[Cystectomy in elderly patients: analysis of complications using the Clavien-Dindo classification]. / Die Zystektomie im Alter : Komplikationsanalyse unter Anwendung der Clavien-Dindo-Klassifikation.

Radical cystectomy (RC) represents the gold standard in the treatment of muscle invasive urothelial cancer of the bladder. Due to improvements in operation techniques and perioperative care it has become a good and safe procedure even in elderly patients. In recent years the Clavien-Dindo classification has been frequently used for complication assessment in urological research. The Charlson comorbidity index without age correction can be used in treatment planning for RC to identify patients at risk.

[Bladder dysfunction caused by a large presacral retention mucocele]. / Blasenfunktionsstörung in Folge einer grossen präsakralen Retentionsmukozele.

Large pelvic masses can displace the urinary bladder and cause bladder dysfunction with various symptoms. We report the case of a 42-year-old man who described a feeling of reduced urinary stream and bladder filling and residual urine since his youth. After various unsuccessful conservative treatments, the patient was evaluated by our neuro-urologic department. The diagnostic workup revealed a large cystic mass that displaced the urinary bladder. Histopathological examination showed a retention mucocele (the patient had been surgically treated for connatal anal atresia). The lesion was surgically excised.

rolling pebbles (rols) is required in Drosophila muscle precursors for recruitment of myoblasts for fusion.

Mutations in the rolling pebbles (rols) gene result in severe defects in myoblast fusion. Muscle precursor cells are correctly determined, but myogenesis does not progress significantly beyond this point because recognition and/or cell adhesion between muscle precursor cells and fusion-competent myoblasts is disturbed. Molecular analysis of the rols genomic region reveals two variant transcripts of rols due to different transcription initiation sites, rols6 and rols7. rols6 mRNA is detectable mainly in the endoderm during differentiation as well as in malpighian tubules and in the epidermis. By contrast, rols7 expression is restricted to the mesoderm and later to progenitor descendants during somatic and pharyngeal muscle development. Transcription starts at the extended germ band stage when progenitor/founder cells are determined and persists until stage 13. The proteins encoded by the rols gene are 1670 (Rols6) and 1900 (Rols7) amino acids in length. Both forms contain an N-terminal RING-finger motif, nine ankyrin repeats and a TPR repeat eventually overlaid by a coiled-coil domain. The longer protein, Rols7, is characterized by 309 unique N-terminal amino acids, while Rols6 is distinguishable by 79 N-terminal amino acids. Expression of rols7 in muscle founder cells indicates a function of Rols7 in these cells. Transplantation assays of rols mutant mesodermal cells into wild-type embryos show that Rols is required in muscle precursor cells and is essential to recruit fusion-competent myoblasts for myotube formation.

Evidence that the hypermutated M protein of a subacute sclerosing panencephalitis measles virus actively contributes to the chronic progressive CNS disease.

Subacute sclerosing panencephalitis (SSPE) is a progressive degenerative disease of the brain uniformly leading to death. Although caused by measles virus (MV), the virus recovered from patients with SSPE differs from wild-type MV; biologically SSPE virus is defective and its genome displays a variety of mutations among which biased replacements of many uridine by cytidine resides primarily in the matrix (M) gene. To address the question of whether the SSPE MVs with M mutations are passive in that they are not infectious, cannot spread within the CNS, and basically represent an end-stage result of a progressive infection or alternatively SSPE viruses are infectious, and their mutations enable them to persist and thereby cause a prolonged neurodegenerative disease, we utilized reverse genetics to generate an infectious virus in which the M gene of MV was replaced with the M gene of Biken strain SSPE MV and inoculated the recombinant virus into transgenic mice bearing the MV receptor. Our results indicate that despite biased hypermutations in the M gene, the virus is infectious in vivo and produces a protracted progressive infection with death occurring as long as 30 to 50 days after that caused by MV. In primary neuron cultures, the mutated M protein is not essential for MV replication, prevents colocalization of the viral N with membrane glycoproteins, and is associated with accumulation of nucleocapsids in cells' cytoplasm and nucleus.

Neither B lymphocytes nor antibodies directed against self antigens of the islets of Langerhans are required for development of virus-induced autoimmune diabetes.

We evaluated the role of the humoral arm of the immune response in causing or contributing to virus-induced diabetes. Transgenic mice expressing the nucleoprotein (NP) or glycoprotein (GP) of the lymphocytic choriomeningitis virus (LCMV) under control of the rat insulin promoter (RIP) in pancreatic beta cells (RIP-LCMV) and RIP-LCMV mice with genetic dysfunction of B cells (RIP-LCMV x microMT/microMT) were compared for development of diabetes after challenge with LCMV. After inoculation with LCMV, B and T lymphocytes and macrophages infiltrated into pancreatic islets in RIP-LCMV mice, and over 50% of these mice generated Abs against host insulin or glutamate decarboxylase. However, neither B cells nor the autoantibodies played a direct role in the initiation, kinetics, or severity of the virus-induced diabetes as judged by comparing disease in RIP-LCMV mice to littermates whose functional B cells were genetically eliminated. Furthermore, the quality and quantity of T lymphocyte and macrophage infiltration was similar in the B cell-deficient and non-B cell-deficient RIP-LCMV mice. Although the development of autoantibodies to islet Ags had no direct influence on the pathogenesis of insulin-dependent (type 1) diabetes mellitus, it served as a prediabetes marker, as such autoantibodies were often elevated before the onset of disease. Hence, the RIP-LCMV model is not only useful for understanding the pathogenetic mechanisms of how islets are destroyed and spared but also for evaluating therapeutic strategies before onset of clinical diabetes.

