Adaptive short-term plasticity in the typical reading network.

The left temporo-parietal cortex (TPC) is crucial for phonological decoding, i.e., for learning and retaining sound-letter mappings, and appears hypoactive in dyslexia. Here, we tested the causal contribution of this area for reading in typical readers with transcranial magnetic stimulation (TMS) and explored the reading network's response with fMRI. By investigating the underlying neural correlates of stimulation-induced modulations of the reading network, we can help improve targeted interventions for individuals with dyslexia. 28 typical adult readers overtly read simple and complex words and pseudowords during fMRI after effective and sham TMS over the left TPC. To explore differences in functional activation and effective connectivity within the reading network, we performed univariate and multivariate analyses, as well as dynamic causal modeling. While TMS-induced effects on reading performance and brain activation showed large individual variability, multivariate analyses revealed a shift in activation in the left inferior frontal cortex for pseudoword reading after effective TMS. Furthermore, TMS increased effective connectivity from the left ventral occipito-temporal cortex to the left TPC. In the absence of effects on reading performance, the observed changes in task-related activity and the increase in functional coupling between the two core reading nodes suggest successful short-term compensatory reorganization in the reading network following TMS-induced disruption. This study is the first to explore neurophysiological changes induced by TMS to a core reading node in typical readers while performing an overt reading task. We provide evidence for remote stimulation effects and emphasize the relevance of functional interactions in the reading network.

[Pathological diagnosis--costs and benefit]. / Die pathologische Diagnostik--Kosten und Nutzen.

The autopsy rate in Germany has drastically diminished in the last decades and is below 10% nowadays. Possible reasons for this development are discussed. Pressure of cost is a quoted cause, although it is not so high. There is a large discrepancy between the clinically supposed cause of death and the by autopsy confirmed diagnosis (40-60%). This especially applies to mycoses. Every year in Germany 1200 crimes of causing death and 11.000 non-natural deaths are not found because of missing autopsy. Another important aspect for a sufficient number of autopsies is their value for the quality assurance in diagnosis and therapy and also in education and further training of physicians and students.

[What distinctions do Candida biofilms have to offer?]. / Was bieten Candida-Biofilme Besonderes?

In a miniature continuous flow cell system we investigated the influence of voriconazole (VCZ) (27 trials) or anidulafungin (ANID) (five trials) on the antimycotic resistance of C. albicans (type strain SC5314 and three strains from blood cultures). The duration of the trials was up to 10 d. After continuous addition of VCZ or ANID to the media, biomass decreased and glucose levels and pH values increased. After exposure to VCZ, the dry weight of biofilm dropped by 90%. There was no evidence of resistance. No resistance also developed against ANID after 1 day or 3 days of exposure. No viable cells were detected in the biofilm after 5 days of exposure to ANID. Therefore, VCZ and ANID effectively inhibited biofilm formation of different C.albicans strains. Our experiments show that biofilm production is not necessarily associated with development of resistance.

The first description of an oesophageal candidosis by Bernhard von Langenbeck in 1839.

In November 1839 the young university lecturer Bernhard (von) Langenbeck (1810-1887) published the first description of a fungus as aetiological agent of an oro-pharyngeal and oesophageal candidosis. We present his in English translated paper entitled 'Finding of fungi on the mucous membrane of the gullet of a typhoid fever corpse' (Germ.) in 'Neue Notizen aus dem Gebiete der Natur- und Heilkunde' (Froriep). There are interesting particulars in Langenbeck's description and discussion. The publication happened at the same time as that by Johann Lukas Schoenlein about fungi as the cause of the favus lesions. In this time Langenbeck lived at Göttingen. Later he went to Kiel and Berlin and became one of the most prominent surgeons of the 19th century. He sponsored the founding of the German Surgical Society, the Berlin Medical Society and the 'Archiv für Klinische Chirurgie'. In 1864 he was ennobled. Some of his assistants were Th. Billroth, R.U. Kroenlein, F. von Esmarch, and F. Trendelenburg.

Candidosis and aspergillosis as autopsy findings from 1994 to 2003.

