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.

[Genetic testing to prevent sudden cardiac death]. / Genetische Diagnostik zur Vermeidung des plötzlichen Herztods.

Successfully incorporating genetic testing into clinical practice to prevent sudden cardiac death (SCD) requires (1) appropriate recognition of an inherited cardiovascular condition, (2) identification of appropriate family members at risk and for genetic testing, (3) selection of the appropriate genetic test and information about the expected diagnostic yield, (4) understanding the complexity of result interpretation and distinct handling of incidental findings and (5) providing effective communication and medical advice regarding the genetic and medical results and implications to the patient and his family. Molecular autopsy in SCD victims will be of future importance to determine the cause of death. Interdisciplinary patient care should be provided in specialized centers with a high level of cardiogenetic expertise and is recommended to provide precise and individualized patient management.

Molecular genetic diagnostics for ventricular arrhythmias and sudden cardiac death syndromes.

Inherited forms of ventricular arrhythmias are rare diseases, but a major cause for severe cardiac events, sudden unexplained death syndromes, and death in young adults, infants, and children. Each disorder is genetically heterogeneous (5-20 genes per disease) and molecular testing may include both core genes and less common disease genes as well. Owing to the rapid development and feasibility of sequencing technologies enabling a parallel analysis of several hundred genes up to a whole exome, disease mutations can be identified very efficiently, but have to be seen in the complexity and natural variance of the human genome. Precise phenotypic knowledge and advanced gene variant interpretation are important to ensure adequate patient diagnostics and management. This article focuses on the genetic causes of inherited arrhythmia forms predisposing patients to sudden cardiac death and discusses practical issues and skills for molecular testing.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

OBJECTIVE: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. METHOD: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. RESULTS: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. CONCLUSION: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.

[The challenge of treating bipolar outpatients]. / Herausforderungen der ambulanten Behandlung von Patienten mit bipolar-affektiven Störungen.

The course of bipolar illness comprises a wide range, which may vary between one single episode once every five years and a severe ultra rapid cycling course with mood changes within days. Even with optimal pharmacological treatment the functional outcome in bipolar patients is still poor. Underlying pathomechanisms are not fully understood yet. This article addresses three possible illness specific-aspects: cognitive defects, high relapse frequency and poor adherence. Causes as well as therapeutic interventions for these therapeutic pitfalls are summarised.

Extreme eutrophication and salinisation in the Coorong estuarine-lagoon ecosystem of Australia's largest river basin (Murray-Darling).

Estuaries in rainfall poor regions are highly susceptible to climatic and hydrological changes. The Coorong, a Ramsar-listed estuarine-coastal lagoon at the end of the Murray-Darling Basin (Australia), has experienced declining ecological health over recent decades. Twenty years of environmental data were analysed to assess patterns and drivers of water quality changes. Large areas of the Coorong are now persistently hyper-saline (salinity >80 psu) and hypereutrophic (total nitrogen, TN > 4 mg L-1, total phosphorus, TP > 0.2 mg L-1, chlorophyll a > 50 µg L-1) which coincided with reduced flushing due to diminished freshwater inflows and increasing evapo-concentration. Sediment quality also was related to flushing, with higher concentrations of organic carbon, TN, TP and sulfides as salinity increased. While total nutrient levels are very high, dissolved inorganic nutrients are generally low. Increased lagoonal flushing would be beneficial to reduce the hypersalinisation and hypereutrophication and improve ecosystem health.

[Bipolar depression. Spectrum of clinical pictures and differentiation from unipolar depression]. / Bipolare Depression. Spektrum klinischer Erscheinungsbilder und Abgrenzbarkeit von der unipolaren Depression.

Patients with bipolar disorder often present initially with a major depressive episode. The correct diagnosis at the first presentation could help to find an effective medication regimen, to prevent antidepressant-induced rapid cycling and to reduce antidepressant-induced manic episodes, e.g. though combination therapy with a mood stabilizer. Consistent predictors for an underlying bipolar illness are an early age of onset, a highly recurrent illness course with more than five episodes, the presentation of atypical features, psychotic symptoms, the presence of psychiatric comorbidities like anxiety disorders, history of suicide attempts (especially at an early age), positive family anamnesis for bipolar disorder, and a rapid evolvement of the depressive episode. So far there are no pathognomonic markers for bipolar disorder. Therefore we propose to assess the risk of each patient for having bipolar disorder individually. Patients who are at a high risk should at least be informed and should be closely monitored for the development of manic episodes.

