[Acceptance and use of web-based interventions for alcohol abstinence]. / Nutzung und Akzeptanz webbasierter Angebote zur Alkoholabstinenz.

INTRODUCTION: In Germany, the prevalence rates for alcohol use disorders amount to approx. 6%, while about 3% are diagnosed as being alcohol dependent. Only 10% of the patients are undergoing treatment. There are apparent deficits with respect to early interventions. The internet presence of "Ohne Alkohol mit Nathalie" (OAmN) (Abstinence with Nathalie) ameliorates options for early treatment interventions using a web-based design; however, this intervention has not been evaluated to date, especially with respect to previous treatments. METHODS: Over a 4-week period, 4 different channels of OAmN posted announcements for a survey participation introducing a link leading to a web-based survey questionnaire on the domain oamn.jetzt. The questionnaire offered open and closed as well as multiple choice questions regarding alcohol use patterns and attempts to change the problematic drinking behavior. RESULTS: Out of 2022 participants 84.3% (n = 1705) stated to have or have had a problem with alcohol use, 17.7% (n = 302) had a diagnosis of alcohol dependence by a physician or psychologist and only 21% (n = 529) had been in therapy before. The majority of responders (85.5%, n = 1457) had stopped alcohol use before participating in the survey. Most of them (48.5%, n = 705) were assisted by OAmN, 97.5% (n = 1662) had been employed while having the abovementioned problem use of alcohol, 34.3% (n = 570) rated their job performance as "very good" and 43.2% (n = 718) as "good". DISCUSSION: This pilot study revealed that OAmN can reach people affected by problematic drinking behavior who had not been in contact with the professional medical system for addiction treatment despite having a problematic alcohol use combined with the willingness to quit.

[Bio-Psycho-Social Characteristics and Therapeutic Aspects of Methamphetamine-Dependent Women - Gender Specific Results of a Systematic Literature Search]. / Bio-psycho-soziale Charakteristika und therapeutische Aspekte bei Methamphetamin-abhängigen Frauen ­ Gendersensible Ergebnisse einer systematischen Literaturrecherche.

SUBJECT: Compared to other illicit drugs Methamphetamine (MethA) is used more frequently by women than by men. Assuming the biopsychosocial etiology model, the dependency is based on several factors in which women and men differ significantly. Systematic gender-differentiated knowledge is missing until today. METHOD: Based on a database research (PUBMED) the review examines biological, social and psychological as well as therapeutic aspects in MethA-dependent women. RESULTS: MethA-induced cognitive disturbance appear to have severer manifestations in women than in men. MethA-addicted women's lifestyle is often characterized by active and passive (sexualized) violence. They show an increased risk behavior; i. e. unprotected sexual intercourse with several partners. Their psychological comorbidities seem to be more pronounced and especially affect anxiety disorders and depressive syndromes. CONCLUSION AND CLINICAL RELEVANCE: In women, abuse and dependence of MethA are determined by psychological as well as social factors. However, further research is needed to improve prevention, counseling and therapy.

Cannabis for Cognitive Enhancement as a New Coping Strategy? Results From a Survey of Students at Four Universities in Germany.

BACKGROUND: Cognitive Enhancement (CE) is often discussed in relation to stimulant drugs, such as amphetamines (AMPH). However, there is some evidence that cannabis (CAN) can be used for CE. OBJECTIVE: This study compares the knowledge, prevalence, and perceived effects of and factors associated with the knowledge of or use of CAN versus AMPH for CE among undergraduate students at four German universities. METHODS: A survey was taken of 1,538 students at four German universities. It investigated their knowledge and use of CAN and AMPH for CE as well as associated factors. Descriptive and analytic (Mann-Whitney-U test, Fisher's exact test, logistic regression) statistics were obtained using SPSS. RESULTS: Responses were obtained from 1,026 participants (57.2%) at three universities from the Universitätsallianz Metropole Ruhr (UAR) (Bochum, Dortmund, Duisburg-Essen) and 512 respondents (68.3%) in Mainz. We observed lifetime prevalence rates of 3.5% for the use of CAN and 2.1% for the use of AMPH for the purpose of CE. CAN users perceived pressure to perform as more of a burden than AMPH users (mean: 3.2, CAN users: 4.7, AMPH: 2.9; p =.042). CAN users used the substances for studying for exams significantly less often than AMPH users (p =.025), and CAN users perceived less of an enhancing effect of the drug compared to AMPH users (p <.001). CONCLUSIONS: A considerable number of students report having used CAN for CE. However, our research indicates differences in perceptions and experiences of CE between CAN and AMPH users. Further research on the role of CAN for CE and conceptual analyses to differentiate between different understandings of CE are warranted.

