Medizin - Open Access LMU - Teil 13/22

This study aimed to test the utility of the ozone challenge model for profiling novel compounds designed to reduce airway inflammation. The authors used a randomized, doubledummy, double-blind, placebo-controlled 3-period crossover design alternating single orally inhaled doses of fluticasone propionate (inhaled corticosteroids, 2mg), oral prednisolone (oral corticosteroids, 50mg), ormatched placebo. At a 2-week interval, 18 healthy ozone responders (>10% increase in sputum neutrophils) underwent a 3-hour ozone (250 ppb)/intermittent exercise challenge starting 1 hour after drug treatment. Airway inflammation was assessed at 2 hours (breath condensate) and 3 hours (induced sputum) after ozone challenge. Compared to placebo, pretreatment with inhaled corticosteroids or oral corticosteroids resulted in a significant reduction (mean [95% confidence interval]) of sputum neutrophils by 62% (35%, 77%) and 64% (39%, 79%) and of sputum supernatant myeloperoxidase by 55% (41%, 66%) and 42% (25%, 56%), respectively. The authors conclude that an optimized ozone challenge model (including ozone responders and ensuring adequate drug levels during exposure) may be useful for testing novel anti-inflammatory compounds in early development.

Background: Bile acid-induced apoptosis in hepatocytes can be antagonized by NF-κBdependent survival pathways. Sulfasalazine modulates NF-κB in different cell types. We aimed to determine the effects of sulfasalazine and its metabolites sulfapyridine and 5-aminosalicylic acid (5-ASA) on bile acid-induced apoptosis in hepatocytes. Methods: Apoptosis was determined by caspase assays and immunoblotting, NF-κB activation by EMSA and reporter gene assays, generation of reactive oxygen species (ROS) fluorometrically, bile secretion gravimetrically and bile acid uptake radiochemically and by gaschromatography in HepG2-Ntcp cells and isolated perfused rat livers. Results: Glycochenodeoxycholic acid (GCDCA, 75μmol/L)-induced apoptosis was reduced by sulfasalazine dose-dependently (1-1000 μmol/L) in HepG2-Ntcp cells, whereas its metabolites 5- ASA and sulfapyridine had no effect. Sulfasalazine significantly reduced GCDCA-induced activation of caspases 9 and 3. In addition, sulfasalazine activated NF-κB, and decreased GCDCA-induced generation of ROS. Bile acid uptake was competetively inhibited by sulfasalazine. In perfused rat livers, GCDCA (25 μmol/L)-induced liver injury and extensive hepatocyte apoptosis were significantly reduced by simultaneous administration of 100 μmol/L sulfasalazine: LDH and GPT activities were reduced by 82% and 87%, respectively, and apoptotic hepatocytes were observed only occasionally. GCDCA uptake was reduced by 45±5% when sulfasalazine was coadministered. However, when 50% of GCDCA (12.5 μmol/L) were administered alone, marked hepatocyte apoptosis and liver injury were again observed questioning the impact of reduced GCDCA uptake for the antiapoptotic effect of sulfasalazine. Conclusion: Sulfasalazine is a potent inhibitor of GCDCA-induced hepatocyte apoptosis in vitro and in the intact liver.

Background/Aims The apical sodium dependent bile acid transporter ASBT (SLC10A2) contributes substantially to the enterohepatic circulation of bile acids by their reabsorption from the intestine. In the rat, its adaptive regulation was observed in the kidneys, cholangiocytes and terminal ileum after bile duct ligation. Whether an adaptive regulation of the human intestinal ASBT exists during obstructive cholestasis is not known. Methods Human ASBT mRNA expression along the intestinal tract was analyzed by real time PCR in biopsies of 14 control subjects undergoing both gastroscopy and colonoscopy. Their duodenal ASBT mRNA expression was compared to 20 patients with obstructive cholestasis. Additionally, in 4 patients with obstructive cholestasis, duodenal ASBT mRNA expression was measured after reconstitution of bile flow. Results Normalized ASBT expression in control subjects was highest (mean arbitrary units± SEM) in the terminal ileum 1010 ± 330. Low ASBT expression was found in the colonic segments (8.3±5, 4.9±0.9, 4.8±1.7 and 1.1±0.2, ascending, transverse, descending, and sigmoid colon, respectively). Duodenal ASBT expression of control subjects was found with 171.8±20.3 at about four fold higher levels when compared to 37.9±6.5 (p

Sat, 1 Jan 2005 12:00:00 +0100 https://epub.ub.uni-muenchen.de/16297/1/10_1159_000083944.pdf Fichter, Manfred M.; Hegerl, Ulrich ddc:610, Medizin

Even if the freedom to suicide is part of our human existence, about 90% of all suicides occur in the context of psychiatric disorders and thus in states of limited power of judgment. Depressive disorders represent the most frequent cause for suicides. Thus, optimization of medical care for depressive patients is one of the most promising strategies to prevent suicides. In the context of the `Nuremberg Alliance Against Depression' it came to an obvious reduction of suicidal acts compared to a baseline year and compared to the control region of Wurzburg. The reduction could be reached by a cooperation with GPs, multipliers such as teachers, priests, geriatric caregivers and the media, through intensive public relations work and through support of self help activities. This approach is carried forward within the Germany-wide `Alliance Against Depression' and within the `European Alliance Against Depression' ( EAAD) which is funded by the European Commission. In the last part of the article the suicide- preventive, but also the possible suicide-inducing effect of antidepressants is discussed.

According to official statistics every year 11,000 persons in Germany die from suicide. 20 years ago nearly 19,000 suicides were registered. What are the causes for this decrease? Do suicide preventive measures contribute to the reduction of suicide rates? Different universal prevention strategies ( e. g. restriction of access to means) and selective approaches ( programs for special high-risk groups; e. g. patients after attempted suicide) are presented and discussed regarding their preventive value. In most cases it is hardly possible to scientifically prove the efficacy of suicide prevention strategies. Neither the role of psychosocial interventions nor the impact of psychotropic agents can be sufficiently quantified. Due to various methodological reasons ( e. g. small sample sizes and the lack of randomization), interpretation of the data is difficult. In terms of a comprehensive approach of suicide prevention a combination of different activities should be most adequate in the long run.

The number of people aged 14 and older that use the Internet in Germany has doubled to 35.7 millions (55.3%) since the year 2000. The Internet also more and more expands into the domain of psychiatry and psychotherapy, and is used by psychiatric patients for information, communication and therapeutic purposes. Nevertheless, the infinite possibilities of the World Wide Web are linked with several advantages and disadvantages. Easily accessible information, numerous opportunities for exchange among like-minded people and therapeutic support from online therapies are juxtaposed with such risks as frequently lacking quality and transparency of the available information, possible enhancement of social withdrawal and certain Websites concerning suicide. If the mentioned risks of the Internet rather provoke new problems and trigger suicidality or if the chance of an easily accessible online discussion rather results in mental relief cannot be answered generally.

