Uptake and phototoxicity of meso-tetrahydroxyphenyl chlorine are highly variable in human biliary tract cancer cell lines and correlate with markers of differentiation and proliferation.

Photodynamic therapy (PDT) using Photofrin and, recently, Foscan has gained broad acceptance for palliative treatment of non-resectable cholangiocarcinoma (CC). No information, however, is available whether the phenotype of CC tumour cells has an effect on the efficiency of the treatment. Using a well-characterised set of n = 9 biliary tract cancer cell lines this study investigated the uptake, phototoxicity, and release of meso-tetrahydroxyphenyl chlorine (mTHPC, Foscan) after incubation with 200 or 400 ng ml(-1) mTHPC. For uptake of mTHPC we found great variations between the individual cell lines (up to a factor 2), resulting in even more pronounced differences in phototoxicity. Based on statistical classification by hierarchical cluster analysis, two groups of cell lines can be distinguished which are characterised by either high or low susceptibility towards mTHPC-based photodynamic treatment. Correlation analysis with previously established immunochemical parameters showed that cells with a low cytokeratin-19 (ductal differentiation), high vimentin (mesenchymal marker), and high proliferative phenotype preferentially show higher uptake of mTHPC and subsequent phototoxicity. These results demonstrate high variability of biliary tract cancer cells when subjected to mTHPC-based photodynamic treatment and identify possible markers that could be used in the clinical setting in order to predict the efficiency of PDT and adjust the dose for complete tumour elimination.

Differential effects of rapamycin in anti-GBM glomerulonephritis.

The immunosuppressive mammalian target of rapamycin inhibitor rapamycin is widely used in solid-organ transplantation, but the effect of rapamycin on kidney disease is controversial. This study evaluated the effect of rapamycin in the autologous phase of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. Disease was induced by preimmunizing the animals with rabbit IgG 5 d before administration of rabbit anti-mouse GBM antiserum. When rapamycin was started on the day of immunization (group 1), mice were protected from glomerulonephritis, suggested by a dramatic decrease in albuminuria, influx of inflammatory cells, and Th1-cytokine expression in the kidneys. Activation of T cells and production of autologous mouse anti-rabbit IgG were also significantly reduced in rapamycin-treated animals. In contrast, when rapamycin was started 14 d after immunization (group 2), mice had a significant increase in albuminuria and renal infiltration of inflammatory cells compared with vehicle-treated animals, and there were no differences in T and B cell responses. A significant decrease in vascular endothelial growth factor-A and an increase in IL-6 were detected in kidneys of these rapamycin-treated mice. In conclusion, rapamycin has the potential to significantly reduce the B and T cell responses and thereby protect from glomerulonephritis when administered early in disease. Once disease is established, however, rapamycin seems to worsen glomerulonephritis by disturbing the endothelial cell/vascular endothelial growth factor system in the kidney.

Efficacy of Farabloc as an analgesic in primary fibromyalgia.

The goal of our study was to determine the efficacy of Farabloc, an electromagnetic shielding fabric compared to placebo fabric when worn as a nightgown, as an analgesic in patients hospitalized with fibromyalgia. In a rheumatologic and rehabilitation hospital, we performed a phase 1, single-blind study of patients using Farabloc (F) or placebo (P) gowns for 8 h per night during the 20-day hospitalization and a phase 2, single-blind crossover study of patients using both F and P gowns randomly and alternatively switching after 10 of 21 days hospitalization (phase 1: 42 F, mean age 49.02 years, 35 female, 7 male; 84 P, mean age 48.08 years, 72 female, 12 males; phase 2: 25 F/P, P/F, or P/P, mean age 44.0 years, 24 female, 1 male). The study involved randomly selected and blinded use of hospital gown 8 h per night of either F or P fabric. The main outcome measures were changes from admission or midpoint to discharge in quantity of pain (QN), quality of pain (QL), and paracetamol use (PU). In phase 1, all three variables significantly favored F over P when using paired t test, two sample t test, Mann-Whitney, and analysis of covariance tests. QN was reduced (F = -2.03 -/+ 0.99*, P = 0.59 -/+ 0.71). QL was reduced (F = -10.64 -/+ 5.69*, P = -2.54 -/+ 3.40). PU was reduced (F = 10.69 -/+ 6.68*, P = 26.12 -/+ 9.37). In phase 2, comparing midpoint to discharge levels in the three variables again favored P/F over F/P and P/P (>0.001): QN (P/F +16.00 -/+ 8.35* F/P -13.27 -/+ 11.40), QL (P/F +8.71 -/+ 4.75* F/P -6.55 -/+ 5.59), and PU (F -9.29 -/+ 4.39* P -18.00 -/+ 5.27) (*p = <0.001). Patients with fibromyalgia had less pain after sleeping in a gown made of Farabloc than with a placebo fabric. This suggests that Farabloc, an electromagnetic shielding fabric, has analgesic properties in fibromyalgia. Reduced pain observation is consistent with previous studies in phantom limb pain and delayed onset muscle pain. Limitations of this study include single blind design, small sample size, and in phase 2, a lack of washout period and a F/F group.

