[The genetics of spinocerebellar ataxias]. / Genetik der spinozerebellären Ataxien.

Spinocerebellar ataxias are genetically heterogeneous autosomal dominant ataxia disorders. To date more than 30 different subtypes are known. In Germany particularly SCA1, SCA2, SCA3 and SCA6 are prevalent, as well as the less frequent subtypes SCA5, SCA14, SCA15, SCA17 and SCA28. Genetic causes range from coding repeat expansions (polyglutamine diseases), to non-coding expansions as well as conventional mutations. In some subtypes the genetic background is currently unknown. Age of onset, typical clinical findings and geographic distribution may help to reach a correct diagnosis; however a definitive diagnosis requires molecular genetic testing.

CXCR3 expression on CD34(+) hemopoietic progenitors induced by granulocyte-macrophage colony-stimulating factor: II. Signaling pathways involved.

CXCR3, known to have four ligands (IFN-gamma inducible protein 10 (gamma IP-10), monokine induced by IFN-gamma (Mig), I-TAC, and 6Ckine), is predominantly expressed on memory/activated T lymphocytes. We recently reported that GM-CSF induces CXCR3 expression on CD34(+) hemopoietic progenitors, in which gamma IP-10 and Mig induce chemotaxis and adhesion. Here we further report that stimulation with GM-CSF causes phosphorylation of Syk protein kinase, but neither Casitas B-lineage lymphoma (Cbl) nor Cbl-b in CD34(+) hemopoietic progenitors can be blocked by anti-CD116 mAb. Specific Syk blocking generated by PNA antisense completely inhibits GM-CSF-induced CXCR3 expression in CD34(+) progenitors at both mRNA and protein as well as at functional levels (chemotaxis and adhesion). Cbl and Cbl-b blocking have no such effects. Thus, GM-CSF binds to its receptor CD116, and consequently activates Syk phosphorylation, which leads to induce CXCR3 expression. gamma IP-10 and Mig can induce Syk, Cbl, and Cbl-b phosphorylation in CD34(+) progenitors by means of CXCR3. gamma IP-10 or Mig has induced neither chemotaxis nor adhesion in GM-CSF-stimulated Cbl-b-blocked CD34(+) hemopoietic progenitors, whereas SDF-1alpha induces both chemotaxis and adhesion in these cells. Interestingly, gamma IP-10 and Mig can induce chemotaxis and adhesion in GM-CSF-stimulated Syk- or Cbl-blocked CD34(+) hemopoietic progenitors. Thus, Cbl-b, but not Syk and Cbl phosphorylation, is essential for gamma IP-10- and Mig-induced chemotaxis and adhesion in CD34(+) hemopoietic progenitors. This study provides a useful insight into novel signaling transduction pathways of the functions of CXCR3/gamma IP-10 and Mig, which may be especially important in the cytokine/chemokine environment for mobilization, homing, and recruitment during proliferation, differentiation, and maturation of hemopoietic progenitor cells.

CGRP-immunoreactive nerves in prurigo nodularis--an exploration of neurogenic inflammation.

BACKGROUND: The present study has explored the localization and distribution of calcitonin gene-related peptide (CGRP)-immunoreactive (IR) nerve fibers in prurigo nodularis, especially emphasizing its relationships to mast cells and eosinophils, which all are important contributors to inflammation. METHODS: The exact localization of CGRP in the nerve fibers of prurigo nodularis lesional skin has been clarified by an ultrastructural immunogold labelling technique; and the relationships of CGRP-IR nerve fibers to tryptase-IR mast cells or eosinophil cationic protein (ECP)-IR eosinophils were also investigated by immunofluorescence double-labelling. RESULTS: This ultrastructural study has demonstrated that CGRP immunoreactivity is increased in the dense-core vesicles in the axons of the prurigo nodularis lesional skin; the axons which contain CGRP are, in addition, enlarged and have more dense-core vesicles than the axons which do not contain CGRP. The immunofluorescence investigation demonstrated that tryptase-containing mast cells and ECP-containing eosinophils also are significantly increased in the lesional skin. CONCLUSIONS: The results indicate that certain neurons increasingly express CGRP, which may dynamically result in a neurogenic inflammation in the lesional skin, through vasodilatation, and recruitment and regulation of inflammatory cells, e.g. eosinophils and mast cells.

