PTCH1+/− Dermal Fibroblasts Isolated from Healthy Skin of Gorlin Syndrome Patients Exhibit Features of Carcinoma Associated Fibroblasts

Gorlin's or nevoid basal cell carcinoma syndrome (NBCCS) causes predisposition to basal cell carcinoma (BCC), the commonest cancer in adult human. Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome. In NBCCS patients, as in the general population, ultraviolet exposure is a major risk factor for BCC development. However these patients also develop BCCs in sun-protected areas of the skin, suggesting the existence of other mechanisms for BCC predisposition in NBCCS patients. As increasing evidence supports the idea that the stroma influences carcinoma development, we hypothesized that NBCCS fibroblasts could facilitate BCC occurence of the patients. WT (n = 3) and NBCCS fibroblasts bearing either nonsense (n = 3) or missense (n = 3) PTCH1 mutations were cultured in dermal equivalents made of a collagen matrix and their transcriptomes were compared by whole genome microarray analyses. Strikingly, NBCCS fibroblasts over-expressed mRNAs encoding pro-tumoral factors such as Matrix Metalloproteinases 1 and 3 and tenascin C. They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts. These data indicate that the PTCH1+/− genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients

Attitudes about tuberculosis prevention in the elimination phase: a survey among physicians in Germany.

BACKGROUND: Targeted and stringent measures of tuberculosis prevention are necessary to achieve the goal of tuberculosis elimination in countries of low tuberculosis incidence. METHODS: We ascertained the knowledge about tuberculosis risk factors and stringency of tuberculosis prevention measures by a standardized questionnaire among physicians in Germany involved in the care of individuals from classical risk groups for tuberculosis. RESULTS: 510 physicians responded to the online survey. Among 16 risk factors immunosuppressive therapy, HIV-infection and treatment with TNF-antagonist were thought to be the most important risk factors for the development of tuberculosis in Germany. Exposure to a patient with tuberculosis ranked on the 10th position. In the event of a positive tuberculin-skin-test or interferon-γ release assay only 50%, 40%, 36% and 25% of physicians found that preventive chemotherapy was indicated for individuals undergoing tumor necrosis factor-antagonist therapy, close contacts of tuberculosis patients, HIV-infected individuals and migrants, respectively. CONCLUSIONS: A remarkably low proportion of individuals with latent infection with Mycobacterium tuberculosis belonging to classical risk groups for tuberculosis are considered candidates for preventive chemotherapy in Germany. Better knowledge about the risk for tuberculosis in different groups and more stringent and targeted preventive interventions will probably be necessary to achieve tuberculosis elimination in Germany

Going left. A comparative study of left displacement in Avatime, Lakhota, Tundra Yukaghir and Whitesands.

Left displaced elements seem to be extremely frequent, if not universal, phenomena across languages. Despite their surface similarity, however, they tend to display strikingly different features, both structurally and functionally (Prince 1998, Lambrecht 2001, papers in Shaer et al. 2009, Gundel et al. 2010, etc.). Our purpose is to investigate (a) the correlation of the structural variability of left-detachment constructions and the overall linguistic type of the language (head- vs. dependent-marking, head-final vs. head-initial, pronominal vs. zero anaphor, etc.), and (b) the range of discourse-pragmatic functions these constructions can perform from the point of view of information structure and discourse organisation. The study is based on a fine-grained analysis of naturally occurring instances of left dislocation in four geographically and genealogically distinct languages, Avatime (Kwa, West Africa), Lakhota (Siouan, northern USA), Tundra Yukaghir (isolate, north-eastern Siberia), and Whitesands (Oceanic, Vanuatu). The formal parameters of variation investigated include prosodic features of pitch assignment and phrasing, the frequency and type of resumption within the clause, integration within the clause via case/cross-referencing on the verb, recursivity, connectivity effects such as binding by quantifiers and island sensitivity, etc. The variation in the functional load of left detached elements is explored on the basis of their anaphoric and cataphoric relevance, the degree and type of activation and their semantic and information-structural relations to the clause. It is shown that the types of left detachment represented in the languages under investigation vary depending on the argument structure marking strategies employed in the language and the types of anaphora resolution employed. Furthermore, the functional variability is shown to be at least in part a function of the linguistic type, the relevant features being the presence of dedicated topic/focus positions in the clause architecture and the pronominal inventory. We provide an RRG-based account of these empirical findings, which both captures the universal features of left detachment and takes the cross-linguistic variability into account. References Gundel J.K., B. Mamadou, G. Bryan, H. Linda & Kh. Amel (2010) Testing predictions of the Givenness Hierarchy framework : A cross-linguistic investigation, Journal of Pragmatics 42: 1770-1785. Lambrecht K. (2001) Dislocation. In: M. Haspelmath et al. (eds.) Language typology and language universals. Berlin: Walter de Gruyter (vol.2: 1050-1078). Prince, E. F. (1998) On the limits of syntax, with reference to Left-Dislocation and Topicalization. In: P. Culicover & L. McNally (eds.), The limits of syntax. NY: Academic Press. (pp. 281-302). Shaer, B., P. Cook, W. Frey & C. Maienborn (eds.) (2009) Dislocated elements in discourse. London: Routledg

