[The influence of different accident types on the process of trauma adaption and psychosocial adjustment]. / Der Einfluss verschiedener Unfalltypen auf den Prozess der Traumaverarbeitung und die psychosoziale Anpassung.

OBJECTIVES: Accidents often have a traumatic impact on the victims. The influence of individual trauma adjustment on psychosocial convalescence is examined according to the different types of accidental event. METHODS: 192 accident victims were consecutively examined over a period of 12 months. Subjective trauma evaluation and characteristics of trauma adjustment were assessed and differentiated according to the type of accidental event (motor-vehicle, work, and recreational activity accident). RESULTS: The three groups varied in their demographics, in injury severity (ISS), in subjective evaluation, in symptoms of mental and posttraumatic stress, and in the predicting variables. The lowest level of stress after 12 months was found after accidents that had occurred during recreational activities. The prevalence of posttraumatic stress symptoms was similar among motor-vehicle and work-accident victims, whereas victims of recreational activity accidents primarily showed symptoms of other Axis I disorders. CONCLUSIONS: Individual adjustment to trauma and the type of accident influence mental health. The role of other variables (work re-entry, claims, financial compensation) also has to be considered. We accentuate the need for immediate psychiatric evaluation and intervention when necessary.

Aristolactams, 1-(2-C-methyl-beta-D-ribofuranosyl)-uracil and other bioactive constituents of Toussaintia orientalis.

The new aristolactam alkaloid toussalactam {2-hydroxy-1,6-dimethoxy-5H-dibenzo[cdf]indol-4-one} and the known ones, namely aristolactam AII, aristolactam BII, piperolactam C and aristolactam FII; 1-(2-C-methyl-beta-D-ribofuranosyl)-uracil, 3,4,5-trimethoxyphenyl-beta-D-glucopyranoside, and three catechinoids were isolated from the cytotoxic Toussaintia orientalis Verdc stem and root bark extracts, and their structures established based on analysis of spectroscopic data. The aristolactams exhibited antimicrobial and antiinflammatory activity, aristolactam FII showing almost the same level of activity as the standard anti-inflammatory agent Indomethacin. The compounds also exhibited either mild or no antiproliferative and cytotoxic activities, except aristolactam FII that showed the same level of cytotoxicity as the standard drug Camptothecin. 1-(2-C-Methyl-beta-D-ribofuranosyl)-uracil, which is being reported for the first time as a natural product, was inactive in the antibacterial, antifungal, antiinflammatory, antiproliferative and cytotoxicity assays.

Psychiatric disorders after an accident: predictors and the influence of the psychiatric condition prior to an accident.

BACKGROUND: The goal of this study is to assess prevalence and incidence of psychiatric sequelae in a sample of inpatient accident survivors. Such an attempt to assess psychiatric conditions that originate due to an accident seems to be important; this does not include psychiatric conditions already present prior to the accident. METHOD: 208 accident victims were consecutively examined over a period of 12months using DSM-IV diagnostic assessment, CAPS, and self-evaluating questionnaires as well as ISS for injury severity. A predictor model for psychiatric disorders was set up. RESULTS: Incidence of newly developed Axis I disorders in our sample was 14.2% (6months) and 12.3% (12months). Incidence of PTSD was 5.9% (6months) and 2.5% (12months). Comorbidity was a general phenomenon. The psychiatric condition prior to the accident could be identified as a predictor for the development of Axis I disorders. The subjectively evaluated intensity of experienced threat to life and female gender were the main predictors for the development of PTSD. CONCLUSIONS: Accidents can lead to different psychiatric disorders. PTSD as a single diagnosis is rare. Without taking into account pre-existing disorders, the incidence may be overestimated. Two predictor models for the development of PTSD and other mental disorders are presented.

Male hormonal contraception: a double-blind, placebo-controlled study.

