[Intersectoral pain treatment. The Algesiologikum group]. / Sektorübergreifende schmerzmedizinische Versorgung. Der Algesiologikum-Verbund.

Cross-sectoral clinical pathways for chronic pain patients in standard and routine care are a major challenge for the German healthcare system. The Algesiologikum group has developed such clinical pathways including an essential infrastructure. Cooperation partners of the Algesiologikum group are two outpatient medical care units, one neurosurgery practice and four hospitals. In the outpatient sector as well as in the inpatient sector the Algesiologikum group provides a multidisciplinary team caring for chronic pain patients. The range of treatment in the hospitals includes multimodal, invasive and surgical pain therapy. The present report illustrates possibilities and frontiers of the Algesiologikum concept based on all patients treated since 2009.

[Static posturography in selected Parkinson syndromes: quantitative analysis of postural control]. / Statische Posturographie bei ausgewählten Parkinson-Syndromen : Quantitative Beurteilung der posturalen Kontrolle.

OBJECTIVES: Idiopathic Parkinson's disease (IPD) is associated with postural disturbances and falls. The assessment of postural instability by the pull test may lead to inconclusive results. Static posturography measurements may give more reliable information regarding the differential diagnosis of Parkinson syndromes. PATIENTS AND METHODS: We compared results of the pull test and static posturography (sway area in eyes-open/eyes-closed conditions) in healthy controls (C) and patients with akinetic-rigid IPD (n=18), atypical Parkinson syndromes (APS; n=18) and secondary Parkinson syndromes (SPS; n=17). RESULTS: Static posturography and the pull test results did not differ significantly between controls and patients with akinetic-rigid IPD. APS patients had significantly greater postural sway areas when tested with eyes open compared to controls (APS: 16.89 vs C: 6.89 mm, p≤0.001) and IPD patients (APS: 16.89 vs IPD: 9.55 mm, p=0.005). The correlation in the APS group between the pull test and sway area in the eyes-open condition was significant (r=0.526, p=0.025). With eyes closed, postural instability in APS patients was not significantly increased (+2%, p=.847). SPS patients were more unstable under the eyes-closed condition compared to controls (sway area SPS: 26.29 vs C: 8.79 mm, p≤0.001), IPD patients (sway area SPS: 26.29 vs IPD: 11.06 mm, p≤0.001) and APS patients (sway area SPS: 26.29 vs APS: 17.28 mm, p=0.027), without a significant correlation to the pull test. The sway area in the SPS patients increased significantly by 67% (p=0.001) under the eyes-closed condition. CONCLUSION: Static posturography may be a helpful tool for the differentiation of Parkinson syndromes.

Induction of pulmonary allergen-specific IgA responses or airway hyperresponsiveness in the absence of allergic lung disease following sensitization with limiting doses of ovalbumin-alum.

Respiratory allergies represent a failure to generate nonpathogenic responses to innocuous foreign materials. Herein we assessed the role of the sensitizing dose of allergen in this response/nonresponse paradigm, sensitizing BALB/c mice with 5 ng-2 microg of OVA-alum and assessing their responses to repeated OVA aerosol challenge. Mice sensitized with < or = 25 ng of OVA-alum did not develop atopic antibodies, airway hyperresponsiveness (AHR), eosinophilia, or pulmonary Th2 responses, but the 25-ng group animals did develop significant IgA responses. The mice sensitized with 100 ng of OVA-alum developed AHR in the absence of detectable allergic disease, while the mice sensitized with 250 ng-2 microg of OVA/alum developed full-spectrum allergic disease (i.e., eosinophilia, IgE, IgG1, pulmonary Th2 cytokine responses, and AHR). These data indicate that limiting doses of allergen can differentially induce IgA or AHR in the absence of atopic disease in mice.

Ethanol inhibits spontaneous activity of central nucleus of the amygdala neurons but does not impair retention in the passive-avoidance task.

