Military policy in the International Women`s Year. Admission of Female Medical officers to the German Federal Armed Forces. Development and Consequences.

Im Mittelpunkt der Dissertation steht im ersten Teil die Frage nach dem politischen und gesellschaftlichen Kontext der Öffnung des Sanitätsdienstes im Jahr 1975 für Frauen. Basierend auf den Akten des Militärarchivs Freiburg /Brsg. wird aus historischer Perspektive nachvollzogen, welchen Einfluss rechtliche, öffentliche und politische Debatten auf die Öffnung der Bundeswehr hatten. Daneben fokussiert die Fragestellung auf die kulturellen Geschlechterkonstruktionen im 20. Jahrhundert, die beispielhaft anhand der Öffnung der Bundeswehr für Frauen aufgezeigt werden sollen. Dazu wird unter dem Gesichtspunkt der Geschlechterordnung und der Gleichberechtigung die Frage beleuchtet, in welchen Funktionen die ersten Ärztinnen und Apothekerinnen im Sanitätsdienst der Bundeswehr eingesetzt wurden und wie ihre rechtliche und soziale Integration verlief. Davon ausgehend werden in einem zweiten Teil die Auswirkungen der Öffnung des Sanitätsdienstes für Frauen auf die Geschlechterkonstruktion und die politische Debatte dargestellt. Es wird untersucht, welche Rolle die ersten Ärztinnen im Sanitätsdienst in der öffentlichen Wahrnehmung in Bezug auf die generelle Öffnung der Bundeswehr spielten und wie sie die spätere Entscheidung beeinflussten. Der Untersuchungszeitraum der Arbeit umfasst das Gründungsjahr der Bundeswehr und endet zeitlich mit dem Datum der Wiedervereinigung (1956-1990).In a first part, the thesis focuses on the political and social background of the decision to first admit female medical officers to the German federal armed forces in the year 1975. Based on a historical review of the files of the military archive in Freiburg/ Brsg., the work describes the influence of the historic political and legal debate on the decision to open the armed forces for women. In addition, exemplifying the opening of the armed forces, the thesis shows the cultural gender constructions in the 20th century. Thus, considering the existing gender construction against the historic women’s rights movement, the author evaluates in which functions female medical officers were employed in the armed forces and how they were socially and legally integrated in an environment formerly dominated by men. Based on the findings of the first part, the thesis describes in a second part the impact of the accession of women to the armed forces on the gender construction and the political debate at that time. The author investigates the role of the first women in the sanitary service in the public debate about the later decision to generally open the armed forces for women. Investigation period of the thesis ranges from the year of the foundation of the federal armed forces until the date of the German reunion (1956-1990)

Pharmacological Targeting of the RAGE-NFκB Signalling Axis Impedes Monocyte Activation under Diabetic Conditions through the Repression of SHP-2 Tyrosine Phosphatase Function

Monocytes play a vital role in the development of cardiovascular diseases. Type 2 diabetes mellitus (T2DM) is a major CVD risk factor, and T2DM-induced aberrant activation and enhanced migration of monocytes is a vital pathomechanism that leads to atherogenesis. We recently reported the upregulation of SHP-2 phosphatase expression in mediating the VEGF resistance of T2DM patient-derived monocytes or methylglyoxal- (MG, a glucose metabolite and advanced glycation end product (AGE) precursor) treated monocytes. However, the exact mechanisms leading to SHP-2 upregulation in hyperglycemic monocytes are unknown. Since inflammation and accumulation of AGEs is a hallmark of T2DM, we hypothesise that inflammation and AGE-RAGE (Receptor-for-AGEs) signalling drive SHP-2 expression in monocytes and blockade of these pathways will repress SHP-2 function. Indeed, monocytes from T2DM patients revealed an elevated SHP-2 expression. Under normoglycemic conditions, the serum from T2DM patients strongly induced SHP-2 expression, indicating that the T2DM serum contains critical factors that directly regulate SHP-2 expression. Activation of pro-inflammatory TNFα signalling cascade drove SHP-2 expression in monocytes. In line with this, linear regression analysis revealed a significant positive correlation between TNFα expression and SHP-2 transcript levels in T2DM monocytes. Monocytes exposed to MG or AGE mimetic AGE-BSA, revealed an elevated SHP-2 expression and co-treatment with an NFκB inhibitor or genetic inhibition of p65 reversed it. The pharmacological inhibition of RAGE was sufficient to block MG- or AGE-BSA-induced SHP-2 expression and activity. Confirming the importance of RAGE-NFκB signalling in regulating SHP-2 expression, the elevated binding of NFκB to the SHP-2 promoter—induced by MG or AGE-BSA—was reversed by RAGE and NFκB inhibition. Besides, we detected elevated RAGE levels in human and murine T2DM monocytes and monocytes exposed to MG or AGE-BSA. Importantly, MG and AGE-BSA treatment of non-T2DM monocytes phenocopied the aberrant pro-migratory phenotype of T2DM monocytes, which was reversed entirely by either SHP-2- or RAGE inhibition. In conclusion, these findings suggest a new therapeutic approach to prevent accelerated atherosclerosis in T2DM patients since inhibiting the RAGE-NFκB-SHP-2 axis impeded the T2DM-driven, SHP-2-dependent monocyte activation

