Die statische Bedeutung der Linea aspera

Ohne ZusammenfassungMit 5 Textabbildungen.     

Axonal swellings in jimpy mice: Does lack of myelin cause neuronal abnormalities?

We have observed focal axonal enlargements in jimpy, a myelin deficient mutant mouse. Similar axonal swellings have also been found in other studies, in two other myelin deficient mutant mice and in a myelin deficient mutant rat. We suggest that this axonal abnormality represents a common secondary reaction to lack of myelin. Such a secondary reaction might also occur in other species including human, in response to deficient myelin or to loss of myelin due to disease.     

RGC-32 regulates reactive astrocytosis and extracellular matrix deposition in experimental autoimmune encephalomyelitis

Extracellular matrix (ECM) deposition in active demyelinating multiple sclerosis (MS) lesions may impede axonal regeneration and can modify immune reactions. Response gene to complement (RGC)-32 plays an important role in the mediation of TGF-β downstream effects, but its role in gliosis has not been investigated. To gain more insight into the role played by RGC-32 in gliosis, we investigated its involvement in TGF-β-induced ECM expression and the upregulation of the reactive astrocyte markers α-smooth muscle actin (α-SMA) and nestin. In cultured neonatal rat astrocytes, collagens I, IV, and V, fibronectin, α-SMA, and nestin were significantly induced by TGF-β stimulation, and RGC-32 silencing resulted in a significant reduction in their expression. Using astrocytes isolated from RGC-32 knock-out (KO) mice, we found that the expression of TGF-β-induced collagens I, IV, and V, fibronectin, and α-SMA was significantly reduced in RGC-32 KO mice when compared with wild-type (WT) mice. SIS3 inhibition of Smad3 phosphorylation was also associated with a significant reduction in RGC-32 nuclear translocation and TGF-β-induced collagen I expression. In addition, during experimental autoimmune encephalomyelitis (EAE), RGC-32 KO mouse astrocytes displayed an elongated, bipolar phenotype, resembling immature astrocytes and glial progenitors whereas those from WT mice had a reactive, hypertrophied phenotype. Taken together, our data demonstrate that RGC-32 plays an important role in mediating TGF-β-induced reactive astrogliosis in EAE. Therefore, RGC-32 may represent a new target for therapeutic intervention in MS.     

Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients

To determine the impact of adjuvant treatment with tamoxifen and aromatase inhibitors (AI) on the survival of men with breast cancer. We analyzed 257 male patients with hormone-receptor-positive breast cancer from numerous German population-based cancer registries treated with tamoxifen (N = 207) or aromatase inhibitors (N = 50). The median follow-up was 42.2 (range 2–115) months. Median age at diagnosis was 68 (range 36–91) years. Thirty-seven (17.9 %) patients treated with tamoxifen and 16 (32.0 %) patients treated with AI died (log rank p = 0.007). After the adjustment for the patient’s age, tumor size, node status, and tumor grading, the AI treatment was linked to a 1.5-fold increase in risk of mortality compared to tamoxifen (HR 1.55; 95 % CI: 1.13–2.13; p = 0.007). The overall survival in male breast cancer was significantly better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor. Tamoxifen should be considered as the treatment of choice for hormone-receptor-positive male breast cancer.     

The complement system as a biomarker of disease activity and response to treatment in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. The complement system has an established role in the pathogenesis of MS, and evidence suggests that its components can be used as biomarkers of disease-state activity and response to treatment in MS. Plasma C4a levels have been found to be significantly elevated in patients with active relapsing-remitting MS (RRMS), as compared to both controls and patients with stable RRMS. C3 levels are also significantly elevated in the cerebrospinal fluid (CSF) of patients with RRMS, and C3 levels are correlated with clinical disability. Furthermore, increased levels of factor H can predict the transition from relapsing to progressive disease, since factor H levels have been found to increase progressively with disease progression over a 2-year period in patients transitioning from RRMS to secondary progressive (SP) MS. In addition, elevations in C3 are seen in primary progressive (PP) MS. Complement components can also differentiate RRMS from neuromyelitis optica. Response gene to complement (RGC)-32, a novel molecule induced by complement activation, is a possible biomarker of relapse and response to glatiramer acetate (GA) therapy, since RGC-32 mRNA expression is significantly decreased during relapse and increased in responders to GA treatment. The predictive accuracy of RGC-32 as a potential biomarker (by ROC analysis) is 90% for detecting relapses and 85% for detecting a response to GA treatment. Thus, complement components can serve as biomarkers of disease activity to differentiate MS subtypes and to measure response to therapy.     

Genfrequenz der hereditären Galaktosämie unter Berücksichtigung der Duarte-Variante

Zusammenfassung Im Einzugsgebiet der Kinderkliniken Graz und Erlangen wurden bei insgesamt 1793 Probanden Blutuntersuchungen vorgenommen, um aus der Aktivität der Galaktose-1-Phosphat-Uridyltransferase die Heterozygoten- bzw. Genfrequenz der Galaktosämie für dieses Gebiet zu berechnen. Im Raum um Erlangen fanden wir unter 862 Personen 10 mit einer Enzymaktivität der Gal-1-PUT zwischen 6,7–9 U/gHb, in der Steiermark (St) 17 unter 931 untersuchten Personen (jeweils gesunde Kinder und Erwachsene). Die Heterozygotenfrequenzen betragen demnach 1:85 (E) bzw. 1:55 (St) mit Genfrequenzen von 0,0059 (E) bzw. 0,0092 (St). 11,38% der Gal-1-PUT-Werte der Gruppe St konnten unter die Duarte-Heterozygoten-Merkmalsträger (Gt^D/Gt⁺) eingereiht werden, in der Gruppe E waren es 13,44%. Die Genfrequenz liegt hierfür bei 0,067 (E) bzw. 0,055 (St). Häufig wird die Diagnose einer Galaktosämie deswegen nicht gestellt, weil die Neugeborenen mit dem klinischen Bild eines Icterus gravis und einer Sepsis zur Aufnahme kommen und oft nach einem foudroyanten Verlauf versterben.

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Estimation of the incidence of galactosemia in the population with reference to the duarte variant

A total of 1793 normal children and adults were examined for galactose-1-phosphate uridyl transferase deficiency. A quantitative enzyme assay (UDPG-consumption test) had been carried out on all samples. In this population, 931 subjects lived in the Graz (St) area and 862 in the region of Erlangen (E). In the first group (St) we found 17 carriers of galactosemia (incidence of gene: 0.0092) and in the second group (E) there were 10 heterozygotes for galactosemia (incidence of gene: 0.0059). The frequency of hereditary galactosemia is therefore in the order of 1:12000 (St) and 1:29000 (E) live births. Another type of transferase deficiency is known, the Duarte Variant (GT^D). Subjects who are homozygous for the Duarte Variant have approximately half the normal enzyme activity, heterozygotes three-quarters. Heterozygotes for this gene were much more common: in the first group 11.38% and in the second 13.48% (incidence of gene: 0.056 (St) and 0.067 (E)). In addition, two patients heterozygous for both the Duarte Variant and the gene for galactosemia were found (Gt^D/gt) in each group, these subjects have approximately one quarter of the normal enzyme activity. Thus it appears the prevalence of galactosemia in these two regions is the same as was found by Beutler in California and Thalhammer in Vienna. Often infants with galactosemia die with icterus gravis or sepsis in the neonatal period. Galactosemia should be considered in the differential diagnosis in any gravely ill infant.

Herrn Professor Dr. Navratil zu seinem 70. Geburtstag.