[Therapeutic alliance, a stake in schizophrenia]. / L'alliance thérapeutique, un enjeu dans la schizophrénie.

INTRODUCTION: Adherence to (or compliance with) a medication is one of the foremost issues in the assumption of patients with psychiatric illness and, in particular, in schizophrenia. Adherence to medication is generally defined as the extent to which patients take medications as prescribed by their health care providers. There is no consensus to define an acceptable compliance. LITERATURE FINDINGS: The methods available for measuring adherence can be broken down into direct and indirect methods of measurement, each one having advantages and disadvantages. Clinical summations of studies were realized, the problem of poor adherence to medication concerned 25% of patients with schizophrenia and 74% of the 1493 schizophrenia patients recruited for the Catie study discontinued their assigned study medication before 18 months, a rate that was considered to be very high in a study in which the primary outcome measure was discontinuation of the study drug for any cause and approximately 30% stopped the treatment of their own motivation. In two thirds of cases, rehospitalisation is the result of complete or partial non-compliance. One year after first hospitalsation, 40% of relapse results from non-adherence to medication. DISCUSSION: Medication adherence problems increase hospitalisation, morbidity and mortality. Social consequences, professional and family problems linked to hospitalisations lead to low quality of life for patients and high cost for society. Indicators of poor adherence to a medication regimen are a useful resource for physicians to help identify patients who are most in need of interventions to improve adherence. It is usual to identify quatre categories of factors causing disparity: 1: factors due to psychiatric disorders; 2: factors due to medication; 3: factors linked to patients; 4: factors depending on the therapeutic relationship with the clinician. Patients with psychiatric illness typically have great difficulty following a medication regimen, but they also have the greatest potential for benefiting from adherence. Some effective actions to improve compliance are described in reply to the factors influencing the adherence. The communication attitude of the clinician, therapeutic relationship and prescription use are main points of alliance. Information and communication with the patient, simplification of the therapeutic plan, consultation planning and account of side effect are simple and effective actions. Social support is very important for improvement of therapeutic alliance. Poor therapeutic alliance is common, contributing to substantial worsening of disease and more research on compliance and therapeutic alliance evaluation is needed. Information and tools must be proposed to practitioners.

[Addiction and brief-systemic therapy: working with compulsion]. / Addictions et thérapie systémique brève : un travail sous contrainte.

