Social inequalities and mortality in europe - results from a large multi-national cohort

Background

Socio-economic inequalities in mortality are observed at the country level in both North America and Europe. The purpose of this work is to investigate the contribution of specific risk factors to social inequalities in cause-specific mortality using a large multi-country cohort of Europeans.

Methods

A total of 3,456,689 person/years follow-up of the European Prospective Investigation into Cancer and Nutrition (EPIC) was analysed. Educational level of subjects coming from 9 European countries was recorded as proxy for socio-economic status (SES). Cox proportional hazard model''s with a step-wise inclusion of explanatory variables were used to explore the association between SES and mortality; a Relative Index of Inequality (RII) was calculated as measure of relative inequality.

Results

Total mortality among men with the highest education level is reduced by 43% compared to men with the lowest (HR 0.57, 95% C.I. 0.52–0.61); among women by 29% (HR 0.71, 95% C.I. 0.64–0.78). The risk reduction was attenuated by 7% in men and 3% in women by the introduction of smoking and to a lesser extent (2% in men and 3% in women) by introducing body mass index and additional explanatory variables (alcohol consumption, leisure physical activity, fruit and vegetable intake) (3% in men and 5% in women). Social inequalities were highly statistically significant for all causes of death examined in men. In women, social inequalities were less strong, but statistically significant for all causes of death except for cancer-related mortality and injuries.

Discussion

In this European study, substantial social inequalities in mortality among European men and women which cannot be fully explained away by accounting for known common risk factors for chronic diseases are reported.     

Proteoglycans Act as Cellular Hepatitis Delta Virus Attachment Receptors

The hepatitis delta virus (HDV) is a small, defective RNA virus that requires the presence of the hepatitis B virus (HBV) for its life cycle. Worldwide more than 15 million people are co-infected with HBV and HDV. Although much effort has been made, the early steps of the HBV/HDV entry process, including hepatocyte attachment and receptor interaction are still not fully understood. Numerous possible cellular HBV/HDV binding partners have been described over the last years; however, so far only heparan sulfate proteoglycans have been functionally confirmed as cell-associated HBV attachment factors. Recently, it has been suggested that ionotrophic purinergic receptors (P2XR) participate as receptors in HBV/HDV entry. Using the HBV/HDV susceptible HepaRG cell line and primary human hepatocytes (PHH), we here demonstrate that HDV entry into hepatocytes depends on the interaction with the glycosaminoglycan (GAG) side chains of cellular heparan sulfate proteoglycans. We furthermore provide evidence that P2XR are not involved in HBV/HDV entry and that effects observed with inhibitors for these receptors are a consequence of their negative charge. HDV infection was abrogated by soluble GAGs and other highly sulfated compounds. Enzymatic removal of defined carbohydrate structures from the cell surface using heparinase III or the obstruction of GAG synthesis by sodium chlorate inhibited HDV infection of HepaRG cells. Highly sulfated P2XR antagonists blocked HBV/HDV infection of HepaRG cells and PHH. In contrast, no effect on HBV/HDV infection was found when uncharged P2XR antagonists or agonists were applied. In summary, HDV infection, comparable to HBV infection, requires binding to the carbohydrate side chains of hepatocyte-associated heparan sulfate proteoglycans as attachment receptors, while P2XR are not actively involved.     

Increased HEV Seroprevalence in Patients with Autoimmune Hepatitis

Background

Hepatitis E virus (HEV) infection takes a clinically silent, self-limited course in the far majority of cases. Chronic hepatitis E has been reported in some cohorts of immunocompromised individuals. The role of HEV infections in patients with autoimmune hepatitis (AIH) is unknown.

Methods

969 individuals were tested for anti-HEV antibodies (MP-diagnostics) including 208 patients with AIH, 537 healthy controls, 114 patients with another autoimmune disease, rheumatoid arthritis (RA), and 109 patients with chronic HCV- or HBV-infection (HBV/HCV). Patients with AIH, RA and HBV/HCV were tested for HEV RNA. HEV-specific proliferative T cell responses were investigated using CFSE staining and in vitro stimulation of PBMC with overlapping HEV peptides.

