Critical review of the use of erythropoietin in the treatment of anaemia during therapy for chronic hepatitis C

Combined pegylated interferon (PegIFN) and ribavirin represents the standard therapy for patients with chronic hepatitis C (CHC), which allows for sustained viral response (SVR) in up to 90% of patients depending on certain viral and host factors. Clinical studies have demonstrated the importance of adherence to therapy, that is, the ability of patients to tolerate and sustain a fully dosed therapy regimen. Adherence is markedly impaired by treatment-related adverse effects. In particular, haemolytic anaemia often requires dose reduction or termination of ribavirin treatment, which compromises treatment efficacy. Recent evidence points to a beneficial role of recombinant erythropoietin (EPO) in alleviating ribavirin-induced anaemia thereby improving quality of life, enabling higher ribavirin dosage and consequently improving SVR. However, no general consensus exists regarding the use of EPO for specific indications: its optimal dosing, treatment benefits and potential risks or cost efficiency. The Swiss Association for the Study of the Liver (SASL) has therefore organized an expert meeting to critically review and discuss the current evidence and to phrase recommendations for clinical practice. A consensus was reached recommending the use of EPO for patients infected with viral genotype 1 developing significant anaemia below 100 g/L haemoglobin and a haematocrit of <30% during standard therapy to improve quality of life and sustain optimal ribavirin dose. However, the evidence supporting its use in patients with pre-existing anaemia, non-1 viral genotypes, a former relapse or nonresponse, liver transplant recipients and cardiovascular or pulmonary disease is considered insufficient.

Cleavage of IgG1 in gingival crevicular fluid is associated with the presence of Porphyromonas gingivalis

BACKGROUND AND OBJECTIVES: Immunoglobulin (Ig) G1 plays an important role in the adaptive immune response. Kgp, a lysine-specific cysteine protease from Porphyromonas gingivalis, specifically hydrolyses IgG1 heavy chains. The purpose of this study was to examine whether cleavage of IgG1 occurs in gingival crevicular fluid (GCF) in vivo, and whether there is any association with the presence of Porphyromonas gingivalis and other periodontopathogens. MATERIAL AND METHODS: GCF was obtained from nine patients with aggressive periodontitis, nine with chronic periodontitis and five periodontally healthy individuals. The bacterial loads of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Treponema denticola, Prevotella intermedia and Tannerella forsythia were analysed by real-time polymerase chain reaction, and the presence and cleavage of IgG1 and IgG2 were determined using Western blotting. Kgp levels were measured by ELISA. RESULTS: Cleaved IgG1 was identified in the GCF from 67% of patients with aggressive periodontitis and in 44% of patients with chronic periodontitis. By contrast, no cleaved IgG1 was detectable in healthy controls. No degradation of IgG2 was detected in any of the samples, regardless of health status. Porphyromonas gingivalis was found in high numbers in all samples in which cleavage of IgG1 was detected (P < 0.001 compared with samples with no IgG cleavage). Furthermore, high numbers of Tannerella forsythia and Prevotella intermedia were also present in these samples. The level of Kgp in the GCF correlated with the load of Porphyromonas gingivalis (r = 0.425, P < 0.01). The presence of Kgp (range 0.07-10.98 ng/mL) was associated with proteolytic fragments of IgG1 (P < 0.001). However, cleaved IgG1 was also detected in samples with no detectable Kgp. CONCLUSION: In patients with periodontitis, cleavage of IgG1 occurs in vivo and may suppress antibody-dependent antibacterial activity in subgingival biofilms especially those colonized by Porphyromonas gingivalis.

Do Central Hypersensitivity and Altered Pain Modulation Predict the Course of Chronic Low Back and Neck Pain?

OBJECTIVES:: Widespread central hypersensitivity and altered conditioned pain modulation (CPM) have been documented in chronic pain conditions. Information on their prognostic values is limited. This study tested the hypothesis that widespread central hypersensitivity (WCH) and altered CPM, assessed during the chronic phase of low back and neck pain, predict poor outcome. METHODS:: A total of 169 consecutive patients with chronic low back or neck pain, referred to the pain clinic during 1 year, were analyzed. Pressure pain tolerance threshold at the second toe and tolerance time during cold pressor test at the hand assessed WCH. CPM was measured by the change in pressure pain tolerance threshold (test stimulus) after cold pressor test (conditioning stimulus). A structured telephone interview was performed 12 to 15 months after testing to record outcome parameters. Linear regression models were used, with average and maximum pain intensity of the last 24 hours at follow-up as endpoints. Multivariable analyses included sex, age, catastrophizing scale, Beck Depression Inventory, pain duration, intake of opioids, and type of pain syndrome. RESULTS:: Statistically significant reductions from baseline to follow-up were observed in pain intensity (P<0.001). No evidence for an association between the measures of WCH or CPM and intensity of chronic pain at follow-up was found. DISCUSSION:: A major predictive value of the measures that we used is unlikely. Future studies adopting other assessment modalities and possibly standardized treatments are needed to further elucidate the prognostic value of WCH and altered CPM in chronic pain.

