Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies.

The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter's syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.

[Surprising mechanism of highly symptomatic tachycardia in a young patient : Diagnosis and treatment]. / Überraschender Pathomechanismus hochsymptomatischer Tachykardien bei einem jugendlichen Patienten : Diagnostik und Therapie.

The diagnosis of paroxysmal tachycardia can be challenging in clinical practice because even with a typical patient history including palpitations, tachycardia, and an on/off phenomenon, 24 h Holter monitoring frequently fails to document the tachycardia. After unsuccessful 24 h Holter monitoring, we managed to document a very fast wide QRS complex tachycardia in a young patient by a mobile portable event monitor. Subsequent invasive electrophysiologic diagnostics followed by catheter ablation clarified the tachycardia mechanism and led to permanent elimination of the tachycardia.

Catchment properties and the photosynthetic trait composition of freshwater plant communities.

Unlike in land plants, photosynthesis in many aquatic plants relies on bicarbonate in addition to carbon dioxide (CO2) to compensate for the low diffusivity and potential depletion of CO2 in water. Concentrations of bicarbonate and CO2 vary greatly with catchment geology. In this study, we investigate whether there is a link between these concentrations and the frequency of freshwater plants possessing the bicarbonate use trait. We show, globally, that the frequency of plant species with this trait increases with bicarbonate concentration. Regionally, however, the frequency of bicarbonate use is reduced at sites where the CO2 concentration is substantially above the air equilibrium, consistent with this trait being an adaptation to carbon limitation. Future anthropogenic changes of bicarbonate and CO2 concentrations may alter the species compositions of freshwater plant communities.

Short-term effects of cardiac steroids on intracellular membrane traffic in neuronal NT2 cells.

Cardiac steroids (CS) are specific inhibitors of Na+, K+-ATPase activity. Although the presence of CS-like compounds in animal tissues has been established, their physiological role is not clear. In a previous study we showed that in pulse-chase membrane-labeling experiments, long term (hours) interaction of CS at physiological concentrations (nM) with Na+, K+-ATPase, caused changes in endocytosed membrane traffic in human NT2 cells. This was associated with the accumulation of large vesicles adjacent to the nucleus. For this sequence of events to function in the physiological setting, however, CS would be expected to modify membrane traffic upon short term (min) exposure and membrane labeling. We now demonstrate that CS affects membrane traffic also following a short exposure. This was reflected by the CS-induced accumulation of FM1-43 and transferrin in the cells, as well as by changes in their colocalization with Na+, K+-ATPase. We also show that the CS-induced changes in membrane traffic following up to 2 hrs exposure are reversible, whereas longer treatment induces irreversible effects. Based on these observations, we propose that endogenous CS-like compounds are physiological regulators of the recycling of endocytosed membrane proteins and cargo in neuronal cells, and may affect basic mechanisms such as neurotransmitter release and reuptake.

Bipolar disorder and violence.

Violent behavior presents many social, legal, and clinical problems. A number of models have been developed to explain violence, representing a variety academic disciplines and theoretical orientations. Unfortunately none of these approaches have led to a comprehensive understanding of violence and aggression. The issue of violence is particularly perplexing in connection with the role of psychiatric disorders as contributing factors. Several psychiatric conditions, including bipolar disorder, have been implicated with increased rates of violent behavior. This paper examines various models of violence, influences on violent behavior, and violence associated with psychiatric disorders. Particular attention is devoted to the connection between bipolar disorder and violence.

Performance of discrete heat engines and heat pumps in finite time

The performance in finite time of a discrete heat engine with internal friction is analyzed. The working fluid of the engine is composed of an ensemble of noninteracting two level systems. External work is applied by changing the external field and thus the internal energy levels. The friction induces a minimal cycle time. The power output of the engine is optimized with respect to time allocation between the contact time with the hot and cold baths as well as the adiabats. The engine's performance is also optimized with respect to the external fields. By reversing the cycle of operation a heat pump is constructed. The performance of the engine as a heat pump is also optimized. By varying the time allocation between the adiabats and the contact time with the reservoir a universal behavior can be identified. The optimal performance of the engine when the cold bath is approaching absolute zero is studied. It is found that the optimal cooling rate converges linearly to zero when the temperature approaches absolute zero.

Violence in medical facilities: a review of 40 incidents.

Workplace violence has become an increasing problem in the United States. This paper reviews 40 such incidents of non-patient violence occurring in medical facilities. Areas of study include categories of violence, weapons used, number of persons killed or wounded, precipitant for the violent act, and the presence of psychopathology. Additional variables such as suicide, drug and alcohol use, stalking, and hostage-taking are also examined. The results indicate that workplace violence in medical settings differs considerably from incidents in other work environments, particularly with respect to motivation, psychiatric diagnoses, weapons used, and stalking. Intervention and management strategies in health care institutions may, therefore, need to be modified in order to deal with violence. An examination of the data allows development of a profile for violence in medical settings and the identification of risk factors. Security issues for hospitals, clinics, and physician offices are also discussed.

