Splice variants of tissue factor promote monocyte-endothelial interactions by triggering the expression of cell adhesion molecules via integrin-mediated signaling.

BACKGROUND: TF is highly expressed in cancerous and atherosclerotic lesions. Monocyte recruitment is a hallmark of disease progression in these pathological states. OBJECTIVE: To examine the role of integrin signaling in TF-dependent recruitment of monocytes by endothelial cells. METHODS: The expression of flTF and asTF in cervical cancer and atherosclerotic lesions was examined. Biologic effects of the exposure of primary microvascular endothelial cells (MVEC) to truncated flTF ectodomain (LZ-TF) and recombinant asTF were assessed. RESULTS: flTF and asTF exhibited nearly identical expression patterns in cancer lesions and lipid-rich plaques. Tumor lesions, as well as stromal CD68(+) monocytes/macrophages, expressed both TF forms. Primary MVEC rapidly adhered to asTF and LZ-TF, and this was completely blocked by anti-ß1 integrin antibody. asTF- and LZ-TF-treatment of MVEC promoted adhesion of peripheral blood mononuclear cells (PBMCs) under orbital shear conditions and under laminar flow; asTF-elicited adhesion was more pronounced than that elicited by LZ-TF. Expression profiling and western blotting revealed a broad activation of cell adhesion molecules (CAMs) in MVEC following asTF treatment including E-selectin, ICAM-1 and VCAM-1. In transwell assays, asTF potentiated PMBC migration through MVEC monolayers by ∼3-fold under MCP-1 gradient. CONCLUSIONS: TF splice variants ligate ß1 integrins on MVEC, which induces the expression of CAMs in MVEC and leads to monocyte adhesion and transendothelial migration. asTF appears more potent than flTF in eliciting these effects. Our findings underscore the pathophysiologic significance of non-proteolytic, integrin-mediated signaling by the two naturally occurring TF variants in cancer and atherosclerosis.

Alternatively spliced tissue factor. A crippled protein in coagulation or a key player in non-haemostatic processes?

Full-length tissue factor (flTF) initiates coagulation, but also exerts non-hemostatic functions such as inflammation and angiogenesis through protease activated receptors (PARs). In 2003 a soluble variant of flTF was described which results from alternative splicing. Since its discovery the role of alternatively spliced tissue factor (asTF) in coagulation has been debated. asTF may have pro-coagulant properties but due to structural differences when compared to flTF, asTF coagulant function may be relatively low. Nevertheless, similar to flTF, asTF appears to have non-hemostatic properties; asTF expression in tumors correlates with increased tumor size, vessel number and poor survival in some cancer types, and drives tumor growth in animal models. Interestingly, unlike flTF, asTF does not promote angiogenesis through activating PARs but rather via integrin ligation. flTF is a critical determinant in cardiovascular disease but little is known about asTF in cardiovascular disease. asTF is produced by monocytes and macrophages, thus macrophage-derived asTF may contribute to atherosclerotic disease. In conclusion, unraveling asTF's non-hemostatic properties may generate new insights in the pathophysiology and diagnostics of cancer and cardiovascular disease.

Alternatively spliced tissue factor induces angiogenesis through integrin ligation.

The initiator of coagulation, full-length tissue factor (flTF), in complex with factor VIIa, influences angiogenesis through PAR-2. Recently, an alternatively spliced variant of TF (asTF) was discovered, in which part of the TF extracellular domain, the transmembrane, and cytoplasmic domains are replaced by a unique C terminus. Subcutaneous tumors produced by asTF-secreting cells revealed increased angiogenesis, but it remained unclear if and how angiogenesis is regulated by asTF. Here, we show that asTF enhances angiogenesis in matrigel plugs in mice, whereas a soluble form of flTF only modestly enhances angiogenesis. asTF dose-dependently upregulates angiogenesis ex vivo independent of either PAR-2 or VIIa. Rather, asTF was found to ligate integrins, resulting in downstream signaling. asTF-alphaVbeta3 integrin interaction induces endothelial cell migration, whereas asTF-dependent formation of capillaries in vitro is dependent on alpha6beta1 integrin. Finally, asTF-dependent aortic sprouting is sensitive to beta1 and beta3 integrin blockade and a TF-antibody that disrupts asTF-integrin interaction. We conclude that asTF, unlike flTF, does not affect angiogenesis via PAR-dependent pathways but relies on integrin ligation. These findings indicate that asTF may serve as a target to prevent pathological angiogenesis.

