[Recurrent failed ICD therapy of ventricular tachycardia]. / Wiederholt ausbleibende ICD-Therapie einer ventrikulären Tachykardie.

Implantable cardioverter defibrillators (ICD) are used as standard therapy to prevent sudden cardiac death in heart failure patients. Today, physicians in emergency and intensive care medicine are often confronted with problems of ICD therapy in these patients. We report a case of a patient suffering from recurrent ventricular tachycardia (VT) requiring antiarrhythmia treatment with amiodarone. With an increasing drug loading, the VT cycle length was progressively prolonged resulting in a slow VT undetectable for the ICD. Subsequently, the patient was scheduled for VT ablation after which the patient became free of arrhythmia recurrences.

Intraseptal muscarinic ligands and galanin: influence on hippocampal acetylcholine and cognition.

The cholinergic neurons in the septohippocampal projection are implicated in hippocampal functions such as spatial learning and memory. The aim of this study was to examine how septohippocampal cholinergic transmission is modulated by muscarinic inputs and by the neuropeptide galanin, co-localized with acetylcholine (ACh) in septohippocampal cholinergic neurons, and how spatial learning assessed by the Morris water maze test is affected. Muscarinic inputs to the septal area are assumed to be excitatory, whereas galanin is hypothesized to inhibit septohippocampal cholinergic function. To test these hypotheses, compounds were microinjected into the medial septum and hippocampal ACh release was assessed by microdialysis probes in the ventral hippocampus of the rat. Blockade of septal muscarinic transmission by intraseptal scopolamine increased hippocampal ACh release suggesting that septal cholinergic neurons are under tonic inhibition. Stimulation of septal muscarinic receptors by carbachol also increased hippocampal ACh release. Despite this increase, both scopolamine and carbachol tended to impair hippocampus-dependent spatial learning. This finding also suggests a revision of the simplistic notion that an increase in hippocampal ACh may be facilitatory for learning and memory. Galanin infused into the medial septum enhanced hippocampal ACh release and facilitated spatial learning, suggesting that septal galanin, contrary to earlier claims, does not inhibit but excites septohippocampal cholinergic neurons. Galanin receptor stimulation combined with muscarinic blockade in the septal area resulted in an excessive increase of hippocampal ACh release combined with an impairment of spatial learning. This finding suggests that the level of muscarinic activity within the septal area may determine the effects of galanin on hippocampal cognitive functions. In summary, a limited range of cholinergic muscarinic transmission may contribute to optimal hippocampal function, a finding that has important implications for therapeutic approaches in the treatment of disorders of memory function.

Hepatitis C virus-associated mixed cryoglobulinemia. Clinical manifestations, histopathological changes, mechanisms of cryoprecipitation and options of treatment.

Chronic hepatitis C virus (HCV) infection is frequently associated with a variety of autoimmune phenomenons. Mixed cryoglobulinemia (MC) appears in up to 50% of chronic HCV-infected patients. Cryoglobulins consist of immunoglobulin complexes precipitating in vitro when cooled below body temperature. In most cases IgM with rheumatoid factor activity is found in cryoprecipitates which could lead to vasculitis induced by the deposition of immnuocomplexes in small vessels. This vasculitis is thought to cause clinical symptoms called Meltzer's triad. This triad is represented by purpura, arthralgia and weakness. One third of patients suffering from HCV-associated mixed cryoglobulinemia are developing typical symptoms during their course of disease. The striking association between HCV infection and MC has conduced to the hypothesis that HCV is of major importance in the production of MC with followed vasculitis. Both hepatrophism and lymphotrophism have been reported for the hepatitis C virus. Infection of B-cells by HCV could probably lead to a bcl-2 translocation and immunoglobulin gene rearrangement which results in clonal lymphoproliferation and in synthesis of monoclonal IgM with rheumatoid factor activity. These IgM form immunocomplexes with IgG in the cold, which are finally responsible for the described vasculitis. Histopathological changes of the liver are dominated by chronic HCV infection. The majority of times mild activity of hepatitis or mild fibrosis could be found. Nevertheless, cirrhosis is more often found in HCV-infected patients suffering from MC compared to patients without MC. Conventional treatment of MC is aimed to reduce circulating immune complexes by immunosupression and plasmapheresis. With the emerging concept of a viral pathogenesis the therapeutic approach has changed during the last decade. Interferon treatment of MC, particularly of HCV-associated MC is well established nowadays.