We analysed the autopsy records of the Greifswald University Institute of Pathology (located in Eastern Germany) in respect of findings of candidosis and aspergillosis from 1994 to 2003. We also present eight immature aborted fetuses and premature infants with a mycosis. In a total of 2027 autopsies we found 164 cases of invasive candidosis and aspergillosis (8.1%) including a combination of both on four occasions. Other authors cited between 0.7 and 7.3%. In these 10 years in our material mycoses and in particular candidosis increased in spite of slightly decreased numbers of autopsies. The differences comparing the 5-years periods (1994-98 and 1999-2003) are highly significant for both mycoses and candidosis. They are not significant for aspergillosis. A similar relationship was observed in the distribution of mycotic organs and causative origin for candidosis alone. In the last 5 years the gastrointestinal and respiratory tracts, including the peritoneum, were more frequently infected by Candida. Non-haematological neoplasia and pneumonia as basic diseases more often appeared in cases of candidosis. All eight immature aborted fetuses and premature infants suffered from candidosis. The survey confirms the importance of autopsy as a tool for education and quality control in medical diagnostic and therapeutic activity in the field of mycoses, too.

Influence of voriconazole and fluconazole on reconstituted multilayered oesophageal epithelium infected by Candida albicans.

Reconstituted multilayered oesophageal epithelium appears to be a good basis to test the efficacy of voriconazole (VOR) and fluconazole (FLU) in the tissue. The resulting model of a Candida oesophagitis was approaching the in vivo situation. We infected the tissue with 2 x 10(6) cfu of the Candida albicans strain SC5314. In the trials with FLU we also used clinical strains. Four hours after infection a good growth of C. albicans appeared mainly with hyphae on the surface of the tissue and a tendency to invasion. The destruction of the tissue began after 36 h. VOR (2 and 16 microg ml-1, respectively) prevented the penetration of hyphae into the tissue, when it was given 4-8 h after infection. It was less effective in reduction of Candida growth on the tissue surface. When VOR was given 16-24 h postinfection, the Candida infiltration stopped more slowly. Thirty-six hours after infection VOR application could not stop the destruction of the tissue despite reducing the fungi. The results with FLU (32 microg ml-1) were in principle the same, but not so distinct. FLU seems to be more effective against clinical strains of C. albicans than against the type strain.

[Candida-specific antibodies in intensive care and non-intensive care patients]. / Candida-spezifische Antikorper bei Intensivtherapiepatienten und Nichtintensivtherapiepatienten.

The titres of indirect anti-Candida haemagglutination test (C-HAT) and specific immunoglobulins C-IgM, C-IgG and C-IgA in 328 intensive care (IT) patients and 166 non-intensive care (NIT) patients were compared by statistical test methods. Positive correlations were found between values of C-HAT and all three Candida-specific immunoglobulins. At an interval of < or =7 days in the first patient group only, the changes in the course of titres were statistically highly significant. For C-IgM the short-term increase of titres can be interpreted in the sense of happened mycotic infection in connection with the clinical picture. In IT patients we found an average increase of C-IgM at 259.3, C-IgG at 174.7, C-IgA at 59.8 U ml(-1) and of three titre steps in C-HAT. In our experience of diagnostics of Candida infections in intensive care area with non-neutropenic patients the short-term determination of the anti-Candida immunoglobulin subclasses C-IgM and C-IgG and of C-HAT as screening test should not be neglected.

[Early signals of systemic mycoses--guidelines for therapeutic decisions?]. / Fruhsignale systemischer Mykosen--Leitlinien fur Therapieentscheidungen?

Clinical applications and in vitro studies show that all antimycotics are most effective against infection when applied as early as possible. An early diagnosis is, therefore, essential. At this time for aspergillosis and particularly candidosis, a statement is only possible by combining several diagnostic methods. Inflammatory parameters like procalcitonin, C-reactive protein and proinflammatory cytokines are most important evidence of infection. Antigen tests are more significant by higher sensitivity. Attention should be focused on the detection of mannan by ELISA test, beta-glucan and D-arabinitol. Given the present research level in the field of proteomics, the diagnostic importance of transmembranal receptor proteins or other regulatory proteins seems promising.

Changes in Candida albicans colonization and morphology under influence of voriconazole.

The aim was the investigation of fungal colonization and morphological alterations under the influence of voriconazole in an in vitro system. Voriconazole stopped growth and colonization of Candida albicans (wild type SC5314) on cover slips in microtiter plates dependent on drug concentration, the time of Candida growth before the input of voriconazole and oxygen concentration. The direct microscopy by fluorescence staining with the optical brightener Blancophor showed short bizarrely deformed mycelia looking swollen. The colonization on cover glass was diminished. Microcolonies or starting of biofilm formation as in the control was not observed. The metabolic activity was demonstrated by vital staining with FUN 1 resulting in red fluorescent structures in the yeast forms and mycelia in the controls. Under voriconazole influence the remaining cells only showed a green or pale yellow fluorescence. Most of the cells lost their metabolic activity.

