[Patient-individual care pathways in phase D neurological rehabilitation]. / Patientenindividuelle Behandlungspfade in der neurologischen Rehabilitation der Phase D.

The "patient-individual neurological care pathways" are a concept for qualified decision-making about rational rehabilitative strategies in the treatment of neurological diseases. Such clinical pathways include available scientific evidence and treatment guidelines. In neurological rehabilitation all treatments have a decidedly interdisciplinary character. All members of the team need highly specialized knowledge, a high potential for teamwork, as well as efficient organisation of work time. Here, computer aided decision-making tools such as the "patient-individual neurological care pathways" facilitate rational decisions and reduce the need for reorganization of therapies. In rehabilitation of neurological patients a symptom-oriented and function-related perspective of the individual treatment goals is indispensable for optimal choice of therapy approaches. This function-oriented classification of patients and creation of individual treatment plans are realized within the Excel-based care pathways. This system has been proved on the one hand as an instrument for streamlining and optimisation and, on the other, as a useful tutoring tool in the medical rehabilitation process.

Rapidly induced changes in neuromagnetic fields following repetitive hand movements.

Sensory feedback plays a major role in movement execution and motor learning, particularly in motor rehabilitation. Whilst elaborating therapeutic strategies, it is of interest to visualize the effect of a therapeutic intervention at the moment of its application. We analyzed the effect of repeated execution of a simple extension and flexion movement of the wrist on the sensorimotor cortex of seven healthy subjects using magnetoencephalography. Spatial filtering based on current dipoles was used to quantify the strength of cortical activation. Our results showed an increase of cortical activation reflecting activity of efferent neurons, whereas the activity of proprioceptive afferent neurons was not affected. Since only efferent activity increased, it is suggested that this reflects phenomena of long-term potentiation.

Alzheimer-related tau-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degree of dementia.

Abnormal phosphorylation of the tau-protein is regarded as a crucial step in the formation of neurofibrillary tangles in the neuronal cell body and neuropil threads in dendrites. We studied the effects of tau-pathology on the clinical expression of dementia in 106 autopsy cases in the entorhinal region, the hippocampal stratum oriens, the stratum radiatum, and the perforant path target zone. The first cytoskeletal lesions were located in the perikarya and dendrites of the pre-alpha cells of the transentorhinal and entorhinal region. Next, abnormally phosphorylated tau-protein (PHF-tau) was found in the neuropil of the CA1-subiculum region. Thereafter, the stratum radiatum and stratum oriens began to be involved in PHF-tau pathology in Braak stage II. In the Braak stages IV and V, the stratum radiatum was completely involved, the stratum oriens increasingly so. Beginning in Braak stage III, we noted cases having PHF-tau pathology in the perforant path target zone of the outer molecular layer of the dentate gyrus. The increase of this pathology with ever greater involvement on the part of the entorhinohippocampal circuit correlated significantly not only with the Braak stages and with the neurochemically determined hippocampal content of PHF-tau but also with the degree of dementia as defined by the clinical dementia rating (CDR) scale. The affection of the stratum oriens in combination with PHF-tau pathology in the stratum radiatum and in the outer molecular layer of the dentate gyrus was encountered almost exclusively in demented individuals (CDR 1-3). These results indicate that axonal PHF-tau pathology in hippocampal pathways presumably is critical for the clinical expression of dementia and may constitute an anatomical substrate of clinically verifiable memory dysfunction in Alzheimer's disease.

Progression of neurofibrillary changes and PHF-tau in end-stage Alzheimer's disease is different from plaque and cortical microglial pathology.

In terminal Alzheimer's disease (AD) the frequency of plaques was found to be reduced in single cases. To test this finding in a larger sample, and in order to determine whether the number of plaques labeled with different markers and the distribution of neurofibrillary tangles are correlated positively to each other and to the degree of dementia, a sample of 134 autopsy brains with and 15 without AD-related pathology has been examined. All of the cases were staged according to Braak and Braak. Both the frequency of plaques immunopositive for beta-amyloid, amyloid precursor protein, and apolipoprotein E and that of microglial cells in the cortex and in the white matter were determined semiquantitatively. The content and distribution of PHF-tau was ascertained by ELISA and immunohistochemistry. Both the clinical dementia rating and the global deterioration scale were used as clinical parameters retrospectively. Correlation coefficients were calculated for all parameters and differences were evaluated statistically. With progressive distribution of neurofibrillary tangles and increasing content of PHF-tau the plaque stages and the degree of cortical microglia reaction increased up to the Braak-stages IV and V, thereafter showing a slightly decreasing tendency in the investigated regions. In end-stage AD resorption of beta-amyloid seems to surpass its deposition. The microglial reaction in the white matter correlated neither with the Braak-stage nor with the accumulation of amyloid. With regard to the degree of dementia, both scales correlated well with the pathological changes. Our data show that neuronal cytoskeletal alterations progressively increase with progressive dementia until the end stage of AD in contrast to the frequencies of plaques and cortical microglial cells, and are therefore preferable for staging purposes.

