If MOH shares some neurophysiological features with addiction, lo

If MOH shares some neurophysiological features with addiction, long-lasting functional alterations of the mesocorticolimbic dopamine system related to medication

overuse should be present. We collected functional magnetic resonance imaging data during the execution of a decision-making under risk paradigm in 8 MOH patients immediately after beginning medication withdrawal, in 8 detoxified MOH patients at 6 months after beginning medication withdrawal, in 8 chronic migraine patients, and in 8 control subjects. Our results revealed that MOH patients present: (1) reduced Tamoxifen concentration task-related activity in the substantia nigra/ventral tegmental area complex and increased activity in the ventromedial prefrontal cortex, when compared with controls; (2) reduced activity in the substantia nigra/ventral tegmental area complex, when compared with chronic migraine patients; (3) increased activity in the ventromedial prefrontal cortex, when compared with detoxified MOH patients. Our study showed that MOH patients present dysfunctions

in the mesocorticolimbic dopamine circuit, in particular in the ventromedial prefrontal cortex and in the substantia nigra/ventral tegmental area complex. The ventromedial prefrontal selleck chemical cortex dysfunctions seem to be reversible and attributable to the acute/chronic headache, whereas the substantia nigra/ventral tegmental area complex dysfunctions are persistent and possibly related to medication medchemexpress overuse. These dysfunctions might be the expression of long-lasting neuroadaptations related to the overuse of medications and/or a pre-existing neurophysiological condition leading to vulnerability to medication overuse. The observed persistent dysfunctions in the midbrain dopamine suggest that MOH may share some neurophysiological

features with addiction. “
“Objective.— Examine whether acceptance and commitment additive therapy is effective in reducing the experience of sensory pain, disability, and affective distress because of chronic headache in a sample of outpatient Iranian females. Background.— Chronic headaches have a striking impact on sufferers in terms of pain, disability, and affective distress. Although several Acceptance and Commitment Therapy outcome studies for chronic pain have been conducted, their findings cannot be completely generalized to chronic headaches because headache-related treatment outcome studies have a different emphasis in both provision and outcomes. Moreover, the possible role of Iranian social and cultural contexts and of gender-consistent issues involved in Acceptance and Commitment Therapy outcomes deserve consideration. Methods.— This study used a randomized pretest–post-test control group design.

Conclusions:  The H pylori-infected children have a lower Bifido

Conclusions:  The H. pylori-infected children have a lower Bifidobacterium microflora in gut. The probiotics-containing yogurt can offer benefits to restore Bifidobacterium spp./E. coli ratio in children and suppress the H. pylori load with increment of serum IgA but with reduction in IL-6 in H. pylori-infected children. “
“The envisaged roles and partly understood LY294002 purchase functional properties of Helicobacter pylori protein HP0986 are

significant in the context of proinflammatory and or proapoptotic activities, the two important facilitators of pathogen survival and persistence. In addition, sequence analysis of this gene predicts a restriction endonuclease function which remained unknown thus far. To evaluate the role of HP0986 in gastric inflammation, we studied its expression profile using a large number of clinical isolates but a limited number of biopsies and patient sera. Also, we studied antigenic role of HP0986 in altering cytokine responses of human gastric epithelial (AGS) cells including its interaction with and localization within the AGS cells. For in vitro expression study of HP0986, 110 H. pylori clinical isolates were cultured from patients with functional dyspepsia. For expression analysis by qRT PCR of HP0986, 10 Buparlisib gastric biopsy specimens were studied. HP0986 was also used to detect antibodies in patient sera. AGS cells were

incubated with recombinant HP0986 to determine cytokine response and NF-κB activation. Transient transfection with HP0986 cloned in pEGFPN1 was used to study

its subcellular localization or homing in AGS cells. Out of 110 cultured H. pylori strains, 34 (31%) were positive for HP0986 and this observation was correlated with in vitro expression profiles. HP0986 mRNA was detected in 7 of the 10 biopsy specimens. Further, HP0986 induced IL-8 secretion in gastric epithelial cells in a dose and time-dependent MCE公司 manner via NF-κB pathway. Serum antibodies against HP0986 were positively associated with H. pylori positive patients. Transient transfection of AGS cells revealed both cytoplasmic and nuclear localization of HP0986. HP0986 was moderately prevalent in clinical isolates and its expression profile in cultures and gastric biopsies points to its being naturally expressed. Collective observations including the induction of IL-8 via TNFR1 and NF-κB, subcellular localization, and seropositivity data point to a significant role of HP0986 in gastroduodenal inflammation. We propose to name the HP0986 gene/protein as ‘TNFR1 interacting endonuclease A (TieA or tieA)’. Helicobacter pylori infection is characterized by the infiltration of mononuclear and polymorphonuclear cells into the gastric mucosa in addition to the accumulation of various cytokines, including IL1β, IL6, IL-8, and TNFα secreted by gastric epithelial and immune cells [1, 2].

