4-Anilino-6,7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-dialkoxyquinazoline inhibitors.

The synthesis and SAR of a series of 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor (EGF-R) kinase are described. Condensation of 3, 4-dialkoxyanilines with ethyl (ethoxymethylene)cyanoacetate followed by thermal cyclization gave, regiospecifically, 6,7-dialkoxy-4-oxo-1, 4-dihydroquinoline-3-carbonitriles. Chlorination (POCl(3)) followed by the reaction with substituted anilines furnished the 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of EGF-R kinase. An alternate synthesis of these compounds starts with a methyl 3, 4-dialkoxybenzoate. Nitration followed by reduction (Fe, NH(4)Cl, MeOH-H(2)O) gave a methyl 2-amino-4,5-dialkoxybenzoate. Amidine formation using DMF-acetal followed by cyclization using LiCH(2)CN furnished a 6,7-dialkoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile, which was transformed as before. Compounds containing acid, ester, amide, carbinol, and aldehyde groups at the 3-position of the quinoline ring were also prepared for comparison, as were several 1-anilino-6,7-dimethoxyisoquinoline-4-carbonitriles. The compounds were evaluated for their ability to inhibit the autophosphorylation of the catalytic domain of EGF-R. The SAR of these inhibitors with respect to the nature of the 6,7-alkoxy groups, the aniline substituents, and the substituent at the 3-position was studied. The compounds were further evaluated for their ability to inhibit the growth of cell lines that overexpress EGF-R or HER-2. It was found that 4-anilinoquinoline-3-carbonitriles are effective inhibitors of EGF-R kinase with activity comparable to the 4-anilinoquinazoline-based inhibitors. A new homology model of EGF-R kinase was constructed based on the X-ray structures of Hck and FGF receptor-1 kinase. The model suggests that with the quinazoline-based inhibitors, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 830. It is proposed that the quinoline-3-carbonitriles bind in a similar manner where the water molecule is displaced by the cyano group which interacts with the same Thr residue.

Uniforming of outpatient health care statistics.

In the process of developing the health care information system, the Public Health Institute of the Republic of Slovenia harmonized the outpatient health care statistics at the national level. This paper presents the goals, contents, methodology and a brief analysis of the new data structure. The main functions of the ZUBSTAT computer program, user training methods, and planned further activities in this field are described.

Experimental infection of Columbian black-tailed deer with the Lyme disease spirochete.

The course of Borrelia burgdorferi-infection in Columbian black-tailed deer. (Odocoileus hemionus columbianus), its effect on the health of these animals, and their reservoir competence for fleas were evaluated experimentally. Four yearling females inoculated intramuscularly with 10(8) organisms of the CA4 strain of B. burgdorferi, and two yearling males unexposed to spirochetes, were monitored daily for 3 mo. Spirochetes were reisolated from the blood of three does at 14 or 70 days postinjection, and from several tissues of the fourth doe at necropsy. Considerable antigenic heterogeneity was observed among the reisolates as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Only two of the four infected deer developed significant antibodies (> or = 1:128) to B. burgdorferi with titers persisting for < or = 2 mo. Hematological values were highly variable and the degree of variation observed was much greater than that reported previously for Columbian black-tailed deer or other subspecies of mule deer. Infected deer did not manifest signs of Lyme disease. On histologic examination of eight tissues per deer, we observed a minimal hepatic lesion in all animals exposed to B. burgdorferi. No spirochetes were detected in 367 fleas (Pulex irritans) that had naturally infested these deer; thus this flea probably is an inefficient host of B. burgdorferi.

Psychoanalytic contributions to psychotherapy: clinical empathy.

The concept of empathy has become a central issue in the debate between classical psychoanalysts and self psychologists. If one recognizes that dilemma is central to the human condition and that the two competing schools of psychoanalysis emphasize opposite sides of several parameters that are fraught with dilemma, it is possible to view them both as empathic. Three levels of empathy are discussed: empathizing with the patient's story as it stands; discovering new themes hidden away in the patient's narrative; and discovering significant patterns in the patient-therapist relationship itself. The concept of therapy as a self-correcting process that approaches but never quite attains objective accuracy is emphasized.

Developing the story in psychotherapy.

Psychotherapeutic work entails many paradoxes. Emphasizing the patient's imagery and deemphasizing theory enhances understanding at the manifest level, the level of hidden themes, and the level of transference-countertransference patterns. A useful therapeutic model embraces dilemma, promotes toleration of puzzlement, and views the therapist as editor of the patient's developing novel.

Psychological patterns in donor insemination couples.

One hundred and twenty couples applying for DI or involved in the procedure were seen in consultation or therapy at various stages. The clinical findings provide evidence that both partners experience conflict in two areas. The discovery of infertility generates transient impotence, loss of self-esteem and withdrawal in husbands, and anger, guilt and a wish to make reparations in wives. The DI procedure itself evokes oedipal conflicts. Clinical vignettes have been presented to illustrate these patterns and to provide evidence for the view that couples should recognize, discuss and come to terms with the conflicts generated by the discovery of infertility before tackling DI and the conflicts this procedure evokes. Although secrecy is advocated by most DI couples and physicians, a questionnaire study of 76 couples in our unit disclosed that many individuals consider it psychologically useful to discuss their infertility problems with others. Although secrecy may be useful, it may also, through the indirect sanction of denial and negation, interfere with the couple's acknowledging and discussing their problems. One useful purpose of a psychiatric assessment is that it can promote such acknowledgement and discussion. Conflict needs to be distinguished from psychopathology which may be the outcome of unresolved conflict.