The Use of Caffeinated Substances by Surgeons for Cognitive Enhancement.

OBJECTIVE: To investigate the use of coffee, caffeinated drinks, and caffeine tablets for pharmacological cognitive enhancement (CE) among surgeons. BACKGROUND: Surgeons have demanding workloads, and the resulting fatigue and concentration deficits can lead to medical errors. Some surgeons use substances that promote wakefulness to counteract these effects. METHODS: A total of 3306 surgeons who attended 5 international conferences in 2011 were surveyed regarding their use of coffee, caffeinated drinks, and caffeine tablets for CE and potential factors derived from professional and private life using an anonymous self-report questionnaire. In this study, we were only interested in surgeons working in hospitals; therefore, 951 questionnaires were statistically analyzed. RESULTS: The most prevalent reason for using caffeine of any kind was to reduce fatigue (54.3%). Further prevalent reasons are working the night shift (32.2%) and overly long and excessive work hours (31.7%). Lifetime, past-year, past-month, and past-week prevalence was 66.8%, 61.9%, 56.9%, and 50.5%, for coffee use; 24.2%, 15.4%, 9.9%, and 6.1%, for caffeinated drinks; and 12.6%, 5.9%, 4.7%, and 3.8%, respectively, for caffeine tablets. Caffeine use was associated with lower age, male sex, divorced marital status, living with children, lack of satisfaction with professional status, pressure to perform in private life, and pressure perceived to be harmful to one's own health. CONCLUSIONS: Surgeons often use caffeinated substances to cope with fatigue and long working hours. Coffee use was more prevalent than the use of caffeinated drinks and caffeine tablets.

Substances used and prevalence rates of pharmacological cognitive enhancement among healthy subjects.

Pharmacological "cognitive enhancement" (CE) is defined as the use of any psychoactive drug with the purpose of enhancing cognition, e.g. regarding attention, concentration or memory by healthy subjects. Substances commonly used as CE drugs can be categorized into three groups of drugs: (1) over-the-counter (OTC) drugs such as coffee, caffeinated drinks/energy drinks, caffeine tablets or Ginkgo biloba; (2) drugs being approved for the treatment of certain disorders and being misused for CE: drugs to treat attention-deficit/hyperactivity disorder (ADHD) such as the stimulants methylphenidate (MPH, e.g. Ritalin(®)) or amphetamines (AMPH, e.g. Attentin(®) or Adderall(®)), to treat sleep disorders such as modafinil or to treat Alzheimer's disease such as acetylcholinesterase inhibitors; (3) illicit drugs such as illicit AMPH, e.g. "speed", ecstasy, methamphetamine (crystal meth) or others. Evidence from randomized placebo-controlled trials shows that the abovementioned substances have limited pro-cognitive effects as demonstrated, e.g. regarding increased attention, increased cognitive speed or shortening of reaction times, but on the same time poses considerable safety risks on the consumers. Prevalence rates for the use of CE drugs among healthy subjects show a broad range from less than 1 % up to more than 20 %. The range in prevalence rates estimates results from several factors which are chosen differently in the available survey studies: type of subjects (students, pupils, special professions, etc.), degree of anonymity in the survey (online, face-to-face, etc.), definition of CE and substances used/misused for CE, which are assessed (OTC drugs, prescription, illicit drugs) as well as time periods of use (e.g. ever, during the past year/month/week, etc.). A clear and comprehensive picture of the drugs used for CE by healthy subjects and their adverse events and safety risks as well as comprehensive and comparable international data on the prevalence rates of CE among healthy subjects are of paramount importance for informing policy makers and healthcare professionals about CE.

Attitudes towards prescribing cognitive enhancers among primary care physicians in Germany.

