Hypothalamic glutamate levels following serotonergic stimulation: A pilot study using 7-Tesla magnetic resonance spectroscopy in healthy volunteers

Introduction and purpose

Functional proton magnetic resonance spectroscopy (MRS) can be applied to measure pharmacodynamic effects of central nervous system (CNS)-active drugs. The serotonin precursor 5-hydroxytryptophan (5-HTP), administered together with carbidopa and granisetron to improve kinetics and reduce adverse effects, acutely enhances central serotonergic neurotransmission and induces hypothalamus-pituitary-adrenal-(HPA) axis activation. We studied the hypothalamic levels of glutamate/glutamine (Glx), choline (Chol), N-acetyl-aspartate (NAA) and creatine using 7-Tesla (7 T) MRS, and adrenocorticotropic hormone (ACTH) and cortisol in peripheral blood, after the administration of the 5-HTP function test in healthy volunteers.

Methods

A randomized, double blind, placebo-controlled, two-way cross-over study was performed in 12 healthy males with a 7 day wash-out period. After administration of the oral 5-HTP function test, ACTH and cortisol were measured over 4 h and MRS scans at 7 T were performed every 30 min over 3 h measuring Glx:Creatine, Chol:Creatine and NAA:Creatine ratios.

Results

In the hypothalamus, the administration of 5-HTP had no effect on the average Glx, Chol or NAA levels over 180 min but induced a significant decrease of Glx at 60 min on post-hoc analysis. 5-HTP-induced significant ACTH release reaching an E_max of 60.2 ng/L at 80 min followed by cortisol with an E_max of 246.4 ng/mL at 110 min.

Conclusions

The reduction in hypothalamic Glx levels after serotonergic stimulation is compatible with activation of excitatory neurons in this region, which is expected to cause depletion of local glutamate stores. The hypothalamic MRS-response reached its maximum prior to subsequent increases of ACTH and cortisol, which support the functional relevance of hypothalamic Glx-depletion for activation of the HPA-axis. This exploratory study shows that MRS is capable of detecting neuronal activation following functional stimulation of a targeted brain area.     

Basal hypercortisolism and trauma in patients with psychogenic nonepileptic seizures

Purpose: Several studies have indicated that psychogenic nonepileptic seizures (PNES) are associated with psychological trauma, but only a few studies have examined the associations with neurobiologic stress systems, such as the hypothalamus–pituitary–adrenal (HPA) axis and its end‐product cortisol. We tested several relevant HPA‐axis functions in patients with PNES and related them to trauma history. Methods: Cortisol awakening curve, basal diurnal cortisol, and negative cortisol feedback (using a 1 mg dexamethasone suppression test) were examined in 18 patients with PNES and 19 matched healthy controls (HCs) using saliva cortisol sampling on two consecutive days at 19 time points. Concomitant sympathetic nervous system (SNS) activity was assessed by analyzing saliva α‐amylase (sAA). Results: Patients with PNES showed significantly increased basal diurnal cortisol levels compared to HCs. This effect was driven mainly by patients reporting sexual trauma who showed a trend toward higher cortisol levels as compared to patients without a sexual trauma report. Importantly, the increased basal diurnal cortisol levels in patients were not explained by depression, medication, or smoking, or by current seizures or group differences in SNS activity. Discussion: This is the first study showing that basal hypercortisolism in patients with PNES is independent of the acute occurrence of seizures. In addition, basal hypercortisolism was more pronounced in traumatized patients with PNES as compared to nontraumatized patients with PNES. These findings suggest that HPA‐axis activity provides a significant neurobiologic marker for PNES.     

Associations of dialysis modality and infectious mortality in incident dialysis patients in Australia and New Zealand

BACKGROUND: The aim of the present investigation is to compare rates, types, causes, and timing of infectious death in incident peritoneal dialysis (PD) and hemodialysis (HD) patients in Australia and New Zealand. STUDY DESIGN: Observational cohort study using the Australian and New Zealand Dialysis and Transplant Registry data. SETTING & PARTICIPANTS: The study included all patients starting dialysis therapy between April 1, 1995, and December 31, 2005. PREDICTOR: Dialysis modality. OUTCOMES & MEASUREMENTS: Rates of and time to infectious death were compared by using Poisson regression, Kaplan-Meier, and competing risks multivariate Cox proportional hazards model analyses. RESULTS: 21,935 patients started dialysis therapy (first treatment PD, n = 6,020; HD, n = 15,915) during the study period, and 1,163 patients (5.1%) died of infectious causes (PD, 529 patients; 7.6% versus HD, 634 patients; 4.2%). Incidence rates of infectious mortality in PD and HD patients were 2.8 and 1.7/100 patient-years, respectively (incidence rate ratio PD versus HD, 1.66; 95% confidence interval [CI], 1.47 to 1.86). After performing competing risks multivariate Cox analyses allowing for an interaction between time on study and modality because of identified nonproportionality of hazards, PD consistently was associated with increased hazard of death from infection compared with HD after 6 months of treatment (<6 months hazard ratio [HR], 1.08; 95% CI, 0.76 to 1.54; 6 months to 2 years HR, 1.31; 95% CI, 1.09 to 1.59; 2 to 6 years HR, 1.51; 95% CI, 1.26 to 1.80; >6 years HR, 2.76; 95% CI, 1.76 to 4.33). This increased risk of infectious death in PD patients was largely accounted for by an increased risk of death caused by bacterial or fungal peritonitis. LIMITATIONS: Patients were not randomly assigned to their initial dialysis modality. Residual confounding and coding bias could not be excluded. CONCLUSIONS: Dialysis modality selection significantly influences risks, types, causes, and timing of fatal infections experienced by patients with end-stage kidney disease in Australia and New Zealand.     