CXC chemokine receptor 3 expression on CD34(+) hematopoietic progenitors from human cord blood induced by granulocyte-macrophage colony-stimulating factor: chemotaxis and adhesion induced by its ligands, interferon gamma-inducible protein 10 and monokine induced by interferon gamma.

CXC chemokine receptor 3 (CXCR3), which is known to be expressed predominately on memory and activated T lymphocytes, is a receptor for both interferon gamma (IFN-gamma)-inducible protein 10 (gamma IP-10) and monokine induced by IFN-gamma (Mig). We report the novel finding that CXCR3 is also expressed on CD34(+) hematopoietic progenitors from human cord blood stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) but not on freshly isolated CD34(+) progenitors. Freshly isolated CD34(+) progenitors expressed low levels of CXCR3 messenger RNA, but this expression was highly up-regulated by GM-CSF, as indicated by a real-time quantitative reverse transcriptase-polymerase chain reaction technique. gamma IP-10 and Mig induced chemotaxis of GM-CSF-stimulated CD34(+) progenitors by means of CXCR3, since an anti-CXCR3 monoclonal antibody (mAb) was found to block gamma IP-10-induced and Mig-induced CD34(+) progenitor chemotaxis. These chemotactic attracted CD34(+) progenitors are colony-forming units-granulocyte-macrophage. gamma IP-10 and Mig also induced GM-CSF-stimulated CD34(+) progenitor adhesion and aggregation by means of CXCR3, a finding confirmed by the observation that anti-CXCR3 mAb blocked these functions of gammaIP-10 and Mig but not of chemokine stromal cell-derived factor 1 alpha. gamma IP-10-induced and Mig-induced up-regulation of integrins (CD49a and CD49b) was found to play a crucial role in adhesion of GM-CSF-stimulated CD34(+) progenitors. Moreover, gamma IP-10 and Mig stimulated CXCR3 redistribution and cellular polarization in GM-CSF-stimulated CD34(+) progenitors. These results indicate that CXCR3-gamma IP-10 and CXCR3-Mig receptor-ligand pairs, as well as the effects of GM-CSF on them, may be especially important in the cytokine/chemokine environment for the physiologic and pathophysiologic events of differentiation of CD34(+) hematopoietic progenitors into lymphoid and myeloid stem cells, subsequently immune and inflammatory cells. These processes include transmigration, relocation, differentiation, and maturation of CD34(+) hematopoietic progenitors. (Blood. 2000;96:1230-1238)

Dendritic mast cells in prurigo nodularis skin.

Mast cells are traditionally recognized as round or oval connective tissue cells containing many specialized cytoplasmic granules. During recent years, more and more mast cell functions and properties have been clarified, and it is now evident that the mast cells are of different subtypes. The present study, utilizing chymase and tryptase immunofluorescence double-labelling and conventional electron microscopy techniques, has identified a kind of mast cells with obvious dendritic features in the lesional dermis of prurigo nodularis skin. This group of mast cell have enlarged cell bodies and contain fewer cytoplasmic granules, especially within certain dendrites. The morphological identification of such subgroups of mast cells could contribute to the understanding of mast cell heterogeneity.

[Pseudoxanthoma elasticum. Skin changes as a marker of systemic illness]. / Pseudoxanthoma elasticum. Hautveränderungen als Wegweiser einer Systemerkrankung.