In our daily practice in public hospitals, we are regularly confronted with the paradox of helping patients, who do not ask for help. Although the French law is clearly defined to allow us to treat patients suffering from psychiatric conditions, who are unable to give their consent, it is not the case for those with addictive disorders. In fact, their disorder does not always (or does not yet) justify treatment without their consent, according to the 1990 law (psychiatric treatment without the patient's consent). However, many of them are referred to us because a third party has forced them (spouse, general practitioner, treatment order) and even though some patients consult spontaneously, they often do so more "for others" than for themselves. Because of this, the therapist (doctor, psychologist or nurse), in addition to the paradox of treating patients who do not ask for treatment, find themselves in a situation with two-fold compulsion, fixed by the social (or family) setting, both as a helper and as a coercive agent, thus, putting the fundamental concepts of treatment into question. A therapeutic agreement, free-will and motivation are in jeopardy when the pressure is strong, which removes the therapist from his mission of treating. Although we would not question the necessity for psychiatric treatment in patients who do not ask for it (addictions are a major public-health problem), we should not forget that motivation is one of the essential elements for making any changes in behavior. Although compulsion (external or internal) is recognized by everyone as a limiting factor, we would like to show here how much it can be a lever for change, as long as this compulsion is identified right from the first meeting with the patient, who consults in an addiction centre. Brief systemic therapy may be of interest for these patients, since it reinforces the motivating approach, which is recommended today and since the compulsive nature of the request for treatment is not an obstacle for such treatment to be started. We try to outline here how the therapist can get out of this two-fold compulsion and help the patient to become the instigator of this change, often imposed on him. Two elements are fundamental to understand the function of brief systemic therapy. First of all, "systemic" means "interaction". A systemic approach to treatment requires working in clinical situations, particular attention being paid to interactions. Second, brief therapy does not mean short therapy, but rather therapy with an objective in view. The objective is determined by the patient together with the therapist and they work out together how to reach it, with or without the family's help. Because of this, we use a five-point assessment to offer a concrete response to the patients in these psychotherapeutic consultations. Firstly, is the patient the one who has asked for treatment? We know that in addictive behavior, it is not always the one with symptoms who asks for help (many couples consult who are persuaded that the other one needs to change). Once we know who has asked for treatment, we clarify (with the patient's help) that his/her objectives are not the same as someone who asks for treatment and we can then redefine them (first step in the therapeutic agreement). Once the request for treatment is clarified, we can clearly define what the problem is, the objectives that the patient fixes for him/herself and how to reach them. A large proportion of therapeutic failures result from the request for treatment being unclear. In this way, we define the problem in concrete terms, without using classifications and the previous attempts to solve it (third point). In fact, we often find that the problem itself is the solution, which is chosen to try to resolve it. Knowing which solutions have been tried (and failed) allows the patient to realize what is effective and what is not. The role of the therapist is to help the family and the patient to find other types of solution to their problem. The therapist only offers concrete tasks, which can be done in the near future (minimal changes). Finally, the therapist takes into account the patient's beliefs, values and personal priorities, to which they are attached and which have determined up to now, how they react to the problem. To work with a patient suffering from addiction, it is important, first of all, to find the elements of compulsion, which are hiding behind each request for treatment. This is because, if the patient does not follow the initial therapeutic objectives, there is always the underlying complaint, which should motivate the patient to improve the situation. An individual patient only has a few possibilities for adapting to this type of situation (agreeing, refusal or negotiation) and the role of the therapist is first of all to help him to realize this. This helps to avoid resistance developing, by underlying the compulsive aspect, which originates from the family's request for treatment. We offer a way for setting up the first meeting: working on the role of the patient in the treatment. Three types of patients consult: patients who are "not concerned" (sent by a third party; their main problem is with the person who asked for them to be treated), "victims" (they complain and consult because they put the responsibility of their problem on someone else) and "clients" (they consult because they consider that their problem depends on themselves and they want help to solve it actively). In fact, changing is not easy and does not happen without making an effort. Change comes from a complex cycle of interactions, for which it is often impossible to find a single origin for the situation in question. The psychological world tends towards homeostasis, just like all human systems, and so, suggesting making changes can only be experienced as an intrusion. Pathology begins when an individual can no longer choose what he/she needs to do. We do not consider that a brief-concrete approach is better than any other approach, but its pragmatic nature seems to fit in with the new conception of addiction therapy, with earlier intervention. However, is it possible to make changes outside of a crisis situation? We are unable to answer this question, except to say that the best time for change is that chosen by the patient.

[Heart rate variability. Applications in psychiatry]. / La variabilité de la fréquence cardiaque. Intérêts en psychiatrie.

BACKGROUND: The autonomic nervous system sends messages through the sympathetic and parasympathetic nervous system. The sympathetic nervous system innervates the cardioaccelerating center of the heart, the lungs (increased ventilatory rhythm and dilatation of the bronchi) and the non-striated muscles (artery contraction). It releases adrenaline and noradrenaline. As opposed to the sympathetic nervous system, it innervates the cardiomoderator center of the heart, the lungs (slower ventilatory rhythm and contraction of the bronchi) and the non-striated muscles (artery dilatation). It uses acetylcholine (ACh) as its neurotransmitter. Sympathetic and parasympathetic divisions function antagonistically to preserve a dynamic modulation of vital functions. These systems act on the heart respectively through the stellar ganglion and the vagus nerve. The interaction of these messages towards the sinoauricular node is responsible for normal cardiac variability, which can be measured by monitoring heart rate variability (HRV). Heart rate is primarily controlled by vagal activity. Sensorial data coming from the heart are fed back to the central nervous system. HRV is an indicator of both how the central nervous system regulates the autonomic nervous system, and of how peripheral neurons feed information back to the central level. HRV measures are derived by estimating the variation among a set of temporally ordered interbeat intervals. The state of perfect symmetry, which, in medical parlance, is called respiratory sinus arrhythmia (RSA), can be described as a state of cardiac coherence. Obtaining a series of interbeat intervals requires a continuous measure of heart rate, typically electrocardiography (ECG). Commercially available software is then used to define the interbeat intervals within an ECG recording. LITERATURE FINDINGS: The autonomic nervous system is highly adaptable and allows the organism to maintain its balance when experiencing strain or stress. Conversely, a lack of flexibility and a rigid system can lead to somatic and psychological pathologies. Several studies have shown a link between reduced HRV in postmyocardial infarction patients and increased risk for adverse cardiovascular events, including ventricular arrhythmias and sudden death. Recently, studies indicate that patients with depression and anxiety disorders exhibit abnormally low HRV compared with non-psychiatric controls. Reduced HRV seems indicate decreased cardiac vagal tone and elevated sympathetic activity in anxious and depressive patients and would reflect deficit in flexibility of emotional physiological mechanisms. A few studies have also revealed that biofeedback using respiratory control, relaxation and meditation techniques can increase HRV. For now, there is insufficient data to determine if paced respiration or subjective relaxation is necessary or sufficient for the efficacy of HRV biofeedback. Although the literature is modest, this review suggests that the use of biofeedback with relaxation and meditation approaches may result in increased HRV and parasympathetic activity. Limitations of the review literature have also been considered to identify areas for future research.