Galanin and spatial learning in the rat. Evidence for a differential role for galanin in subregions of the hippocampal formation.

Anatomical, neurochemical and behavioural evidence support a role for galanin in hippocampally mediated functions such as spatial learning and memory. To obtain more precise information on this role, galanin (3 nmol/rat) was infused via bilateral chronic cannulae into different areas of the hippocampal formation which are characterized by different galanin receptor subtypes and also by different galanin innervation patterns. The effects of infused galanin on spatial learning were examined in the Morris swim maze. Infusions of galanin into both the dorsal and ventral dentate gyrus, which mainly contain GAL-R2 receptor mRNA and a high degree of galanin-noradrenaline coexistence, significantly retarded spatial acquisition without affecting swim speed or performance in the visible platform test. This spatial learning deficit was fully blocked by pretreatment with the non-selective galanin antagonist M35. Analysis of retention performance suggested that the major effect of intrahippocampal galanin is mediated via a specific disruption of acquisition mechanisms of importance for performance in the probe trial. Galanin infused into the ventral CA1 (a mainly GAL-R1 receptor mRNA expressing region) or into anterior, ventral CA3 regions did not produce any deficits in spatial learning compared to control animals. These results suggest that galanin mediates its action on spatial learning mainly through the GAL-R2 receptor subtype in areas where most of the galanin is present in noradrenergic terminals. A possible role for the GAL-R1 receptor subtype in cognition in the dorsal and ventral hippocampus remains to be defined. The results suggest a differential functional role for galanin and galanin receptor subtypes within subregions of the hippocampal formation.

Internalization of intracerebrally administered porcine galanin (1-29) by a discrete nerve cell population in the hippocampus of the rat.

In spite of numerous studies utilizing intraventricular administration of porcine galanin (1-29), little is known about the spread and cellular distribution of exogenous galanin following intraventricular administration. In this study a discrete nerve cell body population with their dendrites became strongly galanin immunoreactive (IR) in the dorsal hippocampus following intraventricular porcine galanin (1.5 nmol/rat). Time course experiments showed that after time intervals of 10 and 20 min, but not at 60 min, scattered small- to medium-sized galanin-IR nerve cell bodies and their dendrites were present in all layers of the dorsal and ventral hippocampus. In double-immunolabeling experiments most of these nerve cells were identified as putative GABA interneurons costoring NPY-IR or somatostatin-IR in some cases. Twenty minutes after intraventricular injection of artificial cerebrospinal fluid (aCSF), only endogenous punctate and coarse galanin-IR terminals were found, but no galanin-IR cell bodies. Intrahippocampal injection of fluorophore-labeled galanin resulted in the appearance of fluorescent nerve cell bodies with the same morphology and localization as in the above experiments. Coadministration of the putative galanin antagonist M35 (0.5 nmol) and galanin (1.5 nmol) resulted in a reduced number of galanin-IR nerve cell bodies in the hippocampus of half of the rats. These findings support the existence of a population of putative hippocampal GABA interneurons with the ability to internalize and concentrate galanin and/or its fragments present in the extracellular fluid, possibly mediated by galanin receptors.

Galanin and learning.

A number of studies indicate that galanin (GAL) is a potent modulator of basal acetylcholine release in the rat forebrain e.g. in the cholinergic neurons of the septo-hippocampal projections. Thus, GAL perfused through the microdialysis probe decreased basal acetylcholine release in the ventral hippocampus, while it enhanced acetylcholine release in the dorsal hippocampus. This finding indicates that GAL may act via different mechanisms within the subsystems of the hippocampus. This hypothesis has received support from studies using the Morris swim maze, a learning task dependent on hippocampal mechanisms. GAL (3 nmol/rat) infused into the ventral hippocampus impaired spatial learning acquisition, while it tended to facilitate when injected into the dorsal hippocampus. However, the effects of GAL on acetylcholine release and on spatial learning, which are due to activation of GAL-receptors, appear to be indirectly mediated possibly via noradrenaline transmission. GAL is also a potent inhibitor of mesencephalic 5-HT neurotransmission in vivo. These findings are discussed in relation to the role of acetylcholine and serotonin in cognition.

