High prevalence and functional effects of serum antineuronal antibodies in patients with gastrointestinal disorders.

BACKGROUND: Antineuronal antibodies can be associated with both gastrointestinal (GI) and brain disorders. For example, antibodies against the potassium channel subunit dipeptidyl-peptidase-like protein-6 (DPPX) bind to neurons in the central nervous system (CNS) and myenteric plexus and cause encephalitis, commonly preceded by severe unspecific GI symptoms. We therefore investigated the prevalence of antineuronal antibodies indicative of treatable autoimmune CNS etiologies in GI patients. METHODS: Serum samples of 107 patients (Crohn's disease n = 42, ulcerative colitis n = 16, irritable bowel syndrome n = 13, others n = 36) and 44 healthy controls were screened for anti-DPPX and further antineuronal antibodies using immunofluorescence on rat brain and intestine and cell-based assays. Functional effects of high-titer reactive sera were assessed in organ bath and Ussing chamber experiments and compared to non-reactive patient sera. KEY RESULTS: Twenty-one of 107 patients (19.6%) had antibodies against the enteric nervous system, and 22 (20.6%) had anti-CNS antibodies, thus significantly exceeding frequencies in healthy controls (4.5% each). Screening on cell-based assays excluded established antienteric antibodies. Antibody-positive sera were not associated with motility effects in organ bath experiments. However, they induced significant, tetrodotoxin (TTX)-insensitive secretion in Ussing chambers compared to antibody-negative sera. CONCLUSIONS & INFERENCES: Antineuronal antibodies were significantly more frequent in GI patients and associated with functional effects on bowel secretion. Future studies will determine whether such antibodies indicate patients who might benefit from additional antibody-directed therapies. However, well-characterized encephalitis-related autoantibodies such as against DPPX were not detected, underlining their rarity in routine cohorts.

IgA NMDA receptor antibodies are markers of synaptic immunity in slow cognitive impairment.

OBJECTIVE: To report that antibodies to synaptic proteins may occur in association with slow, progressive cognitive decline. METHODS: A total of 24 patients with progressive cognitive dysfunction of unclear etiology were examined for onconeuronal and synaptic receptor antibodies. The effect of serum was examined in cultures of dissociated mouse hippocampal neurons. RESULTS: Seven patients had immunoglobulin A (IgA), but no immunoglobulin G (IgG), antibodies against NMDA receptor (NMDAR). Anti-NMDAR IgA positive patients' serum, but not serum from control individuals, caused dramatic decrease of the levels of NMDAR and other synaptic proteins in neurons, along with prominent changes in NMDAR-mediated currents. These effects correlated with the titer of IgA NMDAR antibodies and were reversed after removing patients' serum from the culture media. When available, comprehensive clinical assessment and brain metabolic imaging showed neurologic improvement after immunotherapy. CONCLUSIONS: A subset of patients with slowly progressive cognitive impairment has an underlying synaptic autoimmunity that decreases the density of NMDAR and other synaptic proteins, and alters synaptic currents. This autoimmunity can be demonstrated examining patients' serum and CSF for NMDAR IgA antibodies, identifying possible candidates for immunotherapy.

Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown origin.

BACKGROUND: Anti-NMDA-receptor (NMDAR) encephalitis is a severe disorder that occurs in association with antibodies to the NR1 subunit of the NMDAR and results in a characteristic syndrome. OBJECTIVE: To determine in a single institution setting whether patients previously diagnosed with encephalitis of unknown origin had anti-NMDAR encephalitis. METHODS: Charts of 505 patients aged 18 to 35 years admitted to the intensive care unit (ICU) during a 5-year period were retrospectively reviewed for criteria of encephalitis of unknown etiology. These included encephalitic signs with psychiatric symptoms (agitation, paranoid thoughts, irritability, or hallucinations); seizures; CSF inflammation; and exclusion of viral or bacterial infection. Archived serum and CSF samples of patients fulfilling these criteria were examined for NMDAR antibodies. Follow-up visits allowed the analysis of the natural disease course and estimation of prognosis. RESULTS: Seven patients (all women) fulfilled the indicated criteria; 6 of them had NMDAR antibodies. Ovarian teratomas were detected in 2 patients, in one 3 years after the onset of encephalitis. Outcome was favorable in all patients. One patient without teratoma improved spontaneously along with disappearance of NMDAR antibodies. CONCLUSIONS: Anti-NMDAR encephalitis represented 1% of all young patients' admissions to the ICU. Six of 7 cases with the indicated clinical criteria had anti-NMDAR encephalitis. NMDAR antibodies should be tested in all patients with encephalitis who fulfill these criteria.