Nucleosomes appear spontaneously in elevated concentrations in the serum of patients with malignant diseases as well as during chemo- and radiotherapy. We analyzed whether their kinetics show typical characteristics during radiochemotherapy and enable an early estimation of therapy efficacy. We used the Cell Death Detection Elisaplus ( Roche Diagnostics) and investigated the course of nucleosomes in the serum of 32 patients with a local stage of pancreatic cancer who were treated with radiochemotherapy for several weeks. Ten of them received postsurgical therapy, 21 received primary therapy and 1 received therapy for local relapse. Blood was taken before the beginning of therapy, daily during the first week, once weekly during the following weeks and at the end of radiochemotherapy. The response to therapy was defined according to the kinetics of CA 19-9: a decrease of CA 19-9 650% after radiochemotherapy was considered as `remission'; an increase of >= 100% ( which was confirmed by two following values) was defined as `progression'. Patients with `stable disease' ranged intermediately. Most of the examined patients showed a decrease of the concentration of nucleosomes within 6 h after the first dose of radiation. Afterwards, nucleosome levels increased rapidly, reaching their maximum during the following days. Patients receiving postsurgery, primary or relapse therapies did not show significant differences in nucleosome values during the time of treatment. Single nucleosome values, measured at 6, 24 and 48 h after the application of therapy, could not discriminate significantly between patients with no progression and those with progression of disease. However, the area under the curve of the first 3 days, which integrated all variables of the initial therapeutic phase, showed a significant correlation with the progression-free interval ( p = 0.008). Our results indicate that the area under the curve of nucleosomes during the initial phase of radiochemotherapy could be valuable for the early prediction of the progression-free interval. Copyright (C) 2005 S. Karger AG, Basel.

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin ( trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy. Copyright (C) 2005 S. Karger AG, Basel.

Fluticasone propionate - the first carbothioate corticosteroid - has been classified as a potent anti-inflammatory drug for dermatological use. It is available as 0.05% cream and 0.005% ointment formulations for the acute and maintenance treatment of patients with dermatological disorders such as atopic dermatitis, psoriasis and vitiligo. This glucocorticoid is characterized by high lipophilicity, high glucocorticoid receptor binding and activation, and a rapid metabolic turnover in skin. Although skin blanching following fluticasone propionate exceeds that of corticosteroids of medium strength, several clinical trials demonstrate a low potential for cutaneous and systemic side-effects, even in difficult-to-treat areas like the face, the eyelids and intertriginous areas. Even among paediatric patients with atopic dermatitis, fluticasone propionate proved to be safe and effective. These pharmacological and clinical properties are reflected by the high therapeutic index of this glucocorticoid.

Topical glucocorticoids have always been considered first-line drugs for inflammatory diseases of the skin and bronchial system. Applied systemically, glucocorticoids are used for severe inflammatory and immunological diseases and the inhibition of transplant rejection. Owing to the progress in molecular pharmacology, the knowledge of the mechanism of action has increased during the last years. Besides distinct genomic targets, which are due to the activation of specific cytoplasmatic receptors resulting in the (trans-) activation or (trans-) repression of target genes, there are non-genomic effects on the basis of the interference with membrane-associated receptors as well as with membrane lipids. In fact, various glucocorticoids appear to differ with respect to the relative influence on these targets. Thus, the extended knowledge of glucocorticoid-induced cellular signalling should allow the design and development of even more specifically acting drugs-as it has been obtained with other steroids, e.g. estrogens for osteoporosis prevention. Copyright (C) 2005 S. Karger AG, Basel.

It is well established that sun exposure is the main cause for the development of skin cancer. Chronic continuous UV radiation is believed to induce malignant melanoma, whereas intermittent high-dose UV exposure contributes to the occurrence of actinic keratosis as precursor lesions of squamous cell carcinoma as well as basal cell carcinoma. Not only photocarcinogenesis but also the mechanisms of photoaging have recently become apparent. In this respect the use of sunscreens seemed to prove to be more and more important and popular within the last decades. However, there is still inconsistency about the usefulness of sunscreens. Several studies show that inadequate use and incomplete UV spectrum efficacy may compromise protection more than previously expected. The sunscreen market is crowded by numerous products. Inorganic sunscreens such as zinc oxide and titanium oxide have a wide spectral range of activity compared to most of the organic sunscreen products. It is not uncommon for organic sunscreens to cause photocontact allergy, but their cosmetic acceptability is still superior to the one given by inorganic sunscreens. Recently, modern galenic approaches such as micronization and encapsulation allow the development of high-quality inorganic sunscreens. The potential systemic toxicity of organic sunscreens has lately primarily been discussed controversially in public, and several studies show contradictory results. Although a matter of debate, at present the sun protection factor (SPF) is the most reliable information for the consumer as a measure of sunscreen filter efficacy. In this context additional tests have been introduced for the evaluation of not only the protective effect against erythema but also protection against UV-induced immunological and mutational effects. Recently, combinations of UV filters with agents active in DNA repair have been introduced in order to improve photoprotection. This article reviews the efficacy of sunscreens in the prevention of epithelial and nonepithelial skin cancer, the effect on immunosuppression and the value of the SPF as well as new developments on the sunscreen market. Copyright (C) 2005 S. Karger AG, Basel.

Introduction: Facial lipoatrophy is a crucial problem of HIV-infected patients undergoing highly active antiretroviral therapy (HAART). Poly-L-lactic acid (PLA), provided as New-Fill(R)/Sculptra(TM), is known as one possible treatment option. In 2004 PLA was approved by the FDA as Sculptra(TM) for the treatment of lipoatrophy of the face in HIV-infected patients. While the first trials demonstrated relevant efficacy, this was to some extent linked to unwanted effects. As the depth of injection was considered relevant in this context, the application modalities of the preparation were changed. The preparation was to be injected more deeply into subcutaneous tissue, after increased dilution. Material and Methods: To test this approach we performed a pilot study following the new recommendations in 14 patients. Results: While the efficacy turned out to be about the same, tolerability was markedly improved. The increase in facial dermal thickness was particularly obvious in those patients who had suffered from lipoatrophy for a comparatively small period of time. Conclusion: With the new recommendations to dilute PLA powder and to inject it into the deeper subcutaneous tissue nodule formation is a minor problem. However, good treatment results can only be achieved if lipoatrophy is not too intense; treatment intervals should be about 2 - 3 weeks. Copyright (C) 2005 S. Karger AG, Basel.

Sat, 1 Jan 2005 12:00:00 +0100 https://epub.ub.uni-muenchen.de/16379/1/10_1159_000085352.pdf Soyka, Michael; Krauseneck, T. ddc:610, Medizin

Purpose: To investigate retinal thickness and optic disc parameters by the Retinal Thickness Analyzer (RTA) glaucoma program in older normal subjects and to determine any age effect. Methods: Subjects over 40 years of age without any prior history of eye diseases were recruited. Only subjects completely normal on clinical ophthalmologic examination and on visual field testing by Humphrey Field Analyzer (HFA) using the SITA 24-2 program were included. A total of 74 eyes from 74 subjects with even age distribution over the decades were enrolled and underwent topographic measurements of the posterior pole and of the optic disc by RTA. The `glaucoma full' program in software version 4.11B was applied. Results: Mean patient age was 59.9 +/- 10.3 years with a range from 40 to 80 years. The only parameter intraocular pressure (IOP) correlated with was retinal posterior pole asymmetry (r=0.27, p=0.02). IOP itself increased significantly with age (r=0.341, p=0.003). Mean defect and pattern standard deviation of the HFA did not correlate with any of the retinal or optic disc measurements. Increasing age correlated significantly with some of the morphologic measurements of the RTA: decreasing perifoveal minimum thickness (r=-0.258, p=0.026), increased cup-to-disc area ratio (r=0.302, p=0.016) and increased cup area (r=0.338 p=0.007). Conclusions: An age effect exists for some of the retina and optic disc measurements obtained by the RTA. Copyright (C) 2005 S. Karger AG, Basel.