BACKGROUND: This study was performed to assess spermatogenesis suppression and safety of a new combination of an etonogestrel (ENG) implant combined with testosterone undecanoate (TU) injections for male contraception. This is the first large placebo-controlled study for male hormonal contraception. DESIGN AND STUDY SUBJECTS: In this double-blind, multicenter study, we randomly assigned 354 healthy men to receive either a low- or high-release ENG implant sc combined with im TU injections (750 mg every 10 or 12 wk or 1000 mg every 12 wk) or placebo implant and injections. Treatment duration was 42 or 44 wk and posttreatment follow-up at least 24 wk. RESULTS: Overall, spermatogenesis was suppressed to 1 million/ml or less at wk 16 in 89% of men, with approximately 94% in two high-release ENG groups. Suppression was maintained up to the end of the treatment period in 91% of men. For all men who completed the treatment period, 3% never achieved 1 million/ml or less. Median recovery time to a sperm concentration above 20 million/ml was 15 wk (mean 17 wk, 95% confidence interval 16-18 wk). Treatment was well tolerated. As compared with the placebo group, more men in the active treatment groups reported adverse events such as weight gain, mood changes, acne, sweating, or libido change. For both spermatogenesis suppression and safety, differences were small between the active treatment groups. CONCLUSIONS: The combination of an ENG implant with TU injections is a well-tolerated male hormonal method, providing effective and reversible suppression of spermatogenesis. Although the results are good, there is still room for improvement, possibly by adjusting the dose regimen or changing the mode of application.

Identification of novel small-molecule histone deacetylase inhibitors by medium-throughput screening using a fluorigenic assay.

HDACs (histone deacetylases) are considered to be among the most important enzymes that regulate gene expression in eukaryotic cells. In general, increased levels of histone acetylation are associated with increased transcriptional activity, whereas decreased levels are linked to repression of gene expression. HDACs associate with a number of cellular oncogenes and tumour-suppressor genes, leading to an aberrant recruitment of HDAC activity, which results in changes of gene expression, impaired differentiation and excessive proliferation of tumour cells. Therefore HDAC inhibitors are efficient anti-proliferative agents in both in vitro and in vivo pre-clinical models of cancer, making them promising anticancer therapeutics. In the present paper, we present the results of a medium-throughput screening programme aiming at the identification of novel HDAC inhibitors using HDAH (HDAC-like amidohydrolase) from Bordetella or Alcaligenes strain FB188 as a model enzyme. Within a library of 3719 compounds, several new classes of HDAC inhibitor were identified. Among these hit compounds, there were also potent inhibitors of eukaryotic HDACs, as demonstrated by an increase in histone H4 acetylation, accompanied by a decrease in tumour cell metabolism in both SHEP neuroblastoma and T24 bladder carcinoma cells. In conclusion, screening of a compound library using FB188 HDAH as model enzyme identified several promising new lead structures for further development.

Structure, derivatization, and antitumor activity of new griseusins from Nocardiopsis sp.

Four new griseusins, 4'-dehydro-deacetylgriseusin A (1) and 2a,8a-epoxy-epi-deacetylgriseusin B (2) as new constitutional derivatives and epi-deacetylgriseusin A (3) and epi-deacetylgriseusin B (4) as new stereoisomers, were isolated from Nocardiopsis sp. (YIM80133, DSM16644). 4'-Dehydro-deacetylgriseusin A (1) showed pronounced cytotoxic potency (mean IC50 = 0.430 microM) combined with a significant selectivity for mammary cancer, renal cancer, and melanoma in a panel consisting of 37 tumor cell lines. In a clonogenic assay with tumor cells from 51 solid tumors, 1 inhibited anchorage independent growth and in vitro colony formation of tumor cells in a concentration-dependent and tumor type selective manner. As 1 was only a minor product, a semisynthetic preparation from the major metabolite, epi-deacetylgriseusin A (3), was achieved. Our studies also yielded 9-hydroxy-epi-deacetylgriseusin B methylester (5), 4'-dehydro-9-hydroxy-deacetylgriseusin B methylester (6), and 4'-dehydro-2a,8a-epoxy-deacetylgriseusin B (7) as new synthetic isochromanequinone derivatives, which provided a basic structure-activity relationship study.