Results

HEV-antibodies tested more frequently positive in patients with AIH (n = 16; 7.7%) than in healthy controls (n = 11; 2.0%; p = 0.0002), patients with RA (n = 4; 3.5%; p = 0.13) or patients with HBV/HCV infection (n = 2; 2.8%; p = 0.03). HEV-specific T cell responses could be detected in all anti-HEV-positive AIH patients. One AIH patient receiving immunosuppression with cyclosporin and prednisolone and elevated ALT levels had acute hepatitis E but HEV viremia resolved after reducing immunosuppressive medication. None of the RA or HBV/HCV patients tested HEV RNA positive.

Conclusions

Patients with autoimmune hepatitis but not RA or HBV/HCV patients are more likely to test anti-HEV positive. HEV infection should been ruled out before the diagnosis of AIH is made. Testing for HEV RNA is also recommended in AIH patients not responding to immunosuppressive therapy.     

Olfactory and gustatory sensitivity in adults with attention-deficit/hyperactivity disorder

Recently, research on olfactory functions in attention-deficit/hyperactivity disorder (ADHD) has become prominent, whereas gustation has never been investigated. Increased odor sensitivity was found in medication-na?ve children with ADHD, but not in adult ADHD, which might be due to a dopaminergic dysregulation presumed to underlie this disorder. Taste sensitivity, in particular bitter sensitivity as a hereditary trait, also might be altered in ADHD. To examine olfactory and gustatory functions in adult ADHD patients, we assessed odor sensitivity by Sniffin' Sticks, taste sensitivity by taste strips, and bitter sensitivity by the one-solution test in women with ADHD (n = 12), Bulimia Nervosa (n = 12), and healthy control women (n = 12). Bulimia Nervosa as second patient group was included to control for effects of impulsivity. Preliminary results indicate that ADHD patients were significantly more often classified as tasters, i.e. perceived the bitter taste as more intense, compared to both bulimic patients and healthy controls. No group differences were found with regard to general odor and taste sensitivity. It is proposed that the higher frequency of tasters in ADHD patients might underlie a genetic variation of the bitter receptor-dependent signaling pathway associated with ADHD.     

Anmerkungen zur Bestandsentwicklung des Uhus (Bubo bubo) in Bayern

Zusammenfassung In zwei Kerngebieten des Uhuvorkommens der Bundesrepublik Deutschland hat der Uhu in neuester Zeit scheinbar sehr stark zugenommen. In der Frankenalb (10 000 km²) schätzte man von 1955 bis 1964 etwa 30–40, Anfang der 70er Jahre etwa 50 und 1975–1980 75–83 Paare. In einem Ausschnitt der mittleren bayerischen Alpen (ca. 840 km²) waren um 1937 nur 3 Brutpaare bekannt, um 1975 mindestens 4; 1983/84 konnten jedoch mindestens 14 Brutpaare ermittelt werden. Die Zunahme ist zumindest größtenteils auf intensivere und systematische Kontrollen zurückzuführen. Der für die 30er Jahre vermutete Tiefstand des Bestandes in der Bundesrepublik dürfte weit höher gelegen haben als bisher vermutet, da zeitgenössische Quellen wahrscheinlich nur Teile des Bestandes erfaßten. Sicher lag der Bestand im 20. Jahrhundert wohl nie unter 50 Brutpaaren (bisherige Annahme 35), selbst zur Zeit des Minimums in der Bundesrepublik wahrscheinlich deutlich höher. Eine Obergrenze des bayerischen Brutbestandes von 200 Brutpaaren um 1980 ist durchaus realistisch. In den Alpen ist auch heute noch der Brutbestand völlig unzureichend bekannt. Das Aussetzen von Uhus hat in Bayern sicher keine Bedeutung für die Bestandsentwicklung gehabt. Der Median liegt für Todfunde ausgesetzter Uhus bei 0,43, für als Nestling beringte Wilduhus bei 1,9 Jahren. An Leitungen starben hochsignifikant mehr Wildvögel, an Straßen und Eisenbahnen dagegen hochsignifikant mehr ausgesetzte Vögel. Unterschiedliche Wanderneigung zwischen Wilduhus und ausgesetzten Vögeln ließ sich nicht sichern. Aussetzung und Wiedereinbürgerung sollten in Süddeutschland unbedingt unterbleiben und dürften auch im mittleren und nördlichen Deutschland mittlerweile überflüssig geworden sein. Eine Bestandsüberwachung und Kontrolle in ausgewählten Gebieten ist dagegen vordringlich.

