[Sebaceous gland tumor with a rare gene mutation within a tumor syndrome: Muir-Torre syndrome]. / Talgdrüsenkarzinom mit seltener Genmutation im Rahmen eines Tumorsyndroms: Muir-Torre-Syndrom.

Muir-Torre syndrome is a rare autosomal dominant subtype of hereditary nonpolyposis colorectal carcinoma and is characterized by the simultaneous occurrence of sebaceous gland neoplasms with visceral and urogenital malignancies. This article describes the case of a 72-year-old patient who was referred to our clinic for removal of an upper eyelid tumor, showing the course from the clinical findings to the rare diagnosis of Muir-Torre syndrome.

The prostate stem cell antigen represents a novel glioma-associated antigen.

Gliomas of WHO grades III-IV are malignant brain tumors mostly resistant to conventional therapies. Therefore, novel strategies for the treatment of gliomas are warranted. Although immunotherapy is gaining increased attention for the treatment of malignant gliomas and in particular of glioblastoma multiforme (GBM), this approach requires the identification of appropriate antigens. Our aim was to investigate the expression of the prostate stem cell antigen (PSCA), a highly N-glycosylated phosphatidylinositol (GPI)-anchored cell surface protein, in gliomas of different WHO grades in order to evaluate its potential as a diagnostic marker and as a target for immunotherapy. Tumor specimens and controls were assessed by quantitative RT-PCR, Western blotting and immunohistochemistry. The samples investigated in the study consisted of 210 human glial tumors, among which 31 were oligodendrogliomas, 9 ependymomas and 170 were astrocytomas (including 134 glioblastomas). PSCA was absent in normal brain tissue, but was detected in WHO grade III-IV gliomas. Weak PSCA protein expression was also recognized in some WHO grade I and WHO grade II tumors. The difference between WHO grade I-II tumors and WHO grade III-IV tumors was statistically significant (p<0.001). Our results suggest that increased PSCA expression levels are linked to gliomas of WHO grades III and IV, and may represent a suitable additional target for immunotherapy of gliomas.

Neuronal and glial apoptosis in human traumatic brain injury.

To establish reliable methods to aid the timing of brain damage after traumatic brain injury (TBI), brain tissue from 56 autopsy cases with TBI and known survival times, ranging from a few minutes to 126 days, were tested for apoptotic changes to the neuronal and glial cells. Apoptosis was established using the TdT-mediated dUTP nick end labelling (TUNEL) method of in-situ labelling and immunohistochemical reaction of caspase 3. In addition, cellular reaction and astroglial cell differentiation were investigated using histological and immunohistochemical markers. From a survival time of 120 min up to 12 days, TUNEL-positive apoptotic neuronal cells were frequently detected in the contusion zone. The earliest positive caspase 3 reaction in cortical neurons was evident after a posttraumatic interval of 80 min. Detection of apoptotic glial cells using the TUNEL technique showed that as in the case of neuronal cells, the earliest positive TUNEL reaction was obtained after 110 min. In cases of survival times of 120 min up to 4 days, apoptotic glial cells could frequently be detected. However, the first caspase 3-positive glial cells appeared 5 h after injury. Cerebral apoptosis was significantly associated with TBI cases as compared to control cases (P<0.001). The reference histological findings of neutrophilic granulocytes, CD3-positive T-lymphocytes, CD68-positive activated microglial cells/macrophages and TUNEL-positive neuronal cells increases the degree of certainty in determining the probable age of traumatic brain injury to 87.5%.

Increased polysialic acid neural cell adhesion molecule expression in human hippocampus of heroin addicts.