BACKGROUND: Primary care physicians are gate keepers to the medical system having a key role in giving information and prescribing drugs to their patients. In this respect they are involved in claims of patients/clients for pharmacological Cognitive Enhancement (CE). Therefore, we studied the knowledge of primary care physicians about CE and their attitudes toward prescribing CE drugs to healthy subjects. METHODS: A self-report paper-and-pencil questionnaire and case vignettes describing a hypothetical CE drug were sent out to all 2,753 registered primary care physicians in Rhineland Palatine, Germany. 832, i.e. 30.2% filled in the questionnaire anonymously. RESULTS: 96.0% of all participating physicians had already heard about CE. However, only 5.3% stated to be very familiar with this subject and 43.5% judged themselves as being not familiar with CE. 7.0% had been asked by their clients to prescribe a drug for CE during the last week, 19.0% during the last month, and 40.8% during the last year. The comfort level to prescribe CE drugs was very low and significantly lower than to prescribe sildenafil (Viagra®). Comfort level was mainly affected by the age of the client asking for prescription of CE drugs, followed by the availability of non-pharmacological alternatives, fear of misuse of the prescribed drug by the client and the missing indication of prescribing a drug. CONCLUSIONS: Although a relatively high proportion of primary care physicians have been asked by their clients to prescribe CE drugs, only a small proportion are well informed about the possibilities of CE. Since physicians are gate keepers to the medical system and have a key role regarding a drugs' prescription, objective information should be made available to physicians about biological, ethical and social consequences of CE use.

Use of illicit and prescription drugs for cognitive or mood enhancement among surgeons.

BACKGROUND: Surgeons are usually exposed to high workloads leading to fatigue and stress. This not only increases the likelihood of mistakes during surgery but also puts pressure on surgeons to use drugs to counteract fatigue, distress, concentration deficits, burnout or symptoms of depression. The prevalence of surgeons taking pharmacological cognitive enhancement (CE) or mood enhancement (ME) drugs has not been systematically assessed so far. METHODS: Surgeons who attended five international conferences in 2011 were surveyed with an anonymous self-report questionnaire (AQ) regarding the use of prescription or illicit drugs for CE and ME and factors associated with their use. The Randomized Response Technique (RRT) was used in addition. The RRT guarantees a high degree of anonymity and confidentiality when a person is asked about stigmatizing issues, such as drug abuse. RESULTS: A total of 3,306 questionnaires were distributed and 1,145 entered statistical analysis (response rate: 36.4%). According to the AQ, 8.9% of all surveyed surgeons confessed to having used a prescription or illicit drug exclusively for CE at least once during lifetime. As one would expect, the prevalence rate assessed by RRT was approximately 2.5-fold higher than that of the AQ (19.9%; 95% confidence interval (CI), 15.9% to 23.9%, N = 1,105). An even larger discrepancy between the RRT and AQ was observed for the use of antidepressants with a 6-fold higher prevalence (15.1%; 95% CI, 11.3% to 19.0%, N = 1,099) as compared to 2.4% with the AQ. Finally, logistic regression analysis revealed that pressure to perform at work (odds ratio (OR): 1.290; 95% CI, 1.000 to 1.666; P = 0.05) or in private life (OR: 1.266; 95% CI, 1.038 to 1.543; P = 0.02), and gross income (OR: 1.337; 95% CI, 1.091 to 1.640; P = 0.005), were positively associated with the use of drugs for CE or ME. CONCLUSIONS: The use of illicit and prescription drugs for CE or ME is an underestimated phenomenon among surgeons which is generally attributable to high workload, perceived workload, and private stress. Such intake of drugs is associated with attempts to counteract fatigue and loss of concentration. However, drug use for CE may lead to addiction and to overestimation of one's own capabilities, which can put patients at risk. Coping strategies should be taught during medical education.

Psychiatric Morbidity, Utilization and Quality of Mental Health Care in Long-Term Unemployed People.

Research has shown complex interactions between unemployment and mental health. However, the prevalence of specific mental disorders, utilization of mental health care services and influences on help-seeking behavior have been investigated surprisingly little in the past. In this study, we investigated a sample of long-term unemployed people in a cooperation program of the local unemployment agency and a psychiatric university hospital in a larger city in Germany. Mental disorders, treatment history, accordance of treatment to national treatment guidelines and factors influencing previous treatment were assessed. Participants (n = 879; male 56%, female 44%, mean age 43.9 years) showed a high psychiatric morbidity, mostly with diagnoses from the ICD-10 categories F1 (22%), F3 (61%) and F4 (68%). Currently, 18% were in psychiatric treatment, 6% were in psychotherapeutic treatment, and 28% received psychopharmacological treatment. Mostly young men underutilized the psychiatric-psychotherapeutic system, with middle-aged men and women being most frequently in psychopharmacological treatment. Of those treated, only about 10% of the subjects currently received a treatment according to national guidelines. The utilization of psychotherapeutic treatment was strikingly poor. This study identified high psychiatric morbidity and severe treatment gaps in unemployed people. These results can help to target subjects with specific needs for interventions and to modify counseling programs.

