Effect of Plant Age and Leaf Position on Susceptibility to Wheat Stripe Rust.

In addition to pathogen propagule dispersal, disease spread requires successful infection of host tissue. In plant disease epidemiology, susceptibility of host tissue is often assumed to be constant. This assumption ignores changes in host phenology due to developmental stage. To examine this assumption, 3-, 4-, and 5-week-old wheat plants were inoculated with equal quantities of urediniospores of Puccinia striiformis f. sp. tritici, the causal agent of wheat stripe rust (WSR). Disease severity on each leaf was assessed and fit by mixed-effect linear model as a function of leaf position and plant age. Younger plants had significantly greater disease severity than older plants, with mean severities of 50.4, 30.1, and 12.9% on plants that were 3, 4, and 5 weeks old, respectively, at time of inoculation. This effect was greater on leaves higher on the plant. Within same-aged plants, younger leaves had significantly greater disease severity than older leaves, with mean severities of 40.2, 34.8, and 17.7% on the uppermost, second, and third leaf, respectively. These results suggest that the vertical distribution of WSR lesions in agricultural fields could be driven by differences in host susceptibility more so than propagule dispersal.

First Report of Resistance to QoI Fungicides in North American Populations of Zymoseptoria tritici, Causal Agent of Septoria Tritici Blotch of Wheat.

The G143A mutation in cytb (cytochrome b gene) is associated with high levels of resistance to quinone outside inhibitor (QoI or strobilurin) fungicides that disrupt electron transport during cellular respiration (1). The G143A mutation in Zymoseptoria tritici (synonyms: Mycosphaerella graminicola and Septoria tritici), the causal agent of septoria tritici blotch of wheat (Triticum aestivum), was first reported in Europe in 2001 (1). Although Z. tritici has a global distribution (3), G143A mutants of Z. tritici have not been reported outside of Europe. We used PCR-RFLP (4) to estimate the frequencies of G143A mutants in Z. tritici populations at two locations in the Willamette Valley of western Oregon: the Hyslop Crop Science Field Research Laboratory (Hyslop Farm, HF), Benton County (44°37'52.85″ N, 123°11'55.19″ W) and research plots planted in a commercial wheat field in Washington County (45°33'58.53″ N, 123°00'11.78″ W) (North Valley Farm, NVF). Isolates originated from flag leaf collections from two cultivars ('Bobtail' and 'Tubbs 06') made in April and June of 2012 from plants in a replicated fungicide-treatment experiment, with isolates collected from both sprayed and unsprayed plots. Sixteen of the 169 isolates (9.5%) from HF possessed the G143A mutation (7 of 132 isolates from plots not receiving a QoI fungicide and 9 of 37 isolates collected from plots receiving two applications of the QoI azoxystrobin). One hundred forty six of the 175 isolates (83.4%) from NVF were G143A mutants (101 of 129 isolates from plots receiving no QoI fungicide and 45 of 46 isolates from plots receiving two applications of azoxystrobin). Results of phenotypic assays of a subset of 10 isolates from each location (5 mutants, 5 wild types from each location; 20 isolates altogether) supported a high level of resistance to azoxystrobin only in the G143A mutants. All 10 G143A mutants developed colonies after 8 days of growth on YMA plates amended with SHAM (2) and 1 ppm or 10 ppm azoxystrobin, with nine and eight G143A mutant isolates developing colonies on plates amended with 1 ppm and 10 ppm azoxystrobin, respectively. None of the wild-type isolates developed colonies on plates amended with SHAM and 1 ppm azoxystrobin, nor on plates amended with SHAM and 10 ppm azoxystrobin. All 20 isolates developed colonies on YMA plates lacking azoxystrobin, and treatments produced identical results across three replicates. These results are consistent with findings of higher levels of azoxystrobin resistance in G143A mutants compared to wild types in European populations (1). Isolates from HF and NVF differ in their previous exposure to QoI fungicides. The majority of the wheat area at HF is planted to breeding plots that are not sprayed with fungicide. Plots at NVF were planted in a commercial wheat field in a county where most wheat fields were treated with two to three applications of strobilurins each year over the past 4 years. Future monitoring for G143A mutants of Z. tritici throughout its range in North America will be necessary to assess whether strobilurin resistance will spread via wind-dispersal of ascospores or emerge de novo in treated fields. In Europe, stobilurins were first applied to wheat in 1996. G143A mutants of Z. tritici emerged de novo several times (4) and were widespread by 2007. References: (1) B. A. Fraaje et al. Phytopathology 95:933, 2005. (2) J. A. LaMondia. Tob. Sci. 49:1, 2012. (3) E. S. Orton et al. Mol. Plant Pathol. 12:413, 2011. (4) S. F. F. Torriani et al. Pest Manag. Sci. 65:155, 2008.

