Parking behaviour under the influence of alcohol.

Real-life driving studies evaluating the impact of alcohol influence on the ability to park a car are rare but necessary to assess a possible impairment to drive a car in the event of prosecution. In this study, 29 test persons (13 m, 16 f) completed three test drives with real cars, each made up of three different parking situations. While four test persons remained sober, the majority drank a previously calculated amount of alcohol before the second drive; the aim was to reach a blood alcohol concentration (BAC) of 1.1 g/kg. The third drive took place about 2 h later without any further ingestion of alcohol. The impact of BAC on the number of accidents, time needed to finish the drive, the amount of correction moves and quality of the final parking position (in the centre of the parking space) were analysed. Furthermore, pressure measuring films were applied to the test cars, measuring the average pressure and load in the areas of the accident impact. A significant increase of accidents could be noted with rising BAC. While a single accident happened to both sober and drivers under the influence of alcohol, more than one accident was only seen in drivers after the ingestion of alcohol (> 0.63 g/kg). The BAC had no impact on the other considered aspects. Concludingly, more than one impact site or accident while parking a car can serve as an indication for alcohol impairment of the driver at the time of the accident.

Sudden unexpected cardiac death and postmortem identification of a novel RYR2 gene mutation.

A 13-year-old female was found lifeless at home. The autopsy and consecutive histological and toxicological examinations showed blood-rich and edematous lungs and foamy bloody content in the airways. No morphologic pathological findings were seen, especially no bleeding sources. Toxicological findings were unremarkable. The specific cause of death remained unclear. Due to reported losses of consciousness, a moleculargenetic postmortem testing was performed. A so far undescribed mutation in the cardiac ryanodine receptor gene RyR2 was detected. This mutation is suitable to explain the case history as well as the morphological findings. The cardiac ryanodine receptor gene RyR2 encodes the ryanodine receptor type 2, an ion channel in the cardiomyocytes. The ion channel regulates the influx of calcium ions and thus influences myocardial activity. Mutations in this channel may result in the catecholaminergic polymorphic ventricular tachycardia (CPVT), a cardiac arrhythmia that can lead to syncope and sudden cardiac death. This case demonstrates the usefulness and need of molecular autopsy, in particular to identify and treat possibly affected family members.

["Extended suicide". Homicide-suicide under psychopathological and criminological aspects]. / Der "erweiterte Suizid". Vollendete Homizid-Suizide unter psychopathologischen und kriminologischen Aspekten.

BACKGROUND: Homicide-suicide is a rare and serious phenomenon which mainly occurs in intimate relationships and families. MATERIALS AND METHODS: In this study ten cases of murder-suicide during the period 2006-2011 in the greater area of Düsseldorf were investigated. Data were obtained from coroner and prosecution files. RESULTS: All perpetrators were male. In accordance with the literature the results of the analysis revealed male sex, higher age, intimate partnership, access to firearms and special personality traits, mainly emotionally unstable, narcissistic traits and aggressiveness as the main risk factors. In all cases, at least three risk factors were identified. Breakdown of the marital relationship and social descent emerged as probable leading motives. Shooting was the most frequent method of killing followed by sharp force. CONCLUSIONS: Compared with homicide and suicide, homicide-suicide appears to be a distinct phenomenon. The knowledge and understanding of relevant risk factors could help mental health professionals, police and public authorities to intervene in time.

[Development of Cushing's syndrome during phytotherapy]. / Entwicklung eines Cushing-Syndroms während einer Phytotherapie.