Neuronal ceroid-lipofuscinosis--late-infantile or Jansky-Bielschowsky type--revisited.

The tissues from three patients with late-infantile NCL originally described by Max Bielschowsky became available to apply modern techniques such as fluorescence microscopy, electron microscopy and immunohistochemistry. While regular tinctorial preparations of the tissues documented a neuronal storage disorder in all three patients' tissues, the accumulated material proved to be autofluorescent, showed the ultrastructure of curvilinear lipopigments, and reacted strongly with an antibody against the subunit-C of mitochondrial ATP synthase, a major component of lipopigments in NCL and also with an antibody against sphingolipid activator proteins. Thus, these modern morphological techniques demonstrated that the originally described three siblings with late-infantile "amaurotic familial idiocy" really had neuronal ceroid-lipofuscinosis of the late-infantile or Jansky-Bielschowsky type, according to current diagnostic criteria. This type of archival study may also contribute to the mosaic of medical history.

Preliminary experimental results with the nitrosourea derivative ACNU in the treatment of malignant gliomas.

Comparative studies were carried out to evaluate the cytotoxic effectiveness of the nitrosureas ACNU (Nimustine) and BCNU (Carmustine) at equitoxic dose levels in xenografts from two astrocytomas grades III/IV (Li, Re) and one oligodendroglioma grade III (Oe) on nude mice. Growth delay was measured as the endpoint. All tumours were characterized initially and at regular intervals in later passages as to their histomorphologic pattern, expression of glial fibrillary acid protein and DNA-content by means of flow cytometry. These characteristics were shown to be unchanged in our xenografts over more than 27 passages. Growth delays of 18.7 days (ACNU) and 2.4 days (BCNU) for the Li-xenograft (p less than 0.01) were observed at an LD10 for both drugs. For the Re- and Oe-xenografts, growth delays of 18.0 vs. 14.0 days (p less than 0.001) and greater than 27.0 vs. 14.2 days (p less than 0.02) were observed at an equitoxic dose of 33 mg/kg ACNU or BCNU i.p., respectively. These preclinical data suggest a therapeutic advantage with ACNU for these high grade gliomas and should encourage further experimental and clinical investigations.

A Golgi study on the red nucleus in man.

The different cell types comprising the human red nucleus (RN) from eight patients without neuronal diseases were investigated using the Golgi-Braitenberg method for long-stored autopsy material. No giant cells were found due to regression of the magnicellular part of the human RN. We found larger (40-50 microns) and smaller (30 microns perikaryon size) medium-sized multipolar neurons with long dendrites, mushroom spines and typical distal dendritic tufts. The larger medium-sized RN neurons had some brush-shaped dendritic end portions which could not be observed in the Golgi studies on various other mammals described in the literature. We additionally found small neurons with a perikaryon size of 15 microns. These cells were thought to be intrinsic neurons similar to those in animal investigations. The neuronal types found in the normal human RN corresponded to those in the parvicellular part of the mammalian RN. Dendritic end brushes, however, are typical only for the human RN.

Pathological changes in dendrites of substantia nigra neurons in Parkinson's disease: a Golgi study.

Neurons of the substantia nigra show severe morphological changes in Parkinson's disease. Pathological alterations of cell bodies have been described, whereas those of neuronal processes have hardly been investigated. Golgi impregnation has been the chosen method for demonstrating neuronal processes and dendritic and somatic spines. We therefore used the Golgi-Braitenberg method to qualitatively and semi-quantitatively study the substantia nigra of eight patients with Parkinson's disease compared with eight control cases. Golgi impregnation of substantia nigra neurons was good in all control cases. In full agreement with the analysis of Braak and Braak (1986) three neuronal types within the substantia nigra were found. In cases of Parkinson's disease, severe pathological changes such as decrease of dendritic length, loss of dendritic spines and several types of dendritic varicosities were found only in the melanin-containing pars compacta neurons. Pars reticulata nerve cells were intact. These findings support the predominant role played by the dopaminergic efferent pathway in the degenerative process. The afferent pathway was not affected. This suggests that the substantia nigra lesion is primary in Parkinson's disease. Loss of neurons found in H & E sections corresponded to a lesser amount of impregnated pars compacta neurons in cases with Parkinson's disease when compared to controls. Evidences exist that the duration of the disease may be related to the extent of pathologically altered Golgi-impregnated pars compacta cells. The amount of Lewy bodies in H & E sections corresponded to the quantity of round varicosities in impregnated pars compacta neurons. These round dendritic varicosities were considered to be Lewy body inclusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Familial glioma: occurrence within the "familial cancer syndrome" and systemic malformations.