However, considerable expenses and use of uncommon parameters red

However, considerable expenses and use of uncommon parameters reduce practical utility. A few years later, the Forns’ score (age, GGT, cholesterol, platelets, and prothrombin)5 and the APRI index (AST and platelets)6 overcame these drawbacks by use of only standard laboratory tests in the development of their predictive models. Subsequent models

include the ELF-score,7 the Hepascore8 and the Fibrometer.9 Validation of these models selleck compound in cohorts of CHC patients revealed reliable information on liver fibrosis in about one-third of patients. Still, the APRI and the Forns’ score, although slightly less accurate, offer the benefit of simplicity for use.10,11 Chronic hepatitis B (CHB) is the most frequent infectious cause of CLD worldwide. More than 400 million people are chronically infected with HBV. The virus is responsible for more than 300 000 cases of liver cancer every year and for similar numbers of gastrointestinal hemorrhage and ascites.12 Predictive models designed especially

for CHB patients have been proposed Selleckchem MAPK Inhibitor Library by the Shanghai Liver Fibrosis Group (SLFG),13 Hui et al.14 and Mohamadnejad et al.15 But few of these models mentioned above have been widely validated and implemented in clinical practice. The aim of the present study was to generate a simple, noninvasive model for predicting liver fibrosis in patients with chronic HBV infection based on routine laboratory markers and compare its diagnostic value with that of some typical models, in order to provide references for introducing the noninvasive predictive model into clinical management of patients with chronic HBV infection. A total of 386 patients was selected in the training cohort from a total of 513 consecutive chronic HBV

carriers who underwent a percutaneous liver biopsy in the hospitals of the SLFG13 from 1999 to 2001. Chronic HBV carriers were defined as persons who had positive hepatitis B surface antigen (HBsAg) for at least 6 months before enrolling.16 Exclusion criteria included co-infection with medchemexpress HIV or HCV, alcohol consumption >30 g/day, other causes of chronic liver disease, previous antiviral treatment, and insufficient biopsy samples. Another group of 146 consecutive chronic HBV carriers who underwent a liver biopsy in three hospitals (Renji Hospital, Shanghai; Southeast Hospital, Zhangzhou, Fujian Province; and Taizhou People’s Hospital, Jiangsu Province) between 2005 and 2007 were prospectively enrolled in the validation cohort, using the same criteria. The study was approved by the Ethics Committee of Renji Hospital, Shanghai Jiao Tong University School of Medicine. Informed consent to participate in the study was obtained from each patient. All patients received a liver biopsy directed by ultrasonography within 1 week after inclusion.

Preliminary results of the study are now available

Preliminary results of the study are now available CAL-101 mw [48]. This retrospective

study involved PUPs with haemophilia A who were diagnosed between 2006 and 2011 in participating centres of the eastern German network for coagulation disorders (Kompetenznetzwerk hämorrhagische Diathese Ost; KHDO). By means of a detailed questionnaire developed specifically for study purposes, information collected from patients’ medical charts included: age at diagnosis and at start of prophylaxis; FVIII gene mutation; type of FVIII product; body weight relative to FVIII dose; number of exposure days to FVIII products until inhibitor formation; presence of danger signals; details of immune tolerance induction (ITI)

therapy. All 12 KHDO centres that treat children participated in the study and the number of patients treated per centre ranged from 1 to 24. During the study period 67 patients were newly diagnosed with haemophilia A, of whom 33 had severe, 4 moderate, 20 mild and 10 subclinical disease. The analysis centred around patients with severe haemophilia as this is the group at greatest risk of developing inhibitors. Among the 33 patients with severe haemophilia, eight had been treated with the historical FVIII prophylaxis regimen (30 U kg−1 2–3× per week) none of whom developed an inhibitor. Twenty-five patients had been treated with the low-dose 上海皓元医药股份有限公司 regimen (25 U kg−1 1× per week) of whom 9 (36%) developed an inhibitor (five high-responding, four Maraviroc manufacturer low-responding). At the time of investigation (July 2012), 27 of the 33 patients with severe haemophilia had had more than 100 exposure days to FVIII concentrates; three patients had <20 exposure days and the remaining three patients had between 20 and 100 exposure days. In order to identify possible strategies to avoid inhibitor development, the characteristics of patients with severe haemophilia A treated with prophylaxis (n = 33)