Cross-Sectional Study on Influenza Vaccination, Germany, 1999–2000

To assess influenza vaccination coverage in Germany, we conducted a nationwide telephone survey in November 1999 in adults (>18 yrs) using random-digit dialing. Overall, 23% of 1,190 survey participants reported having been vaccinated (adjusted 18%) with 16% (adjusted 15%) in former West Germany versus 35% (adjusted 32%) in former East Germany. Immunization rates for vaccination target groups were lower in West Germany (21%) than in East Germany (40%). Seven percent of health-care workers were immunized. Previous influenza vaccination, positive attitudes towards immunization, and having a family physician increased the rate of vaccination; fear of adverse effects lowered the rate. Family physicians performed 93% of the vaccinations, which suggests their key role in improving low vaccination coverage in Germany. The fact that >71% (850/1,190) of participants belonged to at least one of the vaccination target groups recommended by the German Standing Commission on Immunization emphasizes the need to focus the definition of target groups

In Vivo Analysis of Disease-Associated Point Mutations Unveils Profound Differences in mRNA Splicing of Peripherin-2 in Rod and Cone Photoreceptors

Point mutations in peripherin-2 (PRPH2) are associated with severe retinal degenerative disorders affecting rod and/or cone photoreceptors. Various disease-causing mutations have been identified, but the exact contribution of a given mutation to the clinical phenotype remains unclear. Exonic point mutations are usually assumed to alter single amino acids, thereby influencing specific protein characteristics;however, they can also affect mRNA splicing. To examine the effects of distinct PRPH2 point mutations on mRNA splicing and protein expression in vivo, we designed PRPH2 minigenes containing the three coding exons and relevant intronic regions of human PRPH2. Minigenes carrying wild type PRPH2 or PRPH2 exon 2 mutations associated with rod or cone disorders were expressed in murine photoreceptors using recombinant adeno-associated virus (rAAV) vectors. We detect three PRPH2 splice isoforms in rods and cones: correctly spliced, intron 1 retention, and unspliced. In addition, we show that only the correctly spliced isoform results in detectable protein expression. Surprisingly, compared to rods, differential splicing leads to lower expression of correctly spliced and higher expression of unspliced PRPH2 in cones. These results were confirmed in qRT-PCR experiments from FAC-sorted murine rods and cones. Strikingly, three out of five cone disease-causing PRPH2 mutations profoundly enhanced correct splicing of PRPH2, which correlated with strong upregulation of mutant PRPH2 protein expression in cones. By contrast, four out of six PRPH2 mutants associated with rod disorders gave rise to a reduced PRPH2 protein expression via different mechanisms. These mechanisms include aberrant mRNA splicing, protein mislocalization, and protein degradation. Our data suggest that upregulation of PRPH2 levels in combination with defects in the PRPH2 function caused by the mutation might be an important mechanism leading to cone degeneration. By contrast, the pathology of rod-specific PRPH2 mutations is rather characterized by PRPH2 downregulation and impaired protein localization

