Societal costs and quality of life analysis in patients undergoing resective epilepsy surgery: A one-year follow-up.

Although effectiveness of Resective Epilepsy Surgery (RES) for patients with drug-resistant epilepsy (DRE) is widely proven, research on the impact of societal costs (SC) is lacking. The aim of this study is to provide both clinical and economic outcomes of RES by offering an overview of treatment effectiveness as well as SC of RES in a cohort of 30 Dutch DRE patients. This project serves as a pilot project to offer an up-to-date model for larger cost-effectiveness studies. Medical consumption, productivity losses, disease-specific and generic health-related quality of life (QoL), and seizure frequency were assessed before and 3-, 6-, and 12-months post-surgery with validated questionnaires. Linear mixed models, ANOVAs, and logistic regressions were performed. SC for the first year after RES entailed €54,376 and decreased over time. Moreover, 50% of patients experienced a clinically important increase in disease-specific QoL and 53% of patients in generic health-related QoL. Lastly, 73% of patients reached seizure freedom 12 months postoperative. Seizure reduction was correlated with increase in disease-specific QoL. Within one year after surgery, RES leads to reduction in SC and improvements in QoL over time. Future research should encompass longer follow-up periods, larger sample size, and a cost-effectiveness analysis with a comparator.

Risk factors for behavioral and psychotic dysregulation at the epilepsy monitoring unit in patients with intracranial electrodes.

OBJECTIVE: Aberrant behavior in patients with epilepsy (PWE) admitted to an epilepsy monitoring unit (EMU) can endanger their safety. We sought to identify predictive factors for post-ictal behavioral dysregulation and psychosis in patients with refractory epilepsy being monitored at an EMU. METHODS: Retrospective data were gathered from electronic patient files of all patients with refractory epilepsy who underwent intracranial registration at our EMU. We assessed behavioral and psychotic dysregulations by reviewing clinical notes, administered emergency medication, and reports of injuries or casualties in patients and nurses. In addition, we compared patient demographic characteristics, clinical characteristics, and antiepileptic drug (AED) profiles between patients with and without behavioral and/or psychotic dysregulation. RESULTS: Out of 73 admissions, 23 patients (32%) experienced behavioral dysregulation, and five patients experienced psychosis (7%). Behavioral dysregulation was only significantly associated with a previous history of interictal or postictal psychosis. Psychotic dysregulation is significantly associated with a psychiatric history, including a history of agitation or psychosis, whether or not epilepsy-related. For both types of dysregulations, there was no relation with a pre-admission frequency of seizures, clustering of seizures during monitoring, or a temporal focus of seizures. We could not report a relationship between AED use, tapering, and the occurrence of dysregulation. CONCLUSION: We conclude that a psychiatric history, including a history of agitation and psychosis, is related to an increased risk of behavioral and psychotic dysregulation in patients undergoing invasive seizure monitoring at the EMU.

Breast magnetic resonance elastography: a review of clinical work and future perspectives.

This review on magnetic resonance elastography (MRE) of the breast provides an overview of available literature and describes current developments in the field of breast MRE, including new transducer technology for data acquisition and multi-frequency-derived power-law behaviour of tissue. Moreover, we discuss the future potential of breast MRE, which goes beyond its original application as an additional tool in differentiating benign from malignant breast lesions. These areas of ongoing and future research include MRE for pre-operative tumour delineation, staging, monitoring and predicting response to treatment, as well as prediction of the metastatic potential of primary tumours.

Pharmacokinetic and pharmacodynamic properties of SOL1: a novel dual inhibitor of neutral endopeptidase and endothelin converting enzyme.