Directed forgetting in depression.

Subjects with depression exhibit deficits in prefrontal function. We posited that as a result, in a supraspan memory test, they would be impaired in their ability to inhibit recall of irrelevant words, and because of consequent overload of working and episodic memory capacity, would be impaired in their ability to recall relevant words. We tested this hypothesis in 30 inpatients and outpatients with a diagnosis of major depressive disorder and 30 controls subjects using a form of the Directed Forgetting Paradigm using exclusively neutral words. The depressed subjects did exhibit deficits in prefrontal function. All subjects were given four lists of 24 items each, in which half the words were followed by the instruction and half by the instruction Our hypothesis found support in a significant group by item type interaction effect exhibited when subjects were instructed to recall only those items followed by the instruction: depressed subjects recalled relatively more words to be forgotten and relatively fewer words to be remembered. A control experiment suggested that these results could not be accounted for by a differential effect of depression on memory encoding.

Directed forgetting in PTSD: a comparative study versus normal controls.

The most characteristic feature of Post-Traumatic Stress Disorder (PTSD) is the reexperiencing syndrome. The patient's memory seems to be fixed on the traumatic event, which may be due to disturbance of the autobiographic memory. To retrieve memories, others have to be inhibited. These inhibition mechanisms have been studied using the Directed Forgetting Paradigm, which measures the capacity to forget recently processed information and to retain the relevant information. Our hypothesis is that during PTSD, the memory is saturated with traumatic memories, so that the patients are no longer able to use the inhibitory processes. Therefore, during a Directed Forgetting Task (DFT) in which words "to remember" and words "to forget" are given, PTSD patients cannot inhibit the words "to forget", and so recall more words than the controls. We studied 30 patients with PTSD and compared them with 30 healthy controls, using DFT. The results show that the patients remembered significantly fewer words overall, and fewer of the words "to remember" than the controls, both for immediate and final recall. Our results are in favor of a reduction in directed forgetting in patients suffering from PTSD, resulting in difficulty in inhibiting irrelevant information from the overall information. There seems to be a deficit in the inhibitory processes in the memory in PTSD.

[In favour of a systemic vision of liaison psychiatry]. / Pour une vision systémique de la psychiatrie de liaison.