Recovery and regression in concentration camp survivors: a psychodynamic re-evaluation.

This paper focuses on the adaptive capacity of survivors, and, by reframing the psychodynamics of the "survivor syndrome", employing Object Relations theory and Self Psychology, attempts to shed light on the recovery process and the subsequent regressive responses in later life. Historically, an understanding of the survivor syndrome was impeded by the severity and uniqueness of the trauma. Survivors demonstrated symptoms that were not always congruent with the established diagnosis "traumatic neurosis", and conventional psychoanalytic psychotherapy which aimed at lifting the repression of the persecution often failed. Despite reports of "late" physiologic sequelae, recent work has focused on the survivor's capacity to recover. Survival during the persecution entailed maintaining perceptual defences, maintaining an attachment to the world and the objects in it, and despite the fragmenting effect of these two sets of mechanisms, maintaining an integrated sense of self. Three clinical vignettes are presented to demonstrate that during the recovery process a degree of reversal of the survival mechanisms was necessary. This required taking into oneself or acknowledging the anger evoked by the persecution, which, associated with the fragmenting effect of the persecution on the sense of self, often resulted in guilt and self-loathing, and affected the vicissitudes of the survivor's personal story. Often the self-selfobject function required bolstering by particular relationships. The triggers for later regression responses in survivors are events that evoke rage or serve as a symbolic bridge to memories of the persecution, and life changes that generate altered relationships that had served a self-selfobject function.(ABSTRACT TRUNCATED AT 250 WORDS)

On the way to empathic understanding.

Empathy in psychotherapy has come to be regarded as useful, although there has been debate about its role. Some feel empathic understanding to be curative in itself; others consider it a step toward insight. Whether empathic understanding should be regarded as conscious or unconscious, affective or intellectual, adaptive or defensive, has received much consideration. A case illustration is used to show that "empathic understanding" is the end result of a complex process; that the ability to tolerate a state of puzzlement enhances and punctuates this process; that many modalities, including identification, projection, and distancing, occurring in any order, contribute to it; that the process places a strain on the therapist's sense of self; and that the essential ingredient is the presence of an overriding integrating capacity. At the moment of empathic responsiveness, the therapist is able to regard himself as separate and autonomous from the patient.

Psychological aspects of donor insemination.

This survey of the psychological literature on Artificial Insemination by Donor (AID) pays particular attention to the secrecy. Studies of couples beforehand do not arrive at criteria for choosing psychologically suitable couples. Follow-up questionnaires are superficial and cannot inform us which couples and what percentage of couples encounter psychological difficulties. Case reports of couples who encountered difficulties are too few to permit generalization and cannot specify AID's role in generating symptoms. A second look at the data suggests that, although overlooked, the secrecy surrounding AID may create psychological difficulties, a view supported by the findings at our clinic. A plea is made with specific recommendations to create an ambience in which openness is possible, and which will allow in-depth research of the psychological aspects of AID.

The teaching and learning of psychotherapy in a general hospital.

A general teaching hospital provides an excellent setting for the teaching of psychiatric residents. The Canadian model for a teaching network, including general and specialty hospitals, allows for special interests to develop within given hospitals. A department of psychiatry which chooses the teaching of psychotherapy as a special interest is examined. The teaching occurs in all areas of the department (ambulatory, inpatient, consultation-liaison) and is backed up by appropriate seminars. Individual supervision provides the backbone of the teaching program. The special interest exists within a department which must answer all of the psychiatric needs of a general hospital population. From the university point of view, the network is strengthened by the existence of various areas of concentrated interest within various component units of the network.

Psychoanalysis, dreaming and the REM state: a clinical vignette.

This presentation examines the effects of the discovery of the REM state of the psychotherapist. A clinical illustration serves as the point of departure. A dream fragment which might be explained in terms of the activation-synthesis hypothesis is shown to connect with conflicts in a way that this hypothesis cannot encompass. Freudian theory requires modification in its explanation of what instigates dreams and in its explanations of energy and drive. The therapist's interventions, to the extent that they imply causation to the dream or an energy that they imply causation to the dream or an energy transformation, also require modification. At the same time psychoanalytic theory does provide a unique understanding of sequential clinical events. The pitfalls of focusing solely on dreams are discussed. Finally, the tentative findings from the REM laboratory concerning the function of dreams are shown to fit nicely with the use to which dreams have been put by psychoanalytic therapists.

Infertility. A psychiatrist's perspective.