AIMS: The pharmacological profile of the novel putative neutral endopeptidase (NEP) and endothelin converting enzyme (ECE) inhibitor SOL1 was examined. MAIN METHODS: The enzyme inhibitory profile of SOL1 was established in vitro. The pharmacokinetic and pharmacodynamic profile was determined in rodents in vivo. KEY FINDINGS: In vitro, at neutral pH, 10 µM SOL1 inhibited NEP-1, NEP-2, and ECE-1 by 99%, 94% and 75%, respectively. The IC(50)s were 25, 25 and 3200 nmol/L, respectively. In anesthetized rats, SOL1 inhibited blood pressure (BP) responses to big-ET-1 and ET-1(1-31) with ED(50)s of 1.9 and 0.03 mg/kg, corresponding to plasma EC(50)s of 4.6 and 0.1 µmol/L, respectively. Pharmacokinetics of SOL1 were examined after single injections in mice and rats. In these species, the estimated clearance of SOL1 varied between 5 and 9 ml/kg.min and T(1/2) between 20 and 60 min. Steady state kinetics of SOL1 were examined after continuous s.c. infusions of SOL1 for 3 weeks at 50mg/kg.day in DOCA-salt hypertensive rats. This treatment lowered BP by 22 mmHg. Steady state concentrations of SOL1 in plasma were 3.9 µmol/L. In heart, lung, and kidney the concentrations of SOL1 were 0.4, 1.8, and 20.5 µmol/kg, respectively. About 63% of the daily dose was retrieved unaltered in the urine. SIGNIFICANCE: These data indicate that SOL1 is primarily a NEP inhibitor in vitro as well as in vivo. Given the preferential renal accumulation and renal clearance of SOL1 additional ECE-1 inhibition in the kidney may have contributed to its chronic BP lowering effects in the DOCA-salt hypertensive rat model.

G-protein ßγ subunits in vasorelaxing and anti-endothelinergic effects of calcitonin gene-related peptide.

BACKGROUND AND PURPOSE: Calcitonin gene-related peptide (CGRP) has been proposed to relax vascular smooth muscle cells (VSMC) via cAMP and can promote dissociation of endothelin-1 (ET-1) from ET(A) receptors. The latter is not mimicked by other stimuli of adenylate cyclases. Therefore, we evaluated the involvement of G-protein ßγ subunits (Gßγ) in the arterial effects of CGRP receptor stimulation. EXPERIMENTAL APPROACH: To test the hypothesis that instead of α subunits of G-proteins (Gαs), Gßγ mediates the effects of CGRP receptor activation, we used (i) rat isolated mesenteric resistance arteries (MRA), (ii) pharmacological modulators of cyclic nucleotides; and (iii) low molecular weight inhibitors of the functions of Gßγ, gallein and M119. To validate these tools with respect to CGRP receptor function, we performed organ bath studies with rat isolated MRA, radioligand binding on membranes from CHO cells expressing human CGRP receptors and cAMP production assays in rat cultured VSMC. KEY RESULTS: In isolated arteries contracted with K(+) or ET-1, IBMX (PDE inhibitor) increased sodium nitroprusside (SNP)- and isoprenaline (ISO)- but not CGRP-induced relaxations. While fluorescein (negative control) was without effects, gallein increased binding of [(125) I]-CGRP in the absence and presence of GTPγS. Gallein also increased CGRP-induced cAMP production in VSMC. Despite these stimulating effects, gallein and M119 selectively inhibited the relaxing and anti-endothelinergic effects of CGRP in isolated arteries while not altering contractile responses to K(+) or ET-1 or relaxing responses to ISO or SNP. CONCLUSION AND IMPLICATIONS: Activated CGRP receptors induce cyclic nucleotide-independent relaxation of VSMC and terminate arterial effects of ET-1 via Gßγ.

Molecular basis for the homophilic activated leukocyte cell adhesion molecule (ALCAM)-ALCAM interaction.

Activated leukocyte cell adhesion molecule (ALCAM/CD166), a member of the immunoglobulin superfamily with five extracellular immunoglobulin-like domains, facilitates heterophilic (ALCAM-CD6) and homophilic (ALCAM-ALCAM) cell-cell interactions. While expressed in a wide variety of tissues and cells, ALCAM is restricted to subsets of cells usually involved in dynamic growth and/or migration processes. A structure-function analysis, using two monoclonal anti-ALCAM antibodies and a series of amino-terminally deleted ALCAM constructs, revealed that homophilic cell adhesion depended on ligand binding mediated by the membrane-distal amino-terminal immunoglobulin domain and on avidity controlled by ALCAM clustering at the cell surface involving membrane-proximal immunoglobulin domains. Co-expression of a transmembrane ALCAM deletion mutant, which lacks the ligand binding domain, and endogenous wild-type ALCAM inhibited homophilic cell-cell interactions by interference with ALCAM avidity, while homophilic, soluble ligand binding remained unaltered. The extracellular structures of ALCAM thus provide two structurally and functionally distinguishable modules, one involved in ligand binding and the other in avidity. Functionality of both modules is required for stable homophilic ALCAM-ALCAM cell-cell adhesion.