Angioid streaks were diagnosed in a 42-year-old woman. Since age 20 she had developed circumscribed atrophic yellow-grey lesions on her neck, axillae and other flexural sites. In spite of highly characteristic skin changes, the diagnosis of pseudoxanthoma elasticum was first confirmed by a biopsy from lesional skin 22 years after the disease onset. Based on the present case and an analysis of the recent literature, the findings characteristic for pseudoxanthoma elasticum in the skin, eyes and cardiovascular system are delineated, the differential diagnosis of the skin lesions, as well as the pathogenesis and the prognosis are discussed, and the new classification of pseudoxanthoma elasticum, based on major and minor criteria, is described.

[Congenital familial plaque-shaped glomus tumors. An unusual variant of multiple regional glomus tumors]. / Kongenitale familiäre plaqueförmige Glomustumoren. Eine aussergewöhnliche Variante multipler regionaler Glomustumoren.

Plaque-like glomus tumours are an unusual and very rare clinical form of multiple regional glomus tumours. We report on a 16-year-old girl with this variety of glomus tumours. The irregular angiomatous plaques localized on her back and right hip were present from birth and enlarged with body growth. In addition, there were some bluish nodules scattered on the right mamma, the abdomen and the left shoulder. The family history showed hereditary influences. The proper diagnosis was based on histological and immunohistochemical findings. In the present case report, the clinical, histopathological and immunohistochemical features and the differential diagnosis of multiple plaque-like glomus tumours are discussed.

Successful outcome of cryosurgery in patients with granuloma annulare.

Several therapeutic methods have been employed in the management of localized granuloma annulare (GA), with varying degrees of success. We performed a prospective trial to evaluate the efficacy, cosmetic results, and safety of cryosurgical treatment in GA. Thirty-one patients with localized GA were treated by cryosurgery, using the contact method. Nitrous oxide (-86 degrees C) or liquid nitrogen (-196 degrees C) were used as refrigerants, and were applied with closed probes; each lesion was treated with one freeze-thaw cycle of 10-60 s per session. If necessary, treatment was repeated after 20-30 days. Resolution of the lesions was obtained in all patients, and in 25 of 31 patients (80.6%) they resolved after a single freeze-thaw cycle. Relapse occurred in only one of 11 patients who were followed for more than 2 years, and this occurred 16 months after treatment. Excellent cosmetic results were obtained in 14 of 28 patients who were eligible for evaluation (50%), and good results in 11 (39.3%). The cosmetic result obtained by cryosurgery with nitrous oxide was independent of the size of the lesion, whereas in the group of patients treated with liquid nitrogen a better cosmetic result was obtained with smaller lesions (comparison of lesions < or = 2.40 cm2 with those > 2.40 cm2; P = 0.04). The duration of the lesion, its location, previous treatment with another method, and the number of treatment sessions, did not have any influence on the cosmetic result. The treatment was generally well tolerated. Blister formation occurred in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Which is the best methotrexate schedule for maintenance therapy of childhood ALL? A randomized study]. / Randomisierte Studie zur Methotrexatapplikation in der Erhaltungstherapie der akuten lymphoblastischen Leukämie im Kindesalter.

58 children were admitted to a prospective randomized leukemia induction and CNS-prophylaxis three different protocols were followed for maintenance. A (n = 20): 6-MP (50 mg/m2) p.o. daily + MTX (20-30 mg/m2) p.o. weekly; B (n = 20): 6-MP (50 mg/m2) p.o. daily + MTX (75-150 mg/m2) i.v. every two weeks; C (n = 18): 6-MP (50 mg/m2) p.o. daily + alternating 8-week-courses of four biweekly i.v. injections of MTX (75-150 mg/m2) and four biweekly i.v. injections of Cyclo (600 mg/m2). After all patients have been followed for at least 48 months, the rates of continuous complete remission are 42% in protocol A, 63% in protocol B, and 29% in protocol C. No encephalopathies have been observed with regimen B.

[Gas-liquid chromatographic determination of etofenamate/ Determination, method and use in biological material (author's transl)]. / Gaschromatographische Bestimmung von Etofenamat. Bestimmungsmethode und Anwendung bei biologischem Material.