Innovative agents for actinic keratosis and nanocarriers enhancing skin penetration.

Actinic keratosis and cutaneous squamous cell carcinoma are of increasing importance with aging and increased ultraviolet light exposure in Western societies. Efficient and well-tolerated therapy is still a matter of concern. As with tumours of other organs, new target sites and innovative drugs selectively addressing them are widely looked for. Due to the relevance for DNA synthesis and thus cell proliferation, human DNA polymerase alpha should be such a target, the more so as the three-dimensional structure of the active site has been proposed based on the application of molecular modelling methods and molecular dynamics simulations. The modelled structure of the active site was used for docking nucleotide analogues in order to design selective inhibitors. Consequently, well-fitting thymidine and guanosine analogues were synthesized and tested in vitro for their influence on normal and transformed human keratinocytes. In fact, the combination of modelling studies and in vitro tests allowed us to design antiproliferative and cytotoxic agents which are new drug candidates for the therapy of skin tumours, given the agents are no relevant substrates of nucleotide transporters (MRP-4, MRP-5) expressed by skin cancer cells. Essential kinases for nucleoside activation were detected, too, corresponding with the observed effects of nucleoside analogues. Due to the rather high molecular weight and poor solubility, however, skin penetration should be poor and thus topical therapy may require carriers to improve the uptake. This becomes feasible by lipidic and non-lipidic nanoparticles which can enhance the uptake of lipophilic agents up to 13-fold.

Embryonic and postnatal development of the serotonergic raphe system and its target regions in 5-HT1A receptor deletion or overexpressing mouse mutants.

The neurotransmitter 5-HT regulates early developmental processes in the CNS. In the present study we followed the embryonic and postnatal development of serotonergic raphe neurons and catecholaminergic target systems in the brain of 5-HT1A receptor knockout (KO) and overexpressing (OE) in comparison with wild-type (WT) mice from embryonic day (E) 12.5 to postnatal day (P) 15.5. Up to P15.5 no differences were apparent in the differentiation and distribution of serotonergic neurons in the raphe area as revealed by the equal number of serotonergic neurons in the dorsal raphe in all three genotypes. However, the establishment of serotonergic projections to the mesencephalic tegmentum and hypothalamus was delayed at E12.5 in KO and OE animals and projections to the cerebral cortex between E16.5 and E18.5 were delayed in OE mice. This delay was only transient and did not occur in other brain areas including septum, hippocampus and striatum. Moreover, OE mice caught up with WT and KO animals postnatally such that at P1.5 serotonergic innervation of the cortex was more extensive in the OE than in KO and WT mice. Tissue levels of 5-HT and of its main metabolite 5-hydroxyindoleacetic acid as well as 5-HT turnover were considerably higher in brains of OE mice and slightly elevated in KO mice in comparison with the WT, starting at E16.5 through P15.5. The initial differentiation of dopaminergic neurons and fibers in the substantia nigra at E12.5 was transiently delayed in KO and OE mice as compared with WT mice, but no abnormalities in noradrenergic development were apparent in later stages. The present data indicate that 5-HT1A receptor deficiency or overexpression is associated with increased 5-HT synthesis and turnover in the early postnatal period. However, they also show that effects of 5-HT1A KO or OE on the structural development of the serotonergic system are at best subtle and transient. They may nonetheless contribute to the establishment of increased or reduced anxiety-like behavior, respectively, in adult mice.