UNLABELLED: HISTORY AND INITIAL FINDINGS: In a 75-year-old woman with unclear weight gain and typical signs of Cushing's syndrome, a pituitary microadenoma and hyperplasia of the left adrenal gland were diagnosed. She was referred for preoperative diagnostics. Her clinical appearance suggested hypercortisolism. INVESTIGATIONS: The lab test suggested external glucocorticoid application. Basal ACTH and cortisol were low. DIAGNOSIS, TREATMENT AND FURTHER COURSE: The patients' phytotherapeutics received from a masseuse were analyzed in a special lab. The analysis showed that the pills were enriched with cortisone and hydrocortisone and were causal for the development of Cushing's syndrome and the symptoms of secondary adrenal insufficiency. CONCLUSION: Symptoms of Cushing's syndrome develop during chronic exposure to glucocorticoids. The development of Cushing's syndrome depends on the patient's sensitivity and on the duration and dose of the glucocorticoid application. Clinical and laboratory studies precede imaging.

Perazine for schizophrenia.

BACKGROUND: Perazine is an old phenothiazine derivative used for the treatment of people with schizophrenia and is reputed to have a low level of extrapyramidal adverse effects. As far as we are aware, its use is limited to Germany, Poland, the former Yugoslavia and the Netherlands. OBJECTIVES: To examine the effects of perazine for those with schizophrenia, and schizophrenia-like psychoses. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's register which includes relevant randomised controlled trials from the bibliographic databases Biological Abstracts, CINAHL, The Cochrane Library, EMBASE, MEDLINE, PsycLIT, LILACS, PSYNDEX, Sociological Abstracts and Sociofile (last update of the review March 2005). We searched references of all included studies for further trials. We contacted pharmaceutical companies and authors of trials. SELECTION CRITERIA: We selected all randomised controlled trials that compared perazine with other treatments for people with schizophrenia and/or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We independently (SL, BH) inspected citations and where possible abstracts and ordered papers for re-inspection and quality assessment. We independently extracted data. We excluded data if loss to follow up was greater than 50%. For homogeneous dichotomous data we calculated the Relative Risk (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD). We inspected all data for heterogeneity. MAIN RESULTS: We included six trials with a total of 288 participants. In only one trial with 95 participants, perazine appeared superior to 'active placebo' (trimipramine) at five weeks for the outcome of 'no important global improvement' (n=95, RR 0.43 CI 0.2 to 0.8, NNT 4 CI 2 to 13), but there was no statistically significant difference in most measures of mental state. Perazine did not induce more general adverse events than placebo, but more participants received at least one dose of antiparkinson medication (n=95, RR 4.50 CI 1.0 to 19.5, NNH 6 CI 4 to 33). Five small trials comparing perazine with other antipsychotics, including in total only 193 participants, were incompletely reported and the outcomes were presented in various ways so that meta-analysis was not possible in most occasions. A similar number of participants receiving perazine or comparator antipsychotics left the studies early (n=193, RR 0.85, CI 0.5 to 1.4). The results on efficacy were controversial and need further assessment by randomised controlled trials. No obvious differences in adverse events between perazine and other antipsychotics could be derived from the limited data. Two haloperidol comparisons did not present extrapyramidal side-effects in a suitable way for use in meta-analysis, but three small comparisons with the atypical antipsychotics zotepine and amisulpride showed no higher risk of akathisia (n=111, RR 0.31 CI 0.1 to 1.1), dyskinesia (n=111, RR 0.47 CI 0.1 to 3.5), parkinsonism (n=81, RR 1.21 CI 0.5 2.8) or tremor (n=40, RR 0.80 CI 0.3 to 2.6) with perazine. AUTHORS' CONCLUSIONS: The number, size and reporting of randomised controlled perazine trials is insufficient to present firm conclusions about the properties of this antipsychotic. It is possible that perazine is associated with a similar risk of extrapyramidal side-effects as some atypical antipsychotics, and this should be clarified in larger, well-designed trials.

Benperidol for schizophrenia.