One of the problems of consultation-liaison psychiatry is the absence of request of the patient. Indeed, the patients do not recognize their disorder and prefer to go to the emergency unit in a general hospital. Thus, we meet in the emergency unit or in medical unit (liaison psychiatry activity). This is the reason why this first meeting has to be prepared. Consultation-liaison Psychiatry proposes to provide medical staff with the competences developed by psychiatry, and the denomination: Consultation and Liaison Psychiatry, indicates the bipolarity of its practice according to whether the intervention is addressed to the patient (consultation) or to the staff (liaison). However collaboration is sometimes difficult and the psychiatrist often meets with resistance. This is the reason why psychiatrists must work on their integration in the general hospital. Indeed, the psychiatrist works in an institution which is unfamiliar and he/she must adapt and create new practices if it is going to work. It is now clearly established that consultation-liaison psychiatry is not limited to consultations with patients, but is based on collaboration with medical staff. There are various ways of studying human problems: psychoanalysis, cognitive therapy, behavioural therapy. It is also possible to focus interest on the communication between individuals. The systemic therapies are interested in the interactions more than with any other aspect of reality, and this always from a pragmatic point of view. This concept is based on a series of designs. First of all, an intervention by problem solving aims at a change: the question is to know how a problem is maintained, hic et nunc. Secondly, humans are a sum of training by tests and errors. Finally, what we call reality is only our perception of reality: the human conflicts emerge when two persons assign a different direction to a reality which is perceived jointly. The human relationship can be defined as interaction circles, which we propose to use in our practice of consultation-liaison psychiatry. The question is no longer to know why the subject has a problem but to know how to resolve it. The call for a consultation of psychiatry is often the result of an interaction between patient and staff. We propose an assessment of the consultation-liaison-psychiatry's demand so as to offer a concrete response to medical teams and patients. 1. First of all, the claimant should be known. This first question is to be asked before even meeting the patient. In the majority of cases, it is the medical staff that suffers from the situation (and wants a change). To work only on the patient, discredits the psychiatric intervention. 2. The definition of the problem is a concrete question, which we want based on the facts and not on the comments. That which requires the consultation (the patient, his/her family or the medical team) awaits concrete answers from the psychiatrist. It is important that the objectives of the intervention are defined before meeting the patient. These preliminary exchanges facilitate the consultation-liaison intervention. 3. By knowing the solutions tried before the request for psychiatric help, the psychiatrist will be able to know the measures already tried (whether they were effective or not). 4. By proposing minimal changes, it defines small but obtainable objectives, which will be as much as to increase therapeutic alliance and the tolerance of patients sometimes difficult to understand. 5. Finally, the consultation-liaison psychiatrist must know the language of his/her interlocutors. Interdisciplinary alliance is a fundamental condition for the success of the intervention: like the patients, the medical staff must feel understood to be able to cooperate. To develop this alliance and to inhibit resistance, it is important to speak the language of the claimant. The demand will progressively become interventions, more adapted, especially when the psychiatrist is recognized and appreciated by the team, like a good consultant, credible and concrete. Thus, mentally distressed patients can benefit from psychiatric care (although they do not request it). However, two phases appear essential. First, we have to define the demand and the claimant (environment, medical staff and patient) and second, we have to support the integration of the psychiatrist in the functioning of the medical unit. Our systemic vision of the consultation-liaison psychiatry proposes a pragmatic collaboration, centred on the problem. This approach allows the patient to prepare to meet the psychiatrist, and does not a priori discredit the intervention. Presented by the staff, who know the problem in concrete terms and are ready to answer it in a concrete way, this mode of intervention is only the first step of subsequent psychiatric care.

Hemoglobin Calais [beta 76 (E20) Ala----Pro]: a hemoglobin variant with decreased intrinsic oxygen affinity.

Hb Calais [beta 76 (E20) Ala----Pro] is a new human hemoglobin variant displaying a decreased oxygen affinity. The only electrophoretical difference with Hb A was a slightly more acidic isoelectric point. A 2-fold decrease in the oxygen affinity was found by equilibrium measurements performed in a suspension of intact red blood cells and in the lysate. It was confirmed by kinetic studies of the purified abnormal hemoglobin. The rate of methemoglobin formation at 37 degrees C of Hb Calais was also increased relative to Hb A. The mechanism by which the Pro for Ala substitution of an external residue in the beta-chains results in these profound functional abnormalities is unclear. Subtle changes at the heme pocket, at a distance from the mutation, may be a plausible explanation for the effects observed.

[Study on psychiatric disorders and defensive process assessed by the "defense style questionnaire" in sterile males SAMPLE consulting in andrology]. / Etude des troubles psychiatriques et des modalités défensives évaluées par le "Defense Style Questionnaire" (DSQ) dans un echantillon d'hommes stériles consultant en andrologie.