Cult membership as a source of self-cohesion: forensic implications.

The study of cults and the types of individuals drawn to them has long been of interest to psychiatrists. Although many studies have been done on personality types and psychopathology in cult members, no consensus has emerged. Studies of psychopathology in cult members have viewed these individuals as having either no significant impairment, displaying elements of character pathology, or being severely impaired. The result is that no clear theoretical framework has been developed to explain cult membership. Psychoanalytic self psychology, as developed by Heinz Kohut, can provide such a framework. The cult may be understood as serving a number of functions for its members, all of which are designed to restore self-cohesion. Such a formulation implies a degree of self, or narcissistic, pathology in many cult members. This article reviews the literature on cults, offers a self psychology formulation to explain the function that cult membership serves for narcissistically vulnerable personalities, and describes forensic applications of these principles.

The application of psychotherapeutic and self psychology principles to hostage negotiations.

Self psychology provides valuable insights into the dynamics that underlie hostage situations and negotiations. Recognition of the similarities between negotiations and psychotherapy further clarifies the complex interactions that occur. The importance of empathy and the development of selfobject relationships will have a significant impact on the resolution of the incident. Recognition of selfobject transferences and the indicators of self fragmentation will help to guide the negotiator and mental health consultants in their conduct of the negotiations. The complex relationships that develop between hostage-taker, hostages, and negotiators can all be understood within the framework of self psychology, leading to the more effective management of these situations.

Self-inflicted eye injuries: case presentations and a literature review.

OBJECTIVE: The authors' aim was to determine demographic and clinical correlates of self-inflicted eye injury. METHODS: The authors reviewed 41 cases of patients with self-inflicted eye injuries identified through MEDLARS searches of medical literature for the period from 1980 to 1993 and four cases from the first author's clinical practice. RESULTS: Most patients with self-inflicted eye injuries were male, about 31 years old, and had a diagnosis of schizophrenia, drug or alcohol abuse, depressive disorders, or other psychosis. Some patients experienced cognitive distortions, often involving religious and sexual ideation, and intense fear around the time they injured themselves. Thirty-three percent of the patients with self-inflicted eye injuries also showed other types of self-injurious behavior. CONCLUSIONS: Enucleation of the eye may serve as a defense against witnessing or experiencing a forbidden act. Psychodynamic theories addressing self-mutilation do not explain self-induced eye injury particularly well but may assist the therapist in understanding motivation and in restructuring patients' behavior. Management of these patients requires multidisciplinary, multimodal efforts involving medical specialists, patients, family members, and staff.

Single exchanges of amino acids in the basic region change the specificity of N-Myc.

We exchanged specific amino acids in the basic region of the murine N-Myc protein and tested the mutant proteins for their DNA binding specificity. The amino acids we exchanged were chosen in analogy to residues of the homologous basic regions of bHLH and bZIP proteins. Mutant N-Myc peptides were expressed in Escherichia coli and specific DNA binding was monitored by gel shift experiments. For this we used palindromic target sequences with systematic base pair exchanges. Several mutants with altered DNA binding specificity were identified. Amino acid exchanges of residues -14 or -10 of the basic region lead to specificity changes (we define leucine 402 of N-Myc as +1; comparable to GCN4 see (1)). The palindromic N-Myc recognition sequence 5'CACGTG is no longer recognized by the mutant proteins, but DNA fragments with symmetrical exchanges of the target sequence are. Exchanges at position -15 broaden the binding specificity. These data were used to build a computer based model of the putative interactions of the N-Myc basic DNA binding region with its target sequence.

In vitro phagocytosis inhibition assay for the screening of potential candidate antigens for sub-unit vaccines against the asexual blood stage of Plasmodium falciparum.

We have previously established a direct correlation between immune protection against the asexual blood stage Plasmodium falciparum infection and the presence of opsonizing antibodies promoting phagocytosis of parasitized red blood cells. In the present communication we describe an in vitro assay for measuring phagocytosis inhibition (PIA) specific for P. falciparum-infected erythrocytes. The phagocytosis inhibition assay is a simple procedure for screening potential candidates for sub-unit vaccines against P. falciparum based on the correlation between opsonizing antibodies and immunoprotection. The assay was used to analyse 18 recombinant molecules, corresponding to 11 distinct antigens of P. falciparum. Pre-incubation and selective antibody depletion experiments demonstrate the antigen-antibody specificity of the PIA. The presence of epitopes participating as targets of opsonic antibodies were demonstrated in six distinct polypeptide antigens.

Juror stress: identification and intervention.

