Adjuvante Chemotherapie humaner kolorektaler Adeno-Carcinome nach Wachstum auf kongenital thymusdysplastischen Mäusen “Nude”

Zusammenfassung Die kombinierte Chemotherapie mit Vincristin (VCR) und 5-Fluorouracil (5-FU) war nach Festlegung der LD₅₀ im humanmedizinischen Dosierungsbereich bei 150 kongenital thymusdysplastischen nude-Mäusen ohne Komplikationen durchführbar. Unter spf-Bedingungen durchliefen ca. 5 Wochen alte syngene Balb/c-nude-Mäuse einen 9 tägigen Therapiezyklus. Die Teilsynchronisation wurde mit VCR am Tag 1 eingeleitet und 5-FU jeweils vom 1. bis 3. Tag intraperitoneal appliziert. Pathohistologisch entstanden unter VCR bei einer Dosis von 20% der LD₅₀ bei allen Tieren Milzatrophien und schwere Jejunitiden. Die durch Verminderung überwiegend segmentkerniger Zellen entstandenen Leukopenien waren erwartungsgemäß reversibel. Nach 5-FU-Applikation entstanden bei einer 20% igen Dosierung der LD₅₀ hauptsächlich Zystitiden, bei 67% Bronchitiden und Lobärpneumonien.In der Kombination mit humanmedizinisch relevanten Dosierungen entwickelten die Tierkollektive regressive Veränderungen an Harnblasen- und Zottenepithelien des Jejunums. Neben Hepatitiden mit Gruppennekrosen fanden sich Pneumonien bei 50% der Tiere; Milzatrophien waren mäßig ausgeprägt. Die Lymphknoten zeigten eine Tendenz zur Strukturauflösung der Follikel ohne spezifische Veränderungen der paracorticalen Region. Hämatologisch war nach reversibler Leukopenie mit Granulozytopenie die Einleitung eines 2. Zyklus am 9. Tag möglich.Nach Kenntnis dieser Befunde ist die Möglichkeit gegeben, die Wirksamkeit von VCR und 5-FU auf das Wachstum humanen kolorektalen Tumorgewebes nach erfolgter Transplantation auf nude-Mäuse in vivo zu testen.Mit Unterstützung der Deutschen Forschungsgemeinschaft     

Numbers of T cell receptor (TCR) alpha beta+ but not of TcR gamma delta+ intraepithelial lymphocytes correlate with the grade of villous atrophy in coeliac patients on a long term normal diet.

Numbers of T cell receptor (TcR) gamma delta+ and alpha beta+ intestinal lymphocytes were studied in 34 coeliac patients in respect of their diet and the grade of villous atrophy. Particular attention was given to a group of 21 patients with coeliac disease according to ESPGAN criteria who were on a well tolerated long term normal diet and in nine of whom the mucosa had returned to normal or nearly normal. A significant increase in TcR gamma delta+ cells was observed in the gut epithelium of coeliac patients compared with age matched controls, and this did not correlate with either the presence of gluten in the diet or with the grade of villous atrophy. Thus, numbers of TcR gamma delta+ intraepithelial lymphocytes (IEL) were considerably above the normal range in four of seven patients on a gluten free diet and in four of nine patients who had recovered a normal or nearly normal mucosa in spite of a normal diet. In contrast, numbers of intestinal TcR alpha beta+ cells varied with the stage of the disease. Their number was high in the epithelium of patients with active coeliac disease (n = 18) but significantly less in patients whose mucosa had returned to normal or nearly normal either after gluten free diet (n = 7) or in spite of a normal diet (n = 9). Immunohistochemical markers of intestinal mononuclear cell activation detected in active coeliac disease were either weakly expressed or absent in the latter patients. It is suggested that TcR alpha beta+ but not TcR gamma delta+ IEL are sensitised to gliadin in coeliac disease, and that only the former cells play a direct part in the pathogenesis of the villous atrophy. The normal counts of TcR alpha beta+ IEL and the absence of detectable mononuclear activation in the biopsy specimens of a few patients who have recovered clinical and histological tolerance to gluten sustains this hypothesis and also suggests that immunological tolerance to gluten may be acquired in a subgroup of coeliac patients. Hte appreciable increase in TcR gamma delta+ IEL observed in some of the latter patients, however, is similar to that observed in latent coeliac disease urging for their careful and prolonged follow up until the role of TcR gamma delta+ IEL in the pathogenesis of coeliac disease is elucidated.     

Quality assurance for the diagnostics of viral diseases to enhance the emergency preparedness in Europe

The threat posed by emerging and re-emerging communicable diseases and, more recently, by the intentional release of infectious agents in a susceptible population, has been receiving considerable attention at the national and international levels. Public health efforts to strengthen disease detection, surveillance and control have been intensified. However, clinicians and clinical microbiology laboratories play an important role in the early detection of disease, the identification of the putative agent, and notification of the appropriate authorities. To be effective in this role, laboratories must be specially prepared to handle viral agents safely, and need, among other things, the appropriate rapid and sensitive diagnostic tests. In 1998 the European Network for Diagnostics of 'Imported' Viral Diseases (ENIVD) was established. ENIVD presently comprises, as permanent members, 44 expert laboratories in 21 European Union (EU) member states and 4 non-EU countries and is one of the networks on infectious diseases funded by the European Commission. ENIVD fulfils many of the important tasks required for the surveillance and control of imported, rare and emerging viral infections such as the exchange of expertise and the organisation of external quality assurance (EQA) programmes, both of which are needed to improve diagnostics. Here, we summarise the data generated by recent EQA activities focussed on the diagnostics of infections with hantavirus, dengue virus, filovirus, Lassa virus, orthopox virus and the SARS-coronavirus (SARS-CoV). These were carried out between 1999 and 2004 and involved 93 laboratories from 41 countries, including laboratories from additional countries outside of Europe. Particularly the EU-candidate countries and Eastern neighbouring countries will be invited to join the network in the near future. A public website is available at http://www.enivd.de.     