Preliminary results of a fine-grain analysis of mood swings and treatment modalities of bipolar I and II patients using the daily prospective life-chart-methodology.

OBJECTIVE: The study aimed to increase the knowledge about the detailed course differences between different forms of bipolar disorder. METHOD: Using the prospective life-chart-clinician version, we compared the fine-grain analysis of mood swings and treatment modalities of 18 bipolar II with 31 bipolar I patients. RESULTS: During an observational period of a mean of 26 months we observed an increase of euthymic days, and a decrease of (sub)depressive and (hypo)manic days. Days in a (sub)depressed state were more frequent than days of (hypo)mania as well as days of subdepression or hypomania in comparison to days of full-blown depression or mania. Bipolar II patients showed an increase in hypomanic days receiving more frequently antidepressants. Bipolar I patients, with a decrease of manic days, were significantly taking more often mood stabilizers. CONCLUSION: Treatment in a specialized bipolar clinic improves the overall outcome, but bipolar II disorder seems to be still treated sub-optimally with a possible iatrogenic increase of hypomanic days.

Contributions to the phylogeny of Platyhelminthes based on partial sequencing of 18S ribosomal DNA.

Partial sequencing of the 18S ribosomal DNA gene of one nemertean and 13 free-living and parasitic Platyhelminthes (556 nucleotides), and of one nemertean and 20 Platyhelminthes (556 nucleotides) was used to test several hypotheses concerning the phylogenetic relationships of Platyhelminthes. The following conclusions were reached: the Neodermata is monophyletic; Trematoda (Aspidogastrea and Digenea) is monophyletic, although a sister group relationship of the Aspidogastrea and all other Neodermata cannot be definitely ruled out; the Cestoda comprising the Eucestoda, Amphilinidea and Gyrocotylidea is monophyletic; it is unresolved whether the Monogenea is paraphyletic; neither Gyrocotylidea and Monopisthocotylea nor Gyrocotylidea and Monogenea as a whole are sister groups; Anoplodiscus is a monopisthocotylean monogenean; none of Proseriata, Pterastericolidae/Umagillidae, Kalyptorhynchia, Rhabdocoela as a whole, Dalyelliida or the Temnocephalidae is the sister group of the Neodermata; there is some evidence that a larger taxon consisting of Proseriata, Tricladida and Rhabdocoela may be the sister group of the Neodermata but definitive evidence for a sister group relationship between the Neodermata and any turbellarian taxon is lacking; Rhabdocoela and Lecithoepitheliata are not closely related; it is unresolved whether the Rhabdocoela is monophyletic; Umagillidae, Pterastericolidae and Temnocephalidae belong to one monophylum; the Temnocephalidae are very close to the dalyelliids; Tricladida and Rhabdocoela are sister groups, the exact position of the Catenulida and Nemertini in relation to the Platyhelminthes has not been resolved, although Catenulida and Lecithoepitheliata may belong to one clade.

Detection and characterization of hepatitis C virus sequence in the serum of a patient with chronic HCV infection.

A cDNA fragment corresponding to the nonstructural gene region of Hepatitis C virus was cloned and sequenced. cDNA was obtained by reverse transcription of viral RNA extracted from serum of a German patient with chronic post transfusion hepatitis. "Nested" PCR resulted in a cDNA fragment of 345 nt. The sequence showed a homology of 96% to the American prototype HCV.

Rapid, easy and economical dot EIA for detection of antibodies to HIV-1 using recombinant env- and gag-proteins.

A rapid and simple screening test for antibodies to HIV-1 was designed on the principle of dot-EIA. Recombinant HIV-1 env and gag polypeptides are fixed on nitrocellulose sheets. Peroxidase conjugated protein A is used for detection of bound antibodies. After addition of hydrogen peroxide and 2-bromo-1-naphtol antigen-antibody complexes are visualized as discrete blue coloured spots. The test is completed within 15 min. Out of 111 sera positive by commercial EIA and Western blot analysis 110 were recognized by dot-EIA (sensitivity: 99.1%). False positive results compared with commercial EIA were found in 2 of 423 healthy blood donors (specificity: 99.5%).

Tuberculosis control in the Caucasus: successes and constraints in DOTS implementation.