This paper discusses issues relevant to psychiatrists working in a reproductive biology unit: 1. The couple's anxiety. 2. The question of whether psychological conflict can cause infertility. 3. Dealing with the outcome of the workup. 4. Donor insemination. The anxiety of couples applying for an infertility workup can usually be countered by supportive and educative measures. More problematic sources of anxiety that require psychiatric consultation are: 1) Fear that the workup may shatter a myth that explains the infertility, a myth reinforced by unconscious conflicts; 2) An untenable wish that having a child will repair problems in the marriage or in the sense of relief. The psychiatrist is often asked whether psychological conflicts can cause infertility. The most understandable manner in which they do is by their effect on sexual performance. Where there is no sexual performance problem, psychotherapy can be offered if one or both partners experiences psychological pain, but with the understanding that therapy cannot be expected to cure the infertility. Psychiatric consultation at the end of the workup is indicated 1) where irreversible infertility is discovered and mourning is excessive, 2) where a myth to explain the infertility has been shattered, 3) to reassess sexual performance and to deal with the uncertainty, where no physical cause has been discovered. Donor insemination (AID) is fraught with legal and ethical problems. There are no criteria for selecting donors or recipient families, and there is concern that AID may lead to genetic engineering. The psychological effects of AID are uncertain. A study at our clinic suggests that the pursuit of AID involves a two-stage process: first, dealing with the outcome of the infertility workup and second, confronting AID itself; and that the secrecy that surrounds AID obstructs resolution of conflict.

Couples' reactions to male infertility and donor insemination.

The author interviewed 16 couples after the husband had been diagnosed as infertile. Eleven husbands experienced a period of impotency. Fourteen of the women experienced anger toward the husband, psychiatric symptoms, and/or dreams about their concern for the husband, a wish to be rid of him, and guilt over this wish. Ten couples had decided to pursue donor insemination; 6 had delayed 1 3/4 to 4 years after the diagnosis of infertility and had a better adjustment than 3 of the 4 couples who did not. The author believes that the total secrecy involved in donor insemination inhibits the working through of conflicts about infertility and donor insemination itself.

Impotence following the discovery of azoospermia.

Sixteen couples were interviewed after the male had been discovered to be infertile. Of these couples, 63% of the men had experienced a period of impotence and 87% of the women had experienced rage toward the husband, symptoms, and/or dreams which incorporated three themes: concern for the husband, a wish to be rid of him, and guilt over this wish. Husbands whose wives were symptom-free did not experience impotence. These findings suggest that impotence following the discovery of azoospermia is common and should be regarded as an interactional problem. Clinical management is recommended which includes reassuring the couple that the impotence is expected and that it will resolve within 3 months, and focusing on the couple's reaction to the diagnosis.

The survivor syndrome: a problem of nosology and treatment.

Many features of the psychologic sequelae in survivors of Nazi persecution are consistent with "traumatic neurosis", but persistent guilt, which appears to be due to having identified with the aggressor, and self-loathing are not. Three cases of psychotherapy with survivors only peripherally affected by the persecution are discussed.

The role of the psychiatrist in a reproductive biology clinic.

The psychiatrist consulting to an infertility clinic is confronted with a variety of clinical issues and problems. The couple arrives with anxiety, for a work-up that in itself will be traumatic. The psychiatrist's role is to weed out distortions and issues that are unreal. Psychosexual and marital conflicts may also masquerade as an infertility problem. The simplest manner in which psychologic factors can be thought of as causing infertility is through their effect on sexual performance. Brief therapeutic techniques include education, encouragement, and behavioral techniques to improve performance. Psychoanalytically oriented techniques include relating the symptom to unconscious conflicts stemming from the past and understanding the secondary gain of the symptom. The psychiatrist's role may also involve helping the couple to deal with the outcome of the infertility work-up, including helping the couple to mourn the fact that they cannot have children, assisting in decisions involving artificial insemination and adoption, and helping the couple to deal with uncertainty when no definite cause for the infertility has been discerned. The multiplicity of possible psychologic interventions requires the psychiatrist to be ubiquitous. In the light of this, a number of suggestions are listed as to how a psychiatrist might best be utilized.

The diagnosis of organic brain syndrome.

Because it stems from a variety of causes and interacting factors, organic brain syndrome is a difficult condition to diagnose. Several factors make it distinguishable from functional disorders, schizophrenia or hysteria. The syndrome cannot be considered in isolation from the patient's personality, however, since this will affect his coping with the disorder.

Symposium--psychiatric education.

The process of learning in groups, as exemplified by the author's experience in a multidiscipline conference on a surgical ward of a general hospital has been examined. A sequence of six developmental states has been identified: initial ambivalence; passive receptivity; resistance; task orientation; the work group and consolidation. These findings have been compared with those of other studies dealing with sequential stages in group development. The psychiatric consultant's role in expediting these phases and some of the difficulties encountered have been mentioned.

Psychological assessment of the infertile couple.

The psychological assessment of the infertile couple involves ruling out major psychopathology, and attempting to uncover psychological factors that may be contributing to the problem of infertility. These factors may be sought out by looking for subtle and unconscious behavior which works against the wife's becoming pregnant, and by uncovering fears relating to pregnancy, attempting to connect these fears to events in the individual's past. Several issues relating to interview technique, particularly those that run counter to traditional medical training, are discussed.