A behavioral analysis of the spatial learning deficit induced by the NMDA receptor antagonist MK-801 (dizocilpine) in the rat.

This study analyzes whether the disruptive effects of the noncompetitive NMDA receptor antagonist MK-801 (0.01-0.1 mg/kg s.c.) on spatial learning can be dissociated from sensorimotor disturbances in the rat. Two different modifications of the Morris swim maze task with a hidden underwater platform were used: with or without local cue. Retention was tested either 24 h or 7 days after training as a probe trial (without platform). The present data indicate that MK-801 produces an impairment of spatial learning that cannot be dissociated from motor or sensory mechanisms. These findings support the view that NMDA receptors probably contribute to, but are not essential for, spatial learning in the water maze.

Clearance of HCV RNA in a chronic hepatitis C virus-infected patient during acute hepatitis B virus superinfection.

The routes of hepatitis B virus and hepatitis C virus transmission are quite similar and coexistence of both viruses in one patient is not a rare phenomenon. Until now, the natural course of liver diseases induced by coinfections has not been well documented and the mechanisms of interaction between the two viruses and the human host have not been fully clarified. We report the case of a patient suffering from chronic hepatitis due to hepatitis C virus who developed an acute hepatitis B virus superinfection. Serum hepatitis C virus ribonucleic acid became undetectable by reverse transcriptase/polymerase chain reaction at diagnosis of acute hepatitis B virus infection. At the same time, there was a striking increase in the serum concentrations of the antibodies against C22 and C33c hepatitis C virus antigens. Four months after clinical resolution of the acute hepatitis, hepatitis B surface antigen was undetectable in serum and three months later antibodies against hepatitis B surface antigen appeared. Two years after acute hepatitis B virus infection, the patient has had no relapse of markers for viral replication of hepatitis B virus. Transaminases are within the reference range and hepatitis C virus ribonucleic acid is undetectable in both serum and liver tissue. We hypothesize that acute hepatitis B virus infection stimulated a specific humoral response against hepatitis C virus as well as triggering non-specific defense mechanisms which finally eliminated both viruses.

Attentional modulation of central odor processing.

Two studies were conducted to investigate the influence of attention on the components of the chemosensory event-related potential (CSERP). In the first study the odors linalool and eugenol were delivered to six male subjects, in the second study three male and two female subjects were presented with their own body odor (axillary hair) and the body odor of a same sex donor. In both studies the odors were presented in an oddball paradigm under ignore and attend conditions via a constant-flow olfactometer. In the ignore condition attention was diverted from the odors with a distractor task, while in the attend condition the subjects were asked to respond to the infrequently occurring odor. In both studies the allocation of attention led to a decrease in the latency of the early components (N1, P2, N2) and to an increase in the amplitude of the late positivities. The modulation of the early components suggests that attentional gating in olfaction might already be effective at an early processing level.

Hepatitis C virus infection-associated non-cryoglobulinaemic monoclonal IgMkappa gammopathy responsive to interferon-alpha treatment.

BACKGROUND/AIMS: An association of HCV infection with lymphoproliferative disorders, particularly B-cell non-Hodgkin's lymphoma has been described. In the majority of reported patients, mixed cryoglobulinaemia was present as well. Rarely, HCV-associated lymphoproliferative disorders have been observed in the absence of cryoglobulinaemia. In these latter patients, the response to interferon-alpha is largely unknown. CASE REPORT: We report a case of an asymptomatic 31-year-old male with chronic HCV infection and non-cryoglobulinaemic monoclonal IgMkappa gammopathy responsive to interferon-alpha therapy. Prior to therapy, elevated plasma transaminase activities known for longer than a year, serum anti-HCV antibodies and HCV RNA detected by reverse transcriptase-polymerase chain reaction were present. Serum IgM concentration was markedly elevated, immunofixation demonstrated monoclonal serum IgM, and urine kappa-light chains were detected. Cryoglobulins were undetectable in several consecutive serum samples. Bone marrow aspirate and biopsy specimens were unremarkable. Further evaluation, e.g. by ultrasonography and radiography, did not reveal evidence for lymphoma. Treatment with interferon-alpha2a for 12 months resulted in a long-term sustained response to HCV infection and in a normalisation of serum IgM concentration. CONCLUSION: Therefore, the corresponding effects of interferon-alpha on HCV infection and on a monoclonal B-cell population observed in the present case might suggest a pathogenetic connection, similarly, to what has been described for HCV and mixed cryoglobulinaemia. The molecular events, however, leading to HCV-induced monoclonal B-cell expansion remain unknown.