The Representation of Motherhood in Polish Cinema

The project aimed to analyse representations of motherhood in Polish cinema as a special case of a more general system within the representation of women. It concentrated on the image of the Polish Mother created during the 19th century in Polish culture under the influence of specific political, social and religious factors. Ms. Ostrowska's initial hypothesis was that this symbolic image became one of the most stable elements in Polish cinema and as her research revealed, it was valuable for the preservation of national identity but nevertheless a fiercely constraining model for Polish femininity. In order to fully understand the nature of this persistent image it was initially necessary to related it to broader contexts and issues in representation. These included the image of the Polish Mother within general mythological structures (using the notion of myth in the Barthesian sense). Following her initial research Ms. Ostrowska felt that it was most appropriate to view the myth of the Polish Mother as a dominant ideological structure in the discourse of motherhood within Polish culture. An analysis of the myth of the Polish Mother can provide an insight into how Polish society sees itself at different periods in time and how a national identity was constructed in relation to particular ideological demands stemming from concrete historical and political situations. The analysis of the film version of this myth also revealed some aspects of the national character of Polish cinema. There the image of woman has become enshrined as the "eternal feminine", with virtues which are inevitably derived directly from Catholicism, particularly in relation to the networks of meanings around the central figure of Mary, Mother of God. In 19th century Poland these were linked with patriotic values and images of woman became part of the defence of the very idea of Poland and Polishness. After World War Two, this religious-political image system was adapted to the demands of the new communist ideology. The possibility of manipulating the ideological dimensions of the myth of the Polish Mother is due to the very nature of the image, which as a symbol of civil religion had been able to function independently of any particular state or church institution. Although in communist ideology the stress was on the patriotic aspect of the myth, its pronounced religious aspect was also transmitted, consciously or not, in the denotation process, this being of great significance in the viewer's response to the female character. This appropriation of elements derived from the national patriotic tradition into the discourse of communist ideology was a very efficient strategy to establish the illusion of continuity in national existence, which was supposed to convince society of the rightness of the new political situation. The analysis of films made in the post-war period showed the persistence of this discourse on motherhood in a range of cinematic texts regardless of the changing political situation. Ms. Ostrowska claims that the stability of this discursive formation is to a certain extent the result of the mythological aspect of the mother figure. This mythological structure also belongs to the ideology of Romanticism which in general continues to prevail in Polish cultural discourse as a meta-language of national community. The analysis of the films confirmed the hypothesis of the Polish Mother as a myth-sign whose signifier is stable whereas the signified depends on the specific historical conditions in which it is set. Therefore in the famous propaganda documentary Kobiety naszych dni (Women of Our Days, 1951) by Jan Zelnik, and in other films made after the October 1956 "thaw" it functions as an "empty sign. She concludes that it would be difficult to deny that the myth of the Polish Mother has offered Polish women a special role in national life, granting them a high moral position in the social, hierarchy. However the processes of idealisation involved have resulted in a deprivation of her subjectivity and the right to decide about her own life. This idealisation also served to strengthen traditional patriarchal structures through this set of female obligations to the mother land. In Polish ideology it is not a man who demands sacrifice from a woman but the motherland, which, deprived of the institutions of male power for nearly 150 years, had functioned as a feminine structure. That is why oppressive aspects of the myth have been obscured for so long. While Polish women were doubtless able to accept the constrictions because of their sense of national duty and any misgivings were overridden by the argument of the cause, it is important to recognise that the strength of these constructions, compounded by the ways in which they spoke of and continue to speak of a certain perfection, make them persist into contemporary Poland. Poland is however no longer embattled and the signs that made these meanings are potentially empty. This space for meaning will be and is already being contested and increasingly colonised by current western models of femininity. Ms. Ostrowska's final question is whether this will help to prevent a possible resentful victimisation of the silent and noble Polish Mother.

Chlorhexidine and preservation of sound tooth structure in older adults. A placebo-controlled trial

The Trial to Enhance Elderly Teeth Health (TEETH) was designed to test the impact of regular rinsing with a 0.12% chlorhexidine (CHX) solution on tooth loss, and the causes of tooth loss (caries, periodontal disease and trauma) were also investigated. This paper reports on the effectiveness of a 0.12% CHX solution for controlling caries using a tooth surface (coronal and root) survival analysis. A total of 1,101 low income elders in Seattle (United States) and Vancouver (Canada), aged 60-75 years, were recruited for a double-blind clinical trial and assigned to either a CHX (n = 550) or a placebo (n = 551) mouth rinse. Subjects alternated between daily rinsing for 1 month, followed by weekly rinsing for 5 months. All sound coronal and root surfaces at baseline were followed annually for up to 5 years. At each follow-up examination, those tooth surfaces with caries, restored, or extracted were scored as 'carious'. The hazard ratio associated with CHX for a sound surface to become filled, decayed, or extracted was 0.87 for coronal surfaces (95% confidence interval: 0.71-1.14, p = 0.20) and 0.91 for root surfaces (95% confidence interval: 0.73-1.14, p = 0.41). These findings suggest that regular rinsing with CHX does not have a substantial effect on the preservation of sound tooth structure in older adults.

