lasers. Laminary flow characteristics and pre-/poststent pressure gradients were determined in either expanded stent, 25% stenosis, or 50% stenosis. RESULTS: Stent implantation induced a decrease of laminary flow compared with an unstented tube with and without concentric 25% stenosis (P < 0.01) at all flow rates and an increase of pressure gradients compared with an unstented tube for flow rates greater than 1.5 L/min (P < 0.01) (except for Cragg EndoPro System 1 stent, which revealed an increase of the pressure gradient at a flow rate of 1.5 L/min [P < 0.01]). Memotherm stent permitted maximum of laminary flow at all flow rates and stenoses (expanded: 79.50% at 1.5 L/min to 69.90% at 10 L/min; P < 0.01). Memotherm and Palmaz permitted lowest pressure gradients (P < 0.01). All of the endoprostheses demonstrated laminary flow at 50% stenosis. CONCLUSIONS: The investigated stents and stent grafts showed different severity of flow disturbances and pressure gradients at different graded stenoses. Inadequate stent depolyment bears the risk of creating less laminary flow and pathologic pressure gradients. Because flow disturbances and pressure gradients may influence neointimal hyperplasia, stent design and completeness of stent unfolding are important regarding the appearance of postinterventional restenoses.

The registration of medicines in The Netherlands.

The working methods and the results of the system for registration of medicines in the Netherlands are reviewed. The new structure of the Committee for the Evaluation of Medicines is identified. The necessity for more international cooperation is emphasized. The authors propose the establishment of a European registration committee. The current system is discussed from the viewpoints of government and industry.

A comparative study of the homogeneous enzyme immunoassay (EMIT) and two radioimmunoassays (RIA's) for digoxin.

Our experience with the determination of digoxin in plasma or serum using a homogeneous enzyme immunoassay technique (EMIT) is reported. The day-to-day precision of the EMIT digoxin assay was investigated with different series of calibrators. Coefficients of variation varied from 10 to 25 percent in the range of 0.65--7.0 ng digoxin/ml. The accuracy was established by determining the mean recovery (96 percen) of spiked serum samples (0.0--6.0 ng digoxin/ml). The cross reactivity of structure related compounds: digitoxin, spironolactone (Aldactone) and prednisone were investigated. Amniotic fluid, umbilical cord serum and serum of pregnant patients were examined for false positive reaction. Serum samples of 111 patients from two hospitals, who were treated with digoxin, were analysed by EMIT and 3H-radioimmunoassay (RIA); 38 of these samples were also determined by 125I-RIA. A good correlation was found between EMIT assay and these techniques (r =0.90 and 0.91, respectively).

Opportunities and hurdles in the treatment of BRCA1-related breast cancer.

BRCA1 functions as a classical tumor suppressor in breast and ovarian cancer. While the role of BRCA1 in homology-directed repair of DNA double-strand breaks contributes to its tumor suppressive activity, it also renders BRCA1-deficient cells highly sensitive to DNA-damaging agents. Although BRCA1 deficiency is therefore considered to be an attractive therapeutic target, re-activation of BRCA1 by secondary mutations has been shown to cause therapy resistance. In this review, we will assess the role of BRCA1 in both hereditary and sporadic breast cancer and discuss how different functionalities of the BRCA1 protein can contribute to its tumor suppressor function. In addition, we will discuss how this knowledge on BRCA1 function can help to overcome the hurdles encountered in the clinic and improve current treatment strategies for patients with BRCA1-related breast cancer.

Site-Dependent Coordination Bonding in Self-Assembled Metal-Organic Networks.

The combination of organic linkers with metal atoms on top of inorganic substrates offers promising perspectives for functional electronic and magnetic nanoscale devices. Typically, coordination bonds between electron-rich end groups and transition-metal atoms lead to the self-assembly of metal-organic nanostructures, whose shape and electronic and magnetic properties crucially depend on the type of ligand. Here, we report on the site-selective bonding properties of Co atoms to the dichotomic dicyanoazobenzene molecule with its carbonitrile and diazo N-based moieties as possible ligands. Using low-temperature scanning tunneling microscopy (STM) and spectroscopy measurements, we resolve the formation of self-assembled metal-organic motifs. Cobalt atoms exhibit a clear spectroscopic fingerprint dependent on the different coordination site, which is further used to map their position, otherwise not clearly visible in the topographic STM images. Density functional theory corroborates the observed bonding patterns and evidences their coordinative nature.

Evaluation of the EMIT-st serum ethyl alcohol assay in toxicology.

An evaluation of the EMIT-st serum alcohol assay is reported. Although the assay was developed as a qualitative procedure, the day-to-day precision of the test with respect to the differences in absorbance (delta A) was evaluated, in order to establish its applicability for quantitative analyses. The mean values +/- SD (n = 10) for the delta A of the positive control and the cutoff calibrator were 146 +/- 14 (CV = 9.6%) and 57 +/- 5 (CV = 8.8%) respectively. The detection limit of the assay was 0.3 mg/ml ethanol. A series of spiked serum samples with ethanol concentrations in the range of 0.1 to 4.0 mg/ml was analyzed in triplicate by EMIT-st and by gas chromatography. Qualitatively, the correlation between these two methods was nearly 100 percent. For the EMIT-st assay, the response was only linear between 0.3 and 2.0 mg/ml ethanol. Concentrations higher than 2.0 mg/ml showed no pronounced difference in absorbance measurements. Serum samples (n = 54) of people involved in automobile driver alcohol blood checks were analyzed by EMIT-st and the results were compared to the corresponding gas chromatographic data. In the range up to 2.0 mg/ml ethanol, a linear regression curve was calculated with a slope of 76.7, a y-intercept of 36.4, and a correlation coefficient of 0.79. Spiked serum samples at concentrations of the calibrator and the positive control as provided by Syva appeared to be identical in delta A response.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term release of copper from two multiload IUD models: MLCu250 and MLCu375.

Decrease of mean copper content was assessed for two commercial types of Multiload IUD with different copper loads. Mean daily loss of copper amounted to about 18 mcg and 30 mcg for MLCu250 and MLCu375 devices, respectively. On the basis of these estimates, we conclude that both these IUD models can be considered long-lasting interceptive agents.