SETTING: The pilot projects for tuberculosis (TB) control, supported by the World Health Organization (WHO) and based on the WHO recommended control strategy, directly-observed treatment, short-course (DOTS) in the Caucasian countries (Armenia, Azerbaijan, Georgia). OBJECTIVE: To evaluate the results 2 years after the implementation of the pilot projects. METHODS: Analysis of data on case detection, sputum conversion and treatment outcome reported quarterly to the WHO from the Ministries of Health in each country. RESULTS: Since the establishment of the project, 1330, 764 and 4866 new cases and relapses, respectively, of TB have been detected in the pilot areas of Armenia, Azerbaijan and Georgia. In Armenia and Azerbaijan, respectively 46% and 57% of all cases were smear positive, whilst in Georgia, the corresponding figure was only 12%. After 3 months' treatment, 93% of new smear-positive patients had become smear-negative. The sputum conversion rate for relapses and other retreatment cases (failure, treatment interrupted) was 85%. In Armenia, 78.1% of new smear-positive patients were treated successfully (cured or completed treatment). The corresponding percentages for Azerbaijan and Georgia were 87.9% and 59.6%. Treatment success rates among retreatment cases was generally low, at respectively 46%, 64%, and 35%, in Armenia, Azerbaijan, and Georgia. CONCLUSION: The results of the implementation of the WHO TB control pilot projects in Armenia, Azerbaijan and Georgia suggest that the DOTS strategy is feasible in emergency situations in general, and in the Caucasus in particular.

Progress in Europe towards the goal of poliomyelitis eradication.

In 1988, the World Health Assembly set a target of global eradication of poliomyelitis due to wild poliovirus by the year 2000. The strategies of the campaign are: reach and maintain high levels of routine vaccination coverage throughout the population; p

Abundance and distribution of small infauna in mangroves of Missionary Bay, north Queensland, Australia.

To assess the occurrence, spatial distribution and species composition of small infauna on a mangrove shore, core samples were taken along a transect in Missionary Bay at Hinchinbrook Island, north-east Australia. Three sites were arranged within the mangrove forest and one site was located in an adjacent mudflat. The sites were surveyed four times between November 1988 and October 1989. Based on the records from all samples and sites, 39 taxa were identified. Diversity (H') ranged from 1.18 to 2.38. Overall, total abundances of small infauna (retained on a 0.25 mm sieve) reached a mean value of 5,477 ind.m-2, with little variation throughout the transect or over time. Species numbers and diversity were higher in the mudflat than at the mangrove sites. The taxonomic composition changed between the mangrove forest and the mudflat: Oligochaeta were more abundant in mangrove sediments, whereas Polychaeta dominated in the mudflat. Of the polychaetes, Capitellidae were almost restricted to the mangrove sites, Sabellidae were recorded frequently at all sites, and Sigambra parva and Myriochele sp. were confined to the mudflat and the mangrove fringe. These species accounted also for dissimilarities between sites. Multivariate analyses showed a distinct assemblage at the mudflat compared to the mangrove sites. This survey showed that small infauna is an abundant component of mangrove sediments, which has been previously underestimated.

[Treatment of acute bipolar disorder. Intriguing balancing act between mania and depression]. / Therapie der akuten bipolaren Erkrankung. Kniffliger Balanceakt zwischen Manie und Depression.

The term bipolar disorder is no longer limited to the classical manic-depressive condition, but now subsumes a wide spectrum of illnesses. As a consequence of this expansion of the classification systems, the therapeutic utility of lithium and other mood stabilizing agents has to be defined anew. The majority treatment recommendations differentiate, symptom-related, between euphoric mania, mixed conditions, mania with psychotic symptoms and rapid cycling manic episodes. Current acute treatment includes, in addition to lithium, in particular carbamazepine and valproate, but also newer antiepileptic drugs such as lamotrigine or atypical neuroleptic agents such as olanzapine and risperidone. Due to the high suicidal risk, patients with bipolar depression often need to be given an antidepressant as well. It must, however, be remembered that in patients with rapid cycling, antidepressants may re-trigger mania.

Lamotrigine in bipolar disorder: results of a mirror-image evaluation using the NIMH Lifechart-Methodology.