Background: HER2 is overexpressed in 20 - 30% of breast cancers. Compared to chemotherapy alone, chemotherapy with trastuzumab improves clinical outcome in patients with HER2- positive metastatic breast cancer ( MBC). In general, HER2 status in a primary lesion predicts the status of metastases, so that biopsy of metastatic lesions appears unnecessary. Case Report: A 39- year old woman was diagnosed with primary breast cancer in November 2000. Using the method and scoring system of the DAKO Hercep Test, the tumor has shown low HER2 expression ( DAKO score 1+). After failure of several chemotherapy regimens for metastatic disease ( liver, skeletal), the patient underwent CT- guided needle biopsy of the liver which showed HER2 positive adenocarcinoma ( DAKO score 3+). In consequence, the patient was treated with vinorelbine ( 30 mg/ m(2) d1,8,15 q4w) and trastuzumab ( 4 mg/ kg loading dose, 2 mg/ kg weekly). During a treatment period of 4 months imaging results as well as tumor marker kinetics indicated an excellent response with sustained decrease of tumor markers. A retrospective analysis of the HER2 shed antigen in metastatic stage revealed excessively increased serum levels and supports HER2 overexpression observed in liver metastasis. The kinetics of the HER2 shed antigen during therapy for metastatic disease were found to be in phase with the kinetics of CEA and CA15- 3. Conclusion: This case report demonstrates that re- evaluation of the HER2 status may be helpful in single patients not sufficiently responding to treatment of metastatic disease. Determination of HER2 overexpression may be facilitated by a determination of the HER2 shed antigen level in peripheral blood.

Vascular endothelial growth factors ( VEGF)- A, - C and - D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma ( EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma ( SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and VEGF-D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending.

Objective: The purpose of this pilot study was to evaluate the feasibility and toxicity of concurrent chemotherapy with vinorelbine and mitomycin C in combination with accelerated radiotherapy (RT) in patients with locally advanced cancer of the head and neck. Patients and Methods: Between January 2003 and March 2004, 15 patients with T4/N2-3 squamous cell carcinoma (12/15) and with N3 cervical lymph node metastases of carcinoma of unknown primary (3/15) were treated with chemotherapy and simultaneous accelerated RT. Results: 11 patients completed therapy without interruption or dose reduction. Grade 3 - 4 acute mucosal toxicity was observed in 9/15 patients, grade 4 hematologic toxicity in 6/15 patients. At a median follow-up of 7.5 months, 2 patients have died of intercurrent disease, 2 patients have experienced local relapse; 5 patients are alive with no evidence of disease at the primary tumor site. Discussion: The described regimen is highly effective, but led to remarkable side effects.

Background: The aim of this retrospective analysis was to evaluate the impact of trastuzumab-based regimens on the survival of patients with HER2-overexpressing metastatic breast cancer (MBC). The study specifically focussed on the influence of the continuation of trastuzumab-based treatment despite tumor progression on survival. Patients and Methods: Patients with HER2 overexpressing MBC were included in this retrospective analysis. HER2 overexpression was determined by the immunohistochemical staining score (DAKO Hercep Test (TM)). Trastuzumab was applied at a loading dose of 4 mg/kg and a maintenance dose of 2 mg/kg. Results: Among 136 HER2 overexpressing patients (DAKO score 3+), 66 patients received first-line trastuzumab, 47 patients received trastuzumab as second-line therapy and 23 patients received trastuzumab beyond disease progression. There was no significant difference regarding the duration of trastuzumab-based treatment (first-line: 29.5 weeks vs. second-line: 25 weeks). Moreover, there was no difference in the response rate (first-line: 37.9% vs. second-line: 35.7%) or the median survival (p = 0.47 log rank). Patients who received >= 2 trastuzumab-based regimens for MBC survived significantly longer compared to those who had received only 1 regimen (>= 2 regimens: 62.4 months vs. 1 regimen: 38.5 months; p = 0.01 log rank). Conclusions: Trastuzumab is highly effective in the treatment of HER2 overexpressing MBC. Compared to historical controls, overall survival appears to be markedly prolonged, particularly in patients who received sequential trastuzumab-based treatment beyond disease progression.

Objective: To determine the expression of endogenous adhesion/growth-regulatory lectins and their binding sites using labeled tissue lectins as well as the binding profile of hyaluronic acid as an approach to define new prognostic markers. Methods: Sections of paraffin-embedded histological material of 481 lungs from lung tumor patients following radical lung excision processed by a routine immunohistochemical method (avidin-biotin labeling, DAB chromogen). Specific antibodies against galectins-1 and - 3 and the heparin-binding lectin were tested. Staining by labeled galectins and hyaluronic acid was similarly visualized by a routine protocol. After semiquantitative assessment of staining, the results were compared with the pT and pN stages and the histological type. Survival was calculated by univariate and multivariate methods. Results: Binding of galectin-1 and its expression tended to increase, whereas the parameters for galectin-3 decreased in advanced pT and pN stages at a statistically significant level. The number of positive cases was considerably smaller among the cases with small cell lung cancer than in the group with non-small-cell lung cancer, among which adenocarcinomas figured prominently with the exception of galectin-1 expression. Kaplan-Meier computations revealed that the survival rate of patients with galectin-3-binding or galectin-1-expressing tumors was significantly poorer than that of the negative cases. In the multivariate calculations of survival lymph node metastases ( p < 0.0001), histological type ( p = 0.003), galectin-3-binding capacity ( p = 0.01), galectin-3 expression ( p = 0.03) and pT status ( p = 0.003) proved to be independent prognostic factors, not correlated with the pN stage. Conclusion: The expression and the capacity to bind the adhesion/growth regulatory galectin-3 is defined as an unfavorable prognostic factor not correlated with the pTN stage. Copyright (C) 2005 S. Karger AG, Basel.