Lesion analysis of the brain areas involved in language comprehension

The cortical regions of the brain traditionally associated with the comprehension of language are Wernicke's area and Broca's area. However, recent evidence suggests that other brain regions might also be involved in this complex process. This paper describes the opportunity to evaluate a large number of brain-injured patients to determine which lesioned brain areas might affect language comprehension. Sixty-four chronic left hemisphere stroke patients were evaluated on 11 subtests of the Curtiss–Yamada Comprehensive Language Evaluation – Receptive (CYCLE-R; Curtiss, S., & Yamada, J. (1988). Curtiss–Yamada Comprehensive Language Evaluation. Unpublished test, UCLA). Eight right hemisphere stroke patients and 15 neurologically normal older controls also participated. Patients were required to select a single line drawing from an array of three or four choices that best depicted the content of an auditorily-presented sentence. Patients' lesions obtained from structural neuroimaging were reconstructed onto templates and entered into a voxel-based lesion-symptom mapping (VLSM; Bates, E., Wilson, S., Saygin, A. P., Dick, F., Sereno, M., Knight, R. T., & Dronkers, N. F. (2003). Voxel-based lesion-symptom mapping. Nature Neuroscience, 6(5), 448–450.) analysis along with the behavioral data. VLSM is a brain–behavior mapping technique that evaluates the relationships between areas of injury and behavioral performance in all patients on a voxel-by-voxel basis, similar to the analysis of functional neuroimaging data. Results indicated that lesions to five left hemisphere brain regions affected performance on the CYCLE-R, including the posterior middle temporal gyrus and underlying white matter, the anterior superior temporal gyrus, the superior temporal sulcus and angular gyrus, mid-frontal cortex in Brodmann's area 46, and Brodmann's area 47 of the inferior frontal gyrus. Lesions to Broca's and Wernicke's areas were not found to significantly alter language comprehension on this particular measure. Further analysis suggested that the middle temporal gyrus may be more important for comprehension at the word level, while the other regions may play a greater role at the level of the sentence. These results are consistent with those seen in recent functional neuroimaging studies and offer complementary data in the effort to understand the brain areas underlying language comprehension

Subordination strategies in Tupian languages

Abstract: Assessing the internal coherence and constituency of language families often centers either around comparing certain form-meaning correspondences, or around identifying the presence or absence of linguistic features across the members of the family. The former approach is generally restricted to the lexicon. The latter approach focuses mostly on structural characteristics of language. In this paper we present an alternative approach to comparing grammatical systems between languages within a language family, which aims at bringing these two approaches and their results closer to each other. We look at subordination strategies in a sample of Tupian languages, taking constructions as the basic unit of comparison, treating them as form-meaning correspondences. The Tupian family offers an especially intriguing case for studying subordination strategies in the South American context, given its enormous geographical spread and the variety of contact situations involving its member languages. Major patterns of subordination strategies can be discerned across the family, e.g. strategies involving nominalization, verbal incorporation and other subtypes of verbal serialization, but there is also a great degree of variability between the different languages. By mapping the structural diversity onto the known genealogy and geographic distribution, we hope to shed more light on the history of the Tupian family and on the diffusability of subordination strategies