[Early description of a pulmonary aspergillosis 1847 from Greifswald]. / Frühe Beschreibung einer pulmonalen Aspergillose 1847 aus Greifswald.

In 1847 the student of medicine Theodor Sluyter (1817-1895) from Greifswald published his thesis in Berlin including the first well-documented case of human pulmonary aspergillosis. In 1856 Rudolf Virchow (1821-1902) classified the depicted fungi as an Aspergillus species. Possibly Carl Ferdinand Eichstedt (1816-1892) carried out the autopsy. He is known by the first description of a fungus as the cause of pityriasis versicolor in 1846. Further involved scientists from Greifswald were Wilhelm Baum (1799-1883), Theodor Litzmann (1815-1890) and the botanist Johann Konrad Schauer (1813-1848). Their curricula vitae are given in further details as well the curriculum of T. Sluyter.

Influence of voriconazole and fluconazole on Candida albicans in long-time continuous flow culture.

We investigated the influence of voriconazole and fluconazole in a long term trial of continuous flow culture (cfc) up to 9 days. The effects of these azoles were different in dependence on the growth circumstances. Under anaerobic conditions a fungicidal effect of voriconazole was detectable, defined by an inhibition of 99.9%. This also applied to fluconazole for the majority of tested strains of C. albicans. Under aerobic conditions with an otherwise similar situation we found only a fungistatic reaction (inhibition of 90%). Fluorescence microscopy comparing fungal morphology in biofilms on glass surfaces in the cfc revealed a differentiation into blastospores, germ tubes, pseudomycelia and mycelia in the control trial after a cultivation of 8 days. Under anaerobic conditions with azoles only some single cells could be found, sometimes in cell detritus. The adhesion was clearly reduced. Under aerobic conditions more blastospores but no differentiated mycelia were to be seen.

Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction.

BACKGROUND: P-Glycoprotein is an efflux pump in many epithelial cells with excretory function. It has been demonstrated that rifampin (INN, rifampicin) induces P-glycoprotein, particularly in the gut wall. We therefore hypothesized that rifampin affects pharmacokinetics of the P-glycoprotein substrate talinolol, a beta1-blocker without appreciable metabolic disposition but intense intestinal secretion in human beings. METHODS: Pharmacokinetics of talinolol (a single dose of 30 mg administered intravenously or 100 mg administered orally for 7 days) and duodenal expression of the MDR1 gene product P-glycoprotein as assessed by reverse transcriptase-polymerase chain reaction of the MDR1-messenger ribonucleic acid, by immunohistochemistry and Western blot analysis were analyzed before and after coadministration of rifampin (600 mg per day for 9 days) in 8 male healthy volunteers (age 22 to 26 years). RESULTS: During rifampin treatment, the areas under the curve of intravenous and oral talinolol were significantly lower (21% and 35%; P < .05). Treatment with rifampin resulted in a significantly increased expression of duodenal P-glycoprotein content 4.2-fold (2.9, 6.51) (Western blot) and messenger RNA was increased in six of the eight volunteers. P-Glycoprotein expression in biopsy specimens of gut mucosa correlated significantly with the systemic clearance of intravenous talinolol (rs = 0.74; P < .001). CONCLUSIONS: Rifampin induces P-glycoprotein-mediated excretion of talinolol predominantly in the gut wall. Moreover, clearance of talinolol from the blood into the lumen of the gastrointestinal tract may be predicted by the individual intestinal P-glycoprotein expression. Thus we describe a new type of steady-state drug interaction affecting compounds that are subject to transport rather than metabolism.

Funguria and Candida-specific immunoglobulins in patients with systemic candidosis.

UNLABELLED: Funguria, indirect anti-Candida haemagglutination test (C-IHT) and Candida-specific immunoglobulins C-IgM, C-IgG and C-IgA were investigated under suspicion of systemic candidosis in critically ill patients. A total of 143 urine cultures were studied for Candida from 74 adults and a median count of log 3.0 CFU ml-1 was found. Most isolated Candida species were Candida albicans and Candida glabrata. In 14 cases of candidaemia there was no regular agreement between the finding of Candida species in blood and urine. In cases with candiduria > = or log 3.0 CFU ml-1 a stronger increase of C-IHT titres and all three Candida-specific immunoglobulins after 5-7 days was observed. Some statistically significant correlations were found between the levels of urinary yeast counts and immunological parameters concerning C-IHT, C-IgA and C-IgG on the first day and after 5-7 days. Clinical findings in some cases coincided well with funguria and courses of titres before and after treatment. CONCLUSION: In critically ill patients suspected of having systemic candidosis not only blood cultures should be made. Cultural studies with specimens taken from different sites including funguria are essential for a complete specific serological investigation.