Background: Docetaxel is one of the most effective antitumor agents currently available for the treatment of metastatic breast cancer (MBC). This phase II multicenter study prospectively analyzed the efficacy and toxicity of docetaxel given on a weekly schedule as first-line treatment of metastatic breast cancer. Patients and Methods: All patients received docetaxel, 35 mg/m(2) weekly for 6 weeks, followed by 2 weeks of rest. Subsequent cycles ( 3 weeks of treatment, 2 weeks of rest) were given until a maximum of 5 cycles or disease progression. Premedication consisted of 8 mg dexamethasone intravenously 30 min prior to the infusion of docetaxel. Results: Fifty-four patients at a median age of 58 years with previously untreated MBC were included in the study. A median of 10 doses ( median cumulative dose 339 mg/m(2)) was administered ( range: 2 - 18). The overall response rate was 48.1% ( 95% CI: 34 - 61%, intent-to-treat). Median survival was 15.8 months and median time to progression was 5.9 months ( intent-to-treat). Hematological toxicity was mild with absence of neutropenia-related complications. Grade 3 neutropenia was observed in 3.7% of patients and grade 3 and 4 anemia was observed in 5.6 and 1.9% of patients, respectively. Conclusion: The weekly administration of docetaxel is highly efficient and safe as first-line treatment for MBC and may serve as an important treatment option specifically in elderly patients and patients with a reduced performance status. Copyright (C) 2005 S. Karger AG, Basel.

Background: Saccadic eye velocity (SEV) has been shown to be a reliable neurophysiological tool for the assessment of gamma-aminobutyric acid GABA(A) receptor sensitivity. Administration of benzodiazepines targeting the GABA(A) receptor decreases SEV in healthy volunteers. Tiagabine is a new antiepileptic drug which acts via selective blockade of GABA reuptake. Therefore, we examined the effects of tiagabine on saccade parameters. Methods: SEV was analyzed in 8 healthy volunteers before and after 7 days of tiagabine treatment. Subjects received tiagabine in a daily dose of 15 mg. Saccades were measured using a noninvasive infrared oculographic device. Amplitude, latency, and SEV were analyzed as a function of treatment and target eccentricity. Results: SEV and saccade latency increased with target amplitude. Treatment with tiagabine had no significant effect on SEV and saccade amplitude. A trend was found for increased latencies after tiagabine. Conclusion: In contrast to findings with benzodiazepines, tiagabine treatment had no impact on SEV in healthy volunteers. The subchronic tolerance effects or the different site of action on the GABA(A)/BZD receptor complex may account for this deviating profile. Copyright (C) 2005 S. Karger AG, Basel.

Objectives: We have previously reported reduced serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) in schizophrenic patients. A single-nucleotide polymorphism ( SNP) of the ICAM-1 gene was described at position 241. The G --> A SNP results in a nonsynonymous amino acid exchange of the ICAM-1 protein, and the A allele was shown to be also associated with several immunological disorders like rheumatoid arthritis. Methods: We investigated 70 schizophrenic patients and 128 unrelated healthy control persons regarding the relationship between the serum levels of sICAM-1 and the ICAM-1 G214A polymorphism. Results: We were able to replicate our previous finding of reduced sICAM-1 levels in schizophrenia. Healthy control persons carrying the polymorphic A allele showed markedly lower sICAM-1 serum levels than carriers of the homozygous GG wild type ( p < 0.004). In contrast, no significant difference in the sICAM-1 serum levels were seen regarding the G241A genotype distribution in schizophrenic patients. Conclusion: We hypothesize that the biochemical effect of the G241A SNP is masked in schizophrenic patients, indicating a disease-related mechanism leading to reduced levels of sICAM-1 in schizophrenia. Copyright (C) 2005 S. Karger AG, Basel.

Gonadal steroids are known to influence hypothalamic functions through both genomic and non-genomic pathways. Sex hormone-binding globulin ( SHBG) may act by a non-genomic mechanism independent of classical steroid receptors. Here we describe the immunocytochemical mapping of SHBG-containing neurons and nerve fibers in the human hypothalamus and infundibulum. Mass spectrometry and Western blot analysis were also used to characterize the biochemical characteristics of SHBG in the hypothalamus and cerebrospinal fluid (CSF) of humans. SHBG-immunoreactive neurons were observed in the supraoptic nucleus, the suprachiasmatic nucleus, the bed nucleus of the stria terminalis, paraventricular nucleus, arcuate nucleus, the perifornical region and the medial preoptic area in human brains. There were SHBG-immunoreactive axons in the median eminence and the infundibulum. A partial colocalization with oxytocin could be observed in the posterior pituitary lobe in consecutive semithin sections. We also found strong immunoreactivity for SHBG in epithelial cells of the choroid plexus and in a portion of the ependymal cells lining the third ventricle. Mass spectrometry showed that affinity-purified SHBG from the hypothalamus and choroid plexus is structurally similar to the SHBG identified in the CSF. The multiple localizations of SHBG suggest neurohypophyseal and neuroendocrine functions. The biochemical data suggest that CSF SHBG is of brain rather than blood origin. Copyright (c) 2005 S. Karger AG, Basel

gamma-Aminobutyric acid (GABA) is an emerging signalling molecule in endocrine organs, since it is produced by endocrine cells and acts via GABA(A) receptors in a paracrine/autocrine fashion. Testicular Leydig cells are producers and targets for GABA. These cells express GABA(A) receptor subunits and in the murine Leydig cell line TM3 pharmacological activation leads to increased proliferation. The signalling pathway of GABA in these cells is not known in this study. We therefore attempted to elucidate details of GABA(A) signalling in TM3 and adult mouse Leydig cells using several experimental approaches. TM3 cells not only express GABA(A) receptor subunits, but also bind the GABA agonist {[}H-3] muscimol with a binding affinity in the range reported for other endocrine cells (K-d = 2.740 +/- 0.721 nM). However, they exhibit a low B-max value of 28.08 fmol/mg protein. Typical GABA(A) receptor-associated events, including Cl- currents, changes in resting membrane potential, intracellular Ca2+ or cAMP, were not measurable with the methods employed in TM3 cells, or, as studied in part, in primary mouse Leydig cells. GABA or GABA(A) agonist isoguvacine treatment resulted in increased or decreased levels of several mRNAs, including transcription factors (c-fos, hsf-1, egr-1) and cell cycle-associated genes (Cdk2, cyclin D1). In an attempt to verify the cDNA array results and because egr-1 was recently implied in Leydig cell development, we further studied this factor. RT-PCR and Western blotting confirmed a time-dependent regulation of egr-1 in TM3. In the postnatal testis egr-1 was seen in cytoplasmic and nuclear locations of developing Leydig cells, which bear GABA(A) receptors and correspond well to TM3 cells. Thus, GABA acts via an untypical novel signalling pathway in TM3 cells. Further details of this pathway remain to be elucidated. Copyright (c) 2005 S. Karger AG, Basel

Background/Aim: Phenotype-driven screening of a great pool of randomly mutant mice and subsequent selection of animals showing symptoms equivalent to human kidney diseases may result in the generation of novel suitable models for the study of the pathomechanisms and the identification of genes involved in kidney dysfunction. Methods: We carried out a large-scale analysis of ethylnitrosourea (ENU)-induced mouse mutants for albuminuria by using qualitative SDS-polyacrylamide gel electrophoresis. Results: The primary albuminuria screen preceded the comprehensive phenotypic mutation analysis in a part of the mice of the Munich ENU project to avoid loss of mutant animals as a consequence of prolonged suffering from severe nephropathy. The primary screen detected six confirmed phenotypic variants in 2,011 G1 animals screened for dominant mutations and no variant in 48 G3 pedigrees screened for recessive mutations. Further breeding experiments resulted in two lines showing a low phenotypic penetrance of albuminuria. The secondary albuminuria screen was carried out in mutant lines which were established in the Munich ENU project without preceding primary albuminuria analysis. Two lines showing increased plasma urea levels were chosen to clarify if severe kidney lesions are involved in the abnormal phenotype. This analysis revealed severe albuminuria in mice which are affected by a recessive mutation leading to increased plasma urea and cholesterol levels. Conclusion: Thus, the phenotypic selection of ENU-induced mutants according to the parameter proteinuria in principle demonstrates the feasibility to identify nephropathy phenotypes in ENU-mutagenized mice. Copyright (C) 2005 S. Karger AG, Basel.

