[Therapeutic effects of venlafaxine extended release for patients with depressive and anxiety disorders in the German outpatient setting - results of 2 observational studies including 8500 patients]. / Klinische Effekte von retardiertem Venlafaxin (Trevilor retard) bei Patienten mit Depression und Angsterkrankungen in der ambulanten Behandlungspraxis in Deutschland - Ergebnisse von zwei Anwendungsbeobachtungen mit 8500 Patienten.

The therapeutic effects of venlafaxine extended release have been investigated by two prospective observational studies including 8506 patients in the outpatient setting of office based general practitioners and specialists. The efficacy has been documented by the Clinical Global Impression (CGI) scale and by the Hamilton depression (HAMD-21) scale. The tolerability has been assessed by the documentation of adverse events. About (2/3) of the patients were treated because of depression and about (1/3) mainly because of anxiety disorder. The patients of specialists did receive higher dosages and were more severely affected. The response rate on the CGI scale was 87.4 for the patients of general practitioners and 74.2 % for the patients of specialists. The results of the HAMD-21 scale, which has been used by specialists, showed a response rate of 71.8 and a remission rate of 56.3 %. These positive effects could be demonstrated even for the more severely and chronically affected patients. The incidence of adverse events was low in both studies and comparable to the tolerability profile of randomized studies. Importantly, the good tolerability profile was similar even for patients with concomitant cardiovascular disease. In conclusion, these results confirm the efficacy and good tolerability of venlafaxine extended release in the outpatient setting in Germany.

[Changeover to risperidone after treatment with conventional low potency neuroleptics in dementia patients. An observation study during usage]. / Umstellung auf Risperidon nach Behandlung mit konventionellen niederpotenten Neuroleptika bei Demenzpatienten -- Eine Anwendungsbeobachtung.

BACKGROUND AND OBJECTIVE: Up to 90% of the patients with dementia develop behavioral and psychological symptoms during the course of their illness. Since 1999 the atypical neuroleptic risperidone is the only drug approved by the German authorities for the treatment of aggressive behavior or psychotic symptoms of dementia, which was defined in March 2004 with respect to severe chronic aggressive behavior, endangering themselves or others, or impoverishing psychotic symptoms. This prospective investigation was aimed at detecting therapeutic efficacy and the tolerability of risperidone after changing from low-potency neuroleptics in patients, for whom the broader indications before March 2004 were still valid. PATIENTS AND METHODS: Symptoms, activities of daily living and caregivers" burden were documented for 6 weeks in 111 demented patients with chronic aggressive behavior and psychotic symptoms. RESULTS: Marked improvements of psychotic symptoms, aggressiveness, other behavioral disorders and activities of daily living were observed. Furthermore, a substantial reduction of caregivers' burden was noted. The treatment with risperidone was well tolerated. No patient died and no cerebrovascular events were observed. CONCLUSION: Changing the treatment of demented patients from low-potency neuroleptics to risperidone led to marked improvement of symptoms and to a substantial decrease of caregivers' burden.

Gradual loss of myelin and formation of an astrocytic scar during Wallerian degeneration in the human spinal cord.