Effects of the immunomodulator diacetyl-splenopentin on antigen-induced arthritis in rabbits.

Long-term treatment with the immunomodulator diacetyl-splenopentin reduces the severity of chronic joint inflammation and cartilage destruction in rabbits with antigen-induced arthritis. The level of specific antibodies as well as specific and non-specific cell-mediated immune reactivities including the proliferative response of spleen lymphocytes to cartilage proteoglycans in treated animals are lower than in untreated arthritic rabbits. Moreover, suppressor cell activity, which normally decreases during the early phase of inflammation, is enhanced and hyperreactive helper cell potential is reduced. These findings suggest that treatment with diacetyl-splenopentin normalizes the immune regulation, which is disturbed in the early phase of inflammation. This might result in a depression of the hyperreactive immune system including the autoimmunity developed against cartilage. Lowered immune reactivity in the joint in turn reduces the severity of chronic joint inflammation.

Demonstration of lipopolysaccharide (LPS) binding sites on the cell surface of guinea pig peritoneal macrophages by means of immunogold technique.

Lipopolysaccharide binding sites of guinea pig peritoneal macrophages were demonstrated by means of immunogold technique. Resident peritoneal macrophages show a strong specific binding of bacterial lipopolysaccharides from E. coli to cell surface structures.

[Heart wall rupture as a grave complication of acute myocardial infarct]. / Die Herzwandruptur als schwerwiegende Komplikation des akuten Herzinfarktes.

The rupture of the heart wall is a severe complication of the acute myocardial infarction. We found it in 3.5% of the deceased patients with an acute myocardial infarction. The average age of these patients was 71 years. 75% of the patients died during the first five days after the event of the myocardial infarction. Apart from elderly patients with myocardial infarction such ones with a transmural myocardial infarction in the region of the left ventricle, an enlargement of the heart and signs of an insufficiency of the left heart, with a hypertension and diabetes mellitus seemed to be endangered. These patients need the most exact control and observation and in case of suspicion (symptomatology of angina pectoris which is continuing to exist) of a developing rupture of the heart wall and aimed diagnostics (echocardiography) and therapy must be begun immediately.

Assay for beta-ureidopropionase by high-performance liquid chromatography.

A sensitive assay for beta-ureidopropionase based on derivatization of the reaction product beta-alanine with phenylisothiocyanate has been developed. Purification of the resulting phenylthiocarbamoyl-beta-alanine is achieved on a LiChrospher 100 C18 reversed-phase high-performance liquid chromatography column using an isocratic elution system. Phenylthiocarbamoyl-beta-alanine is detected by its absorbance at 245 nm and quantitated by automatic peak integration referring to a calibration curve. This technique offers a high degree of sensitivity as beta-alanine quantities in the picomole range can be identified. N-Carbamoyl-beta-alanine, the natural substrate of beta-ureidopropionase, does not interfere with the described assay system. The enzymatic reaction is linear for an incubation time of 45 min with enzyme concentrations of 3.2 micrograms/ml.

Changes of immunoregulatory properties and induction of autoimmune reactivity to cartilage in rabbits with antigen-induced arthritis.

The chronicity of the antigen-induced arthritis is characterized as dependent on the development of cell-mediated immunity to the antigen, but the exact mechanisms underlying are unclear. We have evidenced decreased suppressor and increased helper cell potential in the early phase of arthritis as result of the immunization procedure. In the late phase of arthritis proliferative responses of spleen lymphocytes to cartilage proteoglycans were revealed which were neither present in immunized animals without arthritis induction nor in the early phase of arthritis. The changes of the regulatory properties on the T-cell level are probably responsible for the transition of acute arthritis into the chronic stage. The deficiency of an effective suppression and/or the increased helper cell potential results in the activation of B- and T-lymphocytes with increased cell-mediated and humoral immune responsiveness to the antigen maintaining the inflammatory process for a long time. In this situation the release of cartilage proteoglycans during the acute joint reaction induces autoimmune responses against cartilage which could contribute to the chronification of inflammation and to cartilage degradation.