BACKGROUND: The literature about artificial insemination and the associated psychological, psychiatric and sexual disorders is relatively rich. But the majority of these studies is made in gynaecology, with a feminine approach of the disorder. There are very few works led in andrology. This justified the investigation of new trails in order to understand better the clinical context of the sterile man. We undertake a study about the psychiatric disorders among sterile men and about the defense styles. These are a clinical entity recently introduced in the quantitative psychopathology research. The defense style questionnaire (DSQ) is a psychometric scale used in common practice in order to measure the defense styles. OBJECTIVES: We made this study in order to examine the psychiatric state of a sterile males sample consulting in andrology; to assess the defense style by means of the Bond and al DSQ-88 ; to look into a difference between the defensive process according to their clinical situation of azoospermic males or as the oligoazoospermic males and finally, to reveal a correlation between the psychiatric disorders developed in this sample of sterile males and the defensive process they used. METHOD: There were 42 people (22 azoospermic males and 20 oligoazoospermic males) aged between 23 and 49 years old in the analysed sample. These have been selected at the surgery of andrology at the RUHC of Lille, depending on their arrival order for 6 months. There was no significant difference between the two groups as far as the age and the education standard are concerned. The selection criteria were medical and somatic. Our sample population were divided into two groups: azoospermia (no spermatozoon found in the semen analysis) and oligoasthenospermia (decrease of the number and the mobility of the spermatozoa and an increase of the percentage of atypical forms). The method first consisted in the DSQ, followed by the analysis of the psychiatric state according to the DSM IV, a hetero questionnaire to collect some general information about infertility and a self questionnaire about the sexual, conjugal and social effects of infertility. The DSQ and the interviews took place in the andrology department with the same investigator trained for this job. RESULTS: We found in our sample 26.2% of psychiatric disorders according to the DSM IV with a significant over-representation of generalized anxious disorder and somatization disorder. The comparison between azoospermic males and oligoazoospermic males patients showed the absence of significative difference as far as psychiatric morbidity rate and the use of defense styles are concerned. DISCUSSION: Our sample defended himself in accordance with modalities similar to the general population and used defense mechanisms preferentially belonging to the mature defense style, such as humor, repression and anticipation. The psychiatric pathology was significantly correlated to the preferential use of withdrawal, consumption, reaction formation and lack of humor use. We also confirm in our study the fact that the subjects using especially neurotic defense styles are more likely to develop a psychiatric disorder than the others. Our male sample is a waiting population and threatened by failure. The situation of wait creates anxiety. We also know that infertility is one of the most stressful situations a couple might face. However, our study did not enable us to know the precise relations between generalized anxious disorder and infertility, especially whether the generalized anxious disorder preceded this pathology or not. The over-representation of a somatization disorder only allows us to acknowledge its existence. We can also deduce from that a possible link between infertility and psychic disorder, even if no research permitted to affirm to date the existence of interrelations linking infertility and psychic life. On the whole, this population was suffering despite 73.8% of the patients had no confirmed psychiatric disorder. It is the reason why a liaison psychiatry more inserted into highly specialized teams is interesting, especially because it includes a medical and psychological approach of such disorders. The defense mechanisms preferentially used by this population were humor, repression and anticipation. Humor can only be considered as a defense mechanism when it is applied to oneself. The population who has no psychiatric disorder more uses humor. Does humor protect against the development of a psychiatric pathology, as certain authors proved it ? On the other hand, is repression really protective? It didn't interfere in our study about the development of a psychiatric pathology. So we can suppose that repression was protective for our whole sample, but we can not prove it. However, we wonder if this mechanism works after the failure of an artificial insemination is announced. In which measure such a stress can be repressed out of the conscience field? As for anticipation, it is used by our population who is for the most part in good health. But the question is to know if our sample really envisaged all the different possible solutions or only the success of artificial insemination. As some other works, we confirm that the, psychiatric, people significantly use the neurotic style. Our psychiatric patients used less humor and more consumption, withdrawal and reaction formation than the sane people. Consumption is rarely considered as a defense mechanism by some other authors. And yet, consumption and the existence of psychiatric disorders were very closely linked. This association is found again with anxiety in other studies. The correlation between psychiatric disorder and withdrawal was veryimportant too. The DSM lV defines withdrawal as an apathetic withdrawal. It is not an apathetic withdrawal in our population because the average scores for the ,, activity >, defense mechanism remained high. In our sample, the use of this defense mechanism would encourage the expression of psychiatric troubles. The reaction formation quoted by Freud and Bergeret are both valorised in our society. What kinds of reaction formations use these men ? Are they pathological ? Our study can not answer to these questions. However, the DSQ items examining the reaction formation present its "socially promoted" aspect and forget the pathological one. It has been showed that the evaluation of the defense modalities in a certain type of population can allow the emergence of specific defense mechanisms. This can be considered as predictive factors of development of a mental pathology. The evaluation of specific mental defenses could permit to define vulnerability and affinity for given affections instead of simple personality traits or profiles. Most part of the works shows results in favour of the capacity of DSQ to assess the different defense mechanisms according to the diagnosis groups. But the insufficient numbers of studies moderate on the whole the hypothesis of the existence of specific defense mechanisms--protective factors and factors of vulnerability--linked to a given psychiatric disorder. CONCLUSION: There is not a difference of psychological effect in terms of degree of sterility. On the other hand, the existence of over-represented psychiatric disorders with sterile males compared with a control group force Consultation-Liaison psychiatrists and andrologists would be able to understand the pain beyond the need of acting by the artificial insemination. In our opinion, this justifies the fact that the patients should have the opportunity of expressing, in the department where they are treated, all the feelings inherent to their personal and conjugal drama as part of a specialized treatment. Our study confirms the difficulty to know whether some defense mechanisms are vulnerability factors for a certain psychiatric disorder or whether the defense mechanisms are an epiphenomenon of a particular psychiatric disorder. This is the reason why a lot of authors having worked with DSQ agree to conclude that additional prospective studies, which would permit to make a link between the defense mechanisms anda certain psychiatric pathology, are necessary. In the case we study, it is important to explore the defensive modalities before the infertility diagnosis and after the birth of a child, with a more important sample population. A better knowledge of the defensive modalities of such a population, used in a psychotherapeutic context could help to prevent the appearance of psychiatric disorders or, if not, to anticipate them.

