[Treatment of mental disorders in patients with Parkinson's disease]. / Therapie psychischer Störungen bei Morbus Parkinson.

Patients with Parkinson's disease (PD) have a high risk of psychiatric complications, like depressive or psychotic syndromes, dementia and sleep disorders. Although these disorders may even precede the onset of motor symptoms, they are often not recognized and therefore not adequately treated. This article provides a comprehensive overview of the therapeutic options of the most commonly observed psychopathological syndromes in PD. In the case of depressive syndromes medication could be optimized by making use of dopamine agonists that have been proven to have antidepressant properties. In recent studies tricyclic antidepressants showed stronger effects than SSRI. Psychotic symptoms are most often evoked by dopaminergic therapy or are seen in the course of cognitive decline. The therapeutic regimen should be built mainly on L-Dopa medication in the lowest tolerated dose, if required in combinations with COMT-Inhibitors. When antipsychotic medication is indicated, clozapine is the first choice. Quetiapine might also be useful in many patients. Psychotic symptoms in demented patients may respond to cholinesterase-inhibitors, that also delay cognitive decline. Patients with PD require an individually optimized therapeutic regimen not only for motor symptoms, but also for frequently occurring psychiatric syndromes since these strongly influence the patients' and their caregivers' quality of life, are predictors for hospitalization and therefore have great economic importance for health care systems.

DNA copy-number loss on 1p36.1 harboring RUNX3 with promoter hypermethylation and associated loss of RUNX3 expression in liver fluke-associated intrahepatic cholangiocarcinoma.

Runt-related transcription factor 3 (RUNX3) is a candidate tumor suppressor gene, localized on 1p36, involved in TGF-beta-Smads signaling. To assess its role in liver fluke-associated intrahepatic cholangiocarcinoma (ICC), the promoter methylation status was investigated in 53 ICCs by methylation-specific PCR, with determination of loss of 1p36.1 by microarray comparative genomic hybridization and RUNX3 protein expression by immunohistochemistry. Loss at 1p36.1 was found 41.5% of ICCs (22/53). In addition, DNA hypermethylation of the RUNX3 promoter was found in 49.1% (26/53) of cancers and 57.1% (4/7) of ICC cell lines. The protein was highly expressed in normal bile ducts but mostly decreased in ICCs, 67.9% (n= 36) being negative for immunohistochemical staining. Promoter hypermethylation of RUNX3 was associated with reversible decrease or absence of RUNX3 protein expression (p<0.001), but this was not found to differ with the ICC subtype. In contrast, loss of 1p36.1 demonstrated a significant link (p= 0.020). In conclusion, RUNX3 promoter hypermethylation and loss of 1p36.1 are causal mechanisms for loss of RUNX3 function in liver fluke-associated ICC carcinogenesis.

[Chorea. Causes, diagnosis, and therapy]. / Choreatische Bewegungsstörungen. Ursachen, Diagnostik und Therapie.

The differential diagnosis of chorea includes a growing number of rare diseases. This article gives hints on clinical differences and possible laboratory investigations which may help to identify the underlying disease. The majority of hereditary chorea cases are caused by Huntington's disease. Different courses of disease can be distinguished depending on age at disease onset. The diagnosis can be confirmed genetically. Predictive testing is also possible but should be applied with caution only following internationally accepted guidelines. Our knowledge about treatment of chorea is limited, and studies have focused on the use of neuroleptics only. Their value is often outweighed by serious side effects. All efforts to find disease-modifying therapies for Huntington's disease had negative outcomes so far. To face these therapeutic limitations, the European Huntington's Disease Network was formed as a platform supporting the development and undertaking of clinical studies in Huntington's disease to improve care for these patients.

Use of drotrecogin alpha (recombinant human activated protein C, rhAPC) in the treatment of severe sepsis induced by graft pancreatitis after simultaneous pancreas and kidney transplantation: a case report.