Oxidation of low-density lipoprotein (LDL) generates proinflammatory and prothrombotic mediators that may play a crucial role in cardiovascular and inflammatory diseases. In order to study platelet-activating components of oxidized LDL 1-stearoyl-2-arachidonoyl-sn-glycero-3- phosphocholine, a representative of the major phospholipid species in LDL, the 1-acyl-phosphatidylcholines (PC), was oxidized by CuCl2 and H2O2. After separation by high-performance liquid chromatography, three compounds were detected which induced platelet shape change at low micromolar concentrations. Platelet activation by these compounds was distinct from the pathways stimulated by platelet-activating factor, lysophosphatidic acid, lyso-PC and thromboxane A(2), as evidenced by the use of specific receptor antagonists. Further analyses of the oxidized phospholipids by electrospray ionization mass spectrometry structurally identified them as 1-stearoyl-2-azelaoyl-sn-glycero-3-phosphocholine (m/z 694; SAzPC), 1-stearoyl-2-glutaroyl-snglycero-3- phosphocholine (m/z 638; SGPC), and 1-stearoyl-2-( 5-oxovaleroyl)-sn-glycero-3-phosphocholine (m/z 622; SOVPC). These observations demonstrate that novel 1-acyl-PC which had previously been found to stimulate interaction of monocytes with endothelial cells also induce platelet activation, a central step in acute thrombogenic and atherogenic processes. Copyright (C) 2005 S. Karger AG, Basel.

Background: Early reconstitution after injury to the endothelium is an important feature for reducing a number of vessel wall pathologies. We investigated the effect of vascular endothelial growth factor ( VEGF) and its impact on the vascular remodeling process and reendothelialization after microsurgery. Methods and Results: Microvascular anastomosis was performed in the rat femoral artery. One group was treated with intraluminal administration of VEGF and the other with vehicle. We investigated morphological, ultrastructural and immunohistochemical changes of the vascular wall and the reendothelialization process. After 10 days, reendothelialization was significantly faster in VEGF-treated rats. Transmission electron microscopy revealed a complete healing in contrast to vehicle-treated vessels. Moreover, extracellular matrix proteins, such as fibronectin, collagen types I, III and IV, were significantly increased. Furthermore, VEGF treatment significantly induced VEGF receptor 2, flk-1, osteopontin and TGF-β(1) proteins. Conclusions: Our data clearly document for the first time that intraluminal treatment with VEGF is beneficial to the healing process in vascular microsurgery. Osteopontin and TGF-β(1), both induced by VEGF, may play an important role in the vascular remodeling process. Our results provide clear evidence that VEGF application may represent a useful strategy in accelerating reendothelialization and improving vascular healing after microsurgery. Copyright (C) 2005 S. Karger AG, Basel.

Selective inhibitors of cyclooxygenase- 2 ( COX- 2, ` coxibs') are highly effective anti-inflammatory and analgesic drugs that exert their action by preventing the formation of prostanoids. Recently some coxibs, which were designed to exploit the advantageous effects of non- steroidal anti-inflammatory drugs while evading their side effects, have been reported to increase the risk of myocardial infarction and atherothrombotic events. This has led to the withdrawal of rofecoxib from global markets, and warnings have been issued by drug authorities about similar events during the use of celecoxib or valdecoxib/ parecoxib, bringing about questions of an inherent atherothrombotic risk of all coxibs and consequences that should be drawn by health care professionals. These questions need to be addressed in light of the known effects of selective inhibition of COX- 2 on the cardiovascular system. Although COX- 2, in contrast to the cyclooxygenase-1 ( COX- 1) isoform, is regarded as an inducible enzyme that only has a role in pathophysiological processes like pain and inflammation, experimental and clinical studies have shown that COX- 2 is constitutively expressed in tissues like the kidney or vascular endothelium, where it executes important physiological functions. COX- 2- dependent formation of prostanoids not only results in the mediation of pain or inflammatory signals but also in the maintenance of vascular integrity. Especially prostacyclin ( PGI(2)), which exerts vasodilatory and antiplatelet properties, is formed to a significant extent by COX- 2, and its levels are reduced to less than half of normal when COX- 2 is inhibited. This review outlines the rationale for the development of selective COX- 2 inhibitors and the pathophysiological consequences of selective inhibition of COX- 2 with special regard to vasoactive prostaglandins. It describes coxibs that are currently available, evaluates the current knowledge on the risk of atherothrombotic events associated with their intake and critically discusses the consequences that should be drawn from these insights. Copyright (C) 2005 S. Karger AG, Basel.

The transcriptional activator CadC in Escherichia coli, a member of the ToxR-like proteins, activates transcription of the cadBA operon encoding the lysine decarboxylase CadA and the lysine-cadaverine antiporter CadB. cadBA is induced under conditions of acidic external pH and exogenous lysine; anoxic conditions raise the expression level up to 10 times. To characterize the binding mechanism of CadC, procedures for the purification of this membrane-integrated protein and its reconstitution into proteoliposomes were established. The binding sites of CadC upstream of the cadBA promoter region were determined by in vitro DNaseI protection analysis. Two regions were protected during DNaseI digestion, one from - 144 to - 112 bp, designated Cad1, and another one from - 89 to - 59 bp, designated Cad2. Binding of purified CadC to Cad1 and Cad2 was further characterized by DNA-binding assays, indicating that CadC was able to bind to both DNA fragments. Genetic analysis with promoter-lacZ fusions confirmed that both sites, Cad1 and Cad2, are essential for activation of cadBA transcription. Moreover, these experiments revealed that binding of H-NS upstream of the CadC-binding sites is necessary for repression of cadBA expression at neutral pH and under aerobic conditions. Based on these results, a model for transcriptional regulation of the cadBA operon is proposed, according to which H-NS is involved in the formation of a repression complex under non-inducing conditions. This complex is dissolved by binding of CadC to Cad1 under inducing conditions. Upon binding of CadC to Cad2 cadBA expression is activated. Copyright (C) 2005 S. Karger AG, Basel.