Carbamazepine in the treatment of neuroleptic malignant syndrome.

BACKGROUND: Neuroleptic malignant syndrome (NMS) is a potentially lethal adverse effect to neuroleptic drugs. METHODS: We report on 2 cases where NMS dramatically improved with carbamazepine. Incidental removal and reapplication of carbamazepine attests to its effectiveness for this condition. RESULTS: A 34-year-old woman treated for a major depressive disorder experienced NMS with a phenothiazine. Her condition dramatically improved in 8 hours after she was administered carbamazepine. Since carbamazepine was discontinued, NMS recurred in 10 hours and remitted anew within less than 24 hours after reintroduction. A 31-year-old woman experiencing a schizoaffective disorder displayed NMS with aphenothiazine and a butyrophenone. NMS completely resolved within 8 hours after she was administered carbamazepine. NMS recurred within 12 hours after carbamazepine discontinuation. CONCLUSIONS: These data thus account for a cause-effect relationship between carbamazepine administration and NMS relief, and argue against the neuroleptic withdrawal to be responsible by itself for NMS relief.

Structure determination of the major asparagine-linked sugar chain of human factor VIII--von Willebrand factor.

N-glycosidically-linked glycans released by hydrazinolysis of human factor VIII/von Willebrand factor (FVIII/vWf) were separated by high-voltage electrophoresis. Five fractions were obtained, one of them representing 60% of the total amount of the N-glycosidically-linked glycans of FVIII/vWf. On the basis of the carbohydrate composition, methylation analysis and 500 MHz 1H-NMR spectroscopy, we describe the primary structure of this major glycan which is of the monosialylated and monofucosylated biantennary N-acetyllactosaminic type.

Improved characterization of plasma von Willebrand factor heterogeneity when using 2.5% agarose gel electrophoresis.

Discontinuous sodium dodecyl sulfate electrophoresis in large pore gels, followed by overlay with radiolabelled anti-von Willebrand factor (vWF) antibodies and by autoradiography, permits to analyze the multimeric structure of vWF. The aim of this study was to improve experimental conditions of this technique to satisfactorily resolve the minor forms of plasma vWF while still separating its high, intermediate, and low molecular weight predominant multimers. By using a 2.5% mixture of two selected agaroses, a single electrophoretic analysis of plasma clearly reveals the extreme complexity of the molecular forms of circulating vWF: each multimeric unit of plasma vWF may be separated into five bands, the central one being predominant. The multimeric distribution and "quintuplet" pattern obtained in the electrophoretic system described here permit a convenient classification of the different subtypes of von Willebrand's disease.

Functional and immunological assays of FVIII in 133 haemophiliacs--characterization of a subgroup of patients with mild haemophilia A and discrepancy in 1- and 2-stage assays.

A systematic study of the levels of FVIII antigen and activity was done in 133 haemophiliacs. No measurable antigen was demonstrated in the 60 severe haemophiliacs, with the exception of 3 patients with levels ranging between 1.5 and 4.5 U/dl, which corresponded to a dramatic FVIII deficiency. The situation was more complex with the 73 moderate and mild haemophiliacs: 39 of them (53.4%) had a partial, concordant deficiency of both the antigen and the procoagulant activity (1- and 2-stage methods), likely corresponding to a decrease in the synthesis of normal FVIII. The conclusion for the other 34 patients, was a qualitative abnormality of FVIII, the levels of antigen in comparison with the procoagulant activity (1-stage method) appearing to be either very reduced (n = 6) or even nil (n = 8), or on the contrary very much higher (n = 20) or normal. For 11 patients in this last category, we found a clear discrepancy between the procoagulant activity levels obtained with the 2 different techniques, the 1-stage levels being higher than the 2-stage levels. This discrepancy which was stable with restudy on multiple occasions and found in different members of the same families was remedied when vWF was absent in one-stage assay. This suggests that we have identified a variant of haemophilia A with an inherited abnormality of FVIII characterized by an in vitro vWF-dependent expression of procoagulant activity.

