Wissenschaftliche Validität als Qualitätsmerkmal der Zukunftsforschung

Zukunftsforschung beansprucht, wissenschaftlichen Kriterien zu genügen. Anders als in anderen Disziplinen trifft man jedoch in diesem Fachgebiet auf besondere Herausforderungen hinsichtlich der Kriterien wissenschaftlicher Validität und an die Verfahren ihrer Prüfung, da übliche Ansätze wie die empirische Bewährung oder logische Ableitung in der Zukunftsforschung nicht anwendbar sind. Stattdessen können, so die hier vertretene These, strukturelle Überlegungen aus der Kohärenztheorie der Wahrheit übertragen werden, um die wissenschaftliche Qualität von Zukunftsaussagen konzeptuell zu begreifen und mit Kriterien zur Validierung zu operationalisieren. Entscheidend ist, dass Aussagen der Zukunftsforschung transparent in ihre Bestandteile zerlegt werden und dass sowohl für die Bestandteile als auch für die Art und Weise der Zusammenfügung der Bestandteile belastbare Argumente angeführt werden können. Der Beitrag schließt mit Überlegungen, was von einer explizit wissenschaftlichen Validierung von Zukunftsüberlegungen erwartet werden kann und was nicht.

Apolipoprotein E genotypes and cognitive functions in healthy elderly persons

Objectives- We investigated whether apoE genotypes correlate with cognitive functions in clinically healthy persons. Methods - In 1993 and 1995, we measured information processing speed, delayed free recall and semantic aspects of long-term memory in 227 men and 105 women aged 65 and over, a randomly selected subsample of the prospective Basel Study. Cardiovascular risk factors and education were assessed. Results -E2 were more prevalent in old-old (>75 years, 23.5% vs 15%) compared to E4 than in young-old (<75 years, 19.3% vs 23.5%). Taking into account age and education, subjects with ɛ3/ɛ4 or ɛ4/ɛ4 alleles (E4) performed lowest in all 3 tests compared to those homozygous for ɛ3 (E3) or carriers of one or two ɛ2 alleles (E2) (reaction time P=0.009, free recall P=0.05, WAIS-R vocabulary P<0.05). In old-old there was a significant difference between E2 and E4 for reaction time (P=0.02) and free recall (P<0.02) but not for vocabulary (P=0.086). In all 3 groups there were no significant changes after 2 years. The subgroup with the genotype ɛ2/ɛ4 performed consistently best in the cognitive tests. Cholesterol was significantly increased in the E4 and E3 group compared to the E2 group. Conclusion - ApoE genotype correlates with cognitive performance. The increased prevalence of E2 in the old-old and the significantly lower plasma cholesterol levels suggest differential morbidity and mortality as important factors influencing the prevalence of cognitive disorders in late life.

Zwischen Christen und Juden : Dreyfus, Ferrer, Casement, Chamberlain, Marten

von e. Mohamedaner (Dr. Al-Mohadjer) [d. i. Wilhelm Marten]

16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

Die grenzüberschreitende Übertragung von Wissen über Transitional Justice und ihre Akteure in historischer Perspektive

Historische Ansätze sind in der Betrachtung von Transitional Justice rar geblieben. Den weitreichenden Veränderungen, die das Feld im Zuge seiner Ausdehnung zum weltweit dominierenden Reflexions- und Handlungszusammenhang im Umgang mit historischem Unrecht erfahren hat, ist deshalb in aller Regel keine angemessene Beachtung geschenkt worden. Der vorliegende Beitrag widmet sich aus historischer Sicht den Fragen, wie seit den späten 1980er Jahren über die Grenzen nationaler Aufarbeitungsschauplätze hinaus Wissen über Transitional Justice generiert und übertragen worden ist, welche die beteiligten Akteursgruppen waren und welche Auswirkungen der Wandel in den Wissenstransfers und im Verhältnis zwischen den Akteuren auf die Entwicklungen im Feld hatte. Im Mittelpunkt der Analyse steht dabei das Instrument der Wahrheitskommissionen. Historical approaches to the study of transitional justice are rare. In the process of its expansion to the dominating paradigm in dealing with past injustices, the field experienced far reaching changes. Scholarship about transitional justice, however, has hardly taken into account these shifts in appropriate ways. This article examines from a historical point of view how knowledge about transitional justice was generated and transferred across the borders of the national sites of dealing with the past, what were the groups of actors involved and what effects the transformations of the knowledge circulation as well as of the relationship between the actors since the late 1980s had on the development of the field. The focus of the analysis, thereby, is on the instrument of truth commissions.