Synthesis and Characterization of Polymerized Ionic Liquids: Mechanical and Thermal Properties of a Novel Type of Hydrogels

An easy and efficient route to synthesize gel materials based on polymeric ionic liquids (PILs) is presented. The radical polymerization of imidazolium (Im)‐based ionic liquids (ILs) bearing a vinyl group ([VEIm][Br], [VEIm][Ac], [VBIm][Br], [VBIm][Cl]) with crosslinker (CL) N,N′‐methylenebisacrylamide (Bis) in water results in polyionic liquid hydrogels. Thermal and mechanical properties (tensile and compression tests) are investigated and compared with two different types of hydrogels. One is a polyacrylamide (PAAm) hydrogel having covalent‐type crosslinking. The other is an alginate‐based hydrogel having ionic‐type crosslinking. Prepared IL‐hydrogel materials provide favorable flexibility, adjustable by varying the CL ratio and water content. The higher the CL ratio is, the higher the fragility of the gel matrix. The gelation time of the hydrogels depends on the alkyl chain length, as well as the size of the anion.

     

Unique semantic space in the brain of each beholder predicts perceived similarity

The unique way in which each of us perceives the world must arise from our brain representations. If brain imaging could reveal an individual’s unique mental representation, it could help us understand the biological substrate of our individual experiential worlds in mental health and disease. However, imaging studies of object vision have focused on commonalities between individuals rather than individual differences and on category averages rather than representations of particular objects. Here we investigate the individually unique component of brain representations of particular objects with functional MRI (fMRI). Subjects were presented with unfamiliar and personally meaningful object images while we measured their brain activity on two separate days. We characterized the representational geometry by the dissimilarity matrix of activity patterns elicited by particular object images. The representational geometry remained stable across scanning days and was unique in each individual in early visual cortex and human inferior temporal cortex (hIT). The hIT representation predicted perceived similarity as reflected in dissimilarity judgments. Importantly, hIT predicted the individually unique component of the judgments when the objects were personally meaningful. Our results suggest that hIT brain representational idiosyncrasies accessible to fMRI are expressed in an individual''s perceptual judgments. The unique way each of us perceives the world thus might reflect the individually unique representation in high-level visual areas.Everyone’s perception of the world is unique. Psychologists and psychotherapists, using methods including questionnaires and free association, have long attempted to peer into an individual’s subjective experiential world. The unique aspects of our experience coexist with a shared experiential component. We can all recognize the objects that surround us and name them in a common language. Consistent with this shared component of experience, there is evidence that visual stimuli are processed similarly in the brains of different individuals (1). However, the unique way in which each of us perceives an object also must arise from brain activity. Is there an individually unique component to our brain representations?Unidimensional aspects of subjective visual percepts, ranging from estimates of object size, color, vividness, and emotional valence, have separately been found to correlate with interindividual variation in both univariate regional-average activation and cortical anatomy (2, 3). However, it remains unclear how a person’s multidimensional subjective percept reflects the multivariate brain-activity pattern that represents a particular object.Functional magnetic resonance imaging (fMRI) studies of object vision have focused largely on commonalities among subjects and category averages across particular stimuli. These studies have revealed regions in human inferior temporal cortex (hIT) that preferentially respond to specific categories (4–9) as well as widely distributed category information (10). More recently, similarity analyses of response patterns to particular stimulus images have revealed exemplar-specific representations (11–14), clustering of response patterns by natural categories (15–17), and reinstatement of neural representations during memory recall (18, 19). These prior studies either tacitly assumed similar representations across individuals or explicitly demonstrated commonalities between individuals and even between species (14, 20–29).Previous studies have shown that the hIT representation has a semantic component (23) and is reflected in perception at the level of group averages (30). Here we tested the hypothesis that an individual’s hIT representation predicts idiosyncrasies in his or her perception of natural objects. Because of hIT’s reciprocal connections to the memory regions of the medial temporal lobe (31), we further predicted that personally meaningful objects elicit individually unique mnemonic associations and are more distinctly represented in each individual.We presented familiar and unfamiliar object images to subjects during fMRI and investigated whether early visual cortex (EVC) and hIT exhibit individually unique representations. We characterized the representational geometry of each region by the dissimilarity matrix of activity patterns elicited by particular object images. This matrix is called the “representational dissimilarity matrix” (RDM) (16). To address whether the detailed representational geometries are reflected in behavior, we tested whether individual idiosyncrasies in similarity judgments can be predicted on the basis of a subject’s brain RDM.     

Corallopyronin A specifically targets and depletes essential obligate Wolbachia endobacteria from filarial nematodes in vivo

Doxycycline and rifampicin deplete essential Wolbachia from filarial nematodes that cause lymphatic filariasis or onchocerciasis, resulting in blocked worm development and death. However, doxycycline is contraindicated for children and pregnant/breastfeeding women, as is rifampicin in the latter group with the additional specter of possible resistance development in Mycobacterium spp. Novel antibiotics with a narrower spectrum would aid in eliminating filarial diseases. Corallococcus coralloides synthesizes corallopyronin A, a noncompetitive inhibitor of RNA polymerase ineffective against Mycobacterium spp. Corallopyronin A depleted Wolbachia from infected insect cells (1.89 Thus the antibiotic is effective against intracellular bacteria despite the many intervening surfaces (blood vessels, pleura, worm cuticle) and membranes (worm cell, vesicle, Wolbachia inner and outer membranes). Corallopyronin A is an antibiotic to develop further for filariasis elimination without concern for cross-resistance development in tuberculosis.