[Hypertension and heart failure in patients with cerebrovascular insufficiency]. / Hypertonie und kardiale Insuffizienz bei Patienten mit einer zerebrovaskulären Insuffizienz.

Concerning 150 patients suffering from acute cerebrovascular insufficiency we asked the following questions: 1. How often did cardiac decompensation occur, 2. How often did hypertension and hypertrophic symptoms occur in the electrocardiogram, and 3. How often did arteriosclerosis of the cerebral and coronary vessels occur together in deceased patients? Among the patients examined were 47.3% who showed symptoms of cardiac decompensation. Hypertension was found in 60.7% of the patients. The combination of symptoms of hypertrophy in the electrocardiogram and cardiac dysrhythmia was registered 39 times (26.0%). Arteriosclerosis was found in 68.2% of the post-mortem examinations. A high correlation was found between the sclerosis of the intracranial cerebral vessels (65.9%) and the sclerosis of the coronaries (75.0%). The possibilities of the prevention and deceleration, resp., of cerebrovascular insufficiency by early therapy of hypertension and of cardiac decompensation are pointed out.

[Immunohistology of interstitial lung processes]. / Immunhistologie bei Lungengerüstprozessen.

Immunohistologic investigations were performed in 124 lung tissue test of diffuse pulmonary processes obtained by transthoracic needle biopsy. In 40.3% the unselected material showed a positive immunofluorescence. It appeared in all groups formed by light microscopy. In the exogenic allergic alveolitis with 36.8% it was falling short of the expectations. The investigations allow of the conclusion that the immunohistology in diffuse pulmonary processes shows clearly applicable results neither for the diagnostics nor for the therapy and also not for the prognosis.

[Arteriosclerotic changes of the brain and heart in relation to cardiac decompensation and arrhythmia in patients with cerebrovascular insufficiency]. / Arteriosklerotische Veränderungen am Gehirn und am Herzen in Verbindung mit kardialer Dekompensation und Herzrhythmusstörungen bei Patienten mit einer zerebrovaskulären Insuffizienz.

In 150 patients with an acute cerebrovascular insufficiency we asked the following questions: 1. How often appear together the cardiac decompensation and disturbances of cardiac rhythm, 2. symptoms of hypertrophy and disturbances of cardiac rhythm and 3. arteriosclerosis of the cerebral and coronary vessels in deceased patients. The number of patients examined showed 26.7% of patients in whom a combination of symptoms of cardiac decompensation and disturbances of cardiac rhythm was present. The combination of signs of hypertrophy in the electrocardiogram and disturbances of cardiac rhythm was registered 39 times (26.0%). The arteriosclerosis was found in 68.2% of the patients in post-mortem examination. There was a high correlation between the sclerosis of the intracranial cerebral brains (65.9%) and the sclerosis of the coronary vessels (75.0%). It is referred to the possibilities of the prevention of the cerebrovascular insufficiency and the early therapy of hypertony, the cardiac decompensation and disturbances of cardiac rhythm.

Significance of cell-mediated and humoral immunity in the acute and chronic phase of antigen-induced arthritis in rabbits.

In the course of antigen-induced arthritis of rabbit cell-mediated and humoral immune responses were repeatedly tested in order to prove their significance for the acute and chronic phase of inflammation. The arthritis was monitored during the progression of the inflammation by means of the joint swelling and at the end of experiments by histological evaluation of synovitis and cartilage degradation. Following the arthritis induction a strong increase of specific antibodies and of circulating immune complexes was evident. The correlations between antibody levels and joint swellings confirmed that the local formation of immune complexes is responsible for the initiation and perpetuation of arthritis. In the early phase after immunization the responsiveness of lymphocytes to antigenic and mitogenic stimulation was increased, in the late chronic phase of arthritis proliferative responses of lymphocytes to cartilage matrix components were revealed. No direct correlations could be demonstrated between any cell-mediated immune response and the severity of arthritis. The hyperreactivity of cell-mediated immunity is suggested to be responsible for the transition of the acute arthritis into the chronic stage. The deficiency of an effective suppression results in the activation of B-lymphocytes with increased production of antibodies, maintaining the inflammatory process for a long time. Under these conditions the release of cartilage matrix components during the acute joint reaction induces autoimmune responses against cartilage, which could contribute to the chronification of arthritis and to cartilage degradation.

Connective tissue reactions in early phases of spontaneous regression of experimental malignant histiocytomas. An electron microscopic study.