Immunosuppression and resultant viral persistence by specific viral targeting of dendritic cells.

Among cells of the immune system, CD11c(+) and DEC-205(+) splenic dendritic cells primarily express the cellular receptor (alpha-dystroglycan [alpha-DG]) for lymphocytic choriomeningitis virus (LCMV). By selection, strains and variants of LCMV that bind alpha-DG with high affinity are associated with virus replication in the white pulp, show preferential replication in a majority of CD11c(+) and DEC-205(+) cells, cause immunosuppression, and establish a persistent infection. In contrast, viral strains and variants that bind with low affinity to alpha-DG are associated with viral replication in the red pulp, display minimal replication in CD11c(+) and DEC-205(+) cells, and generate a robust anti-LCMV cytotoxic T lymphocyte response that clears the virus infection. Differences in binding affinities can be mapped to a single amino acid change in the viral glycoprotein 1 ligand that binds to alpha-DG. These findings indicate that receptor-virus interaction on dendritic cells in vivo can be an essential step in the initiation of virus-induced immunosuppression and viral persistence.

Local IL-4 expression in the lung reduces pulmonary influenza-virus-specific secondary cytotoxic T cell responses.

We studied the effect of lung-specific IL-4 expression on the T cell response during primary and secondary heterologous infection with influenza virus by using transgenic mice that express IL-4 under a lung-specific promoter. Subsequent to primary infection with a type A/H1N1 influenza virus these transgenic mice exhibited similar local recruitment of CD4(+) and CD8(+) T cells and only slightly decreased virus-specific CTL activity. However, during secondary challenge with a heterologous influenza virus, the local infiltration with virus-specific, MHC class I-restricted CD8(+) T cells was significantly decreased compared to that of nontransgenic littermates. The ability of IL-4 transgenic mice to clear the heterologous infection was delayed but not abrogated. This was associated with a faster virus-neutralizing antibody response in IL-4 transgenic mice and with their ability to mount significant Th1 responses even in the presence of increased local IL-4 expression. Our observations demonstrate a negative regulatory effect of IL-4 on memory Tc1/CD8(+) T cells, but are also consistent with complementary mechanisms important for virus clearance such as virus-neutralizing antibodies. The reduction of memory CTL in the presence of IL-4 might have consequences for understanding the course of influenza infection in situations where T(H)2 immunity is increased.

Disruption of the STAT4 signaling pathway protects from autoimmune diabetes while retaining antiviral immune competence.

The role of the STAT4 signaling pathway in autoimmune diabetes was investigated using the rat insulin promoter lymphocytic choriomeningitis virus model of virally induced autoimmune diabetes. Abrogation of STAT4 signaling significantly reduced the development of CD4+-T cell-dependent but not CD4+-T cell-independent diabetes, illustrating the fine-tuned kinetics involved in the pathogenesis of autoimmunity. However, the absence of STAT4 did not prevent the generation of autoreactive Th1/Tc1 T cell responses, as well as protective antiviral immunity. Protection from insulin-dependent diabetes mellitus was associated with decreased numbers of autoreactive CTL precursors in the pancreas and the spleen and a general as well as Ag-specific reduction of IFN-gamma secretion by T lymphocytes. A shift from Th1 to Th2 T cell immunity was not observed. Hence, our results implicate both CTL and cytokines in beta cell destruction. Selective inhibition of the STAT4 signal transduction pathway might constitute a novel and attractive approach to prevent clinical insulin-dependent diabetes mellitus in prediabetic individuals at risk.

Molecular and developmental characterization of novel cDNAs of the myelin-associated/oligodendrocytic basic protein.

Several novel myelin-associated/oligodendrocytic basic protein (MOBP) isoforms were identified in this study by cDNA cloning. They are small, highly basic polypeptides comprising 69, 81, and 99 amino acids (8.2, 9.7, and 11.7 kDa, respectively) and show no significant homology with described proteins or domain structures. All (as yet) identified MOBP isoforms are identical in amino acids 1-68 but differ in the length and polarity of the C-terminal region. One isoform, designated MOBP81, was shown to be expressed abundantly during development. Interestingly, MOBP81 has a significant clustering of positively charged residues at positions 69-81, a feature that also has been observed for myelin basic protein (MBP) and Po. As demonstrated by in situ hybridization, MOBP gene expression occurs during development of the rat optic nerve later than that of MBP and proteolipid protein and coincides exactly with the beginning of myelin compaction. The 2.6 kb MOBP81-A transcript is localized in the processes of oligodendrocytes, whereas the 3.8 kb MOBP81-B transcript is restricted to the perinuclear region. Therefore, MOBP81-A and related mRNAs seem to be transported to the periphery of the oligodendrocytes, as is known for the transcripts of the MBP gene. The late developmental expression of the MOBP gene suggests that the MOBP proteins act at the late steps of myelin formation, possibly in myelin compaction and in the maintenance of the myelin sheath.