Background: Immediate-type hypersensitivity to animal proteins is a common problem in people occupationally exposed to animals. Methods: A 19-year-old female working as a voluntary zookeeper in her off-time suffered from hives on her forearms following contact to the fur of a giraffe. For diagnostic evaluation, skin prick tests, assessment of specific serum IgE antibodies, and basophil activation tests were performed. Results: Skin prick tests with a standard series of common aeroallergens were positive for various pollens. Prick testing with native materials was positive for extracts of hair from two different giraffe subspecies in the patient, but not in control subjects. By CAP-FEIA, no specific serum IgE antibodies to dander of a large variety of animals were found in the patient. In the basophil activation test, expression of the activation marker CD63 was induced by extract of giraffe hair on the cells from the patient, but not on those from unaffected controls. Conclusions: This patient suffers from an `exotic' immediate-type contact allergy to giraffe hair. Copyright (C) 2005 S. Karger AG, Basel.

Background: There is evidence that homocysteine contributes to various neurodegenerative disorders. Objective: To assess the values of homocysteine in patients with Creutzfeldt-Jakob disease (CJD) in both cerebrospinal fluid (CSF) and plasma. Methods: Study design: Case control study. Total homocysteine was quantified in CSF and plasma samples of CJD patients (n = 13) and healthy controls (n = 13). Results: Mean values in healthy controls: 0.15 mumol/l +/- 0.07 (CSF) and 9.10 mumol/l +/- 2.99 (plasma); mean values in CJD patients: 0.13 mumol/l +/- 0.03 (CSF) and 9.22 mumol/l +/- 1.81 (plasma). No significant differences between CJD patients and controls were observed (Mann-Whitney U, p > 0.05). Conclusions: The results indicate that the CSF and plasma of CJD patients showed no higher endogenous levels of homocysteine as compared to normal healthy controls. These findings provide no evidence for an additional role of homocysteine in the pathogenetic mechanisms underlying CJD neurodegeneration. Copyright (C) 2005 S. Karger AG, Basel.

Background: The increasing demand for complementary medicine indicates a change in attitudes regarding treatment understanding. Objectives: To investigate the role of attitudes in treatment motivation. (1) Can the study sample be subdivided into homogenous groups as regards attitudes toward complementary treatment? (2) How do these groups relate to motivational variables? Patients and Methods: Four questionnaires on motivation and attitudes were administered to 203 patients of two clinics for complementary medicine. Results were interpreted following Petry's motivational process model that distinguishes treatment disposition, preparedness for treatment and treatment activity. Results: According to a cluster analysis, 3 patient groups could be identified: `Not- convinced' patients (cluster 1, n = 24) demonstrated little conviction regarding any aspect of complementary treatment. `Convinced' patients (cluster 2, n = 103) showed a high degree of agreement on all three scales, being highest on `Role of patient'. `Partially- convinced' patients (cluster 3, n = 70) also evaluated `Role of patient' highest, but aspects of the `Physician- patient relationship' and the `Treatment method' were only partly regarded as important. In all clusters, the pragmatic motive of treatment acceptance was central for the treatment choice, but was highest in cluster 2. As compared to cluster 1, a complementary treatment understanding was higher in patients of clusters 2 and 3 ( highest in cluster 2). Discussion: Even if the pragmatic treatment motivation was high in all groups, the central role of treatment attitudes in the motivational process could be verified. Despite differing attitude structures, a majority of patients displayed a complementary treatment comprehension.

Objectives: Exchanging amniotic fluid (AF) with perfluorocarbon (PFC) may serve as a medium for fetoscopic surgery. This study evaluates the distribution and physiologic effects of intraamniotic PFC as a medium for fetoscopy. Methods: Fetuses of 17 pregnant rabbits underwent either exchange of the AF with PFC, electrolyte solution (ES), or control. The quality of vision during fetoscopy was assessed in AF and PFC. After 6 h, we determined the distribution of PFC in the maternofetal unit. Results: Quality of vision during fetoscopy was better in PFC than with AF. There was no difference in fetal survival between the study groups. PFC was demonstrated on X-ray in the pharynx of 4 fetuses, and the esophagus in 1. Conclusions: PFC provided an ideal medium for fetoscopy without fetal compromise. Copyright (c) 2005 S. Karger AG, Basel.

Inhaled prostacyclin (PGI(2)) aerosol induces selective pulmonary vasodilation. Further, it improves right ventricular ( RV) function, which may largely rely on pulmonary vasodilation, but also on enhanced myocardial contractility. We investigated the effects of the inhaled PGI(2) analogs epoprostenol (EPO) and iloprost (ILO) on RV function and myocardial contractility in 9 anesthetized pigs receiving aerosolized EPO (25 and 50 ng center dot kg(-1) center dot min(-1)) and, consecutively, ILO (60 ng center dot kg(-1) center dot min(-1)) for 20 min each. We measured pulmonary artery pressure ( PAP), RV ejection fraction (RVEF) and RV end-diastolic-volume (RV-EDV), and left ventricular end-systolic pressure-volume-relation (end-systolic elastance, E-es). EPO and ILO reduced PAP, increased RVEF and reduced RVEDV. E-es was enhanced during all doses tested, which reached statistical significance during EPO25ng and ILO, but not during EPO50ng. PGI(2) aerosol enhances myocardial contractility in healthy pigs, contributing to improve RV function. Copyright (C) 2005 S. Karger AG, Basel.

Background/Aims: Degradation of adenine nucleotides to adenosine has been suggested to play a critical role in ischemic preconditioning (IPC). Thus, we questioned in patients undergoing partial hepatectomy whether (i) IPC will increase plasma purine catabolites and whether (ii) formation of purines in response to vascular clamping (Pringle maneuver) can be attenuated by prior IPC. Methods: 75 patients were randomly assigned to three groups: group I underwent hepatectomy without vascular clamping; group II was subjected to the Pringle maneuver during resection, and group III was preconditioned (10 min ischemia and 10 min reperfusion) prior to the Pringle maneuver for resection. Central, portal venous and arterial plasma concentrations of adenosine, inosine, hypoxanthine and xanthine were determined by high-performance liquid chromatography. Results: Duration of the Pringle maneuver did not differ between patients with or without IPC. Surgery without vascular clamping had only a minor effect on plasma purine transiently increased. After the Pringle maneuver alone, purine plasma concentrations were most increased. This strong rise in plasma purines caused by the Pringle maneuver, however, was significantly attenuated by IPC. When portal venous minus arterial concentration difference was calculated for inosine or hypoxanthine, the respective differences became positive in patients subjected to the Pringle maneuver and were completely prevented by preconditioning. Conclusion: These data demonstrate that (i) IPC increases formation of adenosine, and that (ii) the unwanted degradation of adenine nucleotides to purines caused by the Pringle maneuver can be attenuated by IPC. Because IPC also induces a decrease of portal venous minus arterial purine plasma concentration differences, IPC might possibly decrease disturbances in the energy metabolism in the intestine as well. Copyright (C) 2005 S. Karger AG, Basel.