Chronic exposure to heroin is known to cause cognitive deficits. However, little is known about the underlying molecular mechanisms. It has been suggested that opiate-induced neurotoxicity as well as impaired plasticity and regeneration may be relevant. One of the target regions where regeneration still can be observed in the adult brain is the hippocampus. Since polysialic acid neural cell adhesion molecule is regarded as one of the key players involved in plasticity and regeneration of neural tissue, we analyzed polysialic acid neural cell adhesion molecule expression in the fascia dentate hilus of the human hippocampus of 29 lethally intoxicated heroin addicts and matched controls. Immunohistochemistry with an antibody directed against polysialic acid neural cell adhesion molecule revealed its expression in differently sized cells which could be identified as neurons and glial cells. We observed an increase in the percentage of polysialic acid neural cell adhesion molecule positive neurons in hippocampal hilus of heroin addicts compared with controls (P = 0.001).Interestingly, we also observed polysialic acid neural cell adhesion molecule expression in glial cells as evidenced by double immunofluorescence with glial fibrillary acidic protein and polysialic acid neural cell adhesion molecule using confocal laser scanning microscopy. The fraction of polysialic acid neural cell adhesion molecule positive glial cells was also higher in heroin addicts compared with controls (P = 0.009). In addition, within the group of addicts morphine blood concentrations showed a positive correlation with the percentage of polysialic acid neural cell adhesion molecule positive neurons (P = 0.04; r = 0.547). In conclusion, we observed an increase in polysialic acid neural cell adhesion molecule positive neurons and glial cells in hippocampi of heroin addicts. This might reflect an attempt to repair cell damage due to heroin exposure.

[Creutzfeldt-Jakob disease. Lack or correlation between cerebral cortex histology and clinical course of the disease in 22 autopsy cases]. / Creutzfeldt-Jakob-Krankheit. Fehlende Korrelation zwischen zerebraler kortikaler Histologie und klinischem Verlauf der Erkrankung in 22 Obduktionsfällen.

To detect a possible correlation between the neurology and duration of Creutzfeldt-Jakob disease (CJD) and cerebral pathology, we studied 22 autopsy cases by histological and immunohistochemical methods. The duration of disease ranged between 1 and 15 months with an average of 5.2 months. Only in 11 cases was the EEG typical for CJD. Morphologically the changes varied from minimal spongy changes to severe neuronal loss and brain atrophy. For the three cortical regions examined semiquantitatively, there was no correlation between the severity of spongiform changes and the duration of disease or the pattern of neurological symptoms. The study shows that more extensive sampling for the detection of regional heterogeneity of changes is mandatory in spongiform encephalopathies, and that complicating changes such as intermittent infections may play a role for the survival time as well. Moreover, genetic determinants, prion protein polymorphisms and the mode of exposure have to be considered as possible modulating factors.

Ezrin immunoreactivity is associated with increasing malignancy of astrocytic tumors but is absent in oligodendrogliomas.

The actin-binding protein ezrin has been associated with motility and invasive behavior of malignant cells. To assess the presence of this protein in human glial cells of the brain and its potential role in benign and malignant glial tumors, we studied ezrin immunoreactivity (IR), proliferation (MIB-1-IR), and apoptosis (terminal dUTP nick-end labeling) in normal human brain tissues from 10 autopsies and tissues from 115 cases of human glial tumors including astro-cytomas, ependymomas, oligodendrogliomas, and glioblastomas. We found weak staining of peripheral processes in normal human brain astrocytes and in World Health Organization grade II benign astrocytomas. Staining was markedly increased in anaplastic astrocytomas (World Health Organization grade III) and clearly strongest in glioblastomas (World Health Organization grade IV). The increase of ezrin-IR correlated significantly with increasing malignancy of astrocytic tumors (P < 0.0001). Statistical analysis revealed a stronger association with increasing malignancy for ezrin-IR than for MIB-1-IR or terminal dUTP nick-end labeling staining. Ezrin-IR was absent in normal oligodendrocytes and in oligodendrogliomas, but pronounced in normal ependymal cells and ependymomas. Ezrin-IR seems to be specific for astrocytes and ependymal glia in the normal brain. Our results indicate that ezrin-IR may provide a useful tool for the distinction of oligodendrogliomas and astrocytomas and for the grading of astrocytic tumors.

CD5-positive B cells in healthy elderly humans are a polyclonal B cell population.

B cell chronic lymphocytic leukemia (B-CLL) is a disease of the elderly and is characterized by a malignant clone of CD5+ B cells. In old mice, clonal expansions of CD5+ B cells are a common feature, and these animals frequently develop B-CLL. To investigate whether clonal expansion of CD5+ B cells also occurs in elderly humans, predisposing for the development of B-CLL, we analyzed VH gene rearrangements of CD5+ B cells from blood samples of four healthy, 65-82-years-old volunteers as markers of clonality. CD5+ and CD5-B cells were obtained by cell sorting, CDRIII of rearranged VH genes were amplified by polymerase chain reaction, and fragment length analysis was performed. All samples demonstrated a polyclonal pattern of VH gene length distribution. In addition, VH gene rearrangements were amplified and sequenced from sorted single cells of two of the donors. No clonally related CD5+ or CD5- B cells were observed. Thus, development of dominant clones of CD5+ peripheral blood B cells is unlikely to be a common trait of elderly individuals.