Opportunities and risks in reconciling conservation and development in a post-Soviet setting: The example of the Tajik National Park

In the Tajik National Park (TNP) - a high-altitude area of nearly 26,000 km2 in Central Asia - past and present human activities visibly contrast with standard conservation requirements for protected areas worldwide. This paper focuses on resource management, and highlights three major processes that threaten both the sustainable use of natural resources and the preservation of nature per se: (i) intensified use of biomass as a fuel resource, (ii) inappropriate pasture management, and (iii) increased pressure on endangered wildlife. From analysis of these processes - their historical background, root causes, trends and interrelationships - options and needs to improve park management are proposed and discussed.

Reflection, refraction, and rejection : copper smelting heritage and the execution of environmental policy

This dissertation examines the global technological and environmental history of copper smelting and the conflict that developed between historic preservation and environmental remediation at major copper smelting sites in the United States after their productive periods ended. Part I of the dissertation is a synthetic overview of the history of copper smelting and its environmental impact. After reviewing the basic metallurgy of copper ores, the dissertation contains successive chapters on the history of copper smelting to 1640, culminating in the so-called German, or Continental, processing system; on the emergence of the rival Welsh system during the British industrial revolution; and on the growth of American dominance in copper production the late 19th and early 20th centuries. The latter chapter focuses, in particular, on three of the most important early American copper districts: Michigan’s Keweenaw Peninsula, Tennessee’s Copper Basin, and Butte-Anaconda, Montana. As these three districts went into decline and ultimately out of production, they left a rich industrial heritage and significant waste and pollution problems generated by increasingly more sophisticated technologies capable of commercially processing steadily growing volumes of decreasingly rich ores. Part II of the dissertation looks at the conflict between historic preservation and environmental remediation that emerged locally and nationally in copper districts as they went into decline and eventually ceased production. Locally, former copper mining communities often split between those who wished to commemorate a region’s past importance and develop heritage tourism, and local developers who wished to clear up and clean out old industrial sites for other purposes. Nationally, Congress passed laws in the 1960s and 1970s mandating the preservation of historical resources (National Historic Preservation Act) and laws mandating the cleanup of contaminated landscapes (CERCLA, or Superfund), objectives sometimes in conflict – especially in the case of copper smelting sites. The dissertation devotes individual chapters to the conflicts that developed between environmental remediation, particularly involving the Environmental Protection Agency and the heritage movement in the Tennessee, Montana, and Michigan copper districts. A concluding chapter provides a broad model to illustrate the relationship between industrial decline, federal environmental remediation activities, and the growth of heritage consciousness in former copper mining and smelting areas, analyzes why the outcome varied in the three areas, and suggests methods for dealing with heritage-remediation issues to minimize conflict and maximize heritage preservation.

The role of common single-nucleotide polymorphisms on exon 9 and exon 12 skipping in nonmutated CFTR alleles

Classic cystic fibrosis (CF) is caused by two loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, whereas patients with nonclassic CF have at least one copy of a mutant gene that retains partial function of the CFTR protein. In addition, there are several other phenotypes associated with CFTR gene mutations, such as idiopathic chronic pancreatitis. In CFTR-associated disorders and in nonclassic CF, often only one CFTR mutation or no CFTR mutations can be detected. In this study, we screened 23 patients with CFTR-associated disorders for CFTR mutations by complete gene testing and quantitative transcript analysis. Mutations were found in 10 patients. In cells from respiratory epithelium, we detected aberrant splicing of CFTR mRNA in all investigated individuals. We observed a highly significant association between the presence of coding single-nucleotide polymorphisms (coding SNPs, or cSNPs) and increased skipping of exon 9 and 12. This association was found both in patients and in normal individuals carrying the same cSNPs. The cSNPs c.1540A>G, c.2694T>G, and c.4521G>A may have affected pre-mRNA splicing by changing regulatory sequence motifs of exonic splice enhancers, leading to lower amounts of normal transcripts. The analysis of CFTR exons indicated that less frequent and weak exonic splicing enhancer (ESE) motifs make exon 12 vulnerable to skipping. The number of splice variants in individuals with cSNPs was similar to previously reported values for the T5 allele, suggesting that cSNPs may enhance susceptibility to CFTR related diseases. In addition, cSNPs may be responsible for variation in the phenotypic expression of CFTR mutations. Quantitative approaches rather than conventional genomic analysis are required to interpret the role of cSNPs.