The family pedigree across eight generations is presented with an association of osteochondrodysplasia, other skeletal abnormalities, familial glial tumours in a father and his son, colonic and other adenomatous disease, and pigment changes. This family cluster of diseases is considered to be a dysontogenetic process with blastomatous features and grouped within the phakomastoses. A review of the literature indicates that some "familial gliomas" show additional malformations, thus resembling phakomatoses. Others are found to be members within a "familial cancer syndrome". A trait of "hereditary glioma" apart from these syndromes is difficult to identify, especially if only sibships are considered which are likely to share common environmental factors.

Primary cerebral anaplastic T-cell-lymphoma (type Ki-1): review and case report.

We describe the clinical course of a 20-year-old man who suffered generalized convulsive seizures with postictal aphasia and hemiparesis of the right side. Computed tomography (CT) displayed a left postcentral lesion with prominent perifocal edema and only a little contrast medium enhancement. The completely removed tumor proved to be a primary cerebral non-Hodgkin lymphoma consisting of T-cells. Only ten days after the operation the patient once more presented a clinical deterioration. A nuclear magnetic resonance imaging (MRI) displayed an annular structure in the area previously operated upon, suspected to be an abscess. The second operation disclosed a large recurrence of the primary T-cell lymphoma extending diffusely into the white matter. On account of the rapid recurrence, a whole brain irradiation was started twelve days after the second operation. Four cycles of chemotherapy followed. Immunohistochemical studies of the anaplastic large lymphoma cells showed staining with the pan T-cell markers (UCHL1, CD3) and with the CD30 (Ki-1) antibody. The B-cell markers (L26, LN1) were negative. The EMA (epithelial membrane antigen) was only partially expressed. Further investigation excluded the presence of systemic lymphoma manifestation. 24 months after the last operation the patient remained free of symptoms. The last MRI displayed no evidence for the recurrence of a lymphoma. In reference to this unusual clinical course the few previously reported cases of the extremely rare primary cerebral T-cell lymphoma are reviewed.

Rabies encephalitis: immunohistochemical investigations.

Three cases of human rabies encephalitis were studied immunohistochemically using a specific antiserum to rabies ribonucleoprotein (RNP) and the peroxidase-antiperoxidase method. In this way, RNP could be specifically demonstrated in all cerebral regions and the spinal cord with a predilection for virus attack on the diencephalon and the brain stem according to the clinical course of the disease, and possibly reflecting the phenomenon of pathoclisis. Virus antigen was mainly present in the nerve cell bodies and processes, and in glial cells, especially in the interfascicular oligodendroglia, which seems to be a route of rabies virus infection in the later course of this fatal disease. Immunohistochemically, virus antigen was not limited to the Negri bodies: it was also traceable in the cytoplasm. Altogether, many more virus infected cells were established by immunostaining than were to be expected by the presence of Negri bodies in hematoxylin-eosin stained sections.

Multiple sclerosis and cerebral tumor.

Two cases of long-standing multiple sclerosis (MS) are presented. During the course of this disease signs of a space-occupying lesion in the brain developed. An astrocytoma was diagnosed by biopsy in both patients. A later postmortem examination in one of them revealed a diffuse glioma with extension of tumor cells into the brain stem and cerebellum. Current opinions on the development of cerebral gliomatous tumors and of malignant lymphomas in patients with MS are discussed. Recent immunopathologic aspects are considered.

[Computertomographic and morphological findings in cerebral infarctions and intracerebral haematomas in identical sections (author's transl)]. / Computertomographische und morphologische Befunde bei Hirninfarkten und intrazerebralen Hämatomen unter besonderer Berücksichtigung gleicher Schnittebenen.

The paper deals with computertomographic and morphological studies in patients who died suffering from brain ischaemia, haemorrhagical infarction and haemorrhages. These examinations were done in identical sections. Methodically computerized tomograms in living patients, postmortal tomograms, brain sections and macrosections were used. Not in all cases corresponding findings were observed, due to the following factors 1. Size of the lesion 2. Localisation 3. Time of examination 4. Premortal alterations. The different factors are discussed in detail.

Intravascular lymphomatosis of the CNS: clinicopathologic study and search for expression of oncoproteins and Epstein-Barr virus.

Five cases of intravascular lymphomatosis (IVL) are reported. Diffuse or focal cerebral signs suggestive of vascular disease occurred in four cases, but case 5 presented with symptoms similar to Creutzfeld-Jakob disease. Clinical course ranged from two to eight months and diagnosis was made in all cases by autopsy. Neoplastic lymphoid cells mainly lodged in lumina of small vessels in many organs, but infarction was confined to the CNS. Some extravascular tumor cells were regularly seen. All cases corresponded to high-grade Non-Hodgkin lymphomas of B-cell type and displayed high proliferation indices. Different from findings in primary cerebral and nodal lymphomas, neither p53 nor bcl-2 oncoproteins were detectable. Absence of EBV genome and EBV latent membrane protein from IVL was demonstrated for the first time.