BACKGROUND: Benperidol is a relatively old antipsychotic drug that has been marketed since 1966. It has been used in Germany for 30 years, but is also available in Belgium, Greece, Italy, the Netherlands and the UK. Benperidol is a butyrophenone antipsychotic, with the highest neuroleptic potency in terms of D2 receptor blockade. Those taking it are therefore reputed to be at high risk of extrapyramidal side effects, but benperidol's unusual profile may render it valuable to subgroups of people with schizophrenia. OBJECTIVES: To examine the clinical effects and safety of benperidol for those with schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's register (November 2004) for this update. SELECTION CRITERIA: We included all randomised controlled trials that compared benperidol with other treatments for people with schizophrenia, or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We reliably selected studies, quality rated them and extracted data. We independently extracted data but excluded data if loss to follow up was greater than 50%. For dichotomous data, we estimated relative risks (RR), with the 95% confidence intervals (CI). Where possible, we calculated the number needed to treat/harm statistic (NNT/H) and used intention-to-treat analysis. MAIN RESULTS: The update yielded no further studies for inclusion in the review. We identified only one unpublished poorly randomised controlled trial (N=40, duration 30 days, comparison perphenazine). Although benperidol was inferior to perphenazine (1 RCT, N=40, global state no better or worse RR 8.0 CI 2.1 to 30, NNH 1.4 CI 1 to 2) poor reporting suggests that an overestimate of effect is likely. It was not possible to report other outcomes. AUTHORS' CONCLUSIONS: Currently, there are insufficient data from randomised trials to assess the clinical effects of benperidol. This compound merits further research interest.

Perphenazine for schizophrenia.

BACKGROUND: Perphenazine is an old phenothiazine antipsychotic with a potency similar to haloperidol. It has been used for many years and is popular in the northern European countries and Japan. OBJECTIVES: To examine the clinical effects and safety of perphenazine for those with schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's register (June 2001), references of all included studies and contacted pharmaceutical companies and authors of included studies in order to identify further trials. SELECTION CRITERIA: We included all randomised controlled trials that compared perphenazine with other treatments for people with schizophrenia and/or schizophrenia-like psychoses. We excluded trials of depot formulations of perphenazine. DATA COLLECTION AND ANALYSIS: Two reviewers independently inspected citations and, where possible, abstracts. We ordered papers, inspected and quality assessed them. We extracted data, again working independently. If loss to follow up was greater than 50% we considered results as 'prone to bias'. For dichotomous data we calculated the relative risk (RR), the 95% confidence interval (CI) and, where appropriate, the number needed to treat/harm (NNT/H) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD). MAIN RESULTS: The review currently includes 25 studies with 2478 patients, 2285 of whom had been randomised to interventions that were relevant for the review such as perphenazine, other antipsychotic drugs or placebo. The trials were carried out between 1961 and 1993. All but one trial were short term with a duration of between ten days and 12 weeks. Descriptions of allocation and blinding were usually incomplete. Six studies (n=300) compared perphenazine with placebo. Perphenazine was associated with fewer participants leaving the trials early due to relapse or worsening of symptoms (n=84, RR 0.1 CI 0.03 - 0.4, NNT 2 CI 1 to 20). Twenty studies compared perphenazine (n=738) with other antipsychotics (n=1278). Perphenazine seemed as effective as other antipsychotics ('global state unimproved or worse' n=1327, RR 1.0 CI 0.9 to 1.2). We found no clear differences in terms of specific aspects of efficacy, behaviour or tolerability. However, interpretation of findings of the review was limited by poor reporting and the use of 24 different comparator antipsychotics in the 20 trials. AUTHORS' CONCLUSIONS: Although perphenazine has been randomised for more than 40 years, incomplete reporting and the variety of comparators used make it impossible to draw clear conclusions. At best we can say that perphenazine showed similar effects and adverse events as several of the other pooled antipsychotic drugs. Since perphenazine is a relatively inexpensive and frequently used compound, further trials are justified to clarify the properties of this classical antipsychotic drug.

Genomic structure and transcriptional regulation of the human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase gene.

The NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) is a catabolic enzyme that controls the biological activities of prostaglandins by converting them into inactive keto-metabolites. Here we report the genomic organisation of the complete human PGDH gene and characterise its transcriptional regulation. The PGDH gene spans about 31 kb on chromosome 4 and contains 7 exons. Within 2.4 kb of the 5'-flanking sequence we identified two regions with clustered putative transcription factor binding sites. The distal promoter element PGDH-DE (positions-2152/-1944 relative to the start codon) contains binding sites for Ets and activating protein-1 (AP-1) flanked by two cAMP-responsive element-binding protein binding sites (CREB1, CREB2), whereas the proximal element PGDH-PE (-235/-153) includes an Ets and an AP-1 binding sequence. By electrophoretic mobility shift assay, no high affinity binding of Ets or AP-1 factors was observed with PGDH-PE, whereas we confirmed interaction of members of the Ets, AP-1 and CREB families of transcription factors with PGDH-DE. Transcriptional control of the PGDH promoter was assessed by transiently transfecting JEG-3 choriocarcinoma cells. A luciferase reporter gene construct containing the PGDH-PE was not induced by c-jun/c-fos in the absence or presence of co-expressed Ets-1. A construct carrying the PGDH-DE in front of the minimal homologous promoter was activated by co-transfection of expression vectors for AP-1 proteins. Mutation of the AP-1 or CREB2 site reduced the response to c-jun/c-fos, whereas mutation of the Ets site of the distal element reduced basal promoter activity. CREB activated the PGDH-DE construct through the CREB1 site. These results defined the distal element as an integrator of transcriptional regulation by AP-1, Ets and CREB proteins.

Perazine for schizophrenia.

BACKGROUND: Perazine is an old phenothiazine derivative used for the treatment of people with schizophrenia which has a reputed low level of extrapyramidal side-effects. However, its use is restricted in the sense that - to the best knowledge of the reviewers - it is only marketed in Germany, Poland, Yugoslavia and the Netherlands. OBJECTIVES: To examine the effects of perazine for those with schizophrenia, and schizophrenia-like psychoses. SEARCH STRATEGY: Electronic searches of the Cochrane Schizophrenia Group's register which includes relevant randomised controlled trials from the bibliographic databases Biological Abstracts, CINAHL, The Cochrane Library, EMBASE, MEDLINE, PsycLIT, LILACS, PSYNDEX, Sociological Abstracts and Sociofile were undertaken. References of all included studies were searched for further trials. Pharmaceutical companies and authors of trials were contacted. SELECTION CRITERIA: All randomised controlled trials that compared perazine with other treatments for people with schizophrenia and/or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by two reviewers, papers ordered, re-inspected and quality assessed. Data were independently extracted. Data were excluded if loss to follow up was greater than 50%. For homogeneous dichotomous data the Relative Risk (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, weighted mean differences were calculated (WMD). All data were inspected for heterogeneity. MAIN RESULTS: Six trials with a total of 288 participants are included. According to only one trial with 95 participants perazine appeared superior to active placebo (trimipramine) at five weeks for the outcome of 'no important global improvement' (n=95, RR 0.6, CI 0.3-0.9, NNT 4, CI 2-17), but there was no difference in various measures of mental state. The side-effect risk of perazine compared to placebo could not be estimated because they were not reported. Five small trials including only 193 participants which compared perazine with other antipsychotics were incompletely reported and the outcomes were presented in various ways so that meta-analysis was not possible in most occasions. A similar number of participants receiving perazine or comparator antipsychotics left the studies early (n=193, RR 0.9, CI 0.5-1.4). The results on efficacy were controversial and need further assessment by randomised controlled trials. No obvious differences in adverse events between perazine and other antipsychotics could be derived from these limited data. Two haloperidol comparisons did not present extrapyramidal side-effects in a way usable for meta-analysis, but three small comparisons with the atypical antipsychotics zotepine and amisulpride showed no higher risk of akathisia (n=111, RR 0.3, CI 0.1-1.1), dyskinesia (n=111, RR 0.5, CI 0.1-3.5), parkinsonism (n=81, RR 1.2, CI 0.5-2.8) or tremor (n=40, RR 0.8, CI 0.3-2.3) with perazine. REVIEWER'S CONCLUSIONS: The number, size and reporting of randomised controlled perazine trials is insufficient to present firm conclusions about the properties of this antipsychotic. It is possible that perazine is associated with a similar risk of extrapyramidal side-effects as some atypical antipsychotics, and this should be clarified in larger, well-designed trials.