Previous studies showed that mitoxantrone can reduce disability progression in patients with multiple sclerosis (MS). There is, however, concern that it may cause irreversible cardiomyopathy with reduced left ventricular (LV) ejection fraction (EF) and congestive heart failure. The aim of this prospective study was to investigate cardiac side effects of mitoxantrone by repetitive cardiac monitoring in MS patients. The treatment protocol called for ten courses of a combined mitoxantrone (10 mg/m(2) body surface) and methylprednisolone therapy. Before each course, a transthoracic echocardiogram was performed to determine the LV end-diastolic diameter, the end-systolic diameter and the fractional shortening; the LV-EF was calculated. Seventy-three patients participated (32 males; age 48 +/- 12 years, range 20-75 years; 25 with primary progressive, 47 with secondary progressive and 1 with relapsing-remitting MS) who received at least four courses of mitoxantrone. Three of the 73 patients were excluded during the study (2 patients discontinued therapy; 1 patient with a previous history of ischemic heart disease developed atrial fibrillation after the second course of mitoxantrone). The mean cumulative dose of mitoxantrone was 114.0 +/- 33.8 mg. The mean follow-up time was 23.4 months (range 10-57 months). So far, there has been no significant change in any of the determined parameters (end-diastolic diameter, end-systolic diameter, fractional shortening, EF) over time during all follow-up investigations. Mitoxantrone did not cause signs of congestive heart failure in any of the patients. Further cardiac monitoring is, however, needed to determine the safety of mitoxantrone after longer follow-up times and at higher cumulative doses. Copyright (C) 2005 S. Karger AG, Basel.

Sat, 1 Jan 2005 12:00:00 +0100 https://epub.ub.uni-muenchen.de/16798/1/10_1159_000085505.pdf Brandt, T.; Jahn, K.; Strupp, M.; Zingler, V. C. ddc:610, Medizin

Sat, 1 Jan 2005 12:00:00 +0100 https://epub.ub.uni-muenchen.de/16799/1/10_1159_000085507.pdf Pfister, H. W.; Bötzel, Kai; Asmus, F.; Seelos, Klaus; Sporer, B.

Sat, 1 Jan 2005 12:00:00 +0100 https://epub.ub.uni-muenchen.de/16800/1/10_1159_000085510.pdf Hamann, Gerhard F.; Arbusow, Viktor; Holtmannspötter, Markus; Liebetrau, Martin ddc:610, Medizin

Treatment of alcohol-dependent patients was primarily focused on inpatient settings in the past decades. The efficacy of these treatment programs has been evaluated in several studies and proven to be sufficient. However, with regard to the increasing costs in public healthcare systems, questions about alternative treatment strategies have been raised. Meanwhile, there is growing evidence that outpatient treatment might be comparably effective as inpatient treatment, at least for subgroups of alcohol dependents. On that background, the present study aimed to evaluate the efficacy of a high-structured outpatient treatment program in 103 alcohol-dependent patients. 74 patients (72%) terminated the outpatient treatment regularly. At 6 months' follow-up, 95% patients were successfully located and personally re-interviewed. Analyses revealed that 65 patients (64%) were abstinent at the 6-month follow-up evaluation and 37 patients ( 36%) were judged to be non-abstinent. Pretreatment variables which were found to have a negative impact (non-abstinence) on the 6-month outcome after treatment were a higher severity of alcohol dependence measured by a longer duration of alcohol dependence, a higher number of prior treatments and a stronger alcohol craving (measured by the Obsessive Compulsive Drinking Scale). Further patients with a higher degree of psychopathology measured by the Beck Depression Inventory (depression) and State-Trait Anxiety Inventory (anxiety) relapsed more often. In summary, results of this study indicate a favorable outcome of socially stable alcohol-dependent patients and patients with a lower degree of depression, anxiety and craving in an intensive outpatient rehabilitation program.

Sat, 1 Jan 2005 12:00:00 +0100 https://epub.ub.uni-muenchen.de/16849/1/10_1159_000087659.pdf Göke, B. ddc:610, Medizin

Introduction: Various disease-specific serum antibodies were described in patients with inflammatory bowel disease and their yet healthy first-degree relatives. In the latter, serum antibodies are commonly regarded as potential markers of disease susceptibility. The present long-term follow-up study evaluated the fate of antibody-positive first-degree relatives. Patients and Methods: 25 patients with Crohn's disease, 19 patients with ulcerative colitis and 102 first-degree relatives in whom presence of ASCA, pANCA, pancreatic- and goblet-cell antibodies had been assessed were enrolled. The number of incident cases with inflammatory bowel disease was compared between antibody-positive and antibody-negative first-degree relatives 7 years after storage of serum samples. Results: 34 of 102 (33%) first-degree relatives were positive for at least one of the studied serum antibodies. In the group of first-degree relatives, one case of Crohn's disease and one case of ulcerative colitis were diagnosed during the follow-up period. However, both relatives did not display any of the investigated serum antibodies (p = 1). Discussion: The findings of our pilot study argue against a role of serum antibodies as a marker of disease susceptibility in first-degree relatives of patients with inflammatory bowel disease. However, these data have to await confirmation in larger ideally prospective multicenter studies before definite conclusions can be drawn.

Little is known about the effects of spiritual care training for professionals in palliative medicine. We therefore investigated prospectively the effects of such training over a six-month period. All 63 participants of the three and a half-day training were asked to fill out three questionnaires: before and after the training, as well as six months later. The questionnaires included demographic data, numeric rating scales about general attitudes towards the work in palliative care, the Self-Transcendence Scale (STS), the spiritual subscale of the Functional Assessment of Chronic Illness Therapy (FACIT-Sp) and the Idler Index of Religiosity (IIR). Forty-eight participants (76) completed all three questionnaires (91 women, median age 49 years; 51 nurses, 16 hospice volunteers, 14 physicians).Significant and sustained improvements were found in self-perceived compassion for the dying (after the training: P =0.002; 6 months later: P=0.025), compassion for oneself (P < 0.001; P =0.013), attitude towards one's family (P =0.001; P =0.031), satisfaction with work (P < 0.001; P =0.039), reduction in work-related stress (P < 0.001; P =0.033), and attitude towards colleagues (P =0.039; P =0.040), as well as in the FACIT-Sp (P < 0.001; P =0.040). Our results suggest that the spiritual care training had a positive influence on the spiritual well-being and the attitudes of the participating palliative care professionals which was preserved over a six-month period.

In the treatment of dysgeusia, the use of zinc has been frequently tried, with equivocal results. The aim of the present randomized clinical trial, which involved a sufficiently large sample, was therefore to determine the efficacy of zinc treatment. Fifty patients with idiopathic dysgeusia were carefully selected. Zinc gluconate (140 mg/day; n = 26) or placebo (lactose; n = 24) was randomly assigned to the patients. The patients on zinc improved in terms of gustatory function (p < 0.001) and rated the dysgeusia as being less severe (p < 0.05). Similarly, signs of depression in the zinc group were less severe (Beck Depression Inventory, p < 0.05; mood scale, p < 0.05). With the exception of the salivary calcium level, which was higher in the zinc patients (p < 0.05), no other significant group differences were found. In conclusion, zinc appears to improve general gustatory function and, consequently, general mood scores in dysgeusia patients.