BACKGROUND: Behavioral studies using pharmacological manipulations that increase neuronal activity of the central nucleus of the amygdala (CeA) have implicated the CeA in enhancement of memory modulation. To date, however, there has been a dearth of studies investigating the effect of a drug that decreases CeA activity on memory modulation-a drug that inhibits the neuronal activity of the CeA might be expected to impair memory modulation. To determine whether ethanol inhibits CeA activity and, if so, whether decreased CeA activity is associated with impairment of memory modulation, this study investigated the effect of ethanol on spontaneous single-unit activity of CeA neurons and retention in the passive-avoidance task. METHODS: The effect of ethanol (0.35, 0.75, 1.5, 2.5 g/kg) was determined on spontaneously firing neurons in the CeA in urethane-anesthetized rats by use of standard in vivo single-unit electrophysiological recording techniques. Additionally, the effect of ethanol when administered immediately after training in a standard passive-avoidance task was determined on retention the following day. RESULTS: Ethanol profoundly inhibited spontaneous CeA firing rates in urethane-anesthetized rats at all doses tested. Maximal inhibition was related to dose. Each dose of ethanol significantly inhibited CeA activity within 15 min of administration; within 35 min of administration, 0.75 g/kg of ethanol inhibited CeA activity by 65.2%, and the highest dose (2.5 g/kg) produced nearly complete suppression of CeA activity (81.3%). Although ethanol markedly inhibited CeA activity, these same doses of ethanol failed to impair retention in the passive-avoidance task: 0.35, 0.75, 1.5, and 2.5 g/kg of ethanol, administered immediately after training, failed to alter latency to step-through the following day. CONCLUSIONS: These results show that ethanol profoundly inhibits spontaneous CeA activity and suggest that inhibition of the CeA is not sufficient to impair retention in the passive-avoidance task.

Early ultrastructural injuries in the thyroid of the normal rat radioinduced by diagnostic and/or therapeutic amounts of iodine-131.

After irradiation, two principal mechanisms of cytolytic cell death can be involved: apoptosis and necrosis. By using morphological criteria, cells undergoing apoptosis can be distinguished from cells dying by necrosis. In nuclear medicine 131I is used to ablate thyroid remnants or to treat well differentiated thyroid carcinoma. The aim of study was to describe the progressive morphological thyroid changes induced by a diagnostic and/or therapeutic amounts of 131I in the rat using electron microscopy, in an attempt to determine which is the cell death pathway and to analyse "stunned" thyroid tissue to elucidate this effect. Tissular and ultrastructural examinations show that damages induced by 131I irradiation of the normal thyroid gland are heterogeneous. Thyroid cells die by necrosis after this metabolic irradiation, and no signs of apoptosis were observed by electron microscopy. In the other hand, stunning effect did not seem to impair the effectiveness of 131I treatment.

Dose-sensitive excitation and inhibition of spontaneous amygdala activity by propranolol.

The effect of systemically administered propranolol was determined on spontaneous activity of neurons in the central nucleus (CeA) of the amygdala, a brain site implicated in fear-related learning and memory. Extracellular recordings of single units in the CeA were obtained in vivo from rats administered saline or the centrally and peripherally acting beta-adrenergic receptor blocker propranolol (4, 7, 10 mg/kg i.p.). The high dose (10 mg/kg) of propranolol markedly increased spontaneous activity of CeA neurons. In contrast, the low (4 mg/kg) and intermediate (7 mg/kg) doses of propranolol significantly decreased spontaneous CeA activity, with the suppressant effect of propranolol on CeA firing rates weakening as the dosage increased from 4 to 7 mg/kg. These results suggest that (1) spontaneous activity of CeA neurons is tonically influenced by competing excitatory and inhibitory modulatory circuits, and (2) propranolol's effect on the two modulatory circuits is dose dependent: the high dose increasing spontaneous CeA activity by preferentially blocking an inhibitory circuit, the low dose decreasing spontaneous CeA activity by preferentially blocking an excitatory circuit, and the intermediate dose weakly suppressing CeA activity by blocking both the excitatory and inhibitory modulatory circuits. Disinhibition of CeA activity by the high dose of propranolol may explain the enhancement of retention observed in the passive-avoidance task when this dose of the drug is administered systemically, and may have implications for the use of propranolol clinically in treating aversive-memory-related anxiety disorders such as posttraumatic stress syndrome.