We present our experience with recombinant human activated protein C (rhAPC) to treat a 40-year-old preemptive simultaneous pancreas-kidney transplant (spktx) recipient who developed septic shock due to graft pancreatitis. We diagnosed intra-abdominal septic complications with septicemia induced by multiple pathogens and cardiopulmonary insufficiency. Until the 59th posttransplant day, 21 peritoneal lavages were performed to treat peritonitis and intra-abdominal abscesses. On the 53rd day when septic shock was diagnosed, rhAPC was administered, after which the patient improved, vasoconstrictive agents were reduced, and respiratory insufficiency resolved. The Physiologic and Operative Severity Score for enumeration of Mortality and Morbidity (POSSUM) scale showed a decrease in predicted mortality from 93% to 17% on day 7 after rhAPC initiation. The patient was discharged at 128 days after spktx with good function of both grafts. Administration of rhAPC limited systemic inflammatory response syndrome (SIRS) and may be considered when faced with the dilemma of stopping immunosuppression to save a recipient's life but at the cost of rejection of a functioning graft.

Non-traumatic cortical subarachnoid haemorrhage: diagnostic work-up and aetiological background.

Only 15% of all subarachnoid haemorrhages (SAHs) are not of aneurysmal origin. Among those, circumscribed SAHs along the cortical convexity are rare and have only been described in singular case reports so far. Here, we present a collection of 12 cases of SAH along the convexity, of non-traumatic origin. Over a period of 10 years, 12 cases of circumscribed SAH along the convexity were identified at our clinic. The clinical presentations, neuroradiological SAH characteristics, further diagnostic work-up to identify the underlying aetiologies, the therapy and clinical outcome were analysed. The patients' chief complaints were unspecific cephalgia, focal or generalised seizures and focal neurological deficits. Typical signs of basal SAH, such as nuchal rigidity, thunderclap-headache or alteration of consciousness, were rare. Magnetic resonance imaging (MRI) and digital subtraction angiography (DSA) revealed different aetiologies, namely postpartal posterior encephalopathy (three), cerebral vasculitis (two), dural sinus thrombosis (two), cortical venous thrombosis (one), intracerebral abscesses (one) and cerebral cavernoma (one). Two cases remained unresolved. Treatment of the underlying disease and symptomatic medication led to good clinical outcome in almost all cases. On the basis of these findings, we demonstrate that the clinical presentation, localisation and aetiology of cortical SAH differ clearly from other SAHs. A diagnostic work-up with MRI and eventually DSA is essential. Mostly, the causative disease can be identified, and specific treatment allows a favourable outcome.

[Subperiosteal orbital hemorrhage after heart surgery]. / Subperiostales Hämatom der Orbita nach kardiochirurgischem Eingriff.

We report on a patient who suffered sudden diplopia after heart surgery. Computed tomography of the orbita revealed a subperiosteal hemorrhage as the underlying cause. We discuss possible mechanisms that may have led to the bleeding as well as therapeutic options.

[Hypokalemic paralysis with thyrotoxicosis]. / Hypokaliämische Lähmung bei Hyperthyreose.

Hypokalemic periodic paralysis as a complication of thyrotoxicosis (thyrotoxic periodic paralysis) most often occurs in east Asian men. It is characterised by recurrent episodes of flaccid paralysis, hypokalemia, and underlying hyperthyroidism. It needs to be distinguished from sporadic and familial forms of periodic hypokalemic paralysis. No disturbances in the acid-base state and no extracorporal potassium loss are present. We report on the typical case of a young Chinese man presenting with hypokalemic periodic paralysis associated with yet unknown Graves' disease. Intravenous substitution of potassium and oral propranolol were administered. Complete remission was achieved after 10 hours. After medical therapy had normalised thyroid hormone levels, no further hypokalemic paralytic attacks occurred.

The impact of experience of a transplantation center on the outcomes of orthotopic liver transplantation.