Pulpotomy is the accepted therapy for the management of cariously exposed pulps in symptom-free primary molars; however, evidence is lacking about the most appropriate technique. The aim of this study was to compare the relative effectiveness of the Er:YAG laser, calcium hydroxide, and ferric sulfate techniques with that of dilute formocresol in retaining such molars symptom-free. Two hundred primary molars in 107 healthy children were included and randomly allocated to one of the techniques. The treated teeth were blindly re-evaluated after 6, 12, 18, and 24 months. Descriptive data analysis and logistic regression analysis, accounting for each patient's effect by a generalized estimating equation (GEE), were used. After 24 months, the following total and clinical success rates were determined (%): formocresol 85 (96), laser 78 (93), calcium hydroxide 53 (87), and ferric sulfate 86 (100). Only calcium hydroxide performed significantly worse than formocresol (p = 0.001, odds ratio = 5.6, 95% confidence interval 2.0-15.5). In conclusion, calcium hydroxide is less appropriate for pulpotomies than is formocresol.

Diabetic patients with acute coronary syndromes are at high risk for cardiovascular complications but risk stratification in these patients remains challenging. Regularly, diabetic patients have a less typical clinical presentation, which could lead to delayed diagnosis and subsequent delayed initiation of treatment. Since diabetic patients derive particular benefit from aggressive anti-platelet therapy, early diagnostic and therapeutic risk stratification of these patients is of critical importance to improve their adverse outcome. Although the electrocardiogram remains a pivotal diagnostic tool in the evaluation of patients suspected of having an acute coronary syndrome, only significant STsegment changes provide reasonable prognostic information. Therefore, repeated assessment of circulating protein biomarkers represents a valuable diagnostic tool for improving efficacy and safety of decision-making in these patients. The combined use of biomarkers reflecting distinct pathophysiological aspects, such as myocardial necrosis, vascular inflammation, oxidative stress and neurohumoral activation, may significantly improve triage of patients with chest pain. These tools may identify those patients that are at particularly high risk for short-term and/or long-term cardiovascular events. Eventually, tailored medical and interventional treatment of diabetic patients should help to prevent these cardiac events in a cost-effective manner.

Following the current hypothesis that acute schizophrenic psychotic illness is associated with a triatal ‘hyperdopaminergic state’, presynaptic integrity and dopamine transporter (DAT) density in first-episode, neuroleptic-naive schizophrenic patients was measured by single-photonemission- tomography (SPECT) and compared with that in healthy control subjects. A new SPECT-ligand for assessment of the striatal DAT, the Technetium-99m-labelled tropane TRODAT-1 ([99mTc]TRODAT-1), was used. Ten inpatients suffering from a first acute schizophrenic episode and 10 age- and sex-matched healthy control subjects underwent SPECT with [99mTc]TRODAT-1. On the day of SPECT, psychopathological ratings were performed with the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS) and Schedule for Assessment of Negative Symptoms (SANS). Patients had not previously received any neuroleptic or antidepressant medication. Mean specific TRODAT-1 binding in the striatum did not differ significantly between the patient and the age- and sex-matched control group (1.25 vs. 1.28). Variance was significantly higher in the patient group. The data obtained with the new ligand in first-episode, drug-naive schizophrenic patients are in line with the PET results from the group of Laakso et al. in a comparable patient sample. [99mTc]TRODAT-1 seems to be a valuable new SPECTligand in the evaluation of the presynaptic site of the striatal dopaminergic synapse in schizophrenia.

Toll-like receptor (TLR)-9 recognizes CpG motifs in microbial DNA. TLR9 signalling stimulates innate antimicrobial immunity and modulates adaptive immune responses including autoimmunity against chromatin, e.g., in systemic lupus erythematosus (SLE). This review summarizes the available data for a role of TLR9 signalling in lupus and discusses the following questions that arise from these observations: 1) Is CpG-DNA/TLR9 interaction involved in infection-induced disease activity of lupus? 2) What are the risks of CpG motifs in vaccine adjuvants for lupus patients? 3) Is TLR9 signalling involved in the pathogenesis of lupus by recognizing self DNA?

Background: Microvascular alterations contribute to the development of stroke and vascular dementia. The goal of this study was to evaluate age and hypertension related changes of the basal lamina in cerebral microvessels of individuals, who died from non-cerebral causes. Results: We examined 27 human brains: 11 young and 16 old patients. Old patients were divided into two subgroups, those with hypertension (n = 8) and those without hypertension (n = 8). Basal lamina changes of the cerebral microvessels were determined in the putamen using antibodies against collagen type IV and by quantitative analysis of vessel number, total stained area of collagen, thickness of the vessel wall and lumen, and relative staining intensity using immunofluorescence. The total number of collagen positive vessels per microscopic field was reduced in old compared to young subjects (12.0+/-0.6 vs. 15.1+/-1.2, p = 0.02). The relative collagen content per vessel (1.01+/-0.06 vs. 0.76+/-0.05, p = 0.01) and the relative collagen intensity (233.1+/-4.5 vs. 167.8+/- 10.6, p < 0.0001) shown by immunofluorescence were higher in the older compared to the younger patients with a consecutive reduction of the lumen / wall ratio (1.29+/-0.05 vs. 3.29+/-0.15, p < 0.0001). No differences were observed for these parameters between old hypertensive and nonhypertensive patients. Conclusions: The present data show age-related changes of the cerebral microvessels in sections of human putamen for the first time. Due to the accumulation of collagen, microvessels thicken and show a reduction in their lumen. Besides this, the number of vessels decreases. These findings might represent a precondition for the development of vascular cognitive impairment. However, hypertension was not proven to modulate these changes.

Introduction: The treatment of Charcot neuroarthropathy in the feet of diabetic patients has undergone fundamental changes in the last few years. Formerly, treatment was almost exclusively limited to nonoperative measures; since the late 1990s, however, current practice has shifted to early, stage-appropriate surgical therapy. The objective of this prospective study was to investigate the value of two types of positron emission tomography (PET) in the preoperative evaluation of diabetic patients with Charcot foot deformities. Materials and Methods: Ring 18FFDG (2-fluoro-2-deoxy-glucose) and hybrid PET were compared to magnetic resonance imaging (MRI). MRI, ring PET, and hybrid PET imaging were used as part of the preoperative evaluation of 16 patients with type II diabetes mellitus. The diagnosis of Charcot neuropathy of the foot requiring operative treatment had been made on the basis of clinical and radiographic criteria. Results: Of 39 Charcot lesions confirmed at surgery, 37 were detected by ring PET, 30 by hybrid PET, and 31 by MRI. Conclusions: PET (ring or hybrid) can be used in the evaluation of patients with metal implants that would compromise the accuracy of MRI. Another advantage of PET is its ability to distinguish between inflammatory and infectious soft-tissue lesions, and between osteomyelitis and Charcot neuroarthropathy. The differentiation between Charcot neuroarthropathy and florid osteomyelitis provides the surgeon with important additional information that often is unavailable from MRI. Because it provides important additional data, ring PET may be preferable to radiography and MRI in the preoperative evaluation of patients with Charcot neuroarthropathy of the foot. Hybrid PET, because of its poorer resolution compared to ring PET, appears less suitable for routine clinical application.