Damage of purkinje cell axons following chronic phenytoin administration: An animal model of distal axonopathy

Summary An animal model of central distal axonopathy following chronic administration of phenytoin is described. Male C57/BL6J mice received diphenylhydantoin (DPH) in the daily diet (liquid diet Stardit, supplemented with vitamins) over a period of 8 weeks. Control and experimental animals were pair-fed.Twelve mice of both groups were perfused via the left ventricle with glutaraldehyde. Representative samples of the cerebral cortex (area 3), cerebellum (vermis and deep cerebellar nuclei), thalamus, hypothalamus, and liver were embedded in araldite. Semithin sections and electron microscopy of the cerebellar vermis revealed marked dystrophic changes in the Purkinje cell axons. The presynaptic segments of Purkinje cell axons in the deep cerebellar nuclei showed massive enlargement and swelling due to accumulation of spherical particles and tubular structures in the axoplasm. These structures represent a proliferation of the smooth endoplasmic reticulum.Identical changes were found in hepatocytes of treated animals. Because phenytoin induces hepatic microsomal enzymes, we suggest that phenytoin-related Purkinje cell damage may be produced by an induction of Purkinje cell microsomes with proliferation of the smooth endoplasmic reticulum which causes a swelling and enlargement of presynaptic segments of Purkinje cell axons in deep cerebellar nuclei. Chronic phenytoin administration to mice is a new model of phenytoin-induced encephalopathy and of distal axonopathy of cerebellar neurons.Supported by the Deutsche ForschungsgemeinschaftPresented in Part at the Joint Meeting of the German and Scandinavian Neuropathologists, Turku, Finland, June 3–4, 1983     

CT stereotactic biopsy in the differential diagnosis of deeply situated intracerebral hematomas

The diagnosis of intracerebral haematomas, especially of those which are relatively small, occupy little space and are deeply situated, presents considerable problems. The problem is even greater when the expected acute case history and the acute beginning of the symptoms do not occur and unusual localisations are found. The consequences of this are false diagnoses and the treatment of these patients within the framework of blanket diagnosis "intracerebral tumours" or "space occupying processes" without any confirmation of the histological diagnosis. - Using a sample of 26 patients where the histological diagnosis of non-recent intracerebral hemorrhages had been confirmed (out of a series of 818 CT-stereotactically biopsied patients punctured by us from the beginning of 1983 until the end of 1984), the problem of establishing a diagnosis is exposed. - A histological diagnoses should in any case be confirmed before any thorough and deep-reaching therapy is begun, since false diagnoses and misinterpretations can cause serious consequences for the patient.     

Studies for estimating the biologic behavior and prognosis of paragangliomas in the head and neck

Despite a large number of histopathologic and immunohistochemical studies, the biologic behavior and prognosis of paragangliomas (glomus tumors) of the head and neck still remain uncertain. In the present study 36 specimens from 32 patients who underwent surgery for a paraganglioma were examined. The examinations included routine histology, quantitative DNA analysis based on image cytometry, immunohistochemical detection of the proliferating cell nuclear antigen (PCNA) along with visualization of nucleolar organizer regions (AgNOR). According to LeCompte, the paragangliomas were histologically divided into three subcategories: 16 patients had a paragangliomatous tumor. 14 patients had an adenomatous tumor, and 6 patients had an angiomatous tumor. Quantitative DNA analysis revealed three categories of tumors with characteristical DNA pattern; DNA type I tumors were pure diploid, DNA type II tumors had stemlines at 2c and 4c and were therefore recognized as diploid-tetraploid. Aneuploid cells were not apparent in these two groups. DNA type III tumors had stemline ploidies exceeding 2c and 4c. Aneuploid cells were present in all of these tumors. The biologic behavior of these lesions therefore must be recognized as suspicious. DNA type III tumors and adenomatous tumors showed the highest values for the PCNA scores, indicating a higher proliferation rate and a more rapid growth pattern in these lesions. Twenty patients could be followed over a period of up to 110 months. Five of these patients developed a recurrent tumor. All of them had DNA type III tumors. The DNA indices showed significantly higher values in the recurrent tumor group. The 2c deviation index (DI) and the entropy value had the highest prognostic significance. No correlation to clinical follow-up was found for the AgNOR score. Based on these results, prognostic indices for paragangliomas were developed: patients with a tumor having a 2c DI exceeding 2.0, entropy value of more than 4.0. 5c exceeding rate more than 8.0, and a PCNA score more than 20.0% can be recognized as being at high-risk for developing recurrent disease.     

Inflammatory mechanisms in Alzheimer's disease

In recent years many studies have indicated an involvement of inflammatory mechanisms in Alzheimer's disease (AD). Acute-phase proteins such as 1-antichymotrypsin and c-reactive protein, elements of the complement system, and activated microglial and astroglial cells are consistently found in brains of AD patients. Most importantly, also cytokines such as interleukin-6 (IL-6) have been detected in the cortices of AD patients, indicating a local activation of components of the unspecific inflammatory system. Up to now it has remained unclear whether inflammatory mechanisms represent a primary event or only an unspecific reaction to brain tissue damage. Therefore, we investigated whether IL-6 immunoreactivity could be found in plaques prior to the onset of neuritic changes, or whether the presence of this cytokine is restricted to later stages of plaque pathology. we confirmed our previous observation that IL-6 is detectable in a significant proportion of plaques in the brains of demented patients. In AD patients IL-6 was found in diffuse plaques in a significant higher ratio as would have been expected from a random distribution of IL-6 among all plaque types. This observation suggests that IL-6 may precede neuritic changes, and that immunological mechanism may be involved both in the transformation from diffuse to neuritic plaques in AD and in the development of dementia.     