Oesophageal candidosis in intensive care patients.

We conducted upper intestinoscopies in 124 intensive care patients, six of whom had oesophageal candidosis. Of these, two also had Candida plaque in the stomach. The patients at the intensive care unit (ICU) had a mean Apache-II score of 26.7; whereas the score was 29.5 in patients with Candida oesophagitis. A significant increase of Candida antibodies was found in 59 of 124 patients (47.6%), including all patients with oesophageal candidosis. Presumably, mycotic infections of other sites were present. The severity by which mucous membranes were affected correlated well with microscopically evident invasiveness.

[Gastrointestinal microecology of humans and Candida]. / Gastrointestinale Mikroökologie des Menschen und Candida.

Microecology looks for the relationships between microorganisms and their natural environment in definite sites and their physiological and pathological effects. From birth Candida spp. are often but not always detectable in the human gastrointestinal tract. In cases of reduced defense the tract may be a source of infection to the macroorganism. In healthy subjects the incidence of Candida is between 23% and 76% in quantities between 10(2)-10(4) CFU/ml or g dependent on site. Evidence is most frequent in oral cavity and faeces. Tolerance for Candida spp. is different in the stomach and duodenum due to differences in acidity. Changes in the occurrence of Candida spp. are possible depending on age, different diseases and exogenous influences as nutrition, stress and drugs. In an endocrine stress model we found no yeasts in the duodenal juices of 7 subjects before and after stress situation, but a clear decrease of yeasts in the faeces. The formation of metabolic products by Candida is secondary to the whole of microbial fermentation in the human orointestinal tract. Colonizing strains of C. albicans are normally present in small or moderate numbers and only they are regarded as part of the resident gastrointestinal microflora.

The continuous flow culture as an in vitro model in experimental mycology.

We used the model of continuous flow culture (cfc) to study the growth of Candida species. This model allows special test conditions: a long generation time of 15-20 hs, controlled limitation of nitrogen sources and carbohydrates, comparison of the growth under aerobic and anaerobic conditions simultaneously. These conditions were used to study the effect of antimycotic drugs, mainly during a long time of 7 to 10 days. Germ tube formation as a virulence factor was more abundant and faster in cfc of strains with a stronger adherence to buccal epithelium cells. Co-cultivation of C. albicans and C. glabrata allowed conclusions for their colonization in vivo. A biofilm on the glass wall of the culture vessel led to mycelium formation by C. albicans. Concomitantly the growth of C. glabrata was favoured. Growth of C. albicans in the gastrointestinal flora was reduced by masses of bacteria and their multiple metabolic activities. A remarkable growth of C. albicans was only to be seen if the ecosystem was destroyed e.g. by antibacterial antibiotics. The influence of fluconazole in a long-term follow up study under anaerobic conditions showed an inhibition of C. albicans in 99.9%. This means fungicidal efficacy.

Fungal resistance.

Fungal resistance is caused by an acquisition of intrinsically resistant species, by selection of resistant strains from a population or by mutation of an initially susceptible strain. According to different classes of antimycotics there are different resistance mechanisms: differences in the uptake mechanisms, drug target alterations, mostly the ergosterol-biosynthesis pathway, and the efflux or pumping mechanisms to the outside.

The continuous flow culture as an in vitro model in experimental mycology.

We used the model of continuous flow culture (cfc) to study the growth of Candida species. This model allows special test conditions: a long generation time of 15-20 hs, controlled limitation of nitrogen sources and carbohydrates, comparison of the growth under aerobic and anaerobic conditions simultaneously. These conditions were used to study the effect of antimycotic drugs, mainly during a long time of 7 to 10 days. Germ tube formation as a virulence factor was more abundant and faster in cfc of strains with a stronger adherence to buccal epithelium cells. Co-cultivation of C. albicans and C. glabrata allowed conclusions for their colonization in vivo. A biofilm on the glass wall of the culture vessel led to mycelium formation by C. albicans. Concomitantly the growth of C. glabrata was favoured. Growth of C. albicans in the gastrointestinal flora was reduced by masses of bacteria and their multiple metabolic activities. A remarkable growth of C. albicans was only to be seen if the ecosystem was destroyed e.g. by antibacterial antibiotics. The influence of fluconazole in a long-term follow up study under anaerobic conditions showed an inhibition of C. albicans in 99.9 %. This means fungicidal efficacy.