Hippocampal dynorphin B injections impair spatial learning in rats: a kappa-opioid receptor-mediated effect.

The hippocampus plays a central role in the acquisition and storage of information. Long-term potentiation in the mossy fibre pathway to the CA3 region in the hippocampus, an animal model of memory acquisition, is modulated by dynorphin peptides. This study investigated the possible role of hippocampal dynorphin in spatial learning. Male rats were trained in the Morris Water Task after microinjection with different doses of dynorphin B (1, 3.3 or 10 nmol/rat) or artificial cerebrospinal fluid (as control) into the CA3 region of the dorsal hippocampus. Dynorphin B was found to impair spatial learning at all tested doses. The synthetic kappa1-selective opiate receptor antagonist nor-binaltorphimine (2 nmol) also given into the hippocampus fully blocked the acquisition impairment caused by dynorphin B (10 nmol), while nor-binaltorphimine alone did not affect learning performance. These findings suggest that dynorphin peptides could play a modulatory role in hippocampal plasticity by acting on hippocampal kappa-receptors and thereby impair spatial learning.

In vitro reactivity of cryoglobulin IgM and IgG in hepatitis C virus-associated mixed cryoglobulinemia.

BACKGROUND/AIMS: Mixed cryoglobulinemia is frequently associated with chronic hepatitis C virus infection. We aimed to clarify the mechanism, kinetics and participating proteins in cryoprecipitate formation, which are still being debated. METHODS: Eighteen patients with cryoglobulinemia were studied. Isolated serum cryoprecipitates and purified cryoglobulin IgM and IgG fractions were analyzed in vitro by turbidimetry for temperature-dependent complex formation. Immunoglobulin reactivity, i.e. in cryoprecipitates and in cryoglobulin-free sera, was studied using immunoblot and enzyme immunoassays. HCV RNA was detected by reverse transcriptase/polymerase chain reaction. RESULTS: By turbidimetry, purified cryo-IgM precipitated (in the absence of HCV RNA) with cryo-IgG as well as with non-cryoglobulin IgG and with IgG Fc or F(ab')2 fragments. In contrast, purified cryo-IgG did not precipitate with non-cryoglobulin IgM. Anti-HCV IgG reactivity was found in cryoglobulin-free sera, in cryoprecipitates and in purified cryoglobulin IgG fractions. The respective titers were similar. Purified cryo-IgM did not react to HCV-encoded proteins. Binding of cryo-IgM to heterologous IgG was inhibited by intact IgG (up to a mean of about 52%) as well as by IgG Fc (33%) and F(ab')2 fragments (17%). Binding of cryo-IgM to IgG was enhanced at low temperature (4 degrees C vs. 37 degrees C), particularly for type III cryoglobulin IgM. CONCLUSIONS: In hepatitis C virus-associated cryoglobulinemia the in vitro precipitate formation depended on cryo-IgM, while IgG appeared to act as an unspecific antigenic partner. Hepatitis C viral particles were probably not required. Cryo-IgM binding occurred primarily to intact IgG. Anti-HCV reactivity of either cryo-IgM or cryo-IgG was not necessary for precipitate formation. Regarding the pathogenesis, a direct hepatitis C virus protein-dependent stimulation of B-cells producing cryo-IgM seems to be unlikely.

Distribution and kinetics of galanin infused into the ventral hippocampus of the rat: relationship to spatial learning.