Potentiation of Smad transactivation by Jun proteins during a combined treatment with epidermal growth factor and transforming growth factor-beta in rat hepatocytes. role of phosphatidylinositol 3-kinase-induced AP-1 activation.

Cross-talk between Smad and mitogen-activated protein kinase pathways has been described recently, and evidence for Smad cooperation with AP-1 is emerging. Here we report that epidermal growth factor (EGF) potentializes transforming growth factor beta (TGF-beta)-induced Smad3 transactivation in rat hepatocytes, an effect abrogated by TAM-67, a dominant negative mutant of AP-1. Antisense transfection experiments indicated that c-Jun and JunB were involved in the synergistic effect, and endogenous c-Jun physically associated with Smad3 during a combined EGF/TGF-beta treatment. We next investigated which signaling pathway transduced by EGF was responsible for the Jun-induced synergism. Whereas inhibition of JNK had no effect, inhibition of the phosphatidylinositol-3' kinase (PI3-kinase) pathway by LY294002 or by expression of a dominant negative mutant of PI3-kinase reduced EGF/TGF-beta-induced Smad3 transcriptional activity. Transfection of an activated Ras with a mutation enabling the activation of the PI3-kinase pathway alone mimicked the EGF/TGF-beta potentiation of Smad3 transactivation, and TAM-67 abolished this effect, suggesting that the PI3-kinase pathway stimulates Smad3 via AP-1 stimulation. The EGF/TGF-beta-induced activation of Smad3 correlated with PI3-kinase and p38-dependent but not JNK-dependent phosphorylation of c-Jun. Since potentiation of a Smad-binding element-driven gene was also induced by EGF/TGF-beta treatment, this novel mechanism of Jun/Smad cooperation might be crucial for diversifying TGF-beta responses.

Provocative angiography in patients with gastrointestinal hemorrhage of obscure origin.

OBJECTIVE: A standard diagnostic evaluation including upper and/or lower endoscopy, tagged red blood cell scintigraphy, and visceral angiography identifies the source of GI bleeding in the majority of patients who present with acute GI hemorrhage. However, in a small group of patients the source of bleeding remains obscure; this form of GI hemorrhage is uncommon but represents a considerable diagnostic challenge. Some investigators have advocated provocation of bleeding with vasodilators, anticoagulants, and/or thrombolytics in association with tagged red blood cell scans or angiography. Unfortunately, the available literature on this topic is limited. Therefore, the purpose of this study is to report our experience with provocative GI bleeding studies. METHODS: The radiology databases at Duke University Medical Center and the Durham Veterans Administration Medical Center were reviewed from 1994 to 1999. Any patient who received a vasodilator, anticoagulant, or thrombolytic to induce bleeding during a tagged red blood cell scan or visceral angiogram was included. RESULTS: Seven provocative bleeding studies were performed on seven patients. All patients underwent a visceral angiogram with intra-arterial administration of tolazoline (a vasodilator), heparin (an anticoagulant), and/or urokinase (a thrombolytic). Of the seven provocative studies, only two induced angiographically identifiable bleeding. Both of these patients underwent surgical therapy. There were no complications attributed to the provocative bleeding studies. CONCLUSIONS: These results suggest that provocative GI bleeding studies can be performed safely. However, because an active bleeding source was identified in only a small proportion of patients, we believe that further study is required to optimize patient selection and to clarify the cost-effectiveness of this approach in patients with GI hemorrhage of obscure origin.

Use of specialized bone screws for intermaxillary fixation.