ScbA from Streptomyces coelicolor A3(2) has homology to fatty acid synthases and is able to synthesize gamma-butyrolactones.

gamma-Butyrolactones play an important role in the regulation of antibiotic production and differentiation in Streptomyces. However the biosynthetic pathway for these small molecules has not yet been determined, and in vitro synthesis has not been reported. The function of the AfsA family of proteins, originally proposed to catalyse gamma-butyrolactone synthesis, has been in debate. To clarify the function of the AfsA family, and to understand the synthesis of the gamma-butyrolactones, we performed in silico analysis of this protein family. AfsA proteins consist of two divergent domains, each of which has similarity to the fatty acid synthesis enzymes FabA and FabZ. The two predicted active sites in ScbA, which is the AfsA orthologue found in Streptomyces coelicolor, were mutated, and gamma-butyrolactone biosynthesis was abolished in all four constructed mutants, strongly suggesting that ScbA has enzymic activity.

Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans.

In the postgenomic era it has become increasingly apparent that the vast number of predicted biosynthesis genes of microorganisms is not reflected by the metabolic profile observed under standard fermentation conditions. In the absence of a particular (in most cases unknown) trigger these gene loci remain silent. Because these cryptic gene clusters may code for the biosynthesis of important virulence factors, toxins, or even drug candidates, new strategies for their activation are urgently needed to make use of this largely untapped reservoir of potentially bioactive compounds. The discovery of new microbial metabolites through genome mining has proven to be a very promising approach. Even so, the investigation of silent gene clusters is still a substantial challenge, particularly in fungi. Here we report a new strategy for the successful induction of a silent metabolic pathway in the important model organism Aspergillus nidulans, which led to the discovery of novel PKS-NRPS hybrid metabolites.

Prospective analysis of factors associated with work reentry in patients with accident-related injuries.

INTRODUCTION: The objective of this study was to investigate the influence of accidents, the physical and psychological consequences, the patient's predisposition as well as work-related cognitions on return to work (RTW) post accident. Despite the costs of time-off from work after accidental injuries, very few investigations have been carried out so far. METHOD: In a consecutive sample, 163 patients were investigated directly and 12 months after an accident. RESULTS: 32% of the patients had a poor occupational integration 12 months after an accident. As predictors for return to work were found type of prior work: laborer (OR = 4.34; 1.79-10.50 CI 95%), type of accident: recreational (OR = 0.27; 0.11-0.69 CI 95%) and subjective perception of the accident severity (OR = 0.98; 0.96-0.99 CI 95%). CONCLUSION: Laborers after a traffic or work accident, who estimate the accident as severe, are at greater risk of developing long-term disability. Future efforts should be conducted especially for this target group.

Population dynamics and gene flow of Helicoverpa armigera (Lepidoptera: Noctuidae) on cotton and grain crops in the Murrumbidgee Valley, Australia.

The population dynamics of Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) in the Murrumbidgee Valley, Australia, has been characterized using five highly variable microsatellite loci. In the 2001-2002 growing season, there were very high levels of migration into the Murrumbidgee Valley with no detectable genetic structuring, consistent with previous analyses on a national scale. By contrast, there was significant genetic structuring over the 2002-2003 growing season, with three distinct genetic types detected. The first type corresponded to the first two generations and was derived from local individuals emerging from diapause and their progeny. The second genetic type corresponded to generation 3 and resulted from substantial immigration into the region. There was another genetic shift in generation 4, which accounts for the third genetic type of the season. This genetic shift occurred despite low levels of immigration. During the third generation of the 2002-2003 growing season, different population dynamics was characterized for H. armigera on maize, Zea mays L., and cotton Gossipium hirsutum L. Populations on cotton tended to cycle independently with very little immigration from outside the region or from maize within the region. Maize acted as a major sink for immigrants from cotton and from outside the region. If resistance were to develop on cotton under these circumstances, susceptible individuals from maize or from other regions would not dilute this resistance. In addition, resistance is likely to be transferred to maize and be perpetuated until diapause, from where it may reemerge next season. If low levels of immigration were to occur on transgenic cotton, this may undermine the effectiveness of refugia, especially noncotton refugia.

Assessing moth migration and population structuring in Helicoverpa armigera (Lepidoptera: Noctuidae) at the regional scale: example from the Darling Downs, Australia.