Validation of a procedure for potency assessing of a high purity factor VIII concentrate--comparison of different factor VIII coagulant assays and effect of prediluent.

The assessment of factor VIII coagulant activity (FVIII:C) in recently available highly purified and concentrated FVIII therapeutic products calls for careful evaluation of assay methodologies. We assayed more than 130 batches of a concentrate with a specific activity of about 150 FVIII:C units/mg protein, using one-stage and two-stage clotting and chromogenic methods. There was good agreement between the potency estimates obtained with the different methods. We also compared the FVIII:C potencies obtained after predilution in buffer or FVIII-deficient plasma using either calibrated plasma or FVIII concentrate as references. With the one-stage assay we found a marked discrepancy between the potency values obtained with buffer and with FVII-deficient plasma used as prediluents. In order to validate our "in vitro" data we performed 6 "in vivo" analyses in severe haemophilia A patients. On the basis of the overall data obtained we chose to label FVIII potency by using FVIII-deficient plasma as prediluent, reference plasma as standard and the chromogenic assay method.

Characterisation of a monoclonal antibody to von Willebrand factor as a potent inhibitor of ristocetin-mediated platelet interaction and platelet adhesion.

We studied a murine monoclonal antibody (211 A6) to von Willebrand factor (vWF) with a view to investigating structure-relationship of plasma vWF. The specificity of this antibody has been substantiated by ELISA tests and indirect immunofluorescence. It reacts with purified vWF, normal plasma but not with plasma or platelets from a severe von Willebrand's disease patient. Monoclonal antibody 211 A6 is a potent inhibitor of ristocetin-induced platelet aggregation. The 125I-FVIII/vWF binding to platelets in presence of ristocetin is totally inhibited by low 211 A6 concentrations. Thrombin-induced binding of vWF to platelets is not affected by 211 A6. The ability of this antibody to inhibit platelet adhesion to subendothelium and to collagen was investigated with a perfusion model. The complete inhibition of platelet adhesion by 211 A6 questions the similarity or the interrelationship in vWF domains involved in ristocetin-induced platelet functions and platelet adhesion.

Acquired von Willebrand's syndrome in the course of Waldenström's disease.

Acquired von Willebrand's syndrome with a regressive evolution is described in a 66 year old man with Waldenström's disease. An inhibitor electively directed against Ristocetin cofactor activity has been demonstrated, active in vitro after incubation at 37 degrees C. Serum fractionation showed that the inhibitor was independent of the monoclonal IgM and subsequent purification that it was IgG in nature. The results permit its classification as an auto-antibody.

Effect of carbohydrate modifications of factor VIII/von Willebrand factor on binding to platelets.

This study compares the ability of unmodified and carbohydrate-modified forms of factor VIII/von Willebrand factor (FVIII/vWF) protein to bind to platelets in the presence of ristocetin or thrombin. Treatment of intact FVIII/vWF with alpha-D-neuraminidase results in more than 95% desialylation. Asialo FVIII/vWF retains total activity in ristocetin- and thrombin-mediated binding to platelets as demonstrated by direct and competitive binding assays. Examination of its multimeric pattern by sodium dodecyl sulfate-agarose electrophoresis reveals a normal multimeric structure. Treatment of intact FVIII/vWF with beta-D-galactosidase results in the removal of 20% of galactose (agalacto FVIII/vWF) whereas 55% of galactose is released from asialo FVIII/vWF (asialo agalacto FVIII/vWF). Agalacto and asialo-agalacto FVIII/vWF are both unable to bind to platelets in the presence of ristocetin. In contrast, they still bind to thrombin-stimulated human (except thrombasthenic) platelets. Removal of either ultimate (agalacto FVIII/vWF) or ultimate and penultimate (asialo-agalacto FVIII/vWF) galactose results in the same loss of the larger molecular weight multimers and in an increase of smaller multimers. These results suggest (1) that sialic acid does not play a significant role in ristocetin- or thrombin-mediated FVIII/vWF-platelets interactions and multimeric structure of FVIII/vWF (2) that ultimate beta-linked galactose residues are essential for the maintenance of a normal multimer organization (3) that ristocetin- and thrombin-mediated binding of FVIII/vWF to platelets differ in FVIII/vWF galactose requirement.

Clinical features of latent inhibition in schizophrenia.