Fixation of the injured mandible to the maxilla is a proven method of stabilizing mandibular fractures and ensuring proper occlusion. The authors report their results with new specialized intraoral bone screws (IMF Screw System; Howmedica Leibinger, Inc., Carrollton, TX) that are designed for the purpose of achieving intermaxillary fixation (IMF). Nineteen patients were placed into rigid IMF using IMF screws alone. Indications were nondisplaced mandibular fractures; symphyseal, body, and angle fractures; midfacial fractures requiring temporary IMF; and edentulous patients with any of these fracture types and an adequate prosthesis. All procedures were performed with the patient under general anesthesia. The authors found that the operative time was markedly shorter than with standard IMF techniques, patient satisfaction was high, and there were no infections related to the screws. All 19 patients remained in stable, accurate occlusion and had adequate healing. One patient continues to have paraesthesias in the mental nerve distribution after screw removal. Although there is the potential for tooth and nerve injury when screws are placed improperly, the IMF Screw System seems to be a safe and reliable method of achieving secure mandibular fixation.

Opening of the mitochondrial permeability transition pore causes matrix expansion and outer membrane rupture in Fas-mediated hepatic apoptosis in mice.

Although Fas stimulation has been reported to cause outer mitochondrial membrane rupture in Jurkat cells, the mechanism of this effect is debated, and it is not known if outer membrane rupture also occurs in hepatocyte mitochondria. We studied the in vivo effects of Fas stimulation on ultrastructural lesions and mitochondrial function in mice. Four hours after administration of an agonistic anti-Fas antibody (8 microg/animal), caspase activity increased 5.4-fold. Nuclear DNA showed internucleosomal fragmentation, whereas supercoiled mitochondrial DNA was replaced by circular and linear forms. Mitochondrial cytochrome c was partly released into the cytosol. Ultrastructurally, mitochondrial lesions were observed in both apoptotic hepatocytes (with nuclear chromatin condensation/fragmentation) and nonapoptotic hepatocytes (without nuclear changes). In nonapoptotic cells, outer mitochondrial membrane rupture allowed herniation of the inner membrane and matrix through the outer membrane gap. In apoptotic hepatocytes, the matrix became electron-lucent and no longer protruded through the outer membrane gap. Mitochondria clustered around the nucleus, whereas rough endoplasmic reticulum cisternae became peripheral. In liver mitochondria isolated after Fas stimulation, the membrane potential decreased, whereas basal respiration increased. Pretreatment with either z-VAD-fmk (an inhibitor of caspases) or cyclosporin A (a permeability transition inhibitor) totally or mostly prevented mitochondrial outer membrane rupture, membrane potential decrease, cytochrome c release, and apoptosis. In conclusion, in vivo Fas stimulation causes caspase activation, mitochondrial permeability transition (decreasing the membrane potential and increasing basal respiration), mitochondrial matrix expansion (as shown by matrix herniation), outer mitochondrial membrane rupture, and cytochrome c release.

Beta-adrenergic receptor blockade by propranolol enhances retention in a multitrial passive-avoidance procedure.

The effect of beta-adrenergic receptor blockade on retention in a mildly aversive passive-avoidance procedure was investigated. Rats were given passive-avoidance training--1 trial per day for 4 days-and were administered saline, the centrally and peripherally acting beta-adrenergic blocker propranolol (4 or 10 mg/kg ip), or the peripherally acting beta-adrenergic blocker sotalol (4 or 10 mg/kg ip) immediately or 2 hr after the 1st trial. Enhanced retention occurred only with the higher dose (10 mg/kg) of propranolol and only when it was administered immediately after training. The enhanced retention produced by propranolol is discussed in terms of opposing, regionally specific actions of beta-adrenergic receptor-mediated neural circuits on modulation of memory.

Lead hydro sodalite [Pb2(OH)(H2O)3]2[Al3Si3O12]2: synthesis and structure determination by combining X-ray rietveld refinement, 1H MAS NMR FTIR and XANES spectroscopy.