Axons undergo Wallerian degeneration distal to a point of injury. Experimental investigations have documented many of the cellular and molecular events that underlie this behaviour. Since relatively little is known about such events in human CNS pathologies and current experimental intervention strategies indicate the possibility of significant axon regeneration along the original degenerated fibre tract, we performed an immunohistochemical investigation of the dynamics of Wallerian degeneration in post mortem spinal cords of patients who died 2 days to 30 years after either cerebral infarction or traumatic spinal cord injury. Neurofilament (NF) staining demonstrated a spatio-temporal pattern of axonal loss within degenerating descending nerve fibre tracts that could be detected close to the lesion as early as 12 days after injury and progressed to an almost complete loss of NF immunoreactivity at survival times of 1 year and longer. Immunohistochemistry for glial fibrillary acidic protein revealed a late astrocytic reaction starting at 4 months after injury in the degenerating tracts, leading to the long-term deposition of a dense astrocytic scar. These events were accompanied by the gradual reduction of myelin basic protein in affected nerve fibre tracts, leading to almost complete loss by 3 years after injury. Since the extracellular matrix molecule chondroitin sulphate proteoglycan (CSPG) is known to be strongly inhibitory for axonal regeneration and to be a major component of gliotic scar tissues, we investigated the possible deposition of CSPG within the degenerating nerve fibre tracts. Apart from a local up-regulation close to the lesion site, our results show no enhanced CSPG expression within degenerated tracts at any survival time. This suggests that despite the apparent lack of CSPG in Wallerian degeneration, the slow reduction of CNS myelin and the long-term deposition of a dense astrocytic scar may present an environment that is non-supportive for axon regrowth.

Increased expression of the putative axon growth-repulsive extracellular matrix molecule, keratan sulphate proteoglycan, following traumatic injury of the adult rat spinal cord.

Keratan sulphate proteoglycan (KSPG) is a developmentally regulated barrier molecule, directing axonal growth during central nervous system (CNS) formation. The possible re-expression and functional significance of KSPG in preventing axon regeneration following spinal cord injury (SCI) is poorly understood. In the present investigation, the spatio-temporal expression of KSPG was studied following experimental SCI. There was no indication of sparing of axons at the lesion epicentre following severe compression injury. By 7 days post operation (p.o.) a diffuse increase of KSPG immunoreactivity (KSPG-IR) was observed in the parenchyma surrounding the lesion. This was followed by a delayed (21-28 days p.o.) and largely heterogeneous increase of KSPG-IR in the lesion epicentre, which revealed both cellular and extracellular matrix-like distribution patterns. Although no re-growth of anterogradely labelled corticospinal axons was observed, many 200-kDa neurofilament (NF)-positive axons could be detected growing into the connective tissue scar. This phase of spontaneous axonal re-growth was closely associated with a framework of glial cells (including Schwann cells from damaged local spinal nerve roots) that had migrated into the lesion site. The spontaneous nerve fibre re-growth could be detected in both KSPG-rich and KSPG-poor territories. The present data suggest that the lesion-induced up-regulation of KSPG-IR may have contributed to the lack of corticospinal axon re-growth. However, the lack of any direct spatio-temporal correlation between the distribution of raised KSPG-IR and spontaneous NF-positive axonal regeneration suggests that at least some populations of axons can resist the putative inhibitory effects of this extracellular matrix molecule.

Major histocompatibility complex class II expression by activated microglia caudal to lesions of descending tracts in the human spinal cord is not associated with a T cell response.

Lesion-induced microglial/macrophage responses were investigated in post-mortem human spinal cord tissue of 20 patients who had died at a range of survival times after spinal trauma or brain infarction. Caudal to the spinal cord injury or brain infarction, a strong increase in the number of activated microglial cells was observed within the denervated intermediate grey matter and ventral horn of patients who died shortly after the insult (4-14 days). These cells were positive for the leucocyte common antigen (LCA) and for the major histocompatibility complex class II antigen (MHC II), with only a small proportion staining for the CD68 antigen. After longer survival times (1-4 months), MHC II-immunoreactivity (MHC II-IR) was clearly reduced in the grey matter but abundant in the white matter, specifically within the degenerating corticospinal tract, co-localising with CD68. In this fibre tract, elevated MHC II-IR and CD68-IR were still detectable 1 year after trauma or stroke. It is likely that the subsequent expression of CD68 on MHC II-positive microglia reflects the conversion to a macrophage phenotype, when cells are phagocytosing degenerating presynaptic terminals in grey matter target regions at early survival times and removing axonal and myelin debris in descending tracts at later survival times. No T or B cell invasion or involvement of co-stimulatory B7 molecules (CD80 and CD86) was observed. It is possible that the up-regulation of MHC II on microglia that lack the expression of B7 molecules may be responsible for the prevention of a T cell response, thus protecting the spinal cord from secondary tissue damage.