BACKGROUND: Lamotrigine (LTG) is characterized by prophylactic efficacy against bipolar depression (BPD). We evaluated retro- and prospectively the naturalistic treatment outcome with LTG analysing lifecharts of patients from the bipolar outpatient clinic. METHODS: Lifechart-data of 20 patients routinely treated with LTG for the first time were evaluated, comparing number and duration of manic, depressive and mixed episodes prior to LTG and after initiation of treatment (mirror-image evaluation). The mean prospective evaluation period based on the lifechart was 18.1 months. Also we compared the number and severity of "switches" from depression in mania. Additionally, CGI-BP, YMRS, IDS-C and GAF scores at the monthly visits were compared for time after LTG initiation. RESULTS: We found no significant differences in the absolute number of manic, depressive and mixed episodes, respectively, before and after initiation of LTG. The number of "switches" did not differ significantly. A significant difference in duration of time patients suffered from a depressive state before and after initiation of LTG was observed in favour of LTG treatment (p=.006). A similar finding was observed for the time spent in mixed episodes (p<.001). No significant difference was observed for scores of mood scales at the monthly visits (CGI-BP, YMRS, IDS-C, GAF). LIMITATIONS: Generalizability of these results is limited due to the uncontrolled design and the issues in comparing prospective and retrospective data. CONCLUSION: These data underline not only the antidepressant profile of LTG, but also the usefulness of the Lifechart-Methodology (LCM) in the evaluation of treatment outcome under routine conditions.

Association of cognitive deficits with elevated homocysteine levels in euthymic bipolar patients and its impact on psychosocial functioning: preliminary results.

OBJECTIVES: Elevated homocysteine (Hcy) levels have been demonstrated to have a negative impact on cognitive functioning in healthy elderly people. Further studies suggest that they are an independent risk factor for dementia, in particular for Alzheimer's disease. Bipolar disorder is also associated with cognitive impairment. However, the pathophysiological mechanisms of these deficits have not been elucidated yet. This study examines the role of Hcy on cognition and its impact on psychosocial functioning in euthymic bipolar patients. METHODS: A total of 55 euthymic bipolar patients and 17 healthy controls were enrolled in the study. Neuropsychological assessments consisted of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Trail Making Test (TMT), the Weschler Adult Intelligence Scale, 3(rd) edition (WAIS-III) subtest Letter-Number Sequencing Test (LNST) and the HAWIE-R (German version of the WAIS-R) subtest Information. Psychosocial functioning was assessed using the Social Adjustment Scale (SAS). To obtain plasma levels of Hcy, blood samples were collected in EDTA tubes, immediately put on ice, centrifuged within 15 min and stored at -80 degrees C. Total Hcy concentration was measured using high-performance liquid chromatography. RESULTS: In the neuropsychological tests, patients differed significantly from healthy controls on the TMT B and the RBANS composite indices Language, Attention and Total Score. No differences were found on the HAWIE-R subtest Information, the TMT A, LNST or the RBANS composite indices Immediate Memory, Visuospatial/Constructional Abilities and Delayed Memory. Mean Hcy levels were 9.8 +/- 3.2 microm/L in the patient group and 7.8 +/- 2.1 microm/L in the control group, respectively (p = 0.012). In the patient group Hcy levels significantly correlated with gender, diagnosis and RBANS index scores for Immediate Memory, Language, Attention and Total Score. Linear regression analyses revealed a significant and independent association of Hcy levels with Immediate Memory and TMT B scores in the patient group. Homocysteine levels did not correlate with any measure in the control group. Spearman's correlations indicated that psychosocial functioning in bipolar patients is not associated with clinical variables apart from time in remission. However, it correlated significantly with working memory measures (LNST). No relationship could be determined between psychosocial functioning and Hcy plasma levels. CONCLUSIONS: Elevated Hcy levels seem to be associated with cognitive impairment in euthymic bipolar patients, but not with psychosocial functioning. More studies are needed to clarify the role of Hcy in cognition in bipolar disorder.

[Physician's information requirements before providing vaccines]. / Zur Aufklärungspflicht des Arztes vor Impfungen.

Vaccination is one of the most successful and cost-effective tools for disease prevention. However, the success makes vaccination its own worst enemy: adverse vaccine events, i. e., those caused by the vaccine or those associated with immunization by co-incidence or only suspected, become more visible than the consequences of the natural disease itself. Not surprisingly, discussions regarding the benefit and risk of immunization have become increasingly prominent in many industrially developed countries such as Germany. In addition to balanced health information provided to the public and the medical community, increased attention should be paid to the physician's duty of disclosure before providing vaccines. Annually, the German Advisory Committee on Immunization (STIKO) publishes updated recommendations on immunization policies including recommendations for information requirements. Information should be provided on the disease, the nature and benefit of the vaccine, the duration of immunity and the need for boosters, possible side effects and complications, and other important is-sues. Considering a case of a complication following immunization, the German Federal Court of Justice decided recently on the duty of disclosure regarding the risk of vaccines. The decision has been taken into consideration by the STIKO. Special attention should be paid to information requirements when providing licensed but not yet officially recommended vaccines.