Interferon-gamma protects against herpes simplex virus type 1-mediated neuronal death.

Host inflammatory mediators, such as interferons, play a protective role in infection, but the mechanism is undefined and may differ between tissue compartments. To determine whether interferon-gamma (IFN-gamma) elicitation prevents destructive encephalitis in herpes simplex virus type 1 (HSV-1) infection of the central nervous system, IFN-gamma-knockout (GKO) mice were challenged intravitreally with HSV-1 strain F, inciting infection of the eyes and the brain. Indeed, the GKO mice showed encephalitis with ataxia, whereas nontransgenic controls remained asymptomatic. Morphology and digoxigenin labeling of DNA fragments revealed increased apoptosis in the brains of GKO mice compared with controls, although viral replication was not influenced at early stages of infection. Greater numbers of apoptotic cells in the brains of GKO mice correlated with neurological symptoms, as well as lower expression of the protective protooncogene bcl-2. Thus, IFN-gamma inhibits apoptosis, affording neuronal protection from destructive encephalitis during viral infection of the central nervous system.

Ocular production of interferon-gamma and lack of major histocompatibility complex molecules induce immunological changes in the intraocular environment.

The intraocular immune privilege includes the absence of delayed-type hypersensitivity (DTH) to intraocularly presented antigens. To study the role of major histocompatibility complex (MHC) molecules in relation to the activity of the proinflammatory cytokine interferon-gamma (IFN-gamma) in the maintenance of the intraocular immune privilege, we tested DTH to intraocularly presented antigens in MHC class I- or class II-deficient mice and in transgenic mice with production of IFN-gamma in the retina (rho-gamma). MHC class I- and class II-deficient mice and rho gamma mice with or without additional MHC deficiency developed hypersensitivity to intraocularly presented antigens and increased ocular pathology, whereas control animals did not. The abrogation of the intraocular immune privilege by IFN-gamma was independent of MHC expression and was probably due to disturbance of the blood-retina barrier. The sole lack of MHC class I or II expression produced similar effects, confirming the importance of IFN-gamma and MHC molecules for the development of uveitis.

Protective effects of interferon-gamma in intraocular herpes simplex type 1 infection do not depend on major histocompatibility complex class I or class II expression.

Intraocular infection with herpes simplex virus type I strain F (HSV-1) induces bilateral retinitis, the expression of both MHC class I and II molecules and activation of CD4 and CD8 cells. To investigate the role of MHC upregulation in IFN-gamma mediated antiviral effects in intraocular infection with HSV-1, we infected MHC deficient mice and mice with an additional ectopic site of IFN-gamma production in their retina (rho gamma) intravitreally with HSV-1 into one eye. Protective effects of IFN-gamma in intraocular HSV-1 infection were notable as sparing of the contralateral non-inoculated eye from retinitis, and were not dependent on MHC class I and class II expression, thus limiting the importance of MHC expression for the outcome of viral infection in vivo.

Cytokine-mediated survival from lethal herpes simplex virus infection: role of programmed neuronal death.

The mechanisms responsible for cytokine-mediated antiviral effects are not fully understood. We approached this problem by studying the outcome of intraocular herpes simplex (HSV) infection in transgenic mice that express interferon gamma in the photoreceptor cells of the retina. These transgenic mice showed selective survival from lethal HSV-2 infection manifested in both eyes, the optic nerve, and the brain. Although transgenic mice developed greater inflammatory responses to the virus in the eyes, inflammation and viral titers in their brains were equivalent to nontransgenic mice. However, survival of transgenic mice correlated with markedly lower numbers of central neurons undergoing apoptosis. The protooncogene Bcl2 was found to be induced in the HSV-2-infected brains of transgenic mice, allowing us to speculate on its role in fostering neuronal survival in this model. These observations imply a complex interaction between cytokine, virus, and host cellular factors. Our results suggest a cytokine-regulated salvage pathway that allows for survival of infected neurons.