[Karl Wilmanns' theoretical contributions and his clinical practice. What does it mean for contemporary psychiatry?]. / Karl Wilmanns' theoretische Ansätze und klinische Praxis. Ihre Bedeutung für die heutige Psychiatrie.

Karl Wilmanns (1873-1945) is widely known as the founder of the Heidelberg school of psychopathology. His important contributions to criminology and forensic psychiatry and his encouragement of psychoanalysis in the inpatient setting are less known today. During the First World War, he worked as director of the military hospitals in the German county of Baden and as director of the Reichenau Mental Hospital at Lake Constance. Thus, he was familiar with the needs of everyday psychiatric practice under difficult circumstances. In Heidelberg he dealt intensively with criminology, social psychiatry and psychoanalysis. Wilmanns remained sceptical towards deterministic positions including the biological psychiatry of his days, but he fought for psychiatry open to social and political questions and open to different scientific methods. In 1933, the Nazis expelled him from office. Wilmanns remained as a private practitioner in Germany and died shortly after the liberation in 1945.

Loss of precursor B cell expansion but not allelic exclusion in VpreB1/VpreB2 double-deficient mice.

The pre-B cell receptor consists of immunoglobulin (Ig) mu heavy chains and surrogate light chain, i.e., the VpreB and lambda5 proteins. To analyze the role of the two VpreB proteins, mice lacking the VpreB1 and VpreB2 genes were generated. VpreB1(-/-) VpreB2(-/-) mice were impaired in their B cell development at the transition from pre-BI to large pre-BII cells. Pre-BII cells did not expand by proliferation, consequently 40-fold less small pre-BII and immature B cells were found in bone marrow, and the generation of immature and mature conventional B cells in spleen appeared reduced. In addition, only low numbers of B-1a cells were detected in the peritoneum. Surprisingly, Ig heavy chain allelic exclusion was still active, apparently ruling out a signaling role of a VpreB1/VpreB2-containing receptor in this process.

[Treatment of cognitive deficits in schizophrenia. Part 1: Diagnostic and psychological training]. / Behandlung kognitiver Defizite bei Schizophrenie. Teil I: Diagnostik und psychologische Verfahren.

Cognitive dysfunction is a core feature of schizophrenia. Although cognitive deficits in the domains of attention, memory and executive functions have been described for many decades, the focus on therapeutic approaches is new. The recognition that cognitive deficits are the best known predictor of functional outcome in schizophrenic patients explains the increasing interest in the diagnosis and therapy of these impairments. Standards for the reliable evaluation of neurocognitive deficits in schizophrenia have been put forward by the MATRICS initiative (Measurement and Treatment Research to Improve Cognition in Schizophrenia). In German-speaking countries the most popular cognitive training programs for schizophrenic patients are "CogPack" and "Integrated Psychological Therapy (IPT)". Especially in Anglo-Saxon countries cognitive training has become more popular in recent years. Study outcomes can be considered encouraging. They show improvement of cognitive deficits and a positive impact on the functional outcome. Further studies are needed to optimize cognitive training for schizophrenic patients.

[Treatment of cognitive deficits in schizophrenia. Part 2: Pharmacological strategies]. / Behandlung kognitiver Defizite bei Schizophrenie. Teil II: Pharmakologische Strategien.

Cognitive deficits in schizophrenia are a clinically relevant symptom dimension and one of the best predictors for functional outcome. Pharmacological treatment of cognitive deficits in schizophrenia is still a challenge. The objective of this article is to present a detailed review of the literature on strategies for the pharmacological treatment of cognitive deficits. It is not clear whether first-generation antipsychotics have a genuine positive influence on cognition. There is only sparse evidence for the positive effect of second-generation antipsychotics on cognitive processes. Furthermore it is not evident that second-generation antipsychotics are more beneficial than first-generation antipsychotics in the treatment of cognitive deficits. The add-on use of substances which directly influence cognitive processes, so-called cognition-enhancing drugs is more promising.