Ion exchange of the sodium hydro sodalites [Na3(H2O)4]2-[Al3Si3O12]2 [Na4(H3O2)]2[Al3Si3O12]2 and [Na4(OH)]2[Al3Si3O12]2 with aqueous Pb(NO3)2 solutions yielded, whichever reactant sodalite phase was used, the same lead hydro sodalite, [Pb2(OH)-(H2O)3]2[Al3Si3O12]2. Thus, in the case of the non-basic reactant [Na3(H2O)4]2-[Al3Si3O12]2 an overexchange occurs with respect to the number of nonframework cationic charges. Rietveld structure refinement of the lead hydro sodalite based on powder X-ray diffraction data (cubic, a = 9.070 A, room temperature, space group P43n) revealed that the two lead cations within each polyhedral sodalite cage form an orientationally disordered dinuclear [Pb2(micro-OH)(micro-H2O)(H2O)2]3+ complex. Due to additional lead framework oxygen bonds the coordination environment of each metal cation (CN 3+3) is approximately spherical, and clearly the lead 6s electron lone pair is stereochemically inactive. This is also suggested by the absence of a small peak at 13.025 keV, attributed in other Pb2+-O compounds to an electronic 2p-6s transition, in the PbL3 edge XANES spectrum. 1H MAS NMR and FTIR spectra show that the hydrogen atoms of the aqua hydroxo complex (which could not be determined in the Rietveld analysis) are involved in hydrogen bonds of various strengths.

N-methyl-D-aspartate receptor agonists modulate homocysteine-induced developmental abnormalities.

We showed previously that the induction of neural crest (NC) and neural tube (NT) defects is a general property of N-methyl-D-aspartate receptor (NMDAR) antagonists. Since homocysteine induces NC and NT defects and can also act as an NMDAR antagonist, we hypothesized that the mechanism of homocysteine-induced developmental defects is mediated by competitive inhibition of the NMDAR by homocysteine. If this hypothesis is correct, homocysteine-induced defects will be reduced by NMDAR agonists. To test the hypothesis, we treated chicken embryos during the process of neural tube closure with sufficient homocysteine thiolactone to induce NC and NT defects in approximately 40% of survivors or with homocysteine thiolactone in combination with each of a selected set of NMDAR agonists in 0. 05-5000 nmol doses. Glutamate site agonists selected were L-glutamate and N-methyl-D-aspartate. Glycine site agonists were glycine, D-cycloserine, and aminocyclopropane-carboxylic acid. Glycine was the most effective overall, reducing defects significantly at two different doses (each P>0.001). These results support the hypothesis that homocysteine may affect NC and NT development by its ability to inhibit the NMDAR. One potentially important consequence of this putative mechanism is that homocysteine may interact synergistically with other NMDAR antagonists to enhance its effect on development.

Hepatocyte growth factor activates the AP-1 complex: a comparison between normal and transformed rat hepatocytes.

BACKGROUND/AIMS: Stimulation of activator protein-1 (AP-1), a Fos/Jun complex, is a key event in the cell response to growth factors. We have investigated whether hepatocyte growth factor (HGF) induces differential AP-1 responses in normal and transformed rat hepatocytes, the 7777 cells. METHODS: Primocultures of isolated hepatocytes or 7777 cells were stimulated with HGF. Gene expression was evaluated by ribonuclease protection assay and Western blot analysis. AP-1 DNA binding activity was measured by electrophoretic mobility shift assay. Identification of the proteins bound to the probes was made by supershift assays with specific antibodies. Cells were electroporated with plasmids containing an AP-1-dependent chloramphenicol acetyl transferase (CAT) gene, and CAT activity was measured 24 h after treatment with medium alone or HGF. RESULTS: In both cell types, HGF triggered the same program of jun family mRNA activation, but distinct Fos/Jun proteins accumulated in the nucleus. HGF increased DNA-binding activity to the phorbol 12-O-tetradecanoate-13-acetate responsive element (TRE) in both cell types, but distinct TRE-binding proteins were recruited in the AP-1 dimers. HGF also increased consistently binding to a cAMP responsive element (CRE) in hepatocytes only. Finally, HGF triggered TRE- and CRE-dependent gene activations in hepatocytes but TRE-dependent gene activation alone in 7777 cells. CONCLUSIONS: HGF-induced AP-1 activation leads to the formation of distinct dimers with different functional capacities in normal and transformed hepatocytes. These data suggest the importance of qualitative abnormalities of the AP-1 complex for the establishment or maintainance of a transformed phenotype.

