Nocturnal urinary cortisol excretion over a randomized controlled trial with paroxetine vs. placebo combined with relaxation training or aerobic exercise in panic disorder.

INTRODUCTION: Data on basal hypothalamo-pituitary-adrenomedullary (HPA) function over controlled treatment trials with serotonergic drugs in anxiety disorders are still rare. METHODS: 29 patients with panic disorder participating in a 10 week randomized, controlled trial (paroxetine vs. placebo with exercise or relaxation; N=60) collected urine for cortisol excretion over 3 consecutive nights before start and before termination of the treatment episode. Urinary cortisol was measured by radioimmunoassay. Efficacy measures were the Clinical Global Impression Scale (CGI) and the Panic and Agoraphobia Scale (P&A). 83% were female (p<.05 vs. males). 55% received additional aerobic exercise, and 45% relaxation. 55% received paroxetine treatment, and 45% placebo. Significantly fewer males received placebo treatment (p<.05). RESULTS: All subjects improved significantly. Cortisol excretion did not differ between treatment groups or at pre-/post measurements. Females showed a significantly higher variability of cortisol excretion compared to males, at pre-(p<.005) and post (p=.015) assessments. Males displayed a trend to lower basal HPA function at end of treatment (p=.08). HPA variability after treatment showed a trend to be higher in the paroxetine (p=.052) -who clinically improved significantly better- compared to the placebo group. No relationship between HPA activity and treatment response or with exercise was detected. DISCUSSION: HPA function shows significant gender differences, with females having a higher HPA function variability. Future studies on HPA function in treatment trials should address gender and medication effects.

Chronomics, neuroendocrine feedsidewards and the recording and consulting of nowcasts--forecasts of geomagnetics.

A multi-center four-hourly sampling of many tissues for 7 days (00:00 on April 5-20:00 to April 11, 2004), on rats standardized for 1 month in two rooms on antiphasic lighting regimens happened to start on the day after the second extremum of a moderate double magnetic storm gauged by the planetary geomagnetic Kp index (which at each extremum reached 6.3 international [arbitrary] units) and by an equatorial index Dst falling to -112 and -81 nT, respectively, the latter on the first day of the sampling. Neuroendocrine chronomes (specifically circadian time structures) differed during magnetically affected and quiet days. The circadian melatonin rhythm had a lower MESOR and lower circadian amplitude and tended to advance in acrophase, while the MESOR and amplitude of the hypothalamic circadian melatonin rhythm were higher during the days with the storm. The circadian parameters of circulating corticosterone were more labile during the days including the storm than during the last three quiet days. Feedsidewards within the pineal-hypothalamic-adrenocortical network constitute a mechanism underlying physiological and probably also pathological associations of the brain and heart with magnetic storms. Investigators in many fields can gain from at least recording calendar dates in any publication so that freely available information on geomagnetic, solar and other physical environmental activity can be looked up. In planning studies and before starting, one may gain from consulting forecasts and the highly reliable nowcasts, respectively.

Homocysteine induces cell death of rat astrocytes in vitro.

From several disease states as well as from animal models homocysteine is known to be toxic to the central nervous system. Homocysteine is an excitatory amino acid which markedly enhances the vulnerability of neuronal cells to excitotoxic, apoptotic, and oxidative injury in vitro and in vivo. Both beneficent and deleterious effects of astrocytes in the pathogenesis of different neurodegenerative disorders have been described. However, data about the neurotoxic effect of homocysteine on astrocytes are lacking. The present study therefore was undertaken to investigate a possible cytotoxic effect of homocysteine on cortical astrocytes in vitro. Exposure to D,L-homocysteine resulted in a time and dose-dependent gliotoxic effect at doses of 2 mM and above (P<0.001). This is comparable to homocysteine toxicity observed in other cell culture models and implies that a participation of astrocytes in homocysteine-induced neurodegeneration may be considered. The results of the present in vitro studies may therefore have implications for understanding the pathogenesis of neurotoxicity linked to neurodegenerative disorders (e.g. Alzheimer's disease, glaucomatous optic neuropathy). This is the first study to report that homocysteine induces cell death of astrocytes. The mechanisms by which homocysteine induces cell death of astrocytes warrant further study.

Molecular biology of Alzheimer's dementia and its clinical relevance to early diagnosis and new therapeutic strategies.