[Evidence-based therapy of depression: S3 guidelines on unipolar depression]. / Evidenzbasierte Therapie der Depression: Die S3-Leitlinie unipolare Depression.

Unipolar depressive disorders are among the most frequent reasons for utilizing the health care system. Although efficacious treatments are available and further advances have recently been made there is still a need for improving diagnostic and therapeutic procedures. Alignment of treatment on evidence-based treatment guidelines establishes an essential mainstay. The new S3 and National Health Care guidelines on unipolar depression, the compilation of which was coordinated by the German Society of Psychiatry, Psychotherapy and Neurology (DGPPN) and which were approved by 29 scientific and professional associations, is the ambitious effort to present state of the art evidence and clinical consensus for the treatment of depression. For pharmacotherapy of depression differentiated recommendations can be given, also separate from and in addition to psychotherapy.

Intraspecific functional diversity in hosts and its effect on disease risk across a climatic gradient.

The effects of host biodiversity on disease risk may vary greatly depending on host population structure and climatic conditions. Agricultural diseases such as potato late blight, caused by Phytophthora infestans, provide the opportunity to study the effects of intraspecific host diversity that is relatively well-defined in terms of disease resistance phenotypes and may have functional impacts on disease levels. When these systems are present across a climatic gradient, it is also possible to study how season length and conduciveness of the environment to disease may influence the effects of host diversity on disease risk. We developed a simple model of epidemic progress to evaluate the effects on disease risk of season length, environmental disease conduciveness, and host functional divergence for mixtures of a susceptible host and a host with some resistance. Differences in disease levels for the susceptible vs. resistant genotypes shifted over time, with the divergence in disease levels first increasing and then decreasing. Disease reductions from host diversity were greatest for high host divergence and combinations of environmental disease conduciveness and season length that led to moderate disease severity. We also compared the effects of host functional divergence on potato late-blight risk in Ecuador (long seasons), two sites in Peru (intermediate seasons) in El Niño and La Niña years, and the United States (short seasons). There was some evidence for greater disease risk reduction from host diversity where seasons were shorter, probably because of lower regional inoculum loads. There was strong evidence for greater disease reduction when host functional divergence was greater. These results indicate that consideration of season length, environmental conduciveness to disease, and host functional divergence can help to explain the variability in disease response to host diversity.

Prolonged activation EEG differentiates dementia with and without delirium in frail elderly patients.

OBJECTIVE: Delirium in the elderly results in increased morbidity, mortality and functional decline. Delirium is underdiagnosed, particularly in dementia. To increase diagnostic accuracy, we investigated whether maintenance of activation assessed by EEG discriminates delirium in association with dementia (D+D) from dementia without delirium (DP) and cognitively unimpaired elderly subjects (CU). METHOD: Routine and quantitative EEG (rEEG/qEEG) with additional prolonged activation (3 min eyes open period) were evaluated in hospitalised elderly patients with acute geriatric disease. Patients were assigned post hoc to three comparable groups (D+D/DP/CU) by expert consensus based on DSM-IV criteria. Dementia diagnosis was confirmed using cognitive and functional tests and caregiver rating (IQCODE, Informed Questionnaire of Cognitive Decline in the Elderly). RESULTS: While rEEG at rest showed low accuracy for a diagnosis of delirium, qEEG in DP and CU revealed a specific activation pattern of high significance found to be absent in the D+D group. Stepwise logistic regression confirmed that differentiation of D+D from DP was best resolved using activated upper alpha and delta power density which, compared with rEEG, enabled an 11% increase in diagnostic correctness to 83%, resulting in 67% sensitivity and 91% specificity. Among frail CU and D+D subjects, almost 90% were correctly classified. CONCLUSION: Dementia associated with delirium can be discriminated reliably from dementia alone in a meaningful clinical setting. Thus EEG evaluation in chronic encephalopathy should be optimised by a simple activation task and spectral analysis, particularly in the elderly with dementia.

Prevalence, onset and comorbidity of postpartum anxiety and depressive disorders.