Etofenamate in biological specimen can be determined by gas-liquid chromatography with etofenamate benzyl ether as internal standard. Determination in urine is done directly after extraction and concentration, whereas plasma and homogenates from organs have to be prepurified by thin-layer chromatography. Unchanged etofenamate is found in small amounts in human urine (0--4, 6--6, 6--8 h p. appl.). Inflamed rat paws after local application contain up to 75 microgram etofenamate/g in comparison to only 2 microgram flufenamic acid/g tissue. Both compounds are also found in non-inflamed paws, contents being only 3--4% as compared to the inflamed tissue. Elimination of etofenamate from the inflamed area occurs with a half-life of approx. 8.5 h. These results from gas-liquid chromatography correspond to results from t.l.c./fluorescence measurements.

[On the pharmacodynamics of acemetacin (author's transl)]. / Zur Pharmakodynamik von Acemetacin.

Pharmacodynamic studies were carried out on (1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetoxy]acetic acid (acemetacin, TV 1322, Rantudil), a new strongly acting non-steroidal anti-inflammatory agent for elucidation of its mechanism of action. Despite its strong anti-inflammatory activity, acemetacin is only a weak inhibitor of prostaglandin release. Release of histamine from mast cells induced by N-methylhomoanisylamine-formaldehyde condensate (compound 48/80) was strongly inhibited by acemetacin in a dose dependent manner. It was also highly effective in in vitro tests, for example, in the protein turbidity test of Mizushima. In accordance to the weak inhibition of prostaglandin release very little damage was done to the mucous membrane of the gastrointestinal tract by this anti-inflammatory agent. From these data and from the strong anti-inflammatory activity a broad therapeutic margin can be derived. Analgetic properties were shown in the benzoquinone test after oral and in the Randall-Selitto test after i.m. application. Hyperthermia caused by Pyrifer and by yeast is inhibited by acemetacin in a dose dependent manner. Corresponding to the weak influence on prostaglandin release the reduction of diuresis by acemetacin was only small. No tocolytic effect could be detected on the gravid uterus in vitro. Function of the heart (isolated heart of guinea-pig) was unaffected, but we registered an increase in sytolic and diastolic blood pressures in the anesthetized dog. Correspondingly, left ventricular pressure also increased, these changes were accompanied by bradycardia. Coronary flow, peripheral flow and dp/dt did not change, only the pressure in the right atrium rose slightly. In cats, acemetacin caused a short-lasting decrease in the arterial blood pressure. Effects on CNS were not found. Smooth muscles (bronchial/intestinal) were not influenced by acemetacin. Like many non-steroidal anti-inflammatory compounds acemetacin inhibits also platelet aggregation. Motility of animals was lowered. In a granuloma pouch test a strong anti-inflammatory action was shown in vivo even without metabolic degradation of acemetacin. For the explanation of the anti-inflammatory action several mechanisms have to be taken into account.

[Anti-inflammatory action of acemetacin (author's transl)]. / Die antiphlogistische Wirkung von Acemetacin.

The anti-inflammatory efficacy of [1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetoxy]acetic acid (acemetacin, TV 1322, Rantudil) a new non-steroidal anti-inflammatory agent, is described. The stronger inhibition of inflammation in kaolin-induced edema of the rat paw could experimentally be proved with the new compound in comparison with a series of marketed anti-inflammatory agents. Acemetacin is highly effective following both oral and parenteral administration. Following provocation of inflammation in the rat paw by a series of other different agents acemetacin was more strongly effective than indometacin following oral administration. Clear advantage of acemetacin as against indometacin were shown after influencing Freund's adjuvant induced arthritis. In local inflammation too, for example in the wool pellet test, the development of granulation tissue and exudate was inhibited to the same extent as following application of corticosteroid. Both skin erythema and dye-stuff spreading by inhibition of hyaluronidase were antagonised. From the results obtained with acemetacin in numerous inflammatory models conclusion can be drawn as to the multiple sites of action in the reaction chain of inflammation.