An Atypical Mitochondrial Carrier That Mediates Drug Action in Trypanosoma brucei

Elucidating the mechanism of action of trypanocidal compounds is an important step in the development of more efficient drugs against Trypanosoma brucei. In a screening approach using an RNAi library in T. brucei bloodstream forms, we identified a member of the mitochondrial carrier family, TbMCP14, as a prime candidate mediating the action of a group of anti-parasitic choline analogs. Depletion of TbMCP14 by inducible RNAi in both bloodstream and procyclic forms increased resistance of parasites towards the compounds by 7-fold and 3-fold, respectively, compared to uninduced cells. In addition, down-regulation of TbMCP14 protected bloodstream form mitochondria from a drug-induced decrease in mitochondrial membrane potential. Conversely, over-expression of the carrier in procyclic forms increased parasite susceptibility more than 13-fold. Metabolomic analyses of parasites over-expressing TbMCP14 showed increased levels of the proline metabolite, pyrroline-5-carboxylate, suggesting a possible involvement of TbMCP14 in energy production. The generation of TbMCP14 knock-out parasites showed that the carrier is not essential for survival of T. brucei bloodstream forms, but reduced parasite proliferation under standard culture conditions. In contrast, depletion of TbMCP14 in procyclic forms resulted in growth arrest, followed by parasite death. The time point at which parasite proliferation stopped was dependent on the major energy source, i.e. glucose versus proline, in the culture medium. Together with our findings that proline-dependent ATP production in crude mitochondria from TbMCP14-depleted trypanosomes was reduced compared to control mitochondria, the study demonstrates that TbMCP14 is involved in energy production in T. brucei. Since TbMCP14 belongs to a trypanosomatid-specific clade of mitochondrial carrier family proteins showing very poor similarity to mitochondrial carriers of mammals, it may represent an interesting target for drug action or targeting.

Polymorphisms in MIR27A Associated with Early-Onset Toxicity in Fluoropyrimidine-Based Chemotherapy

PURPOSE The microRNA miR-27a was recently shown to directly regulate dihydropyrimidine dehydrogenase (DPD), the key enzyme in fluoropyrimidine catabolism. A common polymorphism (rs895819A>G) in the miR-27a genomic region (MIR27A) was associated with reduced DPD activity in healthy volunteers, but the clinical relevance of this effect is still unknown. Here, we assessed the association of MIR27A germline variants with early-onset fluoropyrimidine toxicity. EXPERIMENTAL DESIGN MIR27A was sequenced in 514 patients with cancer receiving fluoropyrimidine-based chemotherapy. Associations of MIR27A polymorphisms with early-onset (cycles 1-2) fluoropyrimidine toxicity were assessed in the context of known risk variants in the DPD gene (DPYD) and additional covariates associated with toxicity. RESULTS The association of rs895819A>G with early-onset fluoropyrimidine toxicity was strongly dependent on DPYD risk variant carrier status (Pinteraction = 0.0025). In patients carrying DPYD risk variants, rs895819G was associated with a strongly increased toxicity risk [OR, 7.6; 95% confidence interval (CI), 1.7-34.7; P = 0.0085]. Overall, 71% (12/17) of patients who carried both rs895819G and a DPYD risk variant experienced severe toxicity. In patients without DPYD risk variants, rs895819G was associated with a modest decrease in toxicity risk (OR, 0.62; 95% CI, 0.43-0.9; P = 0.012). CONCLUSIONS These results indicate that miR-27a and rs895819A>G may be clinically relevant for further toxicity risk stratification in carriers of DPYD risk variants. Our data suggest that direct suppression of DPD by miR-27a is primarily relevant in the context of fluoropyrimidine toxicity in patients with reduced DPD activity. However, miR-27a regulation of additional targets may outweigh its effect on DPD in patients without DPYD risk variants.