Expression profiling with RNA from formalin-fixed, paraffin-embedded material

<p>Abstract</p> <p>Background</p> <p>Molecular characterization of breast and other cancers by gene expression profiling has corroborated existing classifications and revealed novel subtypes. Most profiling studies are based on fresh frozen (FF) tumor material which is available only for a limited number of samples while thousands of tumor samples exist as formalin-fixed, paraffin-embedded (FFPE) blocks. Unfortunately, RNA derived of FFPE material is fragmented and chemically modified impairing expression measurements by standard procedures. Robust protocols for isolation of RNA from FFPE material suitable for stable and reproducible measurement of gene expression (e.g. by quantitative reverse transcriptase PCR, QPCR) remain a major challenge.</p> <p>Results</p> <p>We present a simple procedure for RNA isolation from FFPE material of diagnostic samples. The RNA is suitable for expression measurement by QPCR when used in combination with an optimized cDNA synthesis protocol and TaqMan assays specific for short amplicons. The FFPE derived RNA was compared to intact RNA isolated from the same tumors. Preliminary scores were computed from genes related to the ER response, HER2 signaling and proliferation. Correlation coefficients between intact and partially fragmented RNA from FFPE material were 0.83 to 0.97.</p> <p>Conclusion</p> <p>We developed a simple and robust method for isolating RNA from FFPE material. The RNA can be used for gene expression profiling. Expression measurements from several genes can be combined to robust scores representing the hormonal or the proliferation status of the tumor.</p

Einleitung

Zweitveröffentlichun

Pharmacological Targeting of the RAGE-NF&kappa;B Signalling Axis Impedes Monocyte Activation under Diabetic Conditions through the Repression of SHP-2 Tyrosine Phosphatase Function

Monocytes play a vital role in the development of cardiovascular diseases. Type 2 diabetes mellitus (T2DM) is a major CVD risk factor, and T2DM-induced aberrant activation and enhanced migration of monocytes is a vital pathomechanism that leads to atherogenesis. We recently reported the upregulation of SHP-2 phosphatase expression in mediating the VEGF resistance of T2DM patient-derived monocytes or methylglyoxal- (MG, a glucose metabolite and advanced glycation end product (AGE) precursor) treated monocytes. However, the exact mechanisms leading to SHP-2 upregulation in hyperglycemic monocytes are unknown. Since inflammation and accumulation of AGEs is a hallmark of T2DM, we hypothesise that inflammation and AGE-RAGE (Receptor-for-AGEs) signalling drive SHP-2 expression in monocytes and blockade of these pathways will repress SHP-2 function. Indeed, monocytes from T2DM patients revealed an elevated SHP-2 expression. Under normoglycemic conditions, the serum from T2DM patients strongly induced SHP-2 expression, indicating that the T2DM serum contains critical factors that directly regulate SHP-2 expression. Activation of pro-inflammatory TNF&alpha; signalling cascade drove SHP-2 expression in monocytes. In line with this, linear regression analysis revealed a significant positive correlation between TNF&alpha; expression and SHP-2 transcript levels in T2DM monocytes. Monocytes exposed to MG or AGE mimetic AGE-BSA, revealed an elevated SHP-2 expression and co-treatment with an NF&kappa;B inhibitor or genetic inhibition of p65 reversed it. The pharmacological inhibition of RAGE was sufficient to block MG- or AGE-BSA-induced SHP-2 expression and activity. Confirming the importance of RAGE-NF&kappa;B signalling in regulating SHP-2 expression, the elevated binding of NF&kappa;B to the SHP-2 promoter&mdash;induced by MG or AGE-BSA&mdash;was reversed by RAGE and NF&kappa;B inhibition. Besides, we detected elevated RAGE levels in human and murine T2DM monocytes and monocytes exposed to MG or AGE-BSA. Importantly, MG and AGE-BSA treatment of non-T2DM monocytes phenocopied the aberrant pro-migratory phenotype of T2DM monocytes, which was reversed entirely by either SHP-2- or RAGE inhibition. In conclusion, these findings suggest a new therapeutic approach to prevent accelerated atherosclerosis in T2DM patients since inhibiting the RAGE-NF&kappa;B-SHP-2 axis impeded the T2DM-driven, SHP-2-dependent monocyte activation

Protein expression of PRPH2 mutants linked to adRP.

<p>(A-F) Immunohistology of retinas transduced with PRPH2 minigenes containing single point mutations as indicated under the control of the hRHO promoter. Scale bar represents 20 μm. (G) Western blot analysis from membrane preparations of four pooled murine retinas from four animals transduced with the PRPH2 minigenes shown in (A-F) on P14. All retinas were collected three weeks post injection. The arrowhead indicates a degradation band detected at 42 kDa. Ctrl, protein lysates from non-injected control retinas. (H) Semi-quantitative analysis of the results shown in (G). For quantification, three technical replicates were conducted and PRPH2 expression was normalized to the ATPase expression. All data are given as mean values and error bars represent the SEM. Statistical analysis was performed using one-way ANOVA followed by the Dunett’s test. *, p< 0.05; **, p< 0.01; ***, p< 0.001. n.s., not significant.</p