Differential distribution of voltage-gated potassium channels Kv 1.1-Kv1.6 in the rat retina during development.

The discharge behavior of neurons depends on a variable expression and sorting pattern of voltage-dependent potassium (Kv) channels that changes during development. The rodent retina represents a neuronal network whose main functions develop after birth. To obtain information about neuronal maturation we analyzed the expression of subunits of the Kv1 subfamily in the rat retina during postnatal development using immunocytochemistry and immunoelectron microscopy. At postnatal day 5 (P5) all the alpha-subunits of Kv1.1-Kv1.6 channels were found to be expressed in the ganglion cell layer (GCL), most of them already at P1 or P3. Their expression upregulates postnatally and the pattern and distribution change in an isoform-specific manner. Additionally Kv1 channels are found in the outer and inner plexiform layer (OPL, IPL) and in the inner nuclear layer (INL) at different postnatal stages. In adult retina the Kv 1.3 channel localizes to the inner and outer segments of cones. In contrast, Kv1.4 is highly expressed in the outer retina at P8. In adult retina Kv1.4 occurs in rod inner segments (RIS) near the connecting cilium where it colocalizes with synapse associated protein SAP 97. By using confocal laser scanning microscopy we showed a differential localization of Kv1.1-1.6 to cholinergic amacrine and rod bipolar cells of the INL of the adult retina.

Regulation of vesicular monoamine and glutamate transporters by vesicle-associated trimeric G proteins: new jobs for long-known signal transduction molecules.

Neurotransmitters of neurons and neuroendocrine cells are concentrated first in the cytosol and then in either small synaptic vesicles ofpresynaptic terminals or in secretory vesicles by the activity of specific transporters of the plasma and the vesicular membrane, respectively. In the central nervous system the postsynaptic response depends--amongst other parameters-on the amount of neurotransmitter stored in a given vesicle. Neurotransmitter packets (quanta) vary over a wide range which may be also due to a regulation of vesicular neurotransmitter filling. Vesicular filling is regulated by the availability of transmitter molecules in the cytoplasm, the amount of transporter molecules and an electrochemical proton-mediated gradient over the vesicular membrane. In addition, it is modulated by vesicle-associated heterotrimeric G proteins, Galphao2 and Galphaq. Galphao2 and Galphaq regulate vesicular monoamine transporter (VMAT) activities in brain and platelets, respectively. Galphao2 also regulates vesicular glutamate transporter (VGLUT) activity by changing its chloride dependence. It appears that the vesicular content activates the G protein, suggesting a signal transduction from the luminal site which might be mediated by a vesicular G protein-coupled receptor or as an alternative possibility by the transporter itself. Thus, G proteins control transmitter storage and thereby probablylink the regulation of the vesicular content to intracellular signal cascades.

Effects of brain-derived neurotrophic factor (BDNF) on glial cells and serotonergic neurones during development.

Serotonergic neurones are among the first to develop in the central nervous system. Their survival and maturation is promoted by a variety of factors, including serotonin itself, brain-derived neurotrophic factor (BDNF) and S100beta, an astrocyte-specific Ca(2+) binding protein. Here, we used BDNF-deficient mice and cell cultures of embryonic raphe neurones to determine whether or not BDNF effects on developing serotonergic raphe neurones are influenced by its action on glial cells. In BDNF-/- mice, the number of serotonin-immunoreactive neuronal somata, the amount of the serotonin transporter, the serotonin content in the striatum and the hippocampus, and the content of 5-hydroxyindoleacetic acid in all brain regions analysed were increased. By contrast, reduced immunoreactivity was found for myelin basic protein (MBP) in all brain areas including the raphe and its target region, the hippocampus. Exogenously applied BDNF increased the number of MBP-immunopositive cells in the respective culture systems. The raphe area displayed selectively reduced immunoreactivity for S100beta. Accordingly, S100beta was increased in primary cultures of pure astrocytes by exogenous BDNF. In glia-free neuronal cultures prepared from the embryonic mouse raphe, addition of BDNF supported the survival of serotonergic neurones and increased the number of axon collaterals and primary dendrites. The latter effect was inhibited by the simultaneous addition of S100beta. These results suggest that the presence of BDNF is not a requirement for the survival and maturation of serotonergic neurones in vivo. BDNF is, however, required for the local expression of S100beta and production of MBP. Therefore BDNF might indirectly influence the development of the serotonergic system by stimulating the expression of S100beta in astrocytes and the production MBP in oligodendrocytes.