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

Hepatic expression of A20, including in hepatocytes, increases in response to injury, inflammation and resection. This increase likely serves a hepatoprotective purpose. The characteristic unfettered liver inflammation and necrosis in A20 knockout mice established physiologic upregulation of A20 as integral to the anti-inflammatory and anti-apoptotic armamentarium of hepatocytes. However, the implication of physiologic upregulation of A20 in modulating hepatocytes' proliferative responses following liver resection remains controversial. To resolve the impact of A20 on hepatocyte proliferation and the liver's regenerative capacity, we examined whether decreased A20 expression, as in A20 heterozygous knockout mice, affects outcome following two-third partial hepatectomy. A20 heterozygous mice do not demonstrate a striking liver phenotype, indicating that their A20 expression levels are still sufficient to contain inflammation and cell death at baseline. However, usually benign partial hepatectomy provoked a staggering lethality (>40%) in these mice, uncovering an unsuspected phenotype. Heightened lethality in A20 heterozygous mice following partial hepatectomy resulted from impaired hepatocyte proliferation due to heightened levels of cyclin-dependent kinase inhibitor, p21, and deficient upregulation of cyclins D1, E and A, in the context of worsened liver steatosis. A20 heterozygous knockout minimally affected baseline liver transcriptome, mostly circadian rhythm genes. Nevertheless, this caused differential expression of >1000 genes post hepatectomy, hindering lipid metabolism, bile acid biosynthesis, insulin signaling and cell cycle, all critical cellular processes for liver regeneration. These results demonstrate that mere reduction of A20 levels causes worse outcome post hepatectomy than full knockout of bona fide liver pro-regenerative players such as IL-6, clearly ascertaining A20's primordial role in enabling liver regeneration. Clinical implications of these data are of utmost importance as they caution safety of extensive hepatectomy for donation or tumor in carriers of A20/TNFAIP3 single nucleotide polymorphisms alleles that decrease A20 expression or function, and prompt the development of A20-based liver pro-regenerative therapies.

Na 1 Nachlass Max Horkheimer, 632 - Aufsätze für die "Zeitschrift für Sozialforschung" (p. IX 4-IX 6)

"Zum Rationalismusstreit in der gegenwärtigen Philosophie" (GS 3, S.163-220), veröffentlicht in: Zeitschrift für Sozialforschung III, 1934, S. 1-53, a) Teilstück, Typoskript mit handschriftlichen Korrekturen, 16 Blatt, b) englische Fassung mit dem Titel "Rationalism and Irrationalism in Recent German Philosophy", Typoskript mit eigenhändigen Korrekturen, 75 Blatt; "Zum Problem der Wahrheit" (GS 3, S.277 - 325), veröffentlicht in: Zeitschrift für Sozialforschung IV, 1935, S. 321-364, englische Fassung mit dem Titel "The Problem of Truth", 45 Blatt; "Egoismus und Freiheitsbewegung" (GS 4, S.9-88), veröffentlicht in: Zeitschrift für Sozialforschung V, 1936, S.161-234, englische Fassung mit dem Titel "Egoism and the Struggle for Freedom", a) Typoskript mit handschriftlichen Korrekturen, 91 Blatt, b) Typoskript mit handschriftlichen Korrekturen, 77 Blatt;

DNA nucleotide excision repair gene single nucleotide polymorphisms and hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease caused by germline mutations in DNA mismatch repair(MMR) genes. The nucleotide excision repair(NER) pathway plays a very important role in cancer development. We systematically studied interactions between NER and MMR genes to identify NER gene single nucleotide polymorphism (SNP) risk factors that modify the effect of MMR mutations on risk for cancer in HNPCC. We analyzed data from polymorphisms in 10 NER genes that had been genotyped in HNPCC patients that carry MSH2 and MLH1 gene mutations. The influence of the NER gene SNPs on time to onset of colorectal cancer (CRC) was assessed using survival analysis and a semiparametric proportional hazard model. We found the median age of onset for CRC among MMR mutation carriers with the ERCC1 mutation was 3.9 years earlier than patients with wildtype ERCC1(median 47.7 vs 51.6, log-rank test p=0.035). The influence of Rad23B A249V SNP on age of onset of HNPCC is age dependent (likelihood ratio test p=0.0056). Interestingly, using the likelihood ratio test, we also found evidence of genetic interactions between the MMR gene mutations and SNPs in ERCC1 gene(C8092A) and XPG/ERCC5 gene(D1104H) with p-values of 0.004 and 0.042, respectively. An assessment using tree structured survival analysis (TSSA) showed distinct gene interactions in MLH1 mutation carriers and MSH2 mutation carriers. ERCC1 SNP genotypes greatly modified the age onset of HNPCC in MSH2 mutation carriers, while no effect was detected in MLH1 mutation carriers. Given the NER genes in this study play different roles in NER pathway, they may have distinct influences on the development of HNPCC. The findings of this study are very important for elucidation of the molecular mechanism of colon cancer development and for understanding why some mutation carriers of the MSH2 and MLH1 gene develop CRC early and others never develop CRC. Overall, the findings also have important implications for the development of early detection strategies and prevention as well as understanding the mechanism of colorectal carcinogenesis in HNPCC. ^