Analysis of gene flow and migration of Helicoverpa armigera (Hübner) in a major cropping region of Australia identified substantial genetic structuring, migration events, and significant population genotype changes over the 38-mo sample period from November 1999 to January 2003. Five highly variable microsatellite markers were used to analyze 916 individuals from 77 collections across 10 localities in the Darling Downs. The molecular data indicate that in some years (e.g., April 2002-March 2003), low levels of H. armigera migration and high differentiation between populations occurred, whereas in other years (e.g., April 2001-March 2002), there were higher levels of adult moth movement resulting in little local structuring of populations. Analysis of populations in other Australian cropping regions provided insight into the quantity and direction of immigration of H. armigera adults into the Darling Downs growing region of Australia. These data provide evidence adult moth movement differs from season to season, highlighting the importance of studies in groups such as the Lepidoptera extending over consecutive years, because short-term sampling may be misleading when population dynamics and migration change so significantly. This research demonstrates the importance of maintaining a coordinated insecticide resistance management strategy, because in some years H. armigera populations may be independent within a region and thus significantly influenced by local management practices; however, periods with high migration will occur and resistance may rapidly spread.

Intramolecular gamma-hydroxylations of nonactivated C-H bonds with copper complexes and molecular oxygen.

Copper(I) complexes incorporating the isomeric bidentate ligands IMPY (iminomethyl-2-pyridines) or AMPY (aminomethylene-2-pyridines) are quite unusual in their ability to bind and activate molecular oxygen. Using these complexes, hydroxylations of nonactivated CH, CH2, or CH3 groups in the gamma-position in relation to the imino-nitrogen atom, and with a specific orientation of one H atom with respect to the binuclear Cu-O species, can be achieved in synthetically useful yields. Through mechanistic studies employing conformationally well-defined molecules (for example, cyclic isoprenoids), coupled with solid-state X-ray structure analyses and force-field calculations, we postulate a seven-membered transition state for this reaction in which six atoms lie approximately in a plane. This plane is defined by the positions of the lone pairs on the nitrogen atoms, as well as the copper and the oxygen atoms. For a successful hydroxylation, one hydrogen atom should be located close to this plane. Prediction of the stereochemical course of these reactions is possible based on a simple geometrical criterion. The convenient introduction of IMPY and AMPY groups as auxiliaries into oxo and primary amino compounds and the simple hydrolysis after the hydroxylation procedure has allowed the synthesis of 3-hydroxy-1-oxo and 3-hydroxy-1-amino compounds. If desired, the 3-hydroxy-1-IMPY and -1-AMPY compounds can be reduced with NaBH4 to obtain 3-hydroxy-1-aminomethylpyridines. For a successful hydroxylation procedure, the method employed for the synthesis of the CuI complexes is very important. Starting either from CuI salts or from CuII salts with a subsequent reduction with benzoin/triethylamine may turn out to be the better way, depending on the ligand and the molecular structure.

Addition reactions at the 16(17) double bond of 3-methoxy-13alpha-estra-1,3,5(10),16-tetraene.

The epoxidation, the addition of hypobromous acid, and the hydroboration of 3-methoxy-13alpha-estra-1,3,5(10),16-tetraene 1 with diborane, catecholborane, and 9-BBN were investigated in order to determine the stereochemical outcome and to synthesize new 13alpha-estra-1,3,5(10)-trienes for biological and conformational investigations. It was shown that the sterically demanding reagent 9-BBN participated in a preferred beta attack (53% 16betaOH 10, 34% 17betaOH 8, 13% 16alphaOH 11). This stereochemical result is in agreement with that from another cis addition reaction, the recently described OsO4 dihydroxylation of 1 [Steroids 68 (2003) 113]. With smaller reagents such as B2H6, catecholborane, or magnesium monoperoxyphthalate, a diminished stereoselectivity was observed with only a slight excess of beta attack. The ionic trans addition of hypobromous acid gave two 17-bromo-16-alcohols with 16beta,17alpha (4, 76%) and 16alpha,17beta configuration (5, 24%) formed by trans cleavage of the 16,17alpha- and beta-bromonium ion at position 16. The same regioselective and stereoselective course was found for the cleavage of the 16alpha,17alpha- and 16beta,17beta-epoxides (3 and 2) with hydrazoic acid (3-->16betaN3,17alphaOH 7, 2-->16alphaN3,17betaOH 6). The stereochemistry of the addition reactions to 1 can be explained in terms of a twist-boat conformation involving the C ring of compound 1. From a synthetic viewpoint the synthesis of the beta-epoxide 2 from the bromohydrin 4, the cleavage of this epoxide to 16alpha-substituted-17beta-hydroxy compounds, such as 6, and hydroboration/oxidation with 9-BBN to the hitherto unknown 16beta-hydroxy compound 10 are useful procedures. The bromohydrin 5 is the first 13alpha-steroid with a 17beta-bromo substituent. X-ray analysis revealed twist-boat and 16beta-envelope conformations for rings C and D, respectively.