Reexpression of nerve growth factor receptor in human traumatic injured spinal cord.

In this study, the reexpression of nerve growth factor receptor (NGFR) on paraffin sections of the human spinal cord was examined with immunohistochemical method in 18 cases with survival periods of 2 hours to 28 months after trauma. The results were as follow: the reexpression of NGFR in motoneurons of the ventral horn began on the fourth day after trauma and decreased within 30 days after trauma. However, it could still be observed in patients who survived up to 28 months. The axons in funiculus dorsalis reexpressed NGFR 7 hours to 9 weeks after injury, which may be interpreted as axoplasmic transport effect of NGFR in the spinal ganglion cells. NGFR labelled intraspinal microvessels were present in the injured spinal cord. Reexpression of NGFR in motoneurons after injury reflects an increased demand of neurotrophic factors, and an increased access exerting the physiological effects of trophic factors mediated by NGFR.

Magnetoelectric coupling at metal surfaces.

Magnetoelectric coupling allows the magnetic state of a material to be changed by an applied electric field. To date, this phenomenon has mainly been observed in insulating materials such as complex multiferroic oxides. Bulk metallic systems do not exhibit magnetoelectric coupling, because applied electric fields are screened by conduction electrons. We demonstrate strong magnetoelectric coupling at the surface of thin iron films using the electric field from a scanning tunnelling microscope, and are able to write, store and read information to areas with sides of a few nanometres. Our work demonstrates that high-density, non-volatile information storage is possible in metals.

A Golgi study of human locus coeruleus in normal brains and in Parkinson's disease.

The locus coeruleus (LC) of eight adults without neurodegenerative disease and eight patients with Parkinson's disease was investigated by means of the Golgi-Braitenberg method for formalin-fixed human autopsy material. As with Golgi studies in the rat and cat, two main neuronal classes could be demonstrated in the human LC: (i) medium-sized fusiform and multipolar LC neurons known to contain neuromelanin and (ii) smaller neurons of widely varying somatic shape and dendritic arborization which are considered to be intermingled neurons of adjacent brain stem nuclei not containing neuromelanin. In Parkinson's disease, the Golgi-impregnated medium-sized LC neurons were reduced in number. They showed marked reduction of dendritic length, severe loss of spines, dendritic varicosities and swollen perikarya. The last two findings could be due in part to Lewy-body inclusions. The smaller non-noradrenergic neurons did not show severe pathological changes by the Golgi impregnation technique, which is in line with the fact that only neuromelanin-containing LC neurons are affected in the pathological process of Parkinson's disease.

Neuritis cordis due to the acute polyneuritis of the Guillain-Barré syndrome.

Three patients with the Guillain-Barré syndrome which followed the course of Landry's acute ascending paralysis died a sudden cardiac death. Autonomic dysfunction had appeared clinically, consisting of sphincter disturbances in one patient and fluctuating blood pressure and bradycardia in the other. In a twenty-three year old female patient cardiac function had been inconspicuous, apart from tachycardia, but the ECG showed S-T segment depression and flat T waves. Postmortem examination revealed acute inflammatory demyelinating polyradiculoneuritis involving the peripheral autonomic nervous system and especially the nerves of the heart. Immunohistochemically, the inflammatory cell infiltrations of this neuritis cordis consisted of macrophages (MAC 387 positive) and T lymphocytes (UCHL1 positive). No indication of a direct viral infection of the inflamed cardiac nerves was detectable by immunohistochemistry (HSV, CMV, influenza virus) nor by electron microscopy. The neuritis cordis was classified as an inflammatory cardio-neuropathy secondary to a patchy acute polyneuritis of the Guillain-Barré syndrome, involving the autonomic nervous system. Myocarditis could be discounted, and the neuritis cordis was thought to be responsible for the sudden cardiac death.

[Intracranial space-occupying processes in psychiatry--30 years' of clinico-neuropathologic catamnesis]. / Intrakranielle raumfordernde Prozesse in der Psychiatrie--dreissigjährige klinisch-neuropathologische Katamnese.

Despite declining frequency of postmortem examinations in mental hospitals no corresponding decline in the proportion of intracranial space-occupying lesions is observed in a 30-years retrospective study. 77.5% of these lesions were meningiomas, gliomas, metastases, and subdural haematomas. 70.4% of all 71 patients had major psychiatric abnormalities during the clinical course. In 58% of these patients no clinical diagnosis of intracranial space-occupying process was made. Reasons for the diagnostic delay and for the postmortem results are discussed. The significance of psychopathological change in the group of long-term residents in mental hospitals is stressed.