Benperidol for schizophrenia.

BACKGROUND: Benperidol is a relatively old antipsychotic drug, marketed since 1966, used in Germany for 30 years, but also available in Belgium, Greece, Italy, the Netherlands and the UK. Benperidol is a butyrophenone antipsychotic, with the highest neuroleptic potency in terms of D2 receptor blockade. Those taking it are, therefore, reputed to be at high risk of extrapyramidal side effects, but benperidol's unusual profile may render it of value to subgroups of people with schizophrenia. OBJECTIVES: To examine the clinical effects and safety of benperidol for those with schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: The reviewers searched the Cochrane Schizophrenia Group's register (January 2001) which includes relevant randomised controlled trials from the bibliographic databases Biological Abstracts, CINAHL, The Cochrane Library, EMBASE, MEDLINE, PsycLIT, LILACS, PSYNDEX, Sociological Abstracts and Sociofile. We also searched the references of all included studies and contacted pharmaceutical companies and authors of included studies in order to identify further trials. SELECTION CRITERIA: Randomised controlled trials that compared benperidol with other treatments for people with schizophrenia and/or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by two reviewers and papers were ordered, re-inspected and quality assessed. We independently extracted data but excluded data if loss to follow up was greater than 50%. For homogeneous dichotomous data, we calculated the relative risk (RR), the 95% confidence interval (CI) and, where appropriate, the number needed to treat/harm (NNT/H), on an intention-to-treat basis. MAIN RESULTS: We identified only one unpublished poorly randomised controlled trial (N=40, duration 30 days, comparison perphenazine). Although benperidol was inferior to perphenazine (1 RCT, N=40, global state no better or worse RR 8.0 CI 2.1 to 30, NNH 1.4 CI 1 to 2) poor reporting suggests that an overestimate of effect is likely. It was not possible to report other outcomes. REVIEWER'S CONCLUSIONS: Currently, there are insufficient data from randomised trials to assess the clinical effects of benperidol. This interesting compound merits further research.

Phosphorylation regulates intracellular trafficking of beta-secretase.

beta-Secretase (BACE) is a transmembrane aspartyl protease, which generates the N terminus of Alzheimer's disease amyloid beta-peptide. Here, we report that BACE can be phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1. Phosphorylation exclusively occurs after full maturation of BACE by propeptide cleavage and complex N-glycosylation. Phosphorylation/dephosphorylation affects the subcellular localization of BACE. BACE wild type and an S498D mutant that mimics phosphorylated BACE are predominantly located within juxtanuclear Golgi compartments and endosomes, whereas nonphosphorylatable BACE S498A accumulates in peripheral EEA1-positive endosomes. Antibody uptake assays revealed that reinternalization of BACE from the cell surface is independent of its phosphorylation state. After reinternalization, BACE wild type as well as BACE S498D are efficiently retrieved from early endosomal compartments and further targeted to later endosomal compartments and/or the trans-Golgi network. In contrast, nonphosphorylatable BACE S498A is retained within early endosomes. Our results therefore demonstrate regulated trafficking of BACE within the secretory and endocytic pathway.

Phosphorylation of the beta-amyloid precursor protein at the cell surface by ectocasein kinases 1 and 2.