Genetic epidemiologic methods in risk determination in Li-Fraumeni syndrome

Li-Fraumeni syndrome (LFS) is characterized by a variety of neoplasms occurring at a young age with an apparent autosomal dominant transmission. Individuals in pedigrees with LFS have high incidence of second malignancies. Recently LFS has been found to be associated with germline mutations of a tumor-suppressor gene, p53. Because LFS is rare and indeed not a clear-cut disease, it is not known whether all cases of LFS are attributable to p53 germline mutations and how p53 plays in cancer occurrence in such cancer syndrome families. In the present study, DNAs from constitutive cells of two-hundred and thirty-three family members from ten extended pedigrees were screened for p53 mutations. Six out of the ten LFS families had germline mutations at the p53 locus, including point and deletion mutations. In these six families, 55 out of 146 members were carriers of p53 mutations. Except one, all mutations occurred in exons 5 to 8 (i.e., the "hot spot" region) of the p53 gene. The age-specific penetrance of cancer was estimated after the genotype for each family member at risk was determined. The penetrance was 0.15, 0.29, 0.35, 0.77, and 0.91 by 20, 30, 40, 50 and 60 year-old, respectively, in male carriers; 0.19, 0.44, 0.76, and 0.90 by 20, 30, 40, and 50 year-old, respectively, in female carriers. These results indicated that one cannot escape from tumorigenesis if one inherits a p53 mutant allele; at least ninety percent of p53 carriers will develop cancer by the age of 60. To evaluate the possible bias due to the unexamined blood-relatives in LFS families, I performed a simulation analysis in which a p53 genotype was assigned to each unexamined person based on his cancer status and liability to cancer. The results showed that the penetrance estimates were not biased by the unexamined relatives. I also determined the sex, site, and age-specific penetrance of breast cancer in female carriers and lung cancer in male carriers. The penetrance of breast cancer in female carriers was 0.81 by age 45; the penetrance of lung cancer in male carriers was 0.78 by age 60, indicating that p53 play a key role for tumorigenesis in common cancers. ^

Situacionalidad del conocimiento, «racionalismo» y dimensión «externa» de la verdad : una intervención en el (no-)debate Habermas - Foucault

En este artículo abordaremos el debate iniciado por la crítica de “paradoja autorreferencial" de Habermas contra Foucault, desde la perspectiva del problema del carácter situado del conocimiento en el mundo mismo conocido (carácter célebremente remarcado por el filósofo francés al hablar de la verdad como “una cosa de este mundo"). Señalaremos que la obra de Habermas no permite rechazar esta crítica como la mera regresión a un “racionalismo"; antes bien, el problema que ella plantea es el de la necesidad de analizar la “historia externa" (Foucault) de la verdad sin, no obstante, reducir la verdad a tal dimensión “externa".

Peligrosidad: entre el Trabajo Social y el Código Penal : Prácticas y tensiones

Frente a la necesidad de generar propuestas analíticas que abandonen la perspectiva primordialmente jurídica de la problemática de la inseguridad civil, centrada en el debate por más/menos penas, libertad condicional/ encierro prolongado e incorpore nuevos elementos que enriquezcan la mirada sobre esta problemática, la siguiente investigación se propone dar cuenta del funcionamiento de una Asesoría Pericial, en su contribución específica en la designación de la peligrosidad de los acusados. Si se considera la "cuestión criminal" como una construcción social, cabe preguntarse: ¿quién realiza esa construcción? y ¿dentro de qué marco institucional?, ¿cómo se realiza?, ¿en función de qué criterios o parámetros? El juez o fiscal pregunta al perito si el sujeto es o no peligroso, en función de lo cual debería o no quedar en libertad; en este marco se entrelaza el discurso científico con el discurso jurídico, representante éste por excelencia del poder simbólico, poder de nombrar y designar, poder de establecer la mirada legitima sobre el mundo social. Desde esta posición de poder, se decide sobre el destino de las personas, sobre su libertad, sobre su inocencia o culpabilidad. Se pone en el centro de la mirada institucional al acusado, a su familia, a su medio comunitario y social. ¿En qué consiste y en función de qué criterios se construye la categoría "peligrosidad" en el discurso y prácticas de los peritos Asistentes/Trabajadores Sociales?; ¿Cómo se articulan con el discurso jurídico? ¿Existen tensiones entre estos discursos? ¿Qué lugar ocupa la dimensión interpretativa - valorativa en la construcción de las mismas?