Over the past few years, molecular biological research has considerably deepened our understanding of the pathophysiological basis of Alzheimer's dementia (AD). Although different genetic origins of the disease have been identified, all of the findings point to a common terminal sequence in familial AD. This consists of an increased production of beta-amyloid peptides from beta-amyloid precursor protein. For the cases of sporadic AD, which far outweigh the number of cases of familial AD, an impaired catabolism of the beta-amyloid peptides may also be pathophysiologically decisive according to the latest findings. Research into the molecular level of AD makes it possible to identify points of attack for rational drug treatment of the disease, while molecular markers of AD are increasingly being used as a part of early and differential neurochemical diagnostics.

[Not Available]. / Die neurobiologische Verankerung psychosozialer Erfahrungen/ The neurobiological affixation ofpsychosocial experiences.

With the increasing application of imaging techniques, characteristic changes in the structure and functional activity of certain neuronal networks and transmitter Systems have been discovered in the brains of patients suffering from various psychiatric disorders. These findings have often been assumed to support biological concepts of the genetic background and causation of these disorders. However, several lines of research are converging to indicate that the initially established genetically programmed neuronal Connectivity is further elaborated, fine tuned and modified by usedependent neuronal and synaptic plasticity. In all socially organized species in general and in human subjects in particular, psychosocial experiences appear to represent the most important trigger of use-dependent adjustments of neuronal Connectivity through the facilitation, modification and reorganization of neuronal networks. In experimental animals, changes in psychosocial rearing conditions were shown to cause profound and persistent changes in the cytoarchitecture, dendritic arborization and synapse formation in individual brain regions as well as in the maturation of monoaminergic afferences. Based on these findings, the mechanisms of the biological affixation of psychosocial experiences are described and the implications of experience dependent neuronal and synaptic plasticity in the prevention and the therapy of mental disorders are outlined.

Microanatomic and vascular aspects of the temporomesial region.

OBJECTIVE: The aim of this work was to provide a detailed description of the arterial vascularization of the temporomesial region (TMR), correlated with the definitions of the macroscopic and cytoarchitectonic subdivisions of this area. METHODS: Selective colored arterial injections were performed in 16 hemispheres to study their blood supply. Four hemispheres were used to illustrate the macroscopic aspect of the TMR and were then cut into thin sections and stained with Nissl's stain to study the cytoarchitectonic areas. RESULTS: The surface of the TMR is subdivided into several areas: anteriorly, the lateral olfactory gyrus is covered by prepiriform cortex; dorsomedially, the semilunar gyrus and uncus hippocampi consist, respectively, of cortical amygdaloid nucleus and hippocampal cytoarchitectonic fields; and ventrolaterally, the anterior part of the parahippocampal gyrus is covered by periamygdaloid cortex, entorhinal, and transentorhinal areas and its posterior part is covered by Fields TH and TF per Von Economo and subicular complex. Six cortical arterial groups were defined: Group I, anterosuperior parahippocampal arteries (mean, 3.9 arteries) vascularize the ambiens, semilunar, and lateral olfactory gyri (origins: middle cerebral artery, anterior choroidal artery [AChA], posterior cerebral artery [PCA], and internal carotid artery); Group II, anteroinferior parahippocampal arteries (mean, 2.8 arteries) irrigate the anterior ventrolateral region of the parahippocampal gyrus (origins: middle cerebral artery, PCA, and AChA); Group III, medial uncal arteries (mean, 1.9 arteries) supply the medial part of uncus hippocampi (origins: AChA and PCA); Group IV, lateral uncal arteries (mean, 2.9 arteries) vascularize the lateral part of the uncus hippocampi (origins: AChA and PCA); Group V, several small posterior parahippocampal arteries irrigate Fields TF and TH per Von Economo (origins: PCA and AChA); and Group VI, posterior hippocampal arteries (mean, 3.2 arteries) irrigate the posterior part of hippocampal formation (origin: PCA). Many anastomoses are found among these arteries, particularly in the ventrolateral part of the TMR. Three groups of amygdaloid arteries were defined: Group I, the anterolateral group (mean, 5.7 arteries) (origin: middle cerebral artery); Group II, the medial group (mean, 6.4 arteries) (origins: AChA, internal carotid artery, and PCA); and Group III, the posterolateral group (mean, 5 arteries) (origins: AChA and internal carotid artery). CONCLUSION: We hope that this work will be useful for any microneurosurgical procedures on the TMR. We have clarified the macroscopic and histological definitions of the cortical and nuclear areas of the TMR and the arterial groups closely related to them. The systematic analysis of the variability of the arterial vascularization of this area was our second goal; such a goal, however, requires more observations to be exhaustive. The numerous interterritorial anastomoses found inside the TMR imply that a selective presurgical injection of short-acting barbiturates to evaluate its functions (Wada test) may well result in its diffusion to other areas of the TMR.