Dynamic regulation of activated leukocyte cell adhesion molecule-mediated homotypic cell adhesion through the actin cytoskeleton.

Restricted expression of activated leukocyte cell adhesion molecule (ALCAM) by hematopoietic cells suggests an important role in the immune system and hematopoiesis. To get insight into the mechanisms that control ALCAM-mediated adhesion we have investigated homotypic ALCAM-ALCAM interactions. Here, we demonstrate that the cytoskeleton regulates ALCAM-mediated cell adhesion because inhibition of actin polymerization by cytochalasin D (CytD) strongly induces homotypic ALCAM-ALCAM interactions. This induction of cell adhesion is likely due to clustering of ALCAM at the cell surface, which is observed after CytD treatment. Single-particle tracking demonstrated that the lateral mobility of ALCAM in the cell membrane is increased 30-fold after CytD treatment. In contrast, both surface distribution and adhesion of a glycosylphosphatidylinositol (GPI)-anchored ALCAM mutant are insensitive to CytD, despite the increase in lateral mobility of GPI-ALCAM upon CytD treatment. This demonstrates that clustering of ALCAM is essential for cell adhesion, whereas enhanced diffusion of ALCAM alone is not sufficient for cluster formation. In addition, upon ligand binding, both free diffusion and the freely dragged distance of wild-type ALCAM, but not of GPI-ALCAM, are reduced over time, suggesting strengthening of the cytoskeleton linkage. From these findings we conclude that activation of ALCAM-mediated adhesion is dynamically regulated through actin cytoskeleton-dependent clustering.

Molecular analysis of the hematopoiesis supporting osteoblastic cell line U2-OS.

OBJECTIVE: Osteoblasts play an important role in regulating hematopoiesis in the bone marrow. Here we show that U2-OS, a widely used osteoblastic cell line derived from an osteosarcoma, has the capacity to support proliferation of human hematopoietic progenitor cells in vitro. In this study, U2-OS cells are characterized at the molecular level to unravel the molecular mechanisms underlying the support of hematopoiesis. MATERIALS AND METHODS: U2-OS was analyzed in great detail using RT-PCR and flow cytometry. In addition, a cDNA library was constructed and randomly sequenced to obtain insight in the repertoire of expressed molecules. RESULTS: A broad panel of growth factors and cytokines is expressed by U2-OS. TGF-beta, GM-CSF, c-kit ligand, and IL-7 are produced constitutively and IL-1beta, IL-6, IL-8, TNF-alpha, IFN-gamma, and MIP1-alpha are upregulated upon stimulation. In addition to those, mRNAs of the CC chemokine LARC and leukemia inhibitory factor were identified. U2-OS cells express high levels of beta1-integrins at the cell surface: VLA-2, VLA-3, VLA-4, VLA-5, VLA-6, and the integrin alphavbeta3. Besides integrins, ALCAM and NCAM are detected on the cell surface of U2-OS. Interestingly, we show that CD34(+) progenitor cells expressing ALCAM are highly proliferative when compared with CD34(+) ALCAM(low) cells, hinting at a role for ALCAM in anchoring progenitor cells to the bone marrow stroma. Interestingly, random sequencing of an U2-OS cDNA library yielded almost 10% of novel cDNAs with a potential role in hematopoiesis. The involvement of these novel molecules in hematopoiesis is an interesting target for future investigations. CONCLUSIONS: We conclude that U2-OS supports outgrowth of hematopoietic progenitor cells and accordingly expresses adhesion molecules and growth factors and a number of novel, as yet uncharacterized potentially interesting genes.

Physical map of the region surrounding the ataxia-telangiectasia gene on human chromosome 11q22-23.