Unemployment and Substance Use: An Updated Review of Studies from North America and Europe.

Since the industrial revolution, the relationship between unemployment and psychiatric disorders has been a subject of high interest. Currently, regarding the correlation between unemployment and substance-use disorders (SUDs), only older, often isolated and fragmented research results are available in the literature. This review was based on an extensive literature search of the European and North American literature in most relevant databases for "unemployment" and "substance use" related to "drugs", "alcohol", "nicotine", and "tobacco" between November 2022 and January 2023, according to the PRISMA (Preferred Reporting Items for Systematic review and Meta-Analysis) guidelines. A total of 59,117 papers were identified, of which only 33 articles were identified as relevant to the research objective. The literature showed significantly higher prevalence rates of SUDs involving divergent psychotropic substances among unemployed people. Unemployment was found to be a risk factor for SUD, and vice versa. However, the correlation between unemployment and relapses or smoking cessation was inconsistent. In addition, there appeared to be a mild effect of business cycles on SUD. The results showed significant multifaceted correlations between unemployment and SUD, indicating that prevention and early intervention are required to prevent harmful psychosocial consequences, such as social disintegration and severe psychiatric disorders.

Stimulant abuse as a coping strategy-Forensic and criminal consequences of stimulant abuse for neuroenhancement.

Pharmacological neuroenhancement (PN) describes the use of divergent psychoactive substances to enhance mental performance (cognition) without medical need. This kind of substance abuse takes place predominantly in stressful situations. Users implicitly-or even explicitly-describe this kind of drug abuse to be a coping strategy. Regarding the decision making process whether to use PN drugs or not, users indicate that legal aspects to be decisive. However, the legal situation has been neglected so far. To elucidate the German legal situation, PN substances have to be divided into over-the-counter drugs, prescription drugs and illegal drugs. Amphetamines have the highest cognition-enhancing potential, followed by modafinil and caffeine-containing substances. It is pointed out that the use of both freely available and prescription PN substances and narcotics without medical indication have so far been largely exempt from punishment under German law. However, individuals (physicians, bus and truck drivers, etc.) taking PN substances may expose others at risk due to wrong decisions (driving or treatment), errors based on side effects of the used substances. Therefore, the protection of life and health of others could legitimize criminal regulation.

Trefoil factor family peptide 2 acts pro-proliferative and pro-apoptotic in the murine retina.

Although expression of trefoil factor family (TFF) peptides has been reported in the brain, nothing is known about TFF expression in the retina. The aim of this study was to test whether TFF peptides are expressed in the murine retina and have any function here. In contrast to most tissues studied, where TFF1 and TFF3 are the predominant peptides, TFF2 is the only peptide expressed in the murine retina. Immunohistochemical studies on murine retinal sections indicate that cells of the ganglion cell layer are the retinal source for murine TFF2 (Tff2). In organotypic murine retina cell cultures recombinant TFF2 exerted a strong pro-apoptotic and pro-proliferative rather than an anti-apoptotic and anti-proliferating effect described in most human cancer cell lines investigated so far. In blockage experiments we were able to demonstrate that the pro-apoptotic effect of TFF2 is caspase-dependent. Western blot analysis of TFF2 treated retinal wholemount homogenates revealed significant reductions in the phosphorylation level of ERK and STAT3 proteins compared to basal conditions, suggesting that in the developing murine retina survival mechanism are down-regulated upon TFF2 administration. Our results suggest that during retinal cell death periods, requiring a tightly regulated balance between cell survival and cell death, TFF2 acts pro-proliferative and pro-apoptotic at least in developing mouse retinae cultured in vivo.

Recent advances in the treatment of opioid use disorders-focus on long-acting buprenorphine formulations.

Oral methadone or sublingual buprenorphine are first-line medications for pharmacotherapy of opioid use disorders (OUDs). Three long-acting buprenorphine depot or implant formulations are currently available for the treatment of OUDs: (1) CAM 2038 (Buvidal) for subcutaneous weekly and monthly application; (2) RBP-6000 (Sublocade™) as a monthly depot formulation; and (3) A six-month buprenorphine implant [Probuphine™]. The pharmacology, clinical efficacy and prospects of these medications are discussed.