Synthesis and conformation of four 16,17-diols in the 3-methoxy-13alpha-estra-1,3,5(10)-triene series.

All four diasteromeric 16,17-diols in the 3-methoxy-13alpha-estra-1,3,5(10)-triene series have been synthesized. The trans-diols 1 and 2 can be obtained by hydroborating the 17-enol acetate 6 (61%, ratio 27:73, preferred alpha attack). OsO(4) dihydroxylation of the olefin 7 yielded the cis-diols 3 and 4 (ratio 13:87). The dihydroxylation proceeds with preference for beta attack caused by a C-ring twist-boat form of 7. The conformations of the diols 2 and 4, the 17-benzyl-17-hydroxy compounds 9 and 10 (obtained by Grignard reaction), and the 16alpha-bromo-17beta-hydroxy compound 8 were determined by X-ray analysis and by 1H NMR spectroscopy in solution. Some compounds, in spite of a 17beta-hydroxy group, had a conformation with a ring C chair form (4, 8, 9) caused by intermolecular interaction in the solid state. The rest of the compounds studied here (2, 10) possessed a conformation with a ring C twist-boat form, which has been also found for all 17beta-substituted compounds in solution. The preferred conformation of the D-ring with 17beta-substituents seems to be the 16beta-envelope form or near this form, but the existence of the 16alpha-envelope form (inversion of the ring D) for some compounds showed great variance in the conformation of ring D, which is substituent dependent.

[Psychic impairment in psychosomatic and psychiatric quality assessment: global assessment of functioning scale (GAF) vs. impairment score (IS)]. / Die Beeinträchtigungsschwere in der psychosomatischen und psychiatrischen Qualitätssicherung: Global Assessment of Functioning Scale (GAF) versus Beeinträchtigungs-Schwere-Score (BSS).

OBJECTIVES: The Global Assessment of Functioning Scale (GAF) and the Impairment-Score (IS) are important instruments for Quality Assessment. There are only few studies examining the quality of statistical power of the GAF-Scale indicating problems in construct validity and no larger studies for the IS. METHODS: For a sample of 263 patients the Psy-BaDo and an OPD-Rating were completed. RESULTS: Though the distribution of both scales show large range, the proportion of explained variance is 58 %. This proportion can be increased to 68 % for the IS by including the OPD-Ratings. The GAF-Scale in contrast is not associated with the OPD-Ratings. CONCLUSIONS: The results indicate, that the combination of both scales is necessary to represent the whole variance of psychic impairment (ICD-10 Chapter F & Z). In addition the valid rating of both scales is very difficult for patients with somatic disorders and somato-psychic problems.

[Motivation for psychotherapy of elderly patients in a clinic for rehabilitation - an empirical study] / Psychotherapiemotivation älterer Patienten in der Rehabilitationsklinik - Eine empirische Studie.

With the increase of elderly patients in psychosomatic clinics the question arise, what about the motivation and expectations of these patients. Here an empirical study is presented, where 189 elderly (55 years and over) and 190 younger (under 55 years) patients are included. They are analysed with different questionnaires. The elderly patients show less psychosocial attribution for their disease, less motivation and expectation for psychotherapy and a more negative accentuated attitude to psychotherapy. But the expectations especially of the elderly differ in a wide range. In a clusteranalysis three groups are separated: low, middle and high motivated patients. The older patients are over represented in the group of the low motivated patients. These older patients doesn't occure any recovery of symptoms. At last some clinical aspects, concerning this group, are discussed.