Biomedical subjects

Gerald Kircheis

Publications and source records attributed to Gerald Kircheis.

8 recordsLinked to original sources

PubMed2005

Neural synchronization in hepatic encephalopathy.

Hepatic encephalopathy (HE) is clinically characterized by a large variety of symptoms including motor symptoms, cognitive deficits, as well as changes in the level of alertness up to hepatic coma. A number of pathological processes affecting glial and neuronal function have been identified, including hyper-ammonia, changes within the excitatory and inhibitory transmitter systems, as well as osmolytic changes with consecutive cell swelling. One explanation how these pathological processes result in neurological deficits in HE is the concept of pathologically synchronized oscillations within and between relevant brain regions. A number of studies suggest that the cognitive deficits and the reduced level of alertness in patients with HE can be attributed to a significantly slowed and pathologically synchronized spontaneous oscillatory brain activity, depending on the grade of HE. Moreover, HE motor symptoms, like postural tremor called"mini asterixis," have recently been shown to be associated with abnormal thalamo-cortical and cortico-muscular synchronization. Indirect evidence exists from studies of processing and recognition of flicker stimuli that in HE slowing of oscillations also occurs in the visual system. Taken together, pathological synchronization of neuronal activity may turn out to be a promising pathophysiological concept for linking neuronal dysfunction to the diversity of clinical deficits in HE.

Animals↗

PubMed2005

Oligonucleotide microarray analysis of differential transporter regulation in the regenerating rat liver.

AIMS: The aim of this study was to investigate the regulation of hepatic transport systems during liver regeneration. METHODS: A DNA oligonucleotide microarray was developed with probes for 400 transcripts. Data were confirmed using real-time PCR and on a functional level in the perfused rat liver. Liver homogenates were taken 3-48 h following 2/3-hepatectomy in rats and compared with sham-operated and non-operated controls. RESULTS: A more than two-fold increase or decrease of expression was obtained in 183 genes following partial hepatectomy and in 16 genes in sham-operated rats. A strong induction during liver regeneration was detected for the amino acid transporters LAT4, SN2 and sodium-dependent neutral amino acid transporter (ASCT)2, whereas amino acid transport system (ATA)2 and ATA3 expressions remained unchanged. The upregulation of ASCT2 may be responsible for the increase in sodium-dependent neutral amino acid influx important for liver cell proliferation. Expression of the osmolyte transporters Smit, TauT and Bgt1 was almost unchanged indicating that osmolytes are not involved in the cell volume increase during liver regeneration. The basolateral bile salt transporter Ntcp messenger RNA (mRNA) was significantly downregulated, whereas bile salt export pump (Bsep) and multidrug resistance protein (Mrp)2 expressions remained almost unchanged. An increased mRNA expression following partial hepatectomy was detected for organic anion transporting polypeptide (Oatp)5, Octn1, Octn2 and SGLT2. In contrast, Mrp6, Oatp 2, Oatp 3, Oatp 4 and Oatp 7 were downregulated. A five-fold upregulation at the protein level was shown for the Na(+)-K(+)-2Cl- cotransporter sodium-potassium-2-chloride cotransporter (NKCC1). CONCLUSIONS: The data show a differential regulation of hepatic transport systems during liver regeneration.

Amino Acid Transport Systems↗

PubMed2004

Neural mechanism underlying impaired visual judgement in the dysmetabolic brain: an fMRI study.