Psychiatric Comorbidity and Stress in Medical Students Using Neuroenhancers.

Background: Pharmacological neuroenhancement (PN) is a common healthcare problem at least among students. PN seems to be associated with stressful situations. There is a lack of data about personal characteristics, comorbidities, and coping strategies regarding stress and factors of resilience in students and medical staff. Methods: A web-based survey about the non-medical use of PN drugs with a focus on neuroenhancement was developed and distributed among medical students throughout Germany; the questionnaire was open in April and May of 2020. The survey contained questions about the use of well-known PN drugs, frequency, special purposes, reasons for the use, psychiatric disorders, use of psychotropic drugs apart from PN purposes, and factors of resilience using the brief resilience scale. Results: Data of 1,159 students of medicine were analyzed. The most frequently used substances for PN were coffee (78.8% lifetime prevalence rate), energy drinks (45.7%), caffeine tablets (24.3%), methylphenidate (5.2%), illicit amphetamines (2.0%), and cocaine (1.7%). 98.4% suspected that PN drug use could lead to addiction. PN drug use specifically for PN was significantly associated with the use of (a) any psychotropic drug (other than neuroenhancers), (b) any psychiatric disorder, and (c) higher values of feeling pressure to perform in professional/students' life and in private life as well as (d) the subjective feeling of pressure to perform to be burdening and (e) harmful to one's own health. PN drug use in general was significantly associated with being less resilient. The use of illicit PN drugs, over the counter drugs and prescription drugs was associated with being less resilient. Conclusion: This study indicates that PN with legal and illegal drugs is a widespread phenomenon among German medical students. Users seem to be more often burdened by psychiatric disorders, especially addictive disorders, the perception of stress, pressure to perform and low levels of resilience. These aspects should be considered in further investigation of PN drug use.

Just "Like Coffee" or Neuroenhancement by Stimulants?

Introduction: Pharmacological neuroenhancement (PN) is a topic of increasing importance and prevalence among students. However, there is a lack of differentiating PN substances, according to their psychoactive effects. In particular, there is a lack of data about PN by caffeinated drinks, even if coffee is a common and broadly used Neuroenhancer because of its cognitively enhancing effects regarding wakefulness, alertness and concentration. Materials and Methods: A web-survey was developed for German students and alumni about the non-medical use of caffeine for PN contained questions about coffee, caffeinated drinks and energy drinks, caffeine pills and methylxanthine tea regarding frequency and further contextual factors. Results: Six hundred and eighty-three participants completed the survey. Nearly all participants knew about PN (97.7%). 88.1% admitted using some over-the-counter substances. For PN purposes, coffee was used by 72.9% followed by energy drinks (68.2%) and cola drinks (62.4%). Methylxanthine containing tea was used for PN purposes, too (black tea 52.3%, green tea 51.7%). 1.8% admitted using illegal substances or prescription drugs, too. Discussion: Using legal methylxanthine containing drinks for PN seems to be extremely common with coffee and energy drinks being the preferred substances, while illegal and prescription drugs are only minimally used. Further studies should investigate the awareness of methylxanthine containing drinks as well as its character to be a flavoring drink or a neuroenhancer.

Pharmacological neuroenhancement and the ability to recover from stress - a representative cross-sectional survey among the German population.

BACKGROUND: Pharmacological neuroenhancement (PNE) refers to the use of psychoactive substances without doctor's prescription to enhance cognitive performance or to improve mood. Although some studies have reported that drugs for PNE are also being used to cope with stressful life situations, nothing is known about the relationship of PNE and resilience, i.e. the ability to recover from stress. This study aimed at investigating the relationship of PNE and resilience in the first representative population sample. METHODS: A cross-sectional survey in a representative sample of 1128 adults (age ≥ 18 yrs.) living in Germany was conducted. The use of PNE and related attitudes, perceptions and behaviours were assessed by structured interviews and self-report questionnaires. Stepwise logistic regression with backward elimination was conducted to identify potential risk factors for PNE use. RESULTS: Lifetime prevalence for the use of stimulating prescription drugs without medical indication was 4.3%, 10.2% for stimulating illicit drugs, 20.3% for mood modulating prescription drugs, and 23.4% for cannabis. Coping with stressful situations was more frequently reported as underlying motive for using stimulant or mood modulating prescription drugs than stimulating illicit drugs or cannabis. The individual perceived stress increased the risk of using stimulating prescription drugs (OR: 2.86; 95% Cl: 1.49-5.46) and the individual ability to recover from stress decreased the risk of using any substance for PNE and especially mood modulating prescription drugs (OR: .62; 95% Cl: .47-.81). CONCLUSIONS: The non-medical use of prescription drugs for PNE appears to be more prevalent in subjects who are less resilient to stress. Tailored resilience interventions that improve the ability to adapt to and recover from stressors may prevent the use of prescription medication for PNE. Further research should disentangle the association between psychological resilience and PNE as well as examine the efficacy of resilience interventions in the prevention of PNE.

