Cerebrospinal fluid analyses for the diagnosis of subarachnoid haemorrhage and experience from a Swedish study. What method is preferable when diagnosing a subarachnoid haemorrhage?

Subarachnoid haemorrhage (SAH) has a high mortality and morbidity rate. Early SAH diagnosis allows the early treatment of a ruptured cerebral aneurysm, which improves the prognosis. Diagnostic cerebrospinal fluid (CSF) analyses may be performed after a negative computed tomography scan, but the precise analytical methods to be used have been debated. Here, we summarize the scientific evidence for different CSF methods for SAH diagnosis and describe their implementation in different countries. The principle literature search was conducted using PubMed and Scopus with the search items "cerebrospinal fluid”, "subarachnoid haemorrhage”, and "diagnosis”. CSF analyses for SAH include visual examination, red blood cell counts, spectrophotometry for oxyhaemoglobin or bilirubin determination, CSF cytology, and ferritin measurement. The methods vary in availability and performance. There is a consensus that spectrophotometry has the highest diagnostic performance, but both oxyhaemoglobin and bilirubin determinations are susceptible to important confounding factors. Visual inspection of CSF for xanthochromia is still frequently used for diagnosis of SAH, but it is advised against because spectrophotometry has a superior diagnostic accuracy. A positive finding of CSF bilirubin is a strong indicator of an intracranial bleeding, whereas a positive finding of CSF oxyhaemoglobin may indicate an intracranial bleeding or a traumatic tap. Where spectrophotometry is not available, the combination of CSF cytology for erythrophages or siderophages and ferritin is a promising alternativ

Chronotype is associated with psychological well-being depending on the composition of the study sample

Past studies examining the effect of chronotype and social jetlag on psychological well-being have been inconsistent so far. Here, we recruited participants from the general population and enquired about their natural sleeping behavior, sleep quality, depressive symptoms, and perceived stress. Partial correlations were computed between sleep variables and indicators of psychological well-being, controlling for age and sex. Less sleep during work days was found a good indicator for impairments in psychological well-being. In exploratory follow-up analyses, the same correlations were calculated within groups of early, intermediate, and late chronotype. We observed that the composition of the sample in terms of chronotype influenced whether associations between sleep variables and psychological well-being could be observed, a finding that is advised to be taken into account in future studies.Peer Reviewe

Long-Term Outcome after Lithium Augmentation in Unipolar Depression: Focus on HPA System Activity

Background: Lithium augmentation is a first-line strategy for depressed patients resistant to antidepressive therapy, but little is known about patients’ subsequent long-term course or outcome predictors. We investigated long-term outcomes of unipolar depressed patients who had participated in a study on the effects of lithium augmentation on the hypothalamic-pituitary-adrenocortical system using the combined dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test. Methods: Twelve to 28 months (mean 18.6 ± 4.6 months) after lithium augmentation, 23 patients were assessed with a standardized interview, of which 18 patients had complete DEX/CRH test results. Relapse was diagnosed by DSM-IV criteria (Structured Clinical Interview for DSM-IV; SCID I). Results: Only 11 patients (48%) had a favorable follow-up, defined as absence of major depressive episodes during the observation period. Patients with a favorable and an unfavorable course did not differ in clinical or sociodemographic parameters, endocrinological results or continuation of lithium. However, fewer previous depressive episodes tended to correlate (p = 0.09) with a favorable course. Conclusion: Results from studies using the DEX/CRH test to predict relapse in depressed patients treated with antidepressants were not replicated for lithium augmentation. Our finding could reflect the elevation of DEX/CRH results by lithium, independent of clinical course. Limitations of the study are its small sample size, the heterogeneous clinical baseline conditions and the lack of lithium serum levels. The fact that lithium continuation did not predict the course might be related to the difference between the efficacy of lithium in controlled studies and its effectiveness in naturalistic settings.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