Differential effects of Rho GTPases on axonal and dendritic development in hippocampal neurones.

Formation of neurites and their differentiation into axons and dendrites requires precisely controlled changes in the cytoskeleton. While small GTPases of the Rho family appear to be involved in this regulation, it is still unclear how Rho function affects axonal and dendritic growth during development. Using hippocampal neurones at defined states of differentiation, we have dissected the function of RhoA in axonal and dendritic growth. Expression of a dominant negative RhoA variant inhibited axonal growth, whereas dendritic growth was promoted. The opposite phenotype was observed when a constitutively active RhoA variant was expressed. Inactivation of Rho by C3-catalysed ADP-ribosylation using C3 isoforms (Clostridium limosum, C3(lim) or Staphylococcus aureus, C3(stau2)), diminished axonal branching. By contrast, extracellularly applied nanomolar concentrations of C3 from C. botulinum (C3(bot)) or enzymatically dead C3(bot) significantly increased axon growth and axon branching. Taken together, axonal development requires activation of RhoA, whereas dendritic development benefits from its inactivation. However, extracellular application of enzymatically active or dead C3(bot) exclusively promotes axonal growth and branching suggesting a novel neurotrophic function of C3 that is independent from its enzymatic activity.

Regulation of vesicular neurotransmitter transporters.

Neurotransmitters are key molecules of neurotransmission. They are concentrated first in the cytosol and then in small synaptic vesicles of presynaptic terminals by the activity of specific neurotransmitter transporters of the plasma and the vesicular membrane, respectively. It has been shown that postsynaptic responses to single neurotransmitter packets vary over a wide range, which may be due to a regulation of vesicular neurotransmitter filling. Vesicular filling depends on the availability of transmitter molecules in the cytoplasm and the active transport into secretory vesicles relying on a proton gradient. In addition, it is modulated by vesicle-associated heterotrimeric G proteins, Galphao2 and Galphaq, which regulate VMAT activities in brain and platelets, respectively, and may also be involved in the regulation of VGLUTs. It appears that the vesicular content activates the G protein, suggesting a signal transduction form the luminal site which might be mediated by a vesicular G-protein coupled receptor or, as an alternative, possibly by the transporter itself. These novel functions of G proteins in the control of transmitter storage may link regulation of the vesicular content to intracellular signal cascades.

Investigations on the predictability of the formation of glassy solid solutions of drugs in sugar alcohols.

A prerequisite for the formation of glassy solid solutions prepared by the melting method is the miscibility of the respective drug and the carrier in the molten state. As could be shown experimentally, all investigated drug/sugar alcohol combinations miscible in the molten state form to some extent glassy solid solutions, dependent on their tendency to recrystallize during preparation. Therefore, the present study focuses on the evaluation of factors that govern the miscibility of molten drugs and sugar alcohols as carriers. In this context, solubility parameters are discussed as a means of predicting miscibility in comparison to a new approach, using calculated interaction parameters derived from molecular dynamics (MD) studies. There is evidence that a Coulomb interaction term C(SR), comprising short-range electrostatic interactions and hydrogen bonding energy is essential for the miscibility of drug and carrier in the molten state. To relate C(SR) to the molecular volume, a non-dimensional parameter P(i) is defined. For this parameter, a limiting value for miscibility exists. Contrary, calculated solubility parameter differences between drug and sugar alcohol in the range of 8-15 MPa(1/2) are not suitable for a prediction of miscibility or immiscibility, since the mixtures deviate from regular solution behavior. In irregular mixtures of drugs and sugar alcohols, an excess entropy and the formation of hydrogen bonds between unlike molecules favor miscibility, that cannot be predicted by regular solution theory.