OBJECTIVE: The study presents data on the 3-month prevalences of postpartum anxiety disorders (PAD) and postpartum depressive disorders (PDD) and their comorbidity in a German community sample. Associations with sociodemographic variables and previous history of psychopathology were analysed. METHOD: Data were gathered in a longitudinal study over the first 3 months postpartum. In a two-stage screening procedure, a population-based representative sample of 1024 postpartum women was assessed for symptoms of anxiety and depression using DSM-IV-based screening instruments. RESULTS: The estimated rates of DSM-IV disorders were 11.1% for PAD and 6.1% for PDD. Comorbidity was found in 2.1%. The rate for PAD with postpartum onset was 2.2% and for PDD 4.6%. Young mothers and mothers with a low education level had a heightened risk of developing depression following delivery. CONCLUSION: Because of the clinical relevance of PAD, controlled studies and specialized programmes for prevention and treatment are urgently required.

Specificity of incomplete resistance to Mycosphaerella graminicola in wheat.

We examined interactions between wheat (Triticum aestivum) and Mycosphaerella graminicola, causal agent of Septoria tritici blotch, to determine whether specific interactions occur between host and pathogen genotypes that could be involved in eroding resistance. The moderate resistance of the wheat cultivar Madsen has eroded significantly in the Willamette Valley of Oregon since its release in 1990. Foote is a replacement cultivar expressing moderate resistance and was released in 2000. Isolates of M. graminicola were collected from Foote and Madsen in 2004 and 2005 and tested on each cultivar in growth chamber and greenhouse experiments. There was a significant (P

Frequency of sexual recombination by Mycosphaerella graminicola in mild and severe epidemics.

The importance of sexual recombination in determining fungal population structure cannot be inferred solely from the relative abundance of sexual and asexual spores and reproductive structures. To complement a previously reported study of proportions of Mycosphaerella graminicola ascocarps and pycnidia, we investigated the share of sexual recombinants among isolates randomly derived from the same field at the same time. Early in three successive growing seasons (those ending in 1998, 1999, and 2000), field plots of the susceptible winter wheat cultivar Stephens were inoculated with suspensions of two M. graminicola isolates that each had rare alleles at restriction fragment length polymorphism (RFLP) loci. Near harvest time, leaves were randomly sampled from the same plots, and a population of over 100 monopycnidial isolates was created for each year of the experiment. Natural populations were also sampled from noninoculated plots in the 1999 and 2000 seasons, in order to compare allele frequencies. Based on RFLP haplotypes and DNA fingerprints, isolates from the inoculated plots were categorized by both inspection and Bayesian methods as inoculant clones, recombinants, or immigrants. Inoculation in the 2000 season was delayed, and the recovery rate of inoculant types was just 1 to 2%. In 1998, a high-disease year, and 1999, a low-disease year, inoculants comprised 36 and 22 to 23% of end-of-season samples, respectively. In those 2 years, recombinants as a percentage of inoculant descendants (both sexual and asexual) were 35 and 32%, respectively. By comparison, the study of fruiting bodies had found 93 and 32% of M. graminicola fruiting bodies were ascocarps in 1998 and 1999, respectively. These findings support the hypothesis that sexual recombination makes a relatively consistent contribution to M. graminicola population structure, despite differences in epidemic severity and ascocarp proportions.

Sexual reproduction facilitates the adaptation of parasites to antagonistic host environments: Evidence from empirical study in the wheat-Mycosphaerella graminicola system.

Most eukaryotes use sexual reproduction to transmit genetic information from generation to generation despite the advantages offered by asexual reproduction. One theory to explain the origin and maintenance of sexual reproduction hypothesises that sexual recombination generates genetic variation that allows faster adaptation to fluctuating and/or stressful environments. We used a combination of ecological, molecular genetic, statistical and experimental evolution approaches to test this hypothesis in an agricultural plant-pathogen system. We inoculated wheat hosts with 10 strains of the fungal pathogen Mycosphaerella graminicola in a field experiment and estimated the contributions of sexual reproduction, asexual reproduction and immigration to the genetic composition of fungal populations sampled from moderately resistant and susceptible hosts through the course of an epidemic cycle. We found that a significant proportion of the M. graminicola population in the late phase of the epidemic originated from sexual reproduction among isolates that had been introduced into the field plots at the beginning of the epidemic. Recombinants were recovered at a higher frequency on the moderately resistant plant host Madsen than on the susceptible host Stephens. By the end of the growing season, we estimated that approximately 13% of the strains sampled from the resistant host were recombinants, compared with 9% in the samples collected from the susceptible host. We also found that pathogen strains originating from the resistant cultivar displayed higher levels of fitness, virulence and fungicide tolerance than those originating from the susceptible cultivar. Our results provide empirical support for the hypothesis that sexual reproduction facilitates the evolution of parasites to overcome host resistance.