The impact of stressful life events has been studied extensively in the psychiatric literature. Crisis debriefing techniques have been shown to be effective in decreasing psychiatric morbidity following exposure to these stressful situations. Stress reactions and crisis debriefing have been reported in many groups including combat veterans, survivors of natural disasters and accidents, victims of violence, and law enforcement and emergency personnel who respond to such events. One group that has not been studied extensively is jurors who are exposed to potentially disturbing material introduced as evidence in trials. Stress reactions in jurors and the value of debriefing of juries have been described by us in an earlier work. This paper describes debriefing sessions with three juries exposed to emotionally distressing material during murder trials. In comparing our experiences with these sets of jurors a number of common reactions were identified. These are discussed and a model for jury debriefing is presented.

The selfobject function of weapons: a self psychology examination.

Weapons serve a variety of functions, both for individuals and for society. One such function is that of a selfobject for narcissistically vulnerable persons. This selfobject function allows the damaged self to maintain cohesion and to offset feelings of vulnerability and powerlessness. Because the weapon allows the personality to feel in control and to exert dominance over others, it may come to be viewed in an idealized manner. This is very similar to the idealizing selfobject transference described by Kohut. Weapons are more likely to become selfobjects for those personalities suffering from some degree of self pathology. The selfobject function of weapons, however, may have significance beyond individual psychopathology. Groups of individuals, societies, and even nations may utilize weapons to counter feelings of vulnerability and to diminish fragmentation of the group's collective self. Their destructive potential may be unleashed in response to an intense narcissistic injury and narcissistic rage. The importance of weapons can thus be better understood by examining them within the context of self psychology.

Crisis debriefing of a jury after a murder trial.

The importance of crisis debriefing for those involved in major accidents, violent crimes, and natural disasters has been demonstrated. Similar debriefing may be warranted for jurors exposed to disturbing material in criminal cases. The authors describe a debriefing session for jurors after the murder trial of a man whose truck had collided with a school bus, killing 27 people. The graphic evidence of the accident, the high levels of emotion of the survivors and the victims' relatives, and the intense community and national attention to the trial placed the jurors under considerable stress. The debriefing enabled the jurors to express their feelings of anger, guilt, and frustration and to begin to accept their role in the event.

Attitudes of medical school faculty and students toward acquired immunodeficiency syndrome.

Attitudes of faculty and students will influence the success of educational programs to address acquired immunodeficiency syndrome (AIDS). In 1988-89, 170 medical school faculty and 227 students completed needs assessment questionnaires at the University of Louisville, and the results were compared to assess the respondents' attitudes about AIDS. Both the faculty and the students were found to be fearful of infection, had strong negative attitudes toward AIDS patients, and had low levels of confidence in the current knowledge about AIDS. Both cognitive and affective training strategies are recommended to help learners distinguish unwarranted from warranted fears of infection and to increase their empathy for patients with AIDS.

Cofactors in the commission of violent crimes: a self-psychology examination.

In many violent crimes a cofactor seems to play a part in the emergence of the violent act. The individuals involved in these cases appear to suffer from significant self pathology. The violent behaviors represent disintegration products of the self designed to maintain cohesion in the face of self-fragmentation. Without the presence of selfobjects, the violent act is less likely to occur. Thus, self psychology provides valuable insights into the commission of certain violent crimes.

Outcomes of AIDS training for supervisory and nonsupervisory personnel in the workplace.

Dealing with AIDS in the workplace is complicated by a variety of complex issues. One factor influencing how AIDS is dealt with is the difference in knowledge and attitudes between supervisory and nonsupervisory personnel. We surveyed 3834 supervisory and nonsupervisory personnel from a number of businesses and corporations in the Louisville metropolitan area. The differences found in this study suggest strategies for training to address the problem of AIDS in the workplace.

Evaluating the outcomes of AIDS education.

AIDS provides a unique challenge to health educators, requiring continuous evaluation and modification of educational strategies. Pretest and posttest questionnaires were thus used to assess the outcomes of AIDS training sessions. Results show that hour-long sessions result in knowledge acquisition and increased confidence among a demographically representative sample of 3,966 U.S. trainees. Results also reveal the dynamic nature of a training session, with some trainees exhibiting learning and others retaining either correct or incorrect responses or changing from one incorrect to another incorrect answer. Content areas that showed the most learning were sharing a glass or food with and being sneezed on by someone infected with the human immunodeficiency virus (HIV). Areas resistant to learning included the possibility of transmission from receiving blood transfusions, eating in a restaurant where a cook is infected, being bitten by a mosquito, giving mouth-to-mouth resuscitation, and providing first aid to someone infected. Repeat training sessions that take into account affective dimensions as well as the diverse needs of adult learners are recommended.

Psychotherapy with AIDS patients.

AIDS patients and others with HIV infections experience a variety of psychosocial stresses. These stresses lead to many situational reactions and adjustment problems. Psychotherapy can be of great benefit in helping AIDS patients to deal with these difficulties. Eight essential content areas are presented that should be addressed in the psychotherapy of all AIDS patients. By examining each of these areas, the intense psychosocial issues associated with HIV infection are dealt with. The overall quality of life for AIDS patients is, therefore, improved.