[Sacroiliac joint blockage caused by bedding after spinal anaesthesia can simulate a neurological complication]. / Lagerungsbedingte Blockierungen des Sakroiliakalgelenkes nach Spinalanästhesien können neurologische Komplikationen vortäuschen - 2 Fallberichte -

Back pain after spinal anaesthesia is often attributed to the spinal anaesthesia and the accompanying puncture. We demonstrate two cases where this problem was not caused by spinal anaesthesia but was due to sacroiliac joint blockage caused by bedding. As far as we know, this complication has not been described yet. When taken into account, it can be treated easily and with success.

[The early axial traction of the cervical spine after anaesthesia with intubation and extreme reclination of the head]. / Die frühe axiale HWS-Traktion bei Gelenkfunktionsstörungen nach extremer Kopfreklination in Intubationsnarkose.

OBJECTIVE: Patients who have an operation under general anaesthesia with muscle relaxation often complain about neck pain if the head needs to be placed in extreme reclination to facilitate surgical access. Patients complain about vertigo, light muscle tenseness but also about severe joint blockages in the neck region. Due to this complication the standard practise in some hospitals is to refer these patients routinely to a physiotherapist postoperatively. This study investigated the influence of an axial traction - a treatment which can easily be learned by anaesthesiologists - on blockages of the cervical spine in those patients. METHODS: In two randomised groups (n = 15 each) of preoperative inconspicuous patients the following directions of motion were investigated: Ante- and retroflexion of C0/1, side inclination C0/1, side nodding and side movement C2/3 to C6/T1, dorsal movement C5/Th2. The examinations took place at the preoperative anaesthetic round, shortly before extubation, two hours after extubation and the next day. Additionally the patients were asked about their discomfort. An axial traction of the cervical spine was performed in one group after extubation. The number of new blockages and the subjective discomfort of the patients was compared with the Chi-Square test. RESULTS: An axial traction of the cervical spine reduces the frequency and the intensity of symptoms significantly. CONCLUSION: It was investigated whether an axial traction of the cervical spine - a treatment that can easily be learned by anaesthesiologists - could improve patients' comfort. The study showed that an axial traction of the cervical spine immediately after extubation reduces the frequency and intensity of symptoms significantly. This treatment is highly effective, not very time consuming and, if done correctly, without any risk for the patient. By using this treatment routinely, additional expenses for physiotherapeutic interventions could be reduced.

Molecular dynamics simulations of stratum corneum lipid models: fatty acids and cholesterol.

We report the results of an investigation on stratum corneum lipids, which present the main barrier of the skin. Molecular dynamics simulations, thermal analysis and FTIR measurements were applied. The primary objective of this work was to study the effect of cholesterol on skin structure and dynamics. Two molecular models were constructed, a free fatty acid bilayer (stearic acid, palmitic acid) and a fatty acid/cholesterol mixture at a 1:1 molar ratio. Our simulations were performed at constant pressure and temperature on a nanosecond time scale. The resulting model structures were characterized by calculating surface areas per headgroup, conformational properties, atom densities and order parameters of the fatty acids. Analysis of the simulations indicates that the free fatty acid fraction of stratum corneum lipids stays in a highly ordered crystalline state at skin temperatures. The phase behavior is strongly influenced when cholesterol is added. Cholesterol smoothes the rigid phases of the fatty acids: the order of the hydrocarbon tails (mainly of the last eight bonds) is reduced, the area per molecule becomes larger, the fraction of trans dihedrals is lower and the hydrophobic thickness is reduced. The simulation results are in good agreement with our experimental data from FTIR analysis and NIR-FT Raman spectroscopy.

Serotonin uptake and release mechanisms in developing cultures of rat embryonic raphe neurons: age- and region-specific differences.

