Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens

CFTR mutations enhance susceptibility for idiopathic chronic pancreatitis (ICP) and congenital bilateral absence of the vas deferens (CBAVD); however, it is unknown why CFTR heterozygotes are at increased disease risk. We recently showed that common CFTR variants are associated with aberrantly spliced transcripts. Here, we genotyped for common CFTR variants and tested for associations in two ICP (ICP-A: 126 patients, 319 controls; ICP-B: 666 patients, 1,181 controls) and a CBAVD population (305 patients, 319 controls). Haplotype H10 (TG11-T7-470V) conferred protection (ICP-A: OR 0.19, P<0.0001; ICP-B: OR 0.78, P = 0.06; CBAVD OR 0.08, P<0.001), whereas haplotype H3 (TG10-T7-470M) increased disease risk (ICP-A: OR 8.34, P = 0.003; ICP-B: OR 1.88, P = 0.007; CBAVD: OR 5.67, P = 0.01). The risk of heterozygous CFTR mutations carriers for ICP (OR 2.44, P<0.001) and CBAVD (OR 14.73, P<0.001) was fully abrogated by the H10/H10 genotype. Similarly, ICP risk of heterozygous p.Asn34Ser SPINK1 mutation carriers (OR 10.34, P<0.001) was compensated by H10/H10. Thus, common CFTR haplotypes modulate ICP and CBAVD susceptibility alone and in heterozygous CFTR and p.Asn34Ser mutation carriers. Determination of these haplotypes helps to stratify carriers into high- and low-risk subjects, providing helpful information for genetic counseling.

Standard Language in Bosna and Hercegovina - in Language Policy Documents

From the beginning of the standardisation of language in Bosnia and Herzegovina, i.e. from the acceptance of Karadzic's phonetic spelling in the mid-19th century, to the present day when there are three different language standards in force - Bosniac (Muslim), Croatian and Serbian, language in Bosnia and Herzegovina has been a subject of political conflict. Documents on language policy from this period show the degree to which domestic and foreign political factors influenced the standard language issue, beginning with the very appellation for the specific norm regulation. The material analysed (proclamations by political, cultural and other organisations as well as corresponding constitutional and statutory provisions on language use) shows the differing treatment of the standard language in Bosnia and Herzegovina in different historical periods. During the period of Turkish rule (until 1878) there was no real political interest in the issue. Under Austro-Hungarian rule (1878-1918) there was an attempt to use the language as a means of forming a united Bosnian nation, but this was later abandoned. During the first Yugoslavia (1918-1941) a uniform solution was imposed on Bosnia and Herzegovina, as throughout the Serbo-Croatian language area, while under the Independent State of Croatia (1941-1945), the official language of Bosnia and Herzegovina was Croatian. The period from 1945 to 1991 had two phases: the first a standard language unity of Serbs, Croats, Muslims and Montenegrins (until 1965), and the second a gradual but stormy separation of national languages, which has been largely completed since 1991. The introductory study includes a detailed analysis of all the expressions used, with special reference to the present state, and accompanies the collection of documents which represent the main outcome of the research.

Economic and Social Changes in Czech Society after 1989: an Alternative View

The group presents an analysis of the development of the Czech society and economy during the 1990s. They believe that the Czech neo-liberal strategy of transformation led to a partial and uneven modernisation and that this strategy is unable to provide a firm basis for a complex process of modernisation. The increasing developmental problems encountered during 1996-1999 can be seen as empirical evidence of the inadequacy of the neo-liberal transformation strategy. These problems are connected to institutional shortcomings due to the excessive speed of privatisation, its form with certain important Czech innovations (particularly the voucher method and an attempt to resuscitate the Czech national capital) and with the overlooking of the importance of the legal framework and its enforcement. The overly hasty privatisation has created a type of 'recombinant property' which lacks the economic order necessary to stimulate efficiency in an atmosphere of prevailing social justice. A second reason for the present difficulties is the long-term lag behind the civilisation and cultural standards typical of the advanced European countries. The first steps of the Czech transformation concentrated mainly on changes in the institutions important for the distribution of power and wealth and largely neglected the necessity of deep-reaching modernisation of Czech society and the economy. The neo-liberal strategy created conditions conducive to predatory and speculative behaviour at the expense of creative behaviour. Inherited principles of egalitarianism combined with undeserved economic privileges survived and were reinforced by important new developments in the same direction. This situation hinders the assertion of meritocratic motivations. The group advocates the development and implementation of a complex strategy of modernisation based on deliberate reforms, institutional changes and restructuring on the basis of strategic planning, and structural and regional policies which stress the role of cultivation of the institutional order and of the most important factors of economic growth and development.

A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.

Do common genetic variants in endotoxin signaling pathway contribute to predisposition to alcoholic liver cirrhosis?

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), produced by endotoxin-activated Kupffer cells, play a key role in the pathogenesis of alcoholic liver cirrhosis (ALC). Alleles TNFA -238A, IL1B -31T and variant IL1RN*2 of repeat polymorphism in the gene encoding the IL-1 receptor antagonist increase production of TNF-alpha and IL-1beta, respectively. Alleles CD14 -159T, TLR4 c.896G and TLR4 c.1196T modify activation of Kupffer cells by endotoxin. We confirmed the published associations between these common variants and genetic predisposition to ALC by means of a large case-control association study conducted on two Central European populations. METHODS: The study population comprised a Czech sample of 198 ALC patients and 370 controls (MONICA project), and a German sample of 173 ALC patients and 331 controls (KORA-Augsburg), and 109 heavy drinkers without liver disease. RESULTS: Single locus analysis revealed no significant difference between patients and controls in all tested loci. Diplotype [IL1RN 2/ 2; IL1B -31T+] was associated with increased risk of ALC in the pilot study, but not in the validation samples. CONCLUSIONS: Although cytokine mediated immune reactions play a role in the pathogenesis of ALC, hereditary susceptibility caused by variants in the corresponding genes is low in Central European populations.

1,25-(OH)2-16ene-23yne-D3 reduces secondary hyperparathyroidism in uremic rats with little calcemic effect

To compare the effects of vitamin D analogs versus calcitriol on serum levels of Ca, P and parathyroid hormone (PTH). A compound better than calcitriol should increase the Ca x P product less than calcitriol for an equivalent decrease in PTH levels.

Potential Cities_

Buildings and urban construction are understood in this paper as representations of the city. Their meanings, however, are often invisible, positing unrealized urban visions, which are both imbedded in and which call up chains of associations expressing desires and fears. Narratives of what the city should be often contain the rejection of the existing urban situation. Understanding architectural objects as potential underscores their imaginary nature. Freud, for example, uses the Roman ruins in Civilization and its Discontents (1929) as a means to imagine stages of history. Yet, meanings of the new can also be covered over and layered. Milan is a city with fragments of the new, which once projected an ideal urban space into the future. The potentiality of Milan’s postwar urban objects is analyzed in relationship to narratives of the city and insertion is framed as an imagining into the city.