Paradigms of Latent Inhibition (LI) are inter-species and derived from learning theories. They are considered as tools which allow the attentional processes to be studied. The absence of LI is interpreted as difficulty in discriminating relevant and irrelevant stimuli. Abolition of LI has been shown in acute schizophrenics. The objectives of our study were partly to validate an LI paradigm, based on a contingency detection between two stimuli, in healthy subjects, and partly to analyse LI in schizophrenics. The study included 105 subjects (65 patients and 40 controls). Patients fulfilled the DSM IV diagnosis of schizophrenia. 35 in the acute phase and 30 in the chronic phase. We observed a loss of LI for acute schizophrenics, and an enhancement of LI for chronic schizophrenics. The variations in LI are interpreted from the perspective of a disturbance in the attentional processes. The LI status in acute schizophrenics appears to correlate with the clinical criteria with a prognostic value (low intensity of the negative dimension, late age at the first hospitalization). Moreover, the enhancement of LI correlates with the negative dimension of schizophrenic disease. This correlation is found in acute and chronic schizophrenics. It suggests that the variations of LI may be an indicator of adaptive strategies to a cognitive dysfunction specific to schizophrenia.

The role of fibronectin in factor VIII/von Willebrand factor cryoprecipitation.

To evaluate the role of fibronectin (Fn) in factor VIII (FVIII) and von Willebrand factor (vWf) cryoprecipitation, factor VIII procoagulant activity, factor VIII coagulant antigen, factor VIII-related antigen and von Willebrand ristocetin cofactor activity were measured in cryoprecipitate and cryosupernatant from normal and Fn-depleted plasmas. Following cryoprecipitation of normal plasmas, most of the FVIII and almost all the FvWf recovered were found with a part of Fn and of fibrinogen in cryoprecipitate. Fn-depleted plasmas prepared either by affinity chromatography on gelatin or by immunoadsorption on monoclonal anti-Fn antibodies behaved differently: although their cryoprecipitate contained normal fibrinogen levels, neither FVIII nor FvWf was precipitated. Experiments performed with Fn-depleted plasma to which purified fibronectin had been added, and samples of plasma with decreased Fn levels (0.01 to 0.2 g/l) suggest that there is a relation between initial Fn level and the extent of FVIII/vWf cryoprecipitation. We conclude that Fn, like fibrinogen, is necessary to induce cryoprecipitation of FVIII/vWf and that an initial plasma level of 0.2 g/l is sufficient to obtain good recovery of FVIII/vWf in cryoprecipitate.

Preliminary results on the carbohydrate moiety of factor VIII/von Willebrand factor (FVIII/vWf).

Human FVIII/vWf, purified 9 000 fold, was prepared from therapeutic concentrates by gel filtration and by immuno-affinity chromatography on insolubilized immunoglobulins isolated from a rabbit immunized with the plasma of a patient devoid of FVIII R:Ag. These preparations which contain coagulant activity and agglutinate normal washed human platelets in the presence of ristocetin are immunologically pure. The carbohydrate moiety of this highly purified FVIII/vWf was submitted to analysis by gas liquid chromatography and thin layer chromatography before and after hydrazinolysis and alkaline-borohydride treatment. The total carbohydrate content is 14.4 p. cent (w/w). Man and GalNAc residues were identified, this result indicating the coexistence of N- and O-glycosidically linked glycans (70 and 30 p. cent respectively). After hydrazinolysis it was demonstrated that the N-glycosidically linked glycans do not contain GalNAc residues. One major glycan belonging to the N-acetyllactosaminic type with a bi-antennary structure has been characterized by thin layer chromatography. The alkaline-borohydride treatment procedure reduced all the FVIII/vWf GalNAc to GalNAc-ol residues, demonstrating that they are all involved in the linkage of the O-glycans with the peptide chain and consequently they cannot be in oligosaccharidic sequences inducing A-blood group activity. Furthermore, at least 10 O-glycosidically linked glycans were identified by thin layer chromatography. Thus, the high degree of heterogeneity of the FVIII/vWf carbohydrate moiety requires further structural studies in order to precise which class of glycans is involved in the biological activity of FVIII/vWf.

Cerebral blood flow in major depression and dysthymia.

Using single photon emission computerized tomography (SPECT) with a 99mTc-HMPAO perfusion technique, we studied the regional cerebral blood flow (rCBF) of 42 drug-free inpatients suffering from Major Depression' (n = 21) or dysthymia with the super-imposed diagnosis of a major depressive episode (n = 21). The patients with Major Depression had a significantly lower frontal and posterior rCBF ratio than those with Double Depression. Left frontal region indices showed a slight overlap between the two groups. There was no correlation between the severity of the illness and the rCBF indices. Different qualitative cerebral dysfunctions may be implicated in these two affective disorder sub-types.