C5 inhibitor rEV576 protects against neural injury in an in vitro mouse model of Miller Fisher syndrome

Guillain-Barré syndrome and its clinical variants, including the anti-GQ1b ganglioside-mediated Miller Fisher syndrome (MFS), comprise the world's leading cause of acute neuromuscular paralysis. Presently, no specific drug therapies exist. The complement cascade, which is activated in these patients, forms an attractive drug target. In this study, we tested whether the complement C5-inhibiting recombinant protein, rEV576, was able to prevent neural injury in a previously developed in vitro mouse model for MFS. Mouse hemidiaphragm preparations were treated with anti-GQ1b antibody and normal human serum as a source of complement with added rEV576 or control protein. Immunohistology in control tissue showed deposition of C3c and membrane attack complex at neuromuscular junctions (NMJs), along with terminal motor axonal neurofilament degradation as well as ethidium homodimer-2 staining showing perisynaptic Schwann cell (pSC) injury. Electrophysiological and functional analyses showed block of synaptic transmission at the NMJ after an initial period of a dramatically high level of asynchronous acetylcholine release. In tissue treated with rEV576, all these indicators of motor neuronal damage were absent, except for the presence of C3c, indicating effective inhibition of C5. These results demonstrate that rEV576 effectively prevents development of neuronal and pSC damage in experimental murine neuropathy.     

Gewerbliche Tätigkeit eines Laborarztes – Beschäftigung eines eigenverantwortlich tätigen freien Mitarbeiters –

Abstrakt  Bedient sich ein Arzt nicht nur vorübergehend der Mithilfe eines Berufskollegen, so erzielt er Einkünfte aus Gewerbebetrieb, wenn er nicht eigenverantwortlich dessen T?tigkeiten überwacht und wenn der Berufskollege auch nicht als Mitunternehmer t?tig ist.     

Reference values for mental health assessment instruments: objectives and methods of the Leiden Routine Outcome Monitoring Study

Rationale, aims and objectives: Routine outcome monitoring (ROM) was developed to establish the outcome of psychotherapeutic and pharmacological treatments through repeated assessments before, during and after treatment. Although standardization of psychiatric assessments and their reference values are essential for patient care, for various ROM instruments reference values are not available. The aim of the Leiden ROM Study is to generate reference values for 22 ROM instruments, covering generic and specific mood, anxiety and somatoform (MAS) disorders, for the general population. This article describes the extensive process of recruitment, as well as baseline characteristics of patient versus non‐patient groups. Method: Cross‐sectional study in randomly selected participants aged 18–65 years from the Dutch population, included through general practitioners. Results: Extensive demographic, psychosocial, mental health, and biological data from 1302 participants, recruited via general practitioners, were collected during a two‐hour standardized assessment including observer‐rated and self‐report scales. These data will be compared with corresponding data from 7840 patients with psychopathology who were referred to secondary care. On‐going quality control and calibration ensured maintenance of high quality during data collection. Conclusions: This reference group study for mental health assessments is the first study of this size carried out in the Netherlands. The results of this study are expected to be of value to secondary psychiatric care because they allow the indication of progress in health, treatment effect and possible termination of treatment. Additionally, the reference values can be used by primary care physicians as decision threshold for referral to specialized mental health care and vice versa.     

Clinically relevant anterograde amnesia and its relationship with blood levels of benzodiazepines in suicide attempters who took an overdose

The relationship between anterograde amnesia, sedation and plasma levels of benzodiazepines was studied prospectively in a group of 24 patients who took an overdose of benzodiazepines. Patients were tested on two sequential days after having taken an overdose. Anterograde amnesia was tested by using a verbal recall test and a photo recognition test. Sedation was scored on a visual analogue scale (VAS) by the patient and the interviewer. The concentration of benzodiazepines in plasma was measured by using a radioreceptor assay that adds benzodiazepines and their active metabolites. The cumulative amount of benzodiazepines was expressed as diazepam equivalents (DZE). Diazepam equivalents determined by this radioreceptor assay were significantly higher on the first day than on the second day. Ratings on the verbal recall test were significantly lower on the first day than on the second day. There was a significant relation between decrease of diazepam equivalents and increase of verbal recall: more than 30% of increase of verbal recall was explained by decrease of diazepam equivalents. There was not a strong relation between decrease of diazepam equivalents and reduction of level of sedation as scored by the patients. There was almost no relation between decrease of diazepam equivalents and reduction of level of sedation as scored by the interviewer. No relation was found between verbal recall, sedation and diazepam equivalents. There was no relation between diazepam equivalents and photo recognition. It was concluded that anterograde amnesia was strongly associated with benzodiazepines in patients who take benzodiazepines in an overdose. Sedation does not predict the degree of anterograde amnesia.     

Correlated measures in longitudinal analysis of daily drug use patterns in a general intensive care unit

PURPOSE: The objective of the present study is to compare two different study designs (with and without corrections for correlated measures) to identify possible determinants of psychotropic drug use in an intensive care unit (ICU). METHODS: In a logistic regression analysis, odds ratios (OR) were calculated for days in which patients were exposed to psychotropics compared with non-exposed days. In order to adjust for correlated measures, logistic regression with a logistic binomial model was applied. RESULTS: We found that adjustment for correlated measures did not result in major changes in the OR. However, with more observations per patient parameter, adjustment for correlation has greater effect. CONCLUSIONS: Adjustment for correlated measures may be useful in longitudinal drug analyses.