N-Methylimidazolidin-4-one organocatalysts: gas-phase fragmentations of radical cations by experiment and theory.

Electron ionisation mass spectra of N-methylimidazolidin-4-one organocatalysts were studied by experimental and theoretical means. The molecular ions mostly undergo alpha cleavages of exocyclic substituents that leave the five-membered ring intact. The type of substituent strongly dominates the appearance of the spectra. Fragmentation cascades are corroborated by metastable ion mass spectra. Quantum Chemistry Electron Ionisation Mass Spectra calculations correlate reasonably well with the experimental electron ionisation spectra and reveal mechanistic details of fragmentation pathways. The drawbacks and benefits of such calculations are discussed. Copyright © 2017 John Wiley & Sons, Ltd.

Local dispersal of Puccinia striiformis f. sp. tritici from isolated source lesions.

Understanding how disease foci arise from single source lesions has not been well studied. Here, single wheat leaves were inoculated with Puccinia striiformis f. sp. tritici urediniospores, and all wheat leaves within two intersecting 0.3 × 3.0 m transects were sampled in eight replicates over three years. The lesions observed on each of the top three leaves on plants within 1.5 m from the source lesion were three-dimensionally mapped. The total number of lesions within a 1.5 m radius was estimated by dividing the number of lesions observed within each 0.025 m-wide annulus by the fraction of the annulus sampled. The estimated total number of lesions produced within 1.5 m of a single source lesion ranged from 27 to 776, with a mean of 288 lesions. Eighty percent of the lesions were recorded within 0.69 m of the source infection. The proportion of total lesions observed at a given distance from the source was fitted well by the Lomax and Weibull distributions, reflecting the large proportion of lesions arising close to the source, and when fitted to an inverse-power distribution had a slope (b) of 2.5. There were more lesions produced on leaves higher in the canopy than on lower leaves, with more lesions being detected above than below the point of inoculation. Simultaneous measurement of lesion gradients and spore dispersal in the final year of the study suggests that this pattern is due to greater susceptibility of upper leaves, rather than increased dispersal to upper leaves.

Use of multiline cultivars and cultivar mixtures for disease management.

The usefulness of mixtures (multiline cultivars and cultivar mixtures) for disease management has been well demonstrated for rusts and powdery mildews of small grain crops. Such mixtures are more useful under some epidemiological conditions than under others, and experimental methodology, especially problems of scale, may be crucial in evaluating the potential efficacy of mixtures on disease. There are now examples of mixtures providing both low and high degrees of disease control for a wide range of pathosystems, including crops with large plants, and pathogens that demonstrate low host specificity, or are splash dispersed, soilborne, or insect vectored. Though most analyses of pathogen evolution in mixtures consider static costs of virulence to be the main mechanism countering selection for pathogen complexity, many other potential mechanisms need to be investigated. Agronomic and marketing considerations must be carefully evaluated when implementing mixture approaches to crop management. Practical difficulties associated with mixtures have often been overestimated, however, and mixtures will likely play an increasingly important role as we develop more sustainable agricultural systems.

How much will we pay to increase steps per day? Examining the cost-effectiveness of a pedometer-based lifestyle program in primary care.

We previously demonstrated the Healthy Eating and Active Living for Diabetes (HEALD) intervention was effective for increasing daily steps. Here, we consider the cost-effectiveness of the HEALD intervention implemented in primary care. HEALD was a pedometer-based program for adults with type-2 diabetes in Alberta, Canada completed between January 2010 and September 2012. The main outcome was the change in pedometer-determined steps/day compared to usual care. We estimated total costs per participant for HEALD, and total costs of health care utilization through linkage with administrative health databases. An incremental cost-effectiveness ratio (ICER) was estimated with regression models for differences in costs and effects between study groups. The HEALD intervention cost $340 per participant over the 6-month follow-up. The difference in total costs (intervention plus health care utilization) was $102 greater per HEALD participant compared to usual care. The intervention group increased their physical activity by 918 steps/day [95% CI 116, 1666] compared to usual care. The resulting ICER was $111 per 1000 steps/day, less than an estimated cost-effectiveness threshold. Increasing daily steps through an Exercise Specialist-led group program in primary care may be a cost-effective approach towards improving daily physical activity among adults with type-2 diabetes. Alternative delivery strategies may be considered to improve the affordability of this model for primary care.