The so-called learning factor has been disregarded for many years in analyzing the causes of surgical complications and post-operative mortality; it is also the case for OLT. In our center until April 2003, 209 OLT were performed in 196 patients. We evaluated the impact of experience of the transplantation team on the outcomes of liver transplantation. Thirty-four patients died (mortality rate, 16%) and 1-year survival rate, 64%. Mortality rates varied during different periods of observation due to increasing experience of the transplantation team. The causes of mortality were assessed for a series of 34 patients: it was 75% at the beginning of transplantation procedures while recent deaths have not recently exceeded 10% of cases.

A case of gliosarcoma appearing as ischaemic stroke.

OBJECTIVES: Ischaemic stroke attributable to malignant brain tumour is a rarely reported phenomenon and even various imaging techniques including angiography do not necessarily lead to an accurate diagnosis. CASE DESCRIPTION: A 46-year-old, previously healthy man developed apoplectic symptoms with slight right sided hemiparesis and global aphasia. The computed tomography (CT) scan showed lesions of the left temporal lobe and the paraventricular white matter suggestive of left middle cerebral artery (MCA) infarction. Carotid angiography demonstrated compression of the M1 segment of the MCA and occlusion of temporal MCA. The patient initially refused magnetic resonance imaging (MRI) because of claustrophobia. Because of fluctuating symptoms and successive worsening of the condition over weeks an MRI scan was conducted under general anaesthesia. Beneath temporal, opercular, and subcortical infarctions it revealed a left temporal tumour. A tumour biopsy disclosed a gliosarcoma (WHO grade IV). Microscopical examination of the surgical specimen demonstrated invasion of tumour cells into the wall of a greater pre-existing blood vessel. CONCLUSIONS: Malignant brain tumours may cause ischaemic infarction. This is a rare but important differential diagnosis for the origin of strokes. The authors describe the first case with infiltration of intracranial blood vessels by tumour cells of a gliosarcoma.

Liver regeneration in living-related donors after harvesting of liver segments II and III or II, III and IV.

BACKGROUND: CT-assisted volumetry permits an estimation of the volume of the graft in liver transplantation, as well as monitoring the donor's liver regeneration. The aim of the study was to observe the restitution of liver tissue in donors after harvesting of the liver fragment for living-related liver transplantation (LRLT). METHODS: The size of the whole liver and of segments II, III and IV was assessed by preoperative CT volumetry in 29 living-related liver donors. Segments II and III were harvested in 22 patients, segments II, III and IV in 6 patients. The remnant liver was assessed by CT volumetry on the 7th and 30th postoperative days. RESULTS: The correlation between the calculated volume of the graft and its weight was linear (r=0.56, p<0.04). Postoperative CT volumetry of the liver of living-related donors showed a different pattern of volume restoration (regeneration index) at both 7 and 30 days between donors who sacrificed segments II and III and those who sacrificed segments II, III and IV. The mean regeneration indexes were significantly higher in donors of segments II, III and IV as compared with donors of segments II and III (7 days, p<0.02; 30 days, p<0.05). DISCUSSION: It is possible that the donor's liver displays a different pattern of growth due to the alteration in blood supply to segment IV.

Evaluation of R6/2 HD transgenic mice for therapeutic studies in Huntington's disease: behavioral testing and impact of diabetes mellitus.

R6/2 transgenic mice express exon 1 of the human Huntington's disease (HD) gene with an increased CAG repeat length. They develop a progressive neurological phenotype, die within 12-14 weeks of age and were also found to develop diabetes mellitus. Since R6/2 mice are broadly used to screen for potential therapies in HD, the aim of this study was (a) to search for behavioral tests that are best applicable to monitor the behavioral abnormalities in therapy studies and (b) to investigate the extent to which diabetes influences the disease phenotype. We found that the rotarod test for motor coordination and the open field test for spontaneous explorative behavior were useful to monitor the progressive behavioral deterioration of R6/2 mice. An accelerating rotarod paradigm was superior over testing with a rotarod at various fixed speeds since it leads to similar results with less repetitive daily trials so that exhaustion cannot contribute substantially to their decline in performance. With the Morris water maze, however, it was only possible to monitor cognitive decline in visuo-spatial learning in the first weeks of disease since, at later stages, mice were not able to learn the task adequately. A latent diabetes mellitus was found in all transgenic mice demonstrated by a pathological glucose tolerance. Only 26% of the mice, however, were found to develop a manifest diabetes with increasing blood glucose levels on normal diet over the disease period. R6/2 mice with manifest and latent diabetes showed no significant differences in survival, weight loss, motor coordination, or spontaneous explorative behavior. These results suggest that diabetes mellitus is not a major contributing factor to the disease phenotype.