A recent study has shown that ventral hippocampal galanin plays a role in spatial learning and that it has an inhibitory effect on basal acetylcholine release [Ogren S. O. et al. (1996) Neuroscience 75, 1127-1140]. The present studies were designed to compare the in vivo tissue distribution and kinetics of infused galanin (porcine) with the temporal effect of galanin on spatial learning in the rat. Daily bilateral microinfusions of galanin (1.5 nmol/side for five days) via chronic cannulae placed in the ventral hippocampus produced a significant impairment of acquisition of the spatial task when infused 20 min, but not 5 or 60 min, before the daily training session. No overall impairment of memory retention (examined 24 h after the last training session) was observed in the galanin-treated rats. These results indicate that galanin given in the ventral hippocampus produces a time-dependent effect on acquisition. Using an antibody to porcine galanin and immunohistochemistry, galanin infused in the ventral hippocampus was found to be distributed mainly within the ventral part of the hippocampus and around the infusion site. The infused galanin was rapidly cleared from the extracellular space between 5 and 20 min after infusion. Five minutes after infusion of galanin, a number of cells in the ventral hippocampus, both within and outside the zone of extracellularly located galanin, showed a positive galanin-like immunoreactivity. These cells appear morphologically to be medium-sized neurons with a similar position as cells showing neuropeptide Y-like immunoreactivity. At 20 and 60 min after infusion of galanin, no cells with detectable levels of galanin-like immunoreactivity could be seen. These results indicate that the temporal kinetics and distribution of infused galanin are of major importance for its behavioural effect in the ventral hippocampus. The rapid clearance of the infused galanin and its internalization by neuronal endocytotic mechanisms may be important for its effect on cognition.

Modulation of acetylcholine and serotonin transmission by galanin. Relationship to spatial and aversive learning.

This paper presents evidence that galanin is a potent in vivo modulator of basal acetylcholine release in the rat brain with qualitatively and quantitatively differential effects in the dorsal and ventral hippocampus. Galanin perfused through the microdialysis probe decreased basal acetylcholine release in the ventral hippocampus, while it enhanced acetylcholine release in the dorsal hippocampus. Galanin (3 nmol/rat) infused into the ventral hippocampus impaired spatial learning acquisition, while it tended to facilitate acquisition when injected into the dorsal hippocampus. These effects appear to be related to activation of GAL-R1 (ventral hippocampus) and GAL-R2 (dorsal hippocampus) receptors, respectively. However, the effects of galanin on acetylcholine release and on spatial learning appear not to be directly related to cholinergic mechanisms, but they may also involve interactions with noradrenaline and/or glutamate transmission. Galanin administered into the lateral ventricle failed to affect acetylcholine release, while this route of administration produced a long-lasting reduction in 5-HT release in the ventral hippocampus, indicating that galanin is a potent inhibitor of mesencephalic 5-HT neurotransmission in vivo. Subsequent studies supported this hypothesis, showing that the effects on 5-HT release in vivo are most likely mediated by a galanin receptor in the dorsal raphe. The implications of these findings are discussed in relation to the role of acetylcholine in cognitive functions in the forebrain and the role of the raphe 5-HT neurons in affective disorders.

Clinical, biochemical, and histological changes in hepatitis C virus infection-associated cryoglobulinemia.

The most common extrahepatic manifestation of HCV infection is mixed cryoglobulinemia (MC). 62 unselected patients with chronic HCV infection were prospectively evaluated for the presence of cryoglobulinemia and associated clinical and biochemical parameters. Furthermore, a putative relationship between the HCV genotypes and cryoglobulinemia was tested. Histological features typical for HCV infection were comparatively analyzed in cases with and without cryoglobulinemia. Whether an intrahepatic Th2-response is responsible for the strong antibody production causing cryoglobulinemia was also examined. Cryoglobulins were detected in sera of 30 patients (approximately equal to 48%). Patients with cryoglobulinemia were on the average elder, showed an apparent longer duration of infection, and suffered more frequently from arthralgia, accompanied by a significant increase of total serum IgM concentration and rheumatoid factor activity. The HCV genotype distribution among patients with cryoglobulinemia was not different from that found in patients without cryoglobulinemia. In cases with cryoglobulinemia, an increased activity of chronic hepatitis and a higher grade of liver fibrosis was noted. The prevalence of HCV-typical histological lesions among all patients were: Portal lymphocytic aggregates (40%), bile duct damage (35%), steatosis (47%), and intracellular acidophilic bodies (29%). A significant correlation, however, could not be found between cryoglobulinemia and the presence of HCV-typical histological lesions. An intrahepatic Th2-response causing an increased antibody production could not be observed in cases with cryoglobulinemia.