[Geriatric wards in a psychiatric and a general hospital: a comparison of problems leading to admission of the patient]. / De afdeling geriatrie in een psychiatrisch en een algemeen ziekenhuis: een vergelijking van de problematiek van opgenomen patiënten.

The aim of this investigation was the comparison and description of actual problems of patients admitted to a geriatric ward of a mental hospital and patients admitted to the geriatric ward of a general hospital. The study was conducted in the geriatric unit of the Vincent van Gogh Institute of Psychiatry, in Venray and the geriatric unit in St. Maartens Gasthuis in Venio, both in the Netherlands. The design was retrospective. Data were obtained from discharge letters. The relevant diagnoses and the aetiology of the problems of all patients admitted in 1994 were categorized and compared by means of classification systems and models (medical, synergistic and causal chain model). Approximately 80 percent of the patients admitted to the geriatric unit of the mental hospital turned out to have a physical diagnosis relevant to the problems and almost every patient had a relevant psychiatric diagnosis. Life events and relationship problems played an important part. More than half of the patients admitted to the geriatric unit of the general hospital had a relevant psychiatric diagnosis and almost every patient had a physical diagnosis relevant to the problems. Mostly the aetiology of the problems of the patients of the geriatric unit of the mental hospital can be described by means of the medical model. The aetiology of the problems of the patients of the geriatric unit of the general hospital can mainly be described by the synergistic model. The causal chain model is seldom found. An event is more frequently found in the geriatric unit of the mental hospital. Often the referring Doctor could not point out adequately the underlying cause of the problems. We conclude that the problems of the patients, admitted to the geriatric unit of a mental and of a general hospital, differ substantially and in both units the problems are complex, in terms of diagnoses, aetiology and/or treatment.

[Three geriatric wards of a psychiatric hospital (GAPZ): a comparison of patient admissions]. / Drie geriatrische afdelingen van een psychiatrisch ziekenhuis (GAPZ): vergelijking van de opgenomen patiënten.

The aim of this investigation was the description and comparison of problems of patients admitted to three geriatric wards of a mental hospital. The study took place in the geriatric units at the Vincent van Gogh Institute of psychiatry in Venray, the Netherlands and was retrospective. Data obtained from discharge letters were analysed and the relevant diagnoses and the aetiology of the problems of all patients admitted in 1994 were categorised and compared. This was done bij means of classification systems and models of Fried et al. The problems of patients admitted to the geriatric unit of a mental hospital very frequently appeared to be combined problems of a psychiatric, somatic and/or social nature. In only 58% there was a simple connection between the cause(s) and the current problems. Differences between the three wards were small and non significant. In conclusion, the problems of the patients, admitted to the geriatric units of a mental hospital, did not differ significantly between the three wards. Furthermore, they are complex in terms of diagnosis, aetiology and/or treatment.

Citalopram in mentally retarded patients with depression: a long-term clinical investigation.

The effect of citalopram was investigated in 20 mentally retarded patients suffering from a depressive disorder characterized by alterations in the domains of affectivity, motivation, motor activity and vital signs. The study followed a baseline-controlled open design. Citalopram was started in a daily dosage of 20 mg that was kept unchanged for 6 weeks. Thereafter dosage was adjusted to maximally 60 mg per day. Treatment effects were assessed according to the Clinical Global Improvement Scale (CGIS) after at least 6 months. In 12 of the 20 patients a moderate to marked improvement in all domains was observed upon treatment with 20-40 mg citalopram daily. Treatment for one year in the effective dose prevented recurrence of depressive symptomatology. Concomitant use of sedative anticonvulsants reduced responsiveness to treatment. No interactions were observed. It is concluded that citalopram is a well-tolerated, safe and effective antidepressant in mentally retarded subjects with depressive disorders.

Stress and self-injurious behavior; hormonal and serotonergic parameters in mentally retarded subjects.