[Glutamate antagonists in neurology]. / Glutamatantagonisten in der Neurologie.

Glutamate is the major excitatory neurotransmitter of the central nervous system. Besides its importance in many physiological processes, increased glutamate release and subsequent excessive stimulation of the various glutamate receptors are thought to play critical roles in the pathophysiological mechanisms underlying many neurologic diseases. Experimental data suggest that blockade of glutamate receptors or inhibition of glutamate release has positive effects in many disease models. Glutamate antagonists are already in clinical use for the treatment of Parkinson's disease, epilepsy, spasticity, and neuropathic pain. Overall, glutamate antagonists have not been found clinically effective for neuroprotective treatment of cerebral ischemia or chronic neurodegenerative diseases, with one exception. Side effects of glutamate antagonists can be mainly attributed to central mechanisms and include psychosis, agitation, and disorientation. It is to be hoped that further development of new glutamate antagonists that block disease-relevant subtypes of glutamate receptors will lead to more effective drugs with fewer side effects.

[Huntington chorea. Animal models reveal new hypotheses for pathophysiology and therapy]. / Chorea Huntington. Tiermodelle eröffnen neue Hypothesen zu Pathophysiologie und Therapie.

Huntington's disease (HD) is member of a growing family of neurodegenerative diseases which are caused by a CAG-Triplet expansion in the coding region of their respective genes. The results of the research of the last years is very suggestive of a common pathomechanisms of all these diseases even though their clinical appearance may be quite different. The development of new animal models by transferring the human gene defect into the mouse genome has led to the finding of so-called intranuclear inclusion bodies. This new observation allowed to come closer to solving the problem how this genetic defect causes neurodegeneration. Recent studies on transgenic HD mice could also demonstrate a possible connection between the genetic defect and glutamate exitotoxicity in the neurodegenerative process of HD which had been emphasized by earlier animal models of the disease. Transgenic animal models of HD will have an important impact on the understanding of the disease mechanisms and may contribute to a faster development and testing of new therapeutic approaches.

Localization of metabotropic glutamate receptor 7 mRNA and mGluR7a protein in the rat basal ganglia.

Metabotropic glutamate receptors (mGluRs) coupled to G-proteins have important roles in the regulation of basal ganglia function. We have examined the localization of the mGluR7 mRNA and mGluR7a protein in the basal ganglia of the rat. Strong mGluR7 hybridization signals are found in cerebral cortex and striatum, but much less intense signals are present in other components of the basal ganglia. Abundant mGluR7a immunoreactivity was found in striatum, globus pallidus (GP), and substantia nigra pars reticulata (SNr). Examination using confocal microscopy together with dendritic and presynaptic markers as well as studies in lesion models provided evidence for the presence of mGluR7a on presynaptic terminals in all three structures. Electron microscopic studies confirmed the presence of mGluR7a in axon terminals in both the striatum and the GP and also revealed the presence of mGluR7a at postsynaptic sites in both of these regions. Our data demonstrate that mGluR7a is located not only on presynaptic glutamatergic terminals of the corticostriatal pathway, where it may serve as an autoreceptor, but also on terminals of striatopallidal and striatonigral projections, where it may modulate the release of gamma-aminobutyric acid (GABA). The presence of mGluR7 at these multiple sites in the basal ganglia suggests that this receptor has a particularly crucial role in modulating neurotransmitter release in major basal ganglia pathways.