Ataxia telangiectasia (A-T) is an autosomal recessive disease affecting multiple systems, including the development of the cerebellum and thymus. This results in a progressive cerebellar ataxia with onset between 1-3 years, telangiectasia occurs within the subsequent 3-5 years. We localized the A-T gene by linkage analysis to chromosome 11q22-23, between the markers D11S384, and D11S535, and constructed a series of contigs using three BACs and twelve cosmids, spanning a region of approximately 400 kb. We developed a set of sequence-tagged site (STS) markers from the ends of the BACs and cosmids. The A-T gene was isolated from within this region. It is now possible to precisely orient specific BACs, cosmids, and STSs with respect to the exons of the A-T gene (ATM). We anticipate that this information will be useful for further studies of functional domains and regulatory elements within the ATM gene, as well as for other genes in this region. In addition, these clones can be used for FISH studies of deletions, translocations and for loss of heterozygosity in various tumors.

The proper age to marry: social norms and behavior in nineteenth-century Netherlands.

"The article compares publicly discussed norms concerning the proper age at marriage for men and women in nineteenth-century Netherlands, and the actual trends present in the empirical evidence about marriage age. Medical professionals (the hygienists) expressed the belief that marriage at too young an age was damaging both to public hygiene and the family's health; other commentators stressed the connection between young marriages and poverty. Yet such norms were put forward vaguely, allowing other influences on marriage age to come into play. Consequently, data on marital behavior suggest considerable diversity in the population, with age at marriage varying strongly by class, sex, and region. Generally, age at marriage did not begin to fall until the period 1860-1870, and even after that decade class differences remained strong."

Lifetime income redistribution by social security.

"This paper discusses the redistributive impact of the Dutch social security system on lifetime basis. Net benefits appear to be positive for the birth generations up to 1960. Social insurances show a declining net benefit, whereas for occupational pensions the reverse holds. It is generally assumed that flat-rated social security schemes are more redistributive ones than wage-related schemes. However, the Dutch social security system shows that on a lifetime basis the redistributive impact of flat-rated general insurances does not necessarily largely differ from the wage-related employee insurances. Social assistance schemes result in a very large income redistribution in view of the small amounts involved. Social insurances and social assistance schemes have an income equalizing effect. On the contrary, occupational pensions increase income inequality."

The impact of population growth on the standard of living: demo-economic scenarios for the Netherlands.

"The core of the article can be comprised in the question: Will population ageing become a threat to [the] standard of living [in the Netherlands]?... In order to explore a broad range of possibilities two strongly contrasting...scenarios serve as the starting-points of the analyses.... The question of whether the ageing process will jeopardize the standard of living, is, for each of the demographic projections, answered by comparing them with three economic targets.... The most important conclusion is that in the long run neither of the scenarios developed will generate an economic growth comparable with that of the 1960s and 1970s." (SUMMARY IN FRE)

Increased frequency of infection after open reduction of fractures in patients who are seropositive for human immunodeficiency virus.

In a prospective study of 214 patients who had elective extensive operations for fractures, we compared the relative frequencies of postoperative infections in the seventeen patients who were seropositive for human immunodeficiency virus and had associated clinical symptoms, in the twenty-six patients who were seropositive and had no associated clinical symptoms, and in the 171 patients who were seronegative. The relative frequency of postoperative infection was significantly higher in patients who were seropositive and had associated clinical symptoms (four of seventeen) than in patients who were seronegative (eight of 171) (Fisher exact test, p = 0.01). In all patients who were seropositive and had a postoperative bacterial infection, treatment with antibiotics was effective. The results of this study suggest that people who are seropositive for human immunodeficiency virus and have associated symptoms are at increased risk for postoperative infection.

Projecting household dynamics: a scenario-based microsimulation approach.

2 methods are brought together to estimate and analyze future household structure. Application of a scenario method results in the construction of differing context scenarios. These context scenarios function as alternative societal environments of the future household system. Given these context scenarios and, tentatively derived, general hypotheses relating relevant elements of the context scenarios and household processes, future input parameters of the household model are postulated. Subsequently, microsimulation is used to calculate the future household structure. Emphasis in the article is on methodology, rather than on substantive issues which have a mainly illustrative function.

Are demographic developments influenced by social security?

"On the basis of the existing literature we examined the points at which social security and family demography meet. The main conclusions are: (1) child allowances will only affect fertility if the level of benefit is rather substantial; (2) unemployment provisions may affect fertility; (3) remarriage frequency is probably affected by public assistance benefits; (4) the same possibly holds for the divorce frequency. These conclusions are tentative: the results are contradictory from many viewpoints, some fields have hardly been investigated and it is unclear whether the effects are temporary or lasting." The geographical focus is on developed countries.