The beta-amyloid precursor protein (betaAPP) is one of the rare proteins known to be phosphorylated within its ectodomain. We have shown previously that betaAPP can be phosphorylated within secretory vesicles and at the cell surface (Walter, J., Capell, A., Hung, A. Y. , Langen, H., Schnölzer, M., Thinakaran, G., Sisodia, S. S., Selkoe, D. J., and Haass, C. (1997) J. Biol. Chem. 272, 1896-1903). We have now specifically characterized the phosphorylation of cell surface-located betaAPP and identified two ectoprotein kinases that phosphorylate betaAPP at the outer face of the plasma membrane. By using selective protein kinase inhibitors and by investigating the usage of ATP and GTP as cosubstrates, we demonstrate that membrane-bound betaAPP as well as secreted forms of betaAPP can be phosphorylated by casein kinase (CK) 1- and CK2-like ectoprotein kinases. The ectodomain of betaAPP was also phosphorylated by purified CK1 and CK2 in vitro, but not by protein kinases A and C. Phosphorylation of betaAPP by ectoprotein kinases and by purified CK1 and CK2 occurred within an acidic domain in the N-terminal half of the protein. Heparin strongly inhibited the phosphorylation of cell-surface betaAPP by ecto-CK1 and ecto-CK2, indicating a regulatory role of this extracellular matrix component in betaAPP phosphorylation.

Intracommunity relationships, dispersal pattern and paternity success in a wild living community of Bonobos (Pan paniscus) determined from DNA analysis of faecal samples.

Differences in social relationships among community members are often explained by differences in genetic relationships. The current techniques of DNA analysis allow explicit testing of such a hypothesis. Here, we have analysed the genetic relationships for a community of wild bonobos (Pan paniscus) using nuclear and mitochondrial DNA markers extracted from faecal samples. Bonobos show an opportunistic and promiscuous mating behaviour, even with mates from outside the community. Nonetheless, we find that most infants were sired by resident males and that two dominant males together attained the highest paternity success. Intriguingly, the latter males are the sons of high-ranking females, suggesting an important influence of mothers on the paternity success of their sons. The molecular data support previous inferences on female dispersal and male philopatry. We find a total of five different mitochondrial haplotypes among 15 adult females, suggesting a frequent migration of females. Moreover, for most adult and subadult males in the group we find a matching mother, while this is not the case for most females, indicating that these leave the community during adolescence. Our study demonstrates that faecal samples can be a useful source for the determination of kinship in a whole community.

Managed care at the crossroads: can managed care organizations survive government regulation?

Attorneys Brown and Hartung provide a comprehensive overview of the development and structural components of managed health care plans. The article discusses the state regulatory controls affecting managed care including Patient Protection Acts, mandated benefit provisions, any willing provider laws, and consumer access provisions. The article considers liability problems facing managed care organizations, in particular liabilities which arise from utilization and medical review discussions as well as gag clauses and financial incentive arrangements. The authors also review relevant federal regulatory initiatives.

[The Myocardial Infarction Register of the District of Rostock]. / Die Herzinfarktregister im Bezirk Rostock.

In the country of Rostock the registers of myocardial infarction were evaluated in 4 districts after a period of one year. Here could be established that the incidence of infarctions in the various districts was 23.7 (Wismar), 18.9 (Bad Doberan), 13.7 (Rostock) and 17.6 (Stralsund). The sex ratio to the disadvantage of men is corresponding at 2 : 1. The incidence of infarctions and the lethality linearly increase with growing age. 4 weeks after the manifestation of the infarction the total lethality varies between 43.6 and 57% in the various districts. More than half to 3/4 of all cases of death are in the prehospital phase. As decisive periods of delay up to the admission to hospital the delay by patients and the delay by transport could be established. With 15 minutes to 30 minute the delay by physician is in every case the shortest period of delay. In comparison to an international WHO-study the periods of delay by physician and transport are in the first ten places among 23 towns.