Use of subatmospheric pressure to prevent progression of partial-thickness burns in a swine model.

The poorly understood, complex series of events that follows thermal injury frequently results in progressive loss of tissue. The concept of reversing this distinctive series of events has focused on the zone of stasis. Tissues in the zone of stasis that surround burn injuries usually die over a period of 48 to 72 hours postinjury, resulting in a more severe injury. Application of a controlled subatmospheric pressure (125 mm Hg) in an artificially closed space to partial-thickness burns in pigs significantly decreased the maximum depth of cellular death under the burn when the pressure was applied within 12 hours after burn creation (depth of control burns = 0.885 +/- 0.115 mm; subatmospheric pressure treated burns (0-hour delay) = 0.095 +/- 0.025 mm). A decrease in the depth of cell death was noted when subatmospheric pressure was applied for as little as 6 hours. In summary, the application of the negative pressure to partial-thickness burn injuries prevented progression of the wound to a deeper injury in this experimental pig model. A 12-hour working window exists between injury and treatment with reduced pressure, with an application time of as little as 6 hours for successful prevention of injury progression. This technique may represent a new, inexpensive, 'low tech' method for the treatment of partial-thickness burn injuries.

Elecsys CEA, PSA and AFP. Clinical results of a multicentre evaluation.

Three tumormarker assays, Elecsys CEA, PSA and AFP, have been evaluated in an international multicentre study to characterize their clinical performance and to verify the comparability with the corresponding tests of the Enzymun-Test product line and other methods. For each of the markers results were obtained from four laboratories. On the basis of 314 and 199 specimens respectively, (preliminary) reference ranges could be established for CEA and PSA. For the prostate marker, the age dependence of the antigen level could be clearly confirmed. Mean concentrations range between 0.51 ng/ml (< 40 years) and 3.57 ng/ml (> 70 years). Referring to CEA, 95th percentiles of 4.31 ng/ml and 2.69 ng/ml were elaborated for smokers and nonsmokers. In general, good to excellent correlations (r > 0.98) were found between the Elecsys and Enzymun-Tests. Regarding the systematic comparability of both systems, most of the slopes derived from the individual method comparison studies are within the +/- 10% range of the respective standardization results. The specific distribution pattern of the individual tumormarker values elaborated with sample material of known clinical background, reflects the well established categorization of different benign and malignant diseases according to their characteristic marker levels. Of utmost importance, however, is the excellent comparability of the Elecsys assays with the corresponding Enzymun-Tests and the FDA approved AIA 1200 tests from TOSOH in follow-up studies. Almost superimposable concentration curves guarantee that identical diagnostic information is derived from all three methods. Especially for PSA, a series of measurements on sera of prostatectomized patients proved the usability and clinical value of the test also for this particular indication. For either one of the Elecsys tests, the feasibility of using plasma as sample material was verified.

Iodine-131-metaiodobenzylguanidine uptake in metastatic carcinoid tumor to the orbit.

Metastatic tumor is one of several etiologies of space-occupying masses in the orbit that accounts for 1%-13% of all orbital masses (1). In the adult patient population, breast cancer is the most common tumor to metastasize to the orbit followed by metastases from the lung, prostate and gastrointestinal tract (2). It is rare for carcinoid tumors to metastasize to the eye or to the orbit. Carcinoid tumors arise from Kulchitsky cells that originate in the neural crest. Histologically, these tumors resemble, but are not as aggressive as, adenocarcinomas. Most carcinoids arise in the gastrointestinal tract or the lung. The most common site for carcinoid metastases is the liver. On anatomical imaging studies, such as CT and magnetic resonance imaging, metastatic orbital carcinoid tumors appear as nonspecific tumor masses. Carcinoid tumors have an affinity for uptake of the radiopharmaceutical 131I-metaiodobenzylguanidine (MIBG) (3). We report a case of a patient with a known carcinoid tumor who developed a left orbital mass that demonstrated abnormal uptake of 131I-MIBG indicative of metastatic carcinoid tumor to the orbit.