Construct Validity and Population-Based Norms of the German Brief Resilience Scale (BRS).

The Brief Resilience Scale (BRS) measures the ability to recover from stress. To provide further evidence for construct validity of the German BRS and to determine population-based norms, a large sample (N = 1,128) representative of the German adult population completed a survey including the BRS and instruments measuring perceived stress and the resilience factors optimism, self-efficacy, and locus of control. Confirmatory factor analyses showed best model fit for a five-factor model differentiating the ability to recover from stress from the three resilience factors. On the basis of latent and manifest correlations, convergent and discriminant validity of the BRS were fair to good. Female sex, older age, lower weekly working time, higher perceived stress, lower optimism, and self-efficacy as well as higher external locus of control predicted lower BRS scores, that is, lower ability to recover from stress.

Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: A double-blind, randomised controlled trial.

Stimulants and caffeine have been proposed for cognitive enhancement by healthy subjects. This study investigated whether performance in chess - a competitive mind game requiring highly complex cognitive skills - can be enhanced by methylphenidate, modafinil or caffeine. In a phase IV, randomized, double-blind, placebo-controlled trial, 39 male chess players received 2×200mg modafinil, 2×20mg methylphenidate, and 2×200mg caffeine or placebo in a 4×4 crossover design. They played twenty 15-minute games during two sessions against a chess program (Fritz 12; adapted to players' strength) and completed several neuropsychological tests. Marked substance effects were observed since all three substances significantly increased average reflection time per game compared to placebo resulting in a significantly increased number of games lost on time with all three treatments. Treatment effects on chess performance were not seen if all games (n=3059) were analysed. Only when controlling for game duration as well as when excluding those games lost on time, both modafinil and methylphenidate enhanced chess performance as demonstrated by significantly higher scores in the remaining 2876 games compared to placebo. In conjunction with results from neuropsychological testing we conclude that modifying effects of stimulants on complex cognitive tasks may in particular result from more reflective decision making processes. When not under time pressure, such effects may result in enhanced performance. Yet, under time constraints more reflective decision making may not improve or even have detrimental effects on complex task performance.

Transforming growth factor-beta and bone morphogenetic proteins: cooperative players in chick and murine programmed retinal cell death.

Transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) are extracellular molecules known to mediate programmed cell death (PCD) in the developing retina. In the present study, we investigated the expression profiles and activity levels of ligands and receptors of the TGF-beta and BMP4 family during the physiological PCD periods of the developing chick and mouse retina and possible interactions of both proapoptotic molecules in mediating apoptosis in chick and murine retinal whole-mount cultures. Immunocytochemical double-labeling studies with the established ganglion cell marker Islet revealed overlapping expression patterns for TGF-beta and BMP4 ligands and receptors on the surface of retinal ganglion cells. The biphasic peak of activity and expression levels of TGF-beta and BMP4 ligands and receptors, revealed by Western blots and mink lung epithelial cell (MLEC) assays, coincided with the two main periods of retinal chick and murine PCD. In organotypic retinal cultures, we were able to increase apoptosis over basal levels by application of recombinant TGF-beta or BMP4. Double-factor treatment induced an additional increase of apoptosis, suggesting a cooperation of both proapoptotic pathways. A significant increase in the number of apoptotic cells in the ganglion cell layer was observed in a TUNEL staining of retinal whole mounts treated with recombinant TGF-beta or BMP4, suggesting a concerted action of both factors in triggering ganglion cell death. Blockage experiments revealed that both pathways do not interact at the ligand, receptor, or Smad protein level but converge at the transcriptional level of the TGF-beta immediate-early response gene TIEG and the transcriptional coactivator Gcn5.