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Some remarks on long term trends in the breeding population of the Eagle Owl (Bubo bubo) in Bavaria

Summary In two centres of its distribution in the Federal Republic of Germany the Eagle Owl has increased remarkably in recent years. Between 1955 and 1965 the population of the Frankonian Jura (ca. 10 000 km²) was estimated between 30 and 40 pairs, at the beginning of the seventies about 50, and in 1975/80 about 75–83 pairs. In an area of the Bavarian Alps (ca. 840 km²) only 3 pairs were known in 1937, at least 4 in 1975. In 1983/84, however, a thorough examination revealed at least 14 pairs in this area. The increase in both areas is most likely due to intensive and systematic checks in recent years. The lowest population level in the FRG, supposed for the thirties, was probably higher than estimated so far as contemporary sources apparently did not cover the whole population. During the 20^th century the population total of the FRG most likely has never been below 50 pairs and was probably higher even in times with minimum level. For 1980 an upper limit of 200 pairs in Bavaria seems to be realistic. In the Alps, however, the population size remains unsufficiently known even today. Release of captive bred birds didn't seem to have any increasing and stabilizing effect on the Bavarian population. The median for released birds found dead was 0,43, for wild chicks 1,9 years. Significantly more released birds died by traffic, whereas significantly more wild birds were victims of overhead lines. Differences in dispersal between wild and released birds seem likely, but could not be proved statistically. Releasing resp. reintroduction should be stopped in southern Germany; even in middle and northern Germany this conservation strategy seems to be unnecessary today. Survey and protection of breeding sites, however, should be continued or reorganized.

     

Inflammatory macrophages induce Nrf2 transcription factor-dependent proteasome activity in colonic NCM460 cells and thereby confer anti-apoptotic protection

Adaptation of epithelial cells to persistent oxidative stress plays an important role in inflammation-associated carcinogenesis. This adaptation process involves activation of Nrf2 (nuclear factor-E2-related factor-2), which has been recently shown to contribute to carcinogenesis through the induction of proteasomal gene expression and proteasome activity. To verify this possible link between inflammation, oxidative stress, and Nrf2-dependent proteasome activation, we explored the impact of inflammatory (M1) macrophages on the human colon epithelial cell line NCM460. Transwell cocultures with macrophages differentiated from granulocyte monocyte-colony-stimulating factor-treated monocytes led to an increased activity of Nrf2 in NCM460 cells along with an elevated proteasome activity. This higher proteasome activity resulted from Nrf2-dependent induction of proteasomal gene expression, as shown for the 19 and 20 S subunit proteins S5a and α5, respectively. These effects of macrophage coculture were preceded by an increase of reactive oxygen species in cocultured NCM460 cells and could be blocked by catalase or by the reactive oxygen species scavenger Tiron, whereas transient treatment of NCM460 cells with H(2)O(2) similarly led to Nrf2-dependent proteasome activation. Through the Nrf2-dependent increase of proteasomal gene expression and proteasome activity, the sensitivity of NCM460 cells to tumor necrosis factor-related apoptosis-inducing ligand- or irinotecan-induced apoptosis declined. These findings indicate that inflammatory conditions such as the presence of M1 macrophages and the resulting oxidative stress are involved in the Nrf2-dependent gain of proteasome activity in epithelial cells, e.g. colonocytes, giving rise of greater resistance to apoptosis. This mechanism might contribute to inflammation-associated carcinogenesis, e.g. of the colon.