CD95/CD95L-mediated apoptosis of the hepatic stellate cell. A mechanism terminating uncontrolled hepatic stellate cell proliferation during hepatic tissue repair.

During liver tissue repair, hepatic stellate cells (HSC), a pericyte-like mesenchymal liver cell population, transform from a "quiescent" status ("resting" HSC) into myofibroblast-like cells ("activated" HSC) with the latter representing the principle matrix synthesizing cell of the liver. Presently, the mechanisms that terminate HSC cell proliferation when tissue repair is concluded are poorly understood. Controlled cell death known as apoptosis could be a mechanism underlying this phenomenon. Therefore, apoptosis and its regulation were studied in HSC using an in vitro and in vivo approach. Spontaneous apoptosis became detectable in parallel with HSC activation because resting cells (2 days after isolation) displayed no sign of apoptosis, whereas apoptosis was present in 8% (+/- 5%) of "transitional" cells (day 4) and in 18% (+/- 8%) of fully activated cells (day 7). Both CD95 (APO-1/Fas) and CD95L (APO-1-/Fas-ligand) became increasingly expressed during the course of activation. Apoptosis could be fully blocked by CD95-blocking antibodies in normal cells and HSC already entering the apoptotic cycle. Using CD95-activating antibodies, transition of more than 95% cells into apoptosis was evident at each activation step. The apoptosis-regulating proteins Bcl-2 and p53 could not be detected in resting cells but were found in increasing amounts at days 4 and 7 of cultivation. Whereas p53 expression was induced by the CD95-activating antibody, no change was inducible in Bcl-2 expression. The Bcl-2-related protein bax could be found at days 2 and 4 in similar expression, was considerably up-regulated at day 7, but was not regulated by CD95-agonistic antibodies. In vivo, acute tissue damage was first accompanied by activation and proliferation of HSC displaying no sign of apoptosis. In the recovery phase, apoptotic HSC were detectable in parallel to a reduction in the total number of HSC present in the liver tissue. The data demonstrate that apoptosis becomes detectable in parallel with HSC activation, which suggests that apoptosis might represent an important mechanism terminating proliferation of activated HSC.

Interferon-alpha treatment of hepatitis C virus-associated mixed cryoglobulinemia.

BACKGROUND/AIMS: Chronic hepatitis C virus infection is frequently associated with mixed cryoglobulinemia. The efficacy of interferon-alpha treatment in the presence of cryoglobulinemia, particularly the rate of sustained responders, has not yet been well defined. METHODS: Fifty-nine consecutive patients with chronic HCV infection were studied prospectively with regard to the presence of cryoglobulinemia and their biochemical and virological response to interferon-alpha2a therapy. RESULTS: Cryoglobulins were detected in sera of 23 patients. For this latter group of patients, significant differences were found compared to the 36 patients without cryoglobulinemia, i.e. the prevalence of female sex was higher, the duration of liver disease was longer and distinctive laboratory abnormalities, e.g. higher rheumatoid factor activity, were noted as well as a higher prevalence of cirrhosis. The distribution of HCV genotypes and serum HCV RNA titers was similar in the two groups. Interferon-alpha treatment regimens were not different regarding mean cumulative dose and mean duration of therapy. The response to therapy was almost identical, i.e. 35% of patients with cryoglobulinemia showed a sustained response compared to 22% of patients without cryoglobulinemia. The percentages of patients showing a relapse or breakthrough were similar in both groups. Pre-treatment viremia levels were higher in non-responders compared to sustained responders. Non-responders appeared to be more frequent among patients infected with genotypes 1a and 1b, especially among male patients without cryoglobulinemia. CONCLUSIONS: The presence of cryoglobulinemia per se in chronic HCV-infected patients does not adversely affect the outcome of interferon-alpha therapy, including the rate of sustained response.