An altered brain metabolism in the parietal and prefrontal regions of the cerebral cortex as well as cognitive alterations have been found in patients suffering from hepatic encephalopathy. The neural mechanisms underlying these metabolically induced cognitive alterations, however, are not known. Since patients with liver cirrhosis without clinically overt encephalopathy already show an impaired performance in a flicker light test, the aim of this study was to analyze the normal and pathologically impaired neural mechanisms of these patients using functional magnetic resonance imaging (fMRI). Nine subjects at the early stage of encephalopathy [nonmanifest hepatic encephalopathy (nmHE)] and ten controls underwent scanning, while they indicated the apparent transition from a steady light to the onset of a flicker light, that is, the critical flicker frequency (CFF). Judgement-related blood oxygenation level-dependent (BOLD) activation was decreased in nmHE compared to controls in the right inferior parietal cortex (IPL). Furthermore, the analysis of psychophysiologic interaction suggests impaired neural interaction in patients with nmHE, especially between the IPL and the parietooccipital cortex (Poc), the intraparietal sulcus, the anterior cingulate cortex (ACC), the right prefrontal cortex (PFC), the medial temporal lobe, and the extrastriate cortex V5. In contrast, nonmanifest patients revealed an enhanced coupling between IPL and the postcentral cortex. Our findings provide evidence of an early-impaired and compensatory neural mechanism during visual judgement already in the earliest stages of hepatic encephalopathy and suggest an aberrant coupling between cerebral regions in the dysmetabolic brain.

Brain↗

PubMed2003

Quantitative T1 mapping of hepatic encephalopathy using magnetic resonance imaging.

Changes are shown in the spin-lattice (T1) relaxation time caused by the putative deposition of manganese in various brain regions of hepatic encephalopathy (HE) patients using a novel and fast magnetic resonance imaging (MRI) method for quantitative relaxation time mapping. A new method, T1 mapping with partial inversion recovery (TAPIR), was used to obtain a series of T1-weighted images to produce T1 maps. Imaging of 15 control subjects and 11 patients was performed on a 1.5T MRI scanner. The measurement time per patient with this technique, including adjustments, was approximately 5 minutes. Regions of interest in the globus pallidus, the caudate nucleus, the posterior and anterior limbs of the internal capsule, the putamen, the frontal and occipital white matter, the white matter of the corona radiata, the occipital visual and frontal cortices, and the thalamus were interactively defined in the left hemisphere and analyzed with respect to their T1 values. T1 changes in the brains of HE patients can be determined quantitatively with TAPIR in short, clinically relevant measurement times. Significant correlations between the change in T1 and HE severity have been shown in the globus pallidus, the caudate nucleus, and the posterior limb of the internal capsule. No significant correlation of T1 with grade of HE was found in the putamen, frontal white matter, white matter of the corona radiata, white matter in the occipital lobe, the anterior limb of the internal capsule, visual cortex, thalamus, or frontal cortex. In conclusion, these measurements show that T1 mapping is feasible in short, clinically relevant acquisition times.

Adult↗

PubMed2002

Pathogenesis of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome during the course of acute or chronic liver disease. It is functional in nature, potentially reversible and precipitated by rather heterogeneous factors. At the neurophysiological level HE is characterized by a low frequent cortico-cortical electrical coupling, which may explain the cognitive deficits and a low frequent corticomuscular coupling, which may explain the fine motor deficits. Current evidence suggests that HE is the consequence of a low grade chronic glial edema with subsequent alterations of glioneuronal communication. Different factors, such as ammonia, benzodiazepines, inflammatory cytokines can induce or aggravate astrocyte swelling, which results in the activation of osmosignaling cascades, protein modifications, alterations in gene expression and neurotransmission. Among the protein modifications nitration of critical tyrosine residues in glial proteins may play an important role. Several proteins, which are nitrated in response to ammonia, benzodiazepines, hypoosmotic astrocyte swelling or inflammatory cytokines have been identified, including glutamine synthetase and the peripheral type benzodiazepine receptor.

Astrocytes↗

PubMed2002

Management of hepatic encephalopathy.

Hepatic encephalopathy (HE) is seen as a clinical manifestation of low grade chronic cerebral edema, which is accompanied by alterations in glioneural communication. Different factors such as ammonia, inflammatory cytokines, benzodiazepines and electrolyte imbalances may precipitate or aggravate glia edema, thereby explaining precipitation of HE episodes by a variety of unrelated factors. Recognition and rigorous treatment of these precipitating factors is the most important measure in HE therapy which may be augmented by dietary and medical approaches. Among these approaches, evidence for proven therapeutical efficacy in HE on the basis of placebo-controlled trials is existing only for transplantation, protein restriction, administration of vegetable proteins, ornithine-aspartate, oral branched-chain amino acid treatment as well as lactulose enemas. The efficacy of oral lactulose has not been demonstrated on the basis of placebo-controlled trials.