Improved electrophoretic separation and immunoblotting of beta-amyloid (A beta) peptides 1-40, 1-42, and 1-43.

Beta-amyloid peptides (A beta peptides) form the main protein component of the amyloid deposits found in the brains of Alzheimer's disease (AD) patients. Soluble A beta peptides, which are proteolytic fragments of the amyloid-precursor protein (APP) are constitutively secreted by cells expressing APP during normal metabolism [1] and are also present in human plasma and cerebrospinal fluid [2]. Missense mutations in Codon 717 of the APP gene are responsible for a small percentage of inherited AD cases (FAD) and increase the amount of A beta peptides containing additional carboxy terminal amino acids (A beta 1-42, A beta 1-43) [3, 4]. Recent findings indicate that FAD mutations in the presenilin 1 and 2 genes also increase the amount of these longer A beta peptides [5]. A beta 1-42 polymerizes more rapidly in vitro [6] than A beta 1-40 and has been identified as the major component of the brain amyloid deposits [7-9]. We recently developed a sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) system [10] for the separation of these two peptides. Here we describe a modified version of the original SDS-PAGE procedure, which allows the separation of A beta 1-40, A beta 1-42, and A beta 1-43 for the first time. Detection of the three A beta peptides in the lower ng and pg range is realized by optimized silver staining or immunoblot procedures. These nonradioactive methods may validate results obtained by ELISA procedures used to study the metabolic fate of APP. They may help to define the neurotoxic potential of the longer A beta peptides in relation to their aggregation state.

[The role of psychosocial stress in childhood for structural and functional brain development:neurobiological basis of developmental psychopathology]. / Die Bedeutung von psychosozialem Stress im Kindesalter für die strukturelle und funktionelle Hirnreifung: neurobiologische Grundlagen der Entwicklungspsychopathologie.

This review summarizes some important principles of human brain development. Special emphasis is placed on the role of psychosocial stress during childhood on the developing brain. Depending on the degree of cognitive, behavioral and socio-emotional maturation, previous experiences and actual context, psychosocial stressors may be perceived by children as being either controllable (challenge) or uncontrollable (disaster). Controllable stress experiences are associated with a preferential activation of the central and peripheral noradrenergic system, i.e., of a system endowed with the gating of cortical information processing and the facilitation and stabilization of neuronal pathways and synaptic connections involved in behavioral responding. Uncontrollable stress responses are elicited if all previously acquired behavioral or cognitive strategies are inadequate or fail to overcome the stressor. The resulting severe and long-lasting activation of the central stress responsive systems will finally lead to a full activation of the HPA system, accompanied by adrenocortical cortisol release. The major central effect of this response is the destabilization of previously established neuronal circuits and synaptic connections. Thus, severe uncontrollable psychosocial stress may act as an important trigger of and a prerequisite for the reorganization of neuronal connectivity. It may, above a certain threshold, threaten the mental and affective stability, integrity, and the future development of a child. The long-term consequences of psychosocial stress on the structural and functional maturation of the brain are documented by findings from animal research and by results in the field of developmental psychopathology in children. The role of risk and protective factors during different phases of child development is briefly summarized and the need for a biopsychosocial model concerning the relationship between human brain development and behavior is emphasized.

[Facilitating cervix dilatation of the non-pregnant uterus by intracervical administration of gels containing prostaglandin and calcium chloride]. / Erleichterung der Zervix-dilatation am nichtgraviden Uterus durch intrazervikale Applikation Prostaglandin- und Calciumchloridhaltiger Gele.

In a prospective, randomised study, 50 non-pregnant patients were treated intracervically with 3 ml 5% tylose, 50 micrograms sulprostone, 100 micrograms sulprostone gel, 3 ml 2.5 mM or 9.0 mM calcium chloride gel in order to soften the cervix 12-14 hours before diagnostic curettage. The gel was not used in a further 20 patients. To objectively demonstrate the priming effect, the force required for dilatation of the cervical canal was measured in Newtons, using a mechanical tonometer both before gel application and before the operation. In comparison with the administration of tylose only, the intracervical application of either sulprostone gel or calcium chloride gel led to a significant improvement in cervical dilatability. Tylose alone had a slight but measurable effect on the cervix. An increase in sulprostone from 50 micrograms to 100 micrograms or calcium molarity from 2.5 mM to 9.0 mM brought no further improvement in the dilatory effect. Dilatation-induced cervical lesions could be avoided by preoperative cervical ripening. After application of sulprostone, 3 out of 20 patients experienced doses-dependent uterine cramps, while all patients treated with calcium chloride gel were free of side effects. The intracervical administration of sulprostone and calcium chloride gel allowed gentle dilatation of the non-pregnant cervix, thus lowering the risk of uterine lesions. Under clinical aspects, cervical priming facilitates diagnostic and therapeutic procedures, which, in exceptional cases, can be performed without anaesthesia.

Impaired permeability of the blood-cerebrospinal fluid barrier in hyperphenylalaninaemia.

In hyperphenylalaninaemic rats the accumulation of 5-hydroxytryptophan (5-HTP) in the cerebrospinal fluid (CSF) could be shown in spite of the fact, that the 5-HTP levels of serum and brain remain constant. In vitro studies of the influx and efflux of 5-HTP and phenylalanine on isolated beef choroid plexus suggested that both aminoacids use the same carrier system. It is concluded that a high concentration of phenylalanine inhibits the re-uptake of 5-HTP by the endothelial cells of the choroid plexus. Additionally, an increased efflux of 5-HTP from choroid plexus leads to the accumulation of 5-HTP in the cerebrospinal fluid.

The multiple forms of brain acetycholinesterase. III. Implications for the histochemical demonstration of acetylcholinesterase.

The multiple forms of acetylcholinesterase (AChE, E.C. 3.1.1.7) have been investigated with regard to their histochemical demonstrability. Their pattern is influenced by buffer treatment, fixation, and by incubation conditions causing aggregation and disaggregation as well as loss or inactivation of individual forms. The standard histochemical method for AChE preferentially demonstrates the high molecular forms. Most of the oligomer forms are washed out or inactivated. A selective demonstration of the highly aggregated forms is possible either by inhibition of the oligomers with diisopropylfluoridate (DFP) or by specifically dissolving them out. No reason could be found for the selective demonstration of the low molecular weight forms.

The multiple forms of brain acetylcholinesterase. II. A suggestion of their functional importance.

The pattern of the multiple forms of the acetylocholinesterase (AChE, E.C. 3.1.1.7) of the rat brain is investigated using polyacrylamide gradient micro-gel electrophoresis with regard to a possible functional importance of this individual forms. The patterns of the AChE-forms of selected regions of the CNS are compared and certain differences could be shown. After increased cholinergic input (into the hippocampus by electrical stimulation of the nc. septi medialis) an aggregation of AChE subunits is detectable. Subletal intoxication with an irreversible inhibitor of AChE is followed by a faster recovery of the smaller forms. A suggestion of a possible functional role of the multiple forms of AChE is discussed.

The multiple forms of brain acetylcholinesterase. I. Micro-electrophoresis and topochemical analysis of the pattern.

Micro-polyacrylamide gradient electrophoresis followed by active staining is applied for the demonstration of the multiple forms of acetylcholinesterase. Among other advantages the very small samples that enable the analysis of well-defined brain material as well as the almost histochemical conditions of incubation enable its successful use in topochemical investigations of the multiple form pattern of brain acetylcholinesterase. The acetylcholinesterase of bovine nc. caudatus could be separated into 4 multiple forms and the pattern was analysed microdensitometrically. These forms differ in their molecular weight as well as in their degree of membrane binding. Increasing ionic strength (NaCl) is followed by changes in the pattern. This result is discussed as caused by aggregation of enzyme subunits.

Demonstration of acetylcholinesterase by semipermeable membrane technique: estimation of soluble and fixation-labile portions in different regions of the central nervous system.

A histochemical method for the demonstration of acetylcholinesterase using semipermeable membranes is described. This technique prevents any loss of enzyme activity caused by dissolution and/or fixation. The soluble and fixation-labile portions of acetylcholinesterase were estimated in several regions of the central nervous system of the rat and differences were found. The method improves the accuracy of the histochemical demonstration of the acetylcholinesterase on the light microscopical level.

The histochemical demonstration of choline acetyltransferase by semipermeable membrane technique.

The application of the semipermeable membrane technique in light microscopical demonstration of choline acetyltransferase is described. The method founds upon earlier developed lead salt techniques. Use of semipermeable membranes fully prevents any loss of enzyme by dissolvement or inactivation during fixation. Addition of NaCl to the incubation medium markedly increases the activity of choline acetyltransferase.