Monthly intravenous methylprednisolone in relapsing-remitting multiple sclerosis - reduction of enhancing lesions, T2 lesion volume and plasma prolactin concentrations

BACKGROUND: Intravenous methylprednisolone (IV-MP) is an established treatment for multiple sclerosis (MS) relapses, accompanied by rapid, though transient reduction of gadolinium enhancing (Gd+) lesions on brain MRI. Intermittent IV-MP, alone or with immunomodulators, has been suggested but insufficiently studied as a strategy to prevent relapses. METHODS: In an open, single-cross-over study, nine patients with relapsing-remitting MS (RR-MS) underwent cranial Gd-MRI once monthly for twelve months. From month six on, they received a single i.v.-infusion of 500 mg methylprednisolone (and oral tapering for three days) after the MRI. Primary outcome measure was the mean number of Gd+ lesions during treatment vs. baseline periods; T2 lesion volume and monthly plasma concentrations of cortisol, ACTH and prolactin were secondary outcome measures. Safety was assessed clinically, by routine laboratory and bone mineral density measurements. Soluble immune parameters (sTNF-RI, sTNF-RII, IL1-ra and sVCAM-1) and neuroendocrine tests (ACTH test, combined dexamethasone/CRH test) were additionally analyzed. RESULTS: Comparing treatment to baseline periods, the number of Gd+ lesions/scan was reduced in eight of the nine patients, by a median of 43.8% (p = 0.013, Wilcoxon). In comparison, a pooled dataset of 83 untreated RR-MS patients from several studies, selected by the same clinical and MRI criteria, showed a non-significant decrease by a median of 14% (p = 0.32). T2 lesion volume decreased by 21% during treatment (p = 0.001). Monthly plasma prolactin showed a parallel decline (p = 0.027), with significant cross-correlation with the number of Gd+ lesions. Other hormones and immune system variables were unchanged, as were ACTH test and dexamethasone-CRH test. Treatment was well tolerated; routine laboratory and bone mineral density were unchanged. CONCLUSION: Monthly IV-MP reduces inflammatory activity and T2 lesion volume in RR-MS

Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain

Einfluss des P-Glykoproteins auf die Blut-Hirn-Schrankenfunktion

Uhr M. Einfluss des P-Glykoproteins auf die Blut-Hirn-Schrankenfunktion. Bielefeld (Germany): Bielefeld University; 2002.Die vorliegende Arbeit zeigt den Einfluss und die Bedeutung des P-Glykoproteins auf die Blut-Hirn-Schrankenfunktion von zentral wirksamen Medikamenten und Steroiden. Das P-Glykoprotein ist das Genprodukt des Multi-Drug-Resistance-Gens. Es ist ein transmembranäres Protein, dessen Funktion darin besteht, seine Substrate unter Energieverbrauch gegen einen Konzentrationsgradienten aus der Zelle zu transportieren. Das P-Glykoprotein wird u.a. an der Blut-Hirn-Schranke auf der dem Gefäßlumen zugewandten Seite der Endothelzellen der kleinen Hirngefäße exprimiert. Es behindert die Penetration seiner Substrate in das Gehirn, indem es sie aktiv zurück ins Blut transportiert und damit die Hirnkonzentrationen niedrig hält. An mdr1ab(-/-) Doppel-Knock-out-Mäusen ohne funktionsfähiges P-Glykoprotein und Kontrollmäusen konnten wir zeigen, dass auch wichtige und klinisch häufig genutzte Medikamente, die zur Therapie zentralvenös verursachter Erkrankungen eingesetzt werden, in ihrer Penetration ins Gehirn durch das P-Glykoprotein beeinflusst werden. Die Antidepressiva Amitriptylin, Citalopram, Paroxetin und Venlafaxin sowie zum Teil auch deren Metabolite erwiesen sich als gute Substrate des P-Glykoproteins an der Blut-Hirn-Schranke. Im einzelnen wurden Experimente nach peripherer Einmalinjektion, nach Langzeittherapie mit osmotischen Pumpen und pharmakokinetische Experimente durchgeführt. Für die Substrate des P-Glykoproteins zeigten sich höhere Medikamentenkonzentrationen in den Gehirnen der Tiere, die kein funktionstüchtiges P-Glykoprotein im Vergleich zu Kontrolltieren hatten. So waren die Hirnkonzentrationen von Citalopram, Venlafaxin und Paroxetin in den Gehirnen der Mutanten nach peripherer Gabe zwei- bis dreimal höher als in den Kontrolltieren. Für Amitriptylin konnte in Kinetik- und Langzeitstudien gezeigt werden, dass die Hirnkonzentrationen der Metabolite in Tieren ohne funktionstüchtiges P-Glykoprotein bis 10fach höher waren als bei den Tieren, in denen ein aktiver Rücktransport durch das P-Glykoprotein in den Endothelzellen der Hirnkapillaren an der Blut-Hirn-Schranke zurück ins Blut stattfindet. Der Einfluss des P-Glykoproteins auf die therapeutische Wirksamkeit zentral wirksamer Medikamente und die Entwicklung von Therapieresistenz bei intaktem aktivem P-Glykoprotein und deren Beeinflussung werden diskutiert. Nicht alle Medikamente stellten sich als Substrate des P-Glykoproteins heraus, so waren Trimipramin, Doxepin und deren Metabolite nur sehr schwache Substrate. Mirtazapin und das Neuroleptikum Melperon waren kein Substrate. Auch endogen vorkommende Steroide wie Aldosteron, Corticosteron und Cortisol und synthetische Steroide wie Dexamethason zeigten sich als Substrate des P-Glykoproteins an der Blut-Hirn-Schranke. In mdr1ab(-/-) Knock-out-Mäusen waren deren Hirnkonzentrationen nach peripherer Gabe bis 5fach höher als in mdr1ab(+/+) Kontrollmäusen. Progesteron und Östradiol erwiesen sich nicht als Substrate. Die regulatorische Funktion des P-Glykoproteins auf den Hypothalamus-Hypophysen-Nebennieren-Achsenregelkreis wird diskutiert. Es bestanden deutliche endokrinologische Differenzen zwischen den Knock-out-Mutanten und den Kontrollen. Die ACTH-Plasmakonzentrationen waren in den mdr1ab(-/-) Mutanten unter Basal- und Stressbedingungen sowie in den Funktionstesten deutlich und signifikant erniedrigt. Des weiteren fanden sich Differenzen in endokrinologischen Funktionstesten wie dem Dexamethason-Suppressionstest. Die wichtige regulatorische Funktion sowie deren Beeinflussbarkeit durch Umweltfaktoren, u.a. auch Komedikation, und genetische Faktoren wie Polymorphismen werden erörtert

Toward adaptive (computer-based) hospital care systems that can grow and improve as a function of user participation

This paper describes a computer-based system that would allow doctors, patients, nurses, researchers and experts to participate in medical care in ways that will enhance the usefulness of the system, and will allow the system to grow, adapt and improve as a function of this participation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23571/1/0000532.pd

MIKROKOSMS AND ROBOTS 2,3

This paper presents a computer program that simulates situations (called "MIKROKOSMS") in which severl entities (called "organisms") wander around in an environment that includes one another plus other, apparently simpler, entities (called "objects"). The program has a rather simple set of "laws " of objects, which can be thought of as the laws of physics of the MIKROKOSM. It also has other specifications for organisms- their input and output functions (called "perception" and "response"), their reward functions (called "motivation " or "needs"), and their mechanisms for building up internal memories (called "learning" and "hypothesis formation") that will'help them to recognize objects in the future, and respond appropriately to them (for example, in order to maximize expected rewards). This program lays bare the processes that are needed to handle interactions among simulated organisms and objects, including the learning of hypotheses that wil