Ammonia↗

PubMed2002

Critical flicker frequency for quantification of low-grade hepatic encephalopathy.

Subclinical hepatic encephalopathy (SHE) is currently diagnosed by psychometric tests or neurophysiologic techniques. In view of its sociomedical relevance, simple and reproducible tests for routine diagnosis are required. This study evaluates critical flicker-frequency thresholds for quantification of low-grade hepatic encephalopathy. A total of 115 patients (92 with cirrhosis, 23 controls) were analyzed for HE severity (mental state, computerized psychometric tests), and the threshold frequencies at which light pulses are perceived as fused (fusion frequency) or flickering light (critical flicker frequency [CFF]). CFF was a highly reproducible parameter with little age, day-time, and training dependency. CFFs in cirrhotic patients without HE (HE 0) were not different from those found in noncirrhotic controls. Significantly lower CFFs were found in cirrhotic patients with subclinical or manifest HE, and the various HE groups separated from each other at a high level of significance (P <.01). By using a CFF cut-off value of 39 Hz, a 100% separation of patients with manifest HE from noncirrhotic controls and HE 0 cirrhotic patients was obtained. SHE patients separated from HE 0 cirrhotic patients with high sensitivity (55%) and specificity (100%). The HE severity-dependent differences were found in both, alcoholic and posthepatitic cirrhosis. Statistically significant correlations (P <.01) were found between CFFs and individual psychometric tests. Aggravation of preexisting HE after transjugular intrahepatic portosystemic stent shunt (TIPS) implantation was accompanied by a corresponding decrease of CFF, whereas improvement of HE increased CFF. In conclusion, CFF is a sensitive, simple, and reliable parameter for quantification of low-grade HE severity in cirrhotic patients and may be useful for the detection and monitoring of SHE.

Aged↗

PubMed2002

Prevention of bile acid-induced apoptosis by betaine in rat liver.

Bile acid-induced apoptosis plays an important role in the pathogenesis of cholestatic liver disease, and its prevention is of therapeutic interest. The effects of betaine were studied on taurolithocholate 3-sulfate (TLCS) and glycochenodeoxycholate (GCDC)-induced apoptosis in rat hepatocytes in vitro and in vivo. Hepatocyte apoptosis, caspase activation, and poly (ADP-ribose) polymerase (PARP) cleavage, which are normally observed in response to both bile acids, were largely prevented after preincubation of hepatocytes with betaine. Betaine uptake was required for this protective effect, which was already observed at betaine concentrations of 1 mmol/L. Betaine did not affect the TLCS-induced membrane trafficking of CD95 and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 2 to the plasma membrane or the TLCS-induced recruitment of Fas-associated death domain (FADD) and caspase 8 to the CD95 receptor. However, betaine largely prevented cytochrome c release and oxidative stress exerted otherwise by TLCS. Inhibition of caspase 9 strongly blunted TLCS-induced caspase-8 activation. Further betaine did not prevent the TLCS-induced c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (Erk), and p38 mitogen-activated protein kinase (p38(MAPK)) activation or TLCS-induced protein kinase B (PKB) dephosphorylation. The protective betaine effect was insensitive to inhibition of Erks by PD089059, of p38(MAPK) by SB203580, or of phosphatidylinositol 3-kinase (PI3-kinase) by LY294002. Betaine supplementation in the drinking water significantly ameliorated in vivo hepatocyte apoptosis following bile duct ligation. In conclusion, this study identifies betaine as a potent protectant against bile acid-induced apoptosis in vivo and in vitro, and its antiapoptotic action largely resides on an inhibition of the proapoptotic mitochondrial pathway.

Animals↗