Disease, frequency-dependent selection, and genetic polymorphisms: experiments with stripe rust and wheat.

Pathogens have the potential to maintain genetic polymorphisms by creating frequency-dependent selection on their host. This can occur when a rare host genotype is less likely to be attacked by a pathogen (frequency-dependent disease attack) and has higher fitness at low frequency (negative frequency-dependent selection). In this study, we used wheat genotypes that were susceptible to different races of the pathogen Puccinia striiformis to test whether disease created frequency-selection on its host and whether such selection could maintain polymorphisms for resistance genes in the wheat populations. Four different two-way mixtures of wheat genotypes were planted at different frequencies in both the presence and absence of disease. Disease created frequency-dependent selection on its host in some populations. Unknown factors other than disease also created frequency-dependent selection in this system because, in some instances, rare genotype advantage was observed in the absence of disease. Although the pathogen created frequency-dependent selection on its host, this selection was not sufficient to maintain genetic polymorphism in the host populations. In all cases where frequency-dependent selection occurred only in the diseased plots, one of the two genotypes was predicted to dominate in the population and the same genotype was predicted to dominate in both the presence and absence of disease. Only in cases where frequency-dependent selection was not caused by disease was there evidence that genetic polymorphisms would be maintained in the population. The frequency-dependent selection described in this study is a consequence of epidemiological effects of disease and differs from the time-lagged frequency-dependent selection resulting from coevolution between hosts and parasites. The impact of this direct frequency-dependent selection on the maintenance of genetic polymorphisms in the host population is discussed.

3H-spiperone binding capacity in mononuclear cells: a family study.

1. A family study was carried out using a putative biological vulnerability trait in families of schizophrenics and schizoaffective indexprobands to investigate, if the clinical phenotype and a biological marker for schizophrenia are cosegregating within families. 2. The binding capacity of the dopamine antagonist spiperone to mononuclear cells was investigated in 21 indexprobands and a total of 147 first and second degree relatives. 3. Increased binding capacity could be found in 17 indexprobands and in their affected relatives, independently from clinical diagnosis and in 22% of their normal relatives. 4. No increased binding capacity was found in 4 indexprobands and in their affected relatives and not n any of the unaffected relatives. These results indicate, that increased spiperone binding may cosegregate with the risk for functional psychoses and that families, loaded with psychiatric disturbances may be distinguished on a biological basis.

Reconfirming the role of life events for the timing of depressive episodes. A two-year prospective follow-up study.

BACKGROUND: Since the 1960s the association of stressful life events and depression seemed to be firmly established. However, a few recent studies did not confirm those earlier findings. One of the reasons discussed for the inconsistencies was the sampling of milder depressed neurotic out-patients in the earlier studies vs. more severely ill endogenous type in-patients in recent studies. METHODS: This investigation was carried out with 50 consecutively admitted in-patients with endogenous depression according to ICD 9 and unipolar major depression according to DSM-III-R as ascertained by SCID. The control sample consisted of 26 healthy volunteers. Life events and chronic distressing life conditions were recorded with the Munich Interview for the Assessment of Life Events and Conditions (MEL) every 3 months over a period of 2 years along with psychopathological symptoms and recurrencies. Hence the design was prospective in the sense that life events were recorded for one 3-month cross-section, the depressive reaction for the subsequent one. BDI scores taken at the respective cross section were used to control for depressive bias of the subjective part of the patient's life event evaluation. RESULTS: Three months prior to the index hospitalization patients were more often affected by life events and conditions than controls. The number of stressful conditions prior to the index hospitalization indicated the time to relapse after discharge. Controls showed more desirable positive conditions than patients. Relapse patients suffered more often stressful life events and conditions than non-relapsers 3 months prior to their relapse. Multivariate analysis indicates that the cumulative number of life events within the 2-year course is the best predictor of the BDI score at the end of the follow-up period. LIMITATIONS: Since the subjective component of life event assessment by MEL displayed a higher impact on the course of depression than the objective part of the assessment, confounding of subjective ratings, attributional styles, and depressive symptoms may be a problem although controlled for in this study. CONCLUSION: The results support the importance of stressful life events and chronic distressing conditions for the 2-year course and outcome of major depression in an in-patient sample. Since the overall consistency of significant results was more pronounced in the subjective than in the objective part of the MEL the results fit best a circular pathogenetic model of interactions between life events, their individual evaluation by the patient, and depressive symptoms.