Interactions between cancer and host are said to comprehend immunologic processes and stromal reactions including an angiofibroblastic response. We studied the latter phenomenon in spontaneously regressing experimental malignant histiocytomas produced by inoculation of an established macrophage-like cell line (WEHI-3) into baby rats. Light and electron microscopic investigations of the tumor tissue showed that there was a clear proliferation of fibroblasts and capillary vessels beginning from the 8th-10th day of the experiment. The vascular structures seemed to be somewhat changed and fibroblasts often displayed close contacts to tumor cells. The significance of these connective tissue reactions is discussed and, finally, the observations led to the conclusion that the angiofibroblastic reaction in the malignant histiocytoma model presented here may actively contribute to tumor breakdown and should not be interpreted as being only a secondary phenomenon after irreversible damage of tumor cells.

[Morphology and pathogenesis of glomerular renal lesions in gold nephropathy]. / Zur Morphologie und Pathogenese glomerulärer Nierenveränderungen bei der Gold-Nephropathie.

Histological, immunofluorescent and electron microscopical investigations on the glomerular renal lesions in gold-induced nephropathy were performed by analyzing biopsy materials from 9 patients with rheumatoid arthritis treated by Sanocrysin (gold sodium thiosulfate). The morphological and immunofluorescent main changes consisted in the characteristic pattern of immune complex nephritis as membranous glomerulonephritis on the one hand (4 cases) and as mesangioproliferative glomerulonephritis (4 cases) on the other hand; in one case there could be demonstrated a focal proliferative glomerulonephritis similar to that observed as visceral manifestation of rheumatoid arthritis in the kidney. These different types of glomerular alterations in gold nephropathy evidently are related to th duration and immunological activity of the main disease and to the individual immune reactivity of the body as a whole determined by this, and not at all, by the combination of gold additionally with other antiinflammatory, especially antirheumatic drugs. The possible pathogenesis of nephropathy is discussed with special regard to definite effects of gold on the immune system.

[Morphology and pathogenesis of penicillamine-induced nephropathy]. / Zur Morphologie und Pathogenese der Penicillamin-Nephropathie.

Histological, immunohistological and electron microscopical investigations on the glomerular renal lesions in penicillamine-induced nephropathy were carried out by studying biopsy material of eight patients with rheumatoid arthritis (4 cases), allergic alveolitis (3 cases) and systemic scleroderma (1 case) under the treatment with D-penicillamine. Summarizing all the findings, the characteristic pattern of immune complex nephritis as membranous type glomerulonephritis on the one hand and proliferative type glomerulonephritis (mesangioproliferative GN, focal proliferative GN or minimal proliferative GN) on the other hand could be demonstrated. The different types of glomerular alterations in penicillamine nephropathy obviously depend on the kind and duration of the primary main disease and on the individual immune reactivity of the body was a whole by this determined. The possible pathogenesis related to definite effects of the D-penicillamine is discussed and compared with the communications in the literature.

Immunocytochemical demonstration of Con A-receptors on the cell surface of guinea pig peritoneal macrophages.

By means of protein A-gold in combination with the replica technique the distribution of Con A-receptors on the surface of guinea pig peritoneal macrophages was investigated. In nonspecifically activated macrophages the arrangement of Con A-binding sites was demonstrated as homogeneous. It could be evidenced that by the combined technique the advantages of the high resolution of transmission electron microscopy could be joined with the possibility of the stereological demonstration of cell surface structures.

Biphasic changes of the immunological reactivity in the course of experimental lectin-induced arthritis of rabbits.

A single injection of Lens culinaris lectin (LcL) into the knee joint cavity of non-sensitized rabbits produces an arthritis with an acute and chronic phase, lasting up to one year. The persistence of the lectin in the joint, related to the strong binding affinity of lectins to glycoproteins of connective tissue structures, and the presence of specific antibodies against LcL in the serum after the intra-articular injection make this model comparable to the antigen-induced arthritis. But in our system these conditions are further modified or amplified by the mitogenic activity of LcL itself. The cell-mediated immunity, studied by mitogenic stimulation of peripheral blood lymphocytes, is characterized by a biphasic change in the course of this experimental arthritis. Hyperresponsiveness to stimulation with LcL and Concanavalin A (Con A), decreased Con A-induced suppressor cell activity, and stimulatory serum factors could be detected in the early phase of inflammation. The late phase of arthritis (8 months after the induction) was characterized by hyporesponsiveness to mitogenic stimulation, normal suppressor cell activity and inhibitory serum factors. In spite of the differences of this experimental arthritis to the human rheumatoid arthritis, concerning mainly the initiation and the lack of systemic manifestation, there are surprising similarities between both, not only in the histopathological feature and the chronicity but also in the cell-mediated immune reactions. Therefore, similar pathogenetic mechanisms for the chronic phase can be suggested.