Reglas y conciencia de las reglas : Significado, ontología y escepticismo

La tesis analiza dos objeciones corrientes a la interpretación del problema de las reglas por el Wittgenstein de Kripke: el PROBLEMA DE LA OBJETIVIDAD DE LA REGLA, ¿puede un individuo estar acertado en contra de la opinión comunitaria consensuada?; y el PROBLEMA DE LAS RELACIONES INTERNAS entre reglas y casos, presuntamente violentada por el rol de la noción de acuerdo en la misma. La estrategia general de la tesis es examinar las vías de ataque al lenguaje privado (LP) previas a la de Kripke. El contraste con las mismas permite conceptualizar adecuadamente la propuesta de Kripke, para mostrar que las objeciones mencionadas no se le aplican. En el marco de la tesis, comprendemos por LP a cualquier tesis que sostenga que las condiciones de significatividad del lenguaje pueden ser provistas por estados mentales subjetivos, p.e. creencias, de ahí el solapamiento de la tesis del lenguaje privado con el escepticismo epistemológico y con posiciones solipsistas, y la convicción de que la refutación del LP acarrea la ruina del escepticismo epistemológico. Hay dos versiones clásicas del argumento del LP. Las versiones epistemológicas (Malcom, Fogelin son los representantes que examinamos) derivan la imposibilidad del LP de la imposibilidad de establecer la verdad/corrección de un uso en el contexto de privacidad. La crítica a estas versiones (Ayer, thomson) muestra un círculo justificatorio entre oraciones subjetivas y objetivas. Las versiones semánticas (Kenny, Canfield, Tugendhat) intentan evitar el círculo, elucidando las presuposiciones que le subyacen. Esta respuesta no es satisfactoria ya que o bien regenera el círculo en un nuevo nivel, o bien no logran derrocar al círculo de la justificación. Con Stroud identificamos el fallo común de estas estrategias en el hecho de que en su intento de derrotar al escéptico-privatista, requieren o bien una PREMISA FÁCTICA que indica que conocemos, o bien la especificación del conocimiento como una NOTA DEFINICIONAL de los criterios/condiciones de significatividad que el argumento trascendental elucida en la pregunta del escéptico. Kripke impone un cambio de rumbo en el argumento, al plantear el desafío como una forma de ESCEPTICISMO SEMÁNTICO ONTOLÓGICO, el cual ya no se basa en las limitaciones cognitivas de la privacidad, sino justamente en las presuntas ventajas que presenta. El desafío de Kripke pregunta por las razones que podemos aportar para sostener que no ha ocurrido un cambio en el uso, lo cual equivale a preguntar ¿cómo sabes que tu uso actual CORRESPONDE con tu intención/significado previo? De la imposibilidad de responder a la cuestión clave del realismo clásico (correspondencia) en el caso del significado, Kripke concluye que no puede haber condiciones de verdad para las oraciones semánticas. Esto motiva una paradoja escéptica y una SOLUCIÓN ESCÉPTICA de la paradoja en términos de condiciones de aseverabilidad. Tener en cuenta el abandono de las condiciones de verdad es la clave para responder al problema de la objetividad, mientras que la forma del desafío y el funcionamiento de la concordancia en los juicios como base de atribución, es la clave para la solución del problema de las relaciones internas.

Los conceptos de verdad y falsedad en Filoctetes de Sófocles

El presente trabajo pretende exponer las particularidades que exhiben los términos (...), verdad, y (...), falsedad, en Filoctetes de Sófocles. Merced al análisis etimológico, morfológico y semántico de dichos términos, de las relaciones que se establecen entre ellos y de su disposición en la tragedia, se busca destacar la manera en que el texto trágico mismo pone en evidencia la naturaleza de ambos conceptos como constructos humanos, arti´Çücios del lenguaje no sólo parciales sino también relativos, subordinados a contextos de enunciación transitorios.