Self-injurious behavior (SIB) and stereotyped behavior (SB) are major challenges for professionals in the field of mental retardation. From animal experiments it has become obvious that these behavioral disturbances are not purposeless but may emerge secondary to restrictive environment and may serve de-arousing objectives. In mentally retarded subjects, several hypotheses have been formulated concerning the pathogenesis of SIB, particularly about the involvement of serotonin and beta-endorphin, which are supported by beneficial treatment effects of the opiate antagonist naltrexone and serotonin modulating compounds, respectively. The present study was designed to investigate basal levels of stress-hormonal and serotonergic parameters as well as plasma levels of amino-acids and the beta-carboline norharman in a group of 64 mentally retarded subjects with SB and/or SIB. Allocation to three different groups comprising 17 retarded controls, 26 subjects with mainly SIB and 21 subjects with mainly SB, was originally performed using the scores on the factors Irritability, Stereotypic Behaviour and Hyperactivity of the Aberrant Behavioral Checklist. Because of the overlapping nature of the behavioral parameters, subjects were subsequently divided into three maximally contrasting groups, viz. predominantly SIB, predominantly SB and retarded controls, each comprising 11 subjects. With respect to beta-endorphin, no differences were found either between both the original and maximally contrasting groups or in comparison to nonretarded controls. As compared to retarded controls, a tendency to lower values for total cortisol and cortisol binding globulin appeared to be present in the SIB group, whereas in the SB group a tendency toward higher levels of the major serotonin metabolite 5-HIAA was found. In the contrasting SB group, a trend toward decreased total cortisol level was observed as compared to the retarded control group. In addition, significantly lower values for norharman and tryptophan were demonstrated in the total group of mentally retarded subjects as compared to non-retarded controls. The results of the present study, yielding co-existent disturbances in stress-hormonal and monoaminergic mechanisms as well as in the metabolism of norharman, are in line with the hypothesis that mentally retarded subjects are at risk for the development of stress-related behavioral disorders such as SIB and SB.

Integratie van opleiding en onderzoek in de opleiding tot psychiater.

In the training program for residents in psychiatry, scientific education and participation in research projects are relatively underdeveloped. This may result in a gap between recently acquired scientific knowledge and its implementation in clinical practice. Since the start of the residency training in psychiatry in 1989 in the Vincent van Gogh Institute for Psychiatry, several research lines have been developed especially concerning dimensional diagnostic procedures, evaluation of treatment effects, stress and psychopathology, pharmacokinetics of psychotropic compounds and disordered impulse and aggression regulation. It is concluded that active participation in research projects by both psychiatrists and residents in psychiatry is increasingly mandatory due to social-economic en scientific developments. Despite several countervailing factors, the Vincent van Gogh Institute for Psychiatry has succeeded in the creation of a scientific orientation in the residency program resulting in a number of publications.

[Favorable development of ability to function in patients during admission in a geriatric unit of a psychiatric hospital]. / Gunstige ontwikkeling van de zelfredzaamheid van patiënten tijdens opname op een geriatrische afdeling van een psychiatrisch ziekenhuis.

OBJECTIVE: To evaluate the course of the functional ability in daily living activities, mobility and faecal and urinary continence, and the interrelationship of these features of ability in patients admitted to the geriatric unit of a psychiatric hospital (GAPZ). DESIGN: Retrospective. SETTING: Geriatric unit, Vincent van Gogh Institute of Psychiatry, Venray, the Netherlands. METHOD: Analysis of data obtained from the National Register of Clinical Gerontology from SIG Care Information in Utrecht. For all patients discharged in 1992 the level of functional ability on admission and discharge was determined and compared, using 9 variables. RESULTS: During the stay all but one of the functional status variables improved significantly: washing of upper and lower body, dressing, going to the toilet, eating, urinary (in)continence and mobility (as measured by radius of action and assistance needed). Faecal incontinence did not improve. On average women functioned more independently than men; however, the improvement in functional status was equal for both sexes. There was a hierarchical decline in the event of decreased functional ability. This hierarchical relationship was more prominent at the time of discharge than at the time of admission. CONCLUSION: On average the functional status of the patients evaluated improved during their stay in the geriatric unit of the psychiatric hospital. There appears to be a hierarchy of changes in aspects of functional condition irrespective of the underlying diseases in elderly people.