Attempted endogenous tissue repair following experimental spinal cord injury in the rat: involvement of cell adhesion molecules L1 and NCAM?

It is widely accepted that the devastating consequences of spinal cord injury are due to the failure of lesioned CNS axons to regenerate. The current study of the spontaneous tissue repair processes following dorsal hemisection of the adult rat spinal cord demonstrates a phase of rapid and substantial nerve fibre in-growth into the lesion that was derived largely from both rostral and caudal spinal tissues. The response was characterized by increasing numbers of axons traversing the clearly defined interface between the lesion and the adjacent intact spinal cord, beginning by 5 days post operation (p.o.). Having penetrated the lesion, axons became associated with a framework of NGFr-positive non-neuronal cells (Schwann cells and leptomeningeal cells). Surprisingly few of these axons were derived from CGRP- or SP-immunoreactive dorsal root ganglion neurons. At the longest survival time (56 days p.o.), there was a marked shift in the overall orientation of fibres from a largely rostro-caudal to a dorso-ventral axis. Attempts to identify which recognition molecules may be important for these re-organizational processes during attempted tissue repair demonstrated the widespread and intense expression of the cell adhesion molecules (CAM) L1 and N-CAM. Double immunofluorescence suggested that both Schwann cells and leptomeningeal cells contributed to the pattern of CAM expression associated with the cellular framework within the lesion.

Peripheral but not central axotomy induces changes in Janus kinases (JAK) and signal transducers and activators of transcription (STAT).

Nerve injury leads to the release of a number of cytokines which have been shown to play an important role in cellular activation after peripheral nerve injury. The members of the signal transducer and activator of transcription (STAT) gene family are the main mediators in the signal transduction pathway of cytokines. After phosphorylation, STAT proteins are transported into the nucleus and exhibit transcriptional activity. Following axotomy in rat regenerating facial and hypoglossal neurons, a transient increase of mRNA for JAK2, JAK3, STAT1, STAT3 and STAT5 was detected using in situ hybridization and semi-quantitative polymerase chain reaction (PCR). Of the investigated STAT molecules, only STAT3 protein was significantly increased. In addition, activation of STAT3 by phosphorylation on position Tyr705 and enhanced nuclear translocation was found within 3 h in neurons and after 1 day in astrocytes. Unexpectedly, STAT3 tyrosine phosphorylation was obvious for more than 3 months. In contrast, none of these changes was found in response to axotomy of non-regenerating Clarke's nucleus neurons, although all the investigated models express c-Jun and growth-associated protein-43 (GAP-43) in response to axonal injury. Increased expression of Janus kinase (JAK) and STAT molecules after peripheral nerve transection suggests changes in the responsiveness of the neurons to signalling molecules. STAT3 as a transcription factor, which is expressed early and is activated persistently until the time of reinnervation, might be involved in the switch from the physiological gene expression to an 'alternative program' activated only after peripheral nerve injury.

Lesion-induced changes of electrophysiological properties in astrocytes of the rat dentate gyrus.

Reorganization of the adult dentate gyrus following unilateral entorhinal cortex lesion (ECL) is a well-established model for studying mechanisms of trauma-induced neuronal plasticity. The lesion induces deafferentiation of the outer molecular layer, which is accompanied by a strong astroglial reaction. This glial response is thought to contribute to subsequent repair processes, but the underlying mechanisms are poorly understood. In this study we addressed the question whether denervation leads to modifications in the electrophysiological properties of astrocytes, assuming that such changes might be involved in the remodeling of neural circuitry. Patch-clamp recordings were obtained from astrocytes in the dentate gyrus of adult rats that underwent ECL and compared to corresponding data from control animals. We observed a significant reduction of inward rectifier K(+) current densities, a positive shift of resting potentials, and an increase in input resistance in astrocytes of the denervated molecular layer. Current densities were reduced between 6 and 19 days postlesion (dpl), reaching a minimum at 10 dpl. Voltage-gated outward K(+) currents were not affected by the lesion. Inward rectifier K(+) currents increase with maturation in astrocytes. Thus, our results provide evidence that, following ECL, mature astrocytes dedifferentiated and readapted an immature current pattern. Presumably, these changes lead to stronger and prolonged depolarization of glial cells and neurons in response to activity-dependent K(+) release, which in turn might enhance the synthesis of neurotrophic factors and contribute to a permissive environment for neuronal reorganization.