The development of serotonergic neurons of the rat raphe was followed in primary neuronal cell cultures taken at embryonic days embryonic day 13 and embryonic day 14 from three different raphe sub-groups, topographically defined with respect to their position to the isthmus as rostral (R1), intermediate (R2) and caudal (R3). In neurons cultivated from embryonic day 13 raphe serotonin, immunoreactivity was detected after only two days in vitro in the rostral R1 and the intermediate R2 sub-groups. Within two weeks of cultivation the number of serotonergic neurons as well as the dendritic branching continuously increased in all three sub-groups. In cultures obtained from embryonic day 13 raphe a specific uptake of [3H]serotonin could not be detected during the first days in vitro. Specific uptake as well as regulated serotonin release, however, was clearly discernible in these cultures after nine days in vitro, indicating developmental differentiation of the initially immature serotonergic neurons in culture. In contrast, serotonergic neurons obtained from the three raphe sub-groups at embryonic day 14 took up and released [3H]serotonin, as early as after two days in culture. Basal as well as stimulated serotonin release was diminished when preincubating the cells with tetanus toxin, which cleaves synaptobrevin thereby blocking exocytosis. Our data indicate that the differential development of serotonergic neurons in the various raphe sub-groups in vivo is also sustained in culture. The differences observed when comparing neurons from embryonic days 13 and 14 suggest that a short time-period of about 24h appears to be crucial for the developmental upregulation of serotonin uptake, storage and release.

Low-dose dopexamine in patients undergoing hemihepatectomy: an evaluation of effects on reduction of hepatic dysfunction and ischaemic liver injury.

BACKGROUND: Hepatic dysfunction is a common problem in patients after hemihepatectomy. Treatment with low-dose dopamine has been shown to be beneficial in hemihepatectomy patients. We hypothesized that dopexamine, a synthetic vasoactive catecholamine, due to its specific pharmocodynamic profile may be more effective in reducing hidden ischaemic episodes in the hepato-splanchnic region during and after temporary total cross-clamping of hepatic inflow in these patients. METHODS: The effects of low-dose dopexamine on hepatic venous haemoglobin oxygen saturation (ShvO2), hepatic venous lactate level, monoethylglycinxylid (MEGX) formation, hepatic synthetic function and indicators for hepatic cell damage were studied during hemihepatectomy and for 16 h postoperatively in hemihepatectomy patients and compared to those of low-dose dopamine. In a prospective, double-blind clinical study 20 patients received randomly either dopexamine (DPX) 0.5 microg kg(-1) min(-1) (n=10) or dopamine (DO) 2.5 microg kg(-1) min(-1) (n= 10). Infusions were started after induction of anaesthesia and continued 16 h postoperatively. Hepatic vein, radial and pulmonary artery were catheterized. Measurements were carried out after induction of anaesthesia, after total cross-clamping of hepatic inflow, and at 2 h and 16 h postoperatively. RESULTS: There were no differences in systemic haemodynamics, oxygenation, ShvO2, serum aminotransferases or MEGX levels between the groups. At 16 h postoperatively prothrombin and antithrombin III levels were significantly lower while hepatic venous lactate was significantly higher in the DPX group compared to the DO group. CONCLUSION: In patients undergoing hemihepatectomy, we could not reveal superior hepatoprotective effects of low-dose dopexamine compared to low-dose dopamine.

The neuronal monoamine transporter VMAT2 is regulated by the trimeric GTPase Go(2).

Monoamines such as noradrenaline and serotonin are stored in secretory vesicles and released by exocytosis. Two related monoamine transporters, VMAT1 and VMAT2, mediate vesicular transmitter uptake. Previously we have reported that in the rat pheochromocytoma cell line PC 12 VMAT1, localized to peptide-containing secretory granules, is controlled by the heterotrimeric G-protein Go(2). We now show that in BON cells, a human serotonergic neuroendocrine cell line derived from a pancreatic tumor expressing both transporters on large, dense-core vesicles, VMAT2 is even more sensitive to G-protein regulation than VMAT1. The activity of both transporters is only downregulated by Galphao(2), whereas comparable concentrations of Galphao(1) are without effect. In serotonergic raphe neurons in primary culture VMAT2 is also downregulated by pertussis toxin-sensitive Go(2). By electron microscopic analysis from prefrontal cortex we show that VMAT2 and Galphao(2) associate preferentially to locally recycling small synaptic vesicles in serotonergic terminals. In addition, Go(2)-dependent modulation of VMAT2 also works when using a crude synaptic vesicle preparation from this brain area. We conclude that regulation of monoamine uptake by the heterotrimeric G proteins is a general feature of monoaminergic neurons that controls the content of both large, dense-core and small synaptic vesicles.