were examined based on the presence or absence of inhibitors (Table 5). In both groups, prophylaxis had been initiated at an early age – slightly earlier in patients with than without inhibitors (11.5 vs. 15 months) – although the range was broad in both groups. The FVIII dose at the start of once-weekly prophylaxis was the same in patients with or without inhibitors. In patients treated with the historical prophylaxis regimen, the FVIII dose was slightly lower in patients with than without inhibitors (22 vs 28 IU kg−1), but the clinical significance of this difference remains uncertain. Overall, 14 PUPs with severe haemophilia received plasma-derived products and 19 received recombinant products. All nine patients who developed inhibitors had been treated with recombinant FVIII (rFVIII) concentrates.

3A) To determine whether C/EBPβ functioned to prevent RALA hepat

3A). To determine whether C/EBPβ functioned to prevent RALA hepatocyte death from TNFα, the effect of C/EBPβ overexpression on TNFα-induced apoptosis in RALA hepatocytes BMN 673 supplier with an inhibition of NF-κB activation was assessed. Cells infected with the C/EBPβ-expressing

adenovirus WT-C/EBPβ alone or coinfected with WT-C/EBPβ and either Ad5LacZ or Ad5IκB expressed increased levels of C/EBPβ compared with cells infected with Ad5LacZ alone (Fig. 3B). Cells were coinfected with Ad5IκB and either Ad5LacZ as a control or WT-C/EBPβ and treated with TNFα. When compared with Ad5IκB/Ad5LacZ-coinfected cells, the amount of cell death after TNFα treatment was significantly decreased in Ad5IκB/WT-C/EBPβ–coinfected cells at 6 and 12 hours by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (Fig. 3C). The ability of C/EBPβ expression to block cell death from TNFα was confirmed by fluorescence microscopic studies of Idasanutlin concentration cells costained with acridine orange/ethidium bromide to quantify the numbers of apoptotic and necrotic cells. As previously established, death from NF-κB inactivation and TNFα was predominantly apoptotic, and no significant increase occurred in

the numbers of necrotic cells (data not shown). The marked increase in apoptotic cells with TNFα administration was significantly reduced by adenoviral expression of C/EBPβ (Fig. 3D). Thus, the NF-κB–dependent increase in C/EBPβ in TNFα-treated RALA hepatocytes is a mechanism

of cellular resistance to TNFα-induced apoptosis. The sensitization of hepatocytes to TNFα toxicity by NF-κB inhibition occurs through caspase-dependent apoptosis.17, 33 The ability of C/EBPβ to function as a caspase inhibitor suggested that the mechanism of C/EBPβ’s inhibition of TNFα-induced apoptosis may be through blocking caspase activation. Adenoviral expression of C/EBPβ significantly decreased levels of activity of the initiator caspase 8 in both untreated and TNFα-treated cells in which NF-κB was inhibited by Ad5IκB (Fig. 4A). Inhibition of caspase 8 by C/EBPβ prevented TNFα-induced activation of the mitochondrial death pathway as WT-C/EBPβ decreased 上海皓元医药股份有限公司 the amount of truncated Bid that translocated to the mitochondria and blocked the cytochrome c release from mitochondria into cytoplasm that occurred in Ad5IκB/Ad5LacZ-coinfected cells (Fig. 4B). In contrast, levels of cytochrome oxidase, a mitochondrial protein not released during apoptosis, were equivalent in Ad5LacZ- and WT-C/EBPβ–infected cells after TNFα treatment and indicated equal protein loading (Fig. 4B). As a result of the inhibition of cytochrome c release, downstream effector caspase 3 and caspase 7 activation was blocked in cells overexpressing C/EBPβ as detected by decreases in the active, cleaved caspase forms on immunoblots (Fig. 4C).