Über Melanin und Melanosomen im ZNS im Vergleich zu extracerebralen Erscheinungsformen und synthetischem Melanin aus Dopamin und Serotonin

Summary Melanosomes and isolated melanosomal fragments (melanin particles) originating from gangliocytes (substantia nigra), astroglia (melanosis cerebelli), and melanocytes (melanotic meningeoma; metastases of melanoblastoma; melanosis thalami of the goat) were compared with synthetic melanins prepared from dopamine and serotonin, respectively. Samples were examined by electron microscopy, X-ray diffraction analysis according to Debye-Scherrer and by infrared spectrophotometry, and the results were evaluated with regard to characteristic features as they may relate to specific cell types or chemical structures.On electron microscopy all three types of melanosomes could be differentiated unequivocally as could the two synthetic melanins. Thus, there were similarities between synthetic melanin from dopamine and the gliogenic melanins of the cerebellum; the synthetic melanin from serotonin resembled melanin of melanocytes.X-ray diffraction analysis yielded 2-4 Debye diffraction rings with all human and synthetic samples, suggesting short range orders between 3.8 to 5 Å the sample obtained from a goat with thalamic melanosis showed a specific reflex pattern. While diffraction patterns of some melanins were partially identical, in particular that of melanin from dopamine and melanin of substantia nigra and dentate nucleus, respectively, they were different for the various melanocytic melanins. Further investigations are required to determine whether these differences are due to disparities in basic chemical structures or conformations or else, to particular compositional features of the various types of melanocytes as they arise from benign or malignant tumors or a specific species.Infrared spectrophotometry at higher wave numbers revealed the well known patterns of melanins, which are not, however, very suitable, for their further differentiation. At lower wave numbers (fingerprinting) melanin of substantia nigra and the glial melanin in melanosis cerebelli yielded additional absorption bands of identical configuration. In contrast to melanin from dopamine, melanin from serotonin exhibited a closely similar absorption pattern in this spectral range, suggesting that the neuroectodermal melanins may contain a component possibly arising from serotonin.

Herrn Prof. Dr. Wilhelm Doerr zum 25. 8. 1979     

Optical-thermal simulation of human tonsillar tissue irradiation: clinical implications

BACKGROUND AND OBJECTIVE: Mucosa intact laser tonsillar ablation is an alternative to conventional tonsillectomy. The efficacy of this procedure was demonstrated in canines, but establishing the safety of irradiating human tonsils is paramount. STUDY DESIGN/MATERIALS AND METHODS: An optical-thermal simulation of tonsillar tissue irradiation was previously developed, but the effect of varying parameters was not investigated. The tissue response to irradiation at 5-25 watts for 1 minute and 10 watts for 10 seconds to 162 seconds is simulated. RESULTS: At 15 watts and greater, the peak temperature is over 100 degrees C and the mucosal temperature is over 70 degrees C. At the depth of the tonsil, the temperature does not vary significantly. The peak temperature is at 1 mm. The radial temperature profile is not significantly altered by longer irradiation times. CONCLUSIONS: The optimal dosimetry parameters for irradiation of human tonsillar tissue at 805 nm with the MILTA technique is under 15 watts for approximately 1 minute.     

Mechanisms behind flare of renal lupus during murine pregnancy

The outcome of pregnancy in systemic lupus erythematosus is still controversial. The authors recently reported the disappearance of the manifestation of the skin disease but a diminished survival rate in lupus-prone animals undergoing several pregnancies. It was postulated that lupus-prone animals must have subclinical renal symptoms at an early age and that immune and hormonal changes during pregnancy exacerbate immune reactions in the kidneys, leading to a shortened life span. Here, the authors analysed changes at day 14 of pregnancy in lupus-prone LPR (MRL/lpr) mice and MRL controls regarding cytokines, regulatory T (Treg) cells and deposition of immunocomplexes. Worsened kidney function was observed during pregnancy, even in the absence of lupus signs. This was accompanied by renal inflammation and higher interferon-gamma and interleukin-10 levels. C3 and immunoglobulin G deposition was enhanced in kidney and placenta from lupus-prone pregnant animals. Pregnancy enhanced the levels of Treg cells in control animals but not in lupus-prone animals. As pregnancy-induced Treg cells were shown to be specific for paternal antigens it is not to be expected that these Treg cells can help to destroy autoreactive cells. The authors conclude that early subclinical kidney disease in lupus-prone animals exacerbates during pregnancy. Albeit obtained with an experimental animal model, their data are potentially of importance for lupus patients of reproductive age.