[Circulatory function and oxygenation during hemihepatectomy. Dopamine versus dopexamine]. / Kreislaufverhalten und Oxygenierung während Hemihepatektomien. Dopamin versus Dopexamin.

OBJECTIVE: The aim of this study was to compare low dose dopamine and dopexamine with respect to of liver-venous oxygen saturation, oxygen delivery and--demand, liver function tests and cardiocirculatory effects in the reperfusion period during a hemihepatectomy operation with occlusion of the liver hilus. METHODS: Twenty patients were studied in a randomised, doubleblind setting. They either received 2 micrograms/kg per min dopamine or 0.5 microgram/kg per min dopexamine perioperatively. For monitoring purposes a pulmonary artery and a liver venous catheter were placed. At four different time points hemodynamic parameter were assessed and blood samples were drawn. RESULTS: Significant changes between groups were found 5 min after opening the liver hilus for the cardiac index and the systemic oxygen delivery, as well as at the end of the operation for pulmonary shunt volume, which had increased more in the dopexamine group. No significant difference between liver venous oxygen saturation and liver function tests was found. CONCLUSION: Until more detailed studies concerning the influence of dopamine on the hepatic-splanchnic region during liver surgery are performed, dopexamine can not be considered superior to dopamine during these operations.

[The continuous monitoring of hepatic venous oxygen saturation in patient monitoring following hemihepatectomy]. / Die kontinuierliche Uberwachung der lebervenösen Sauerstoffsättigung als erweitertes Monitoring während einer Hemihepatektomie.

UNLABELLED: Increasing numbers of liver tumours and liver metastases from other tumours are treated by liver resection. During resection the ligamentum hepatoduodenale is occluded and the liver is exposed to warm ischemia. Duration and intensity of resulting liver ischemia can not be evaluated without special monitoring devices. A fiberoptic catheter placed in a liver vein facilitates continuous recording of the hepatic-venous oxygen saturation (ShvO2). CASE REPORT: We present a case where such a catheter was placed perioperatively in a patient undergoing hemihepatectomy. The liver venous catheter was positioned by guidance of the saturation curve and X-ray. The preoperative oxygen saturation in this liver vein was 80%. During the whole operation, the ShvO2 was continuously monitored. Blood for blood gas analyses was drawn before, during and after the occlusion of the ligamentum hepatoduodenale. Hemodynamic parameters were documented at the same time. The ShvO2 already decreased in the preparation period before the actual occlusion of the ligamentum hepatoduodenale. During the occlusion the ShvO2 dropped to an average of 30% with the lowest value being 13%. After reopening of the hepatic hilus the ShvO2 increased rapidly but did not reach preoperative values which were recorded not earlier than at the end of the operation. CONCLUSION: Duration and intensity of the decreased ShvO2 were recognized early by the liver venous catheter. It was demonstrated that desaturation of the hepatico-splanchnic region already occurred during the period of liver preparation before the ligamentum hepatoduodenale was occluded. Interventions to protect the liver from ischemia should therefore be applied some time before occlusion of the liver hilus. However, clearly defined indications for this invasive monitoring cannot be given at this time. In situations of extended liver resection or in cases of expected technical difficulties a continuous monitoring of the liver-venous oxygen saturation might be beneficial.

The development of nonpeptide angiotensin II receptor antagonists: a success story.

The modulation of the renin-angiotensin system continues to be an important target in drug design. The development of nonpeptide angiotensin II receptor antagonists offers a new tool in treatment of hypertension. Starting from benzimidazole lead structures detailed structure-activity analyses, molecular modeling methods, and dedicated syntheses led to the development of potent, orally active antihypertensive drugs.