[Nerve regeneration after spinal cord trauma. Neurobiological progress and clinical expectations]. / Nervenregeneration nach Rückenmarkstrauma. Neurobiologische Fortschritte und klinische Erwartungen.

In recent years, a more precise neurobiological knowledge has been gained concerning the various cellular parameters which mediate successful peripheral nerve regeneration, and also those which prevent repair of damaged nerve fibre pathways following traumatic injury to the the central nervous system (CNS). On this basis, a range of experimental therapeutical approaches for promoting axonal regeneration and functional recovery after spinal cord injury have been developed in animal models. Such intervention strategies focus on the molecular inactivation of glial-associated growth-inhibitory factors and on the application of trophic molecules and cellular substrates which enhance the postlesional regenerative potential of intrinsic CNS neurons. At the present, these experimental therapies cannot be transferred to the clinical situation for the treatment of spinal cord injured patients. This overview briefly summarizes current progress in the neurobiology of spinal cord trauma, the main findings of which are discussed in the light of clinical expectations.

GAP-43 (B-50) and C-Jun are up-regulated in axotomized neurons of Clarke's nucleus after spinal cord injury in the adult rat.

The growth-associated protein GAP-43 (B-50) and the transcription factor C-Jun are involved in regeneration of the injured nervous system. In this study, we investigated the possibility of the induction of GAP-43 and C-Jun in axotomized neurons of Clarke's nucleus (CN) in adult rats, of which a large population undergoes degeneration several weeks after a low thoracic lateral funiculotomy of the spinal cord. In situ hybridization and immunohistochemistry revealed a transient up-regulation of GAP-43 mRNA, C-Jun protein, and its activated, phosphorylated form, peaking around 7 days after injury in preferentially large diameter CN-neurons ipsilateral and caudal to the lesion. Our results document that some populations of axotomized central nervous system neurons, similar to axotomized regenerating neurons of the peripheral nervous system, can up-regulate GAP-43 and C-Jun, even if they are destined to degenerate. This might reflect a transient regenerative capacity, which fails over time.

[Neuroborreliosis with extensive cerebral vasculitis and multiple cerebral infarcts]. / Neuroborreliose mit ausgeprägter zerebraler Vaskulitis und multiplen Hirninfarkten.

We report on a patient who suffered from borreliosis-induced severe cerebral vasculitis accompanied by multiple cerebral infarctions leading to hemiparesis, hemianopsia and reduced consciousness. Despite antibiotic and immunosuppressive therapy with ceftriaxon and prednisolone the patients condition deteriorated. Cerebral angiography showed multiple stenoses of large arteries of the posterior circulation and ubiquitous irregularities of small vessel wails. General reduced perfusion reflected an increased peripheral resistance. After 4 weeks of additional immunosuppressive treatment with cyclophosphamide the neurological status and angiographic findings improved dramatically.

Dynamics of microglial activation in the spinal cord after cerebral infarction are revealed by expression of MHC class II antigen.