3A) To determine whether C/EBPβ functioned to prevent RALA hepat

3A). To determine whether C/EBPβ functioned to prevent RALA hepatocyte death from TNFα, the effect of C/EBPβ overexpression on TNFα-induced apoptosis in RALA hepatocytes Wnt inhibitor with an inhibition of NF-κB activation was assessed. Cells infected with the C/EBPβ-expressing

adenovirus WT-C/EBPβ alone or coinfected with WT-C/EBPβ and either Ad5LacZ or Ad5IκB expressed increased levels of C/EBPβ compared with cells infected with Ad5LacZ alone (Fig. 3B). Cells were coinfected with Ad5IκB and either Ad5LacZ as a control or WT-C/EBPβ and treated with TNFα. When compared with Ad5IκB/Ad5LacZ-coinfected cells, the amount of cell death after TNFα treatment was significantly decreased in Ad5IκB/WT-C/EBPβ–coinfected cells at 6 and 12 hours by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (Fig. 3C). The ability of C/EBPβ expression to block cell death from TNFα was confirmed by fluorescence microscopic studies of Pexidartinib ic50 cells costained with acridine orange/ethidium bromide to quantify the numbers of apoptotic and necrotic cells. As previously established, death from NF-κB inactivation and TNFα was predominantly apoptotic, and no significant increase occurred in

the numbers of necrotic cells (data not shown). The marked increase in apoptotic cells with TNFα administration was significantly reduced by adenoviral expression of C/EBPβ (Fig. 3D). Thus, the NF-κB–dependent increase in C/EBPβ in TNFα-treated RALA hepatocytes is a mechanism

of cellular resistance to TNFα-induced apoptosis. The sensitization of hepatocytes to TNFα toxicity by NF-κB inhibition occurs through caspase-dependent apoptosis.17, 33 The ability of C/EBPβ to function as a caspase inhibitor suggested that the mechanism of C/EBPβ’s inhibition of TNFα-induced apoptosis may be through blocking caspase activation. Adenoviral expression of C/EBPβ significantly decreased levels of activity of the initiator caspase 8 in both untreated and TNFα-treated cells in which NF-κB was inhibited by Ad5IκB (Fig. 4A). Inhibition of caspase 8 by C/EBPβ prevented TNFα-induced activation of the mitochondrial death pathway as WT-C/EBPβ decreased 上海皓元 the amount of truncated Bid that translocated to the mitochondria and blocked the cytochrome c release from mitochondria into cytoplasm that occurred in Ad5IκB/Ad5LacZ-coinfected cells (Fig. 4B). In contrast, levels of cytochrome oxidase, a mitochondrial protein not released during apoptosis, were equivalent in Ad5LacZ- and WT-C/EBPβ–infected cells after TNFα treatment and indicated equal protein loading (Fig. 4B). As a result of the inhibition of cytochrome c release, downstream effector caspase 3 and caspase 7 activation was blocked in cells overexpressing C/EBPβ as detected by decreases in the active, cleaved caspase forms on immunoblots (Fig. 4C).

pylori eradication rates between probiotic and

pylori eradication rates between probiotic and DNA Damage inhibitor placebo group (45.5 vs 37.5%; p = NS) [71]. In a study of our group, aimed to evaluate the efficacy of probiotics to reduce antibiotic side effects, we found no differences in the eradication rates according to the presence/absence of the probiotic: treatment was successful in 17 of 20 patients supplemented

with L. reuteri ATCC 55730 (SD2112) as compared to 16 of 20 patients in the placebo group (85 vs 80%; p = NS) [72]. Recently, in a double-blind placebo-controlled randomized clinical trial performed in 66 children no difference was found with respect to H. pylori eradication rates between children receiving standard triple therapy supplemented with L. rhamnosus GG or placebo (69 vs 68%; p = NS) [77]. Pooled data, derived from children and adults’ studies selleck chemicals on more than 1900 treated patients, show eradication

rates of 82.5% (95%CI: 80.1–84.7%) in patients with probiotic supplementation as compared to 73.7% (95%CI: 71–76.4%) in patients receiving placebo (RR: 1.11; 95%CI: 1.07–1.17). These data do not represent convincing evidence to support the use of probiotics as an adjunct with the aim of increasing the H. pylori eradication rate. Nevertheless, further studies are needed to clarify their role in this particular issue. The major limit to establish whether a probiotic is able to significantly increase the eradication rate is represented by the power of the study. Indeed, due to the high eradication rates that we mostly achieve with standard antibiotic treatment, to detect a 10% increase in eradication (secondary to the use of a probiotic strain), given a power of al least 80% and an alpha error level of 5%, 150 patients in each arm are needed to be enrolled. In our own experience on 40 adults, we were able to demonstrate a favorable effect of L. reuteri ATCC 55730 (SD2112) on dyspeptic symptoms

induced by