Microglial reactivity associated with induction of MHC class II (HLA-DR) antigen is a sensitive indicator for pathological events in the CNS. To assess the response of glial cells after lesions of supraspinal descending tracts, HLA-DR, CD68 and GFAP were studied immunohistochemically on spinal cord tissue of 5 patients who died after unilateral infarction of the middle cerebral artery territory, and 5 control cases. In patients who died shortly after a stroke (4-14 days) increased HLA-DR-immunoreactivity (HLA-DR-IR) could be observed in the intermediate grey matter and in the ventral horn. The CD68-IR was much less intense. After longer survival times (5 weeks to 4 months). HLA-DR-IR in the grey matter was clearly lower than that observed in the spinal cord of short survival times, but very abundant in the dorsolateral funiculus, specifically within the corticospinal tract. In white matter areas, CD68-IR was almost identical to the HLA-DR-IR. Within the grey matter, CD68-IR was similar to the control tissue. A moderate increase of GFAP-positive astrocytes could be seen only in the grey matter after longer survival times. It seems probable, that the dynamics of HLA-DR-positive microglia reflect the early phagocytosis of presynaptic terminals by microglia in target regions of descending fibre tracts. In the white matter, the removal of degenerating axons by phagocytosing microglia expressing HLA-DR and CD68 antigens is a slower process which occurs over a period of months.

Spontaneous longitudinally orientated axonal regeneration is associated with the Schwann cell framework within the lesion site following spinal cord compression injury of the rat.

Spontaneous cellular reorganisation at the lesion site has been investigated following massive spinal cord compression injury in adult rats. By 2 days post operation (p.o.), haemorrhagic necrosis, widespread axonal degeneration, and infiltration by polymorphnuclear granulocytes and OX42-positive macrophages were observed in the lesion site. By 7 days p.o., low affinity nerve growth factor receptor-positive Schwann cells, from activated spinal roots, were identified as they migrated far into the lesion. Between 7 and 14 days p.o., the overlapping processes of Schwann cells within the macrophage-filled lesion formed a glial framework which was associated with extensive longitudinally orientated ingrowth by many neurofilament-positive axons. Relatively few of these axons were calcitonin gene-related peptide (CGRP)-, substance P (SP)-, or serotonin (5HT)-positive; however, many were glycinergic or gamma aminobutyric acid (GABA)ergic. At 21 and 28 days p.o. (the longest survival times studied), a reduced but still substantial amount of orientated Schwann cells and axons could be detected at distances of up to 5 mm within the lesion. Glial fibrillary acidic protein (GFAP) immunoreactivity demonstrated the slow formation of astrocytic scarring which only became apparent at the lesion interface between 21 and 28 days p.o. The current data suggest the possibility of developing future therapeutic strategies designed to maintain or even enhance these spontaneous and orientated regenerative events.

Distribution of B-50(GAP-43) mRNA and protein in the normal adult human spinal cord.

B-50(GAP-43) is a phosphoprotein mainly found in the nervous system which plays a major role in neurite growth during development and regeneration as well as in synaptic remodelling. In the mature intact central nervous system, intense B-50 immunoreactivity (B-50-IR) can still be detected in regions which maintain residual capacity for structural re-organization. B-50 expression has been studied extensively in laboratory animals; however, its distribution and regulation in the human spinal cord is largely unknown. As a first step to analyze lesion-induced structural alterations, we investigated the distribution of B-50 protein and mRNA in the normal adult human spinal cord and dorsal root ganglia. Intense B-50-IR was localized to the superficial laminae of the dorsal horn at all segmental levels, the intermediolateral nucleus at thoracic levels and Onuf's nucleus at sacral levels. Scattered neurons, particularly in the ventral horn of lumbar and sacral segmental levels (and occasionally also in Clarke's nucleus) displayed intense B-50-IR in close apposition to the perikaryal and proximal dendritic surfaces. Nonradioactive in situ hybridization indicated that B-50 mRNA could also be detected in neurons of the ventral horn and also in the intermediolateral nucleus. The distribution of B-50 mRNA and protein in the normal human spinal cord shows a marked similarity to that reported in experimental animals, including the selective labelling of Onuf's nucleus. However, the strong B-50-IR on the surface of some large anterior horn motor neurons has not been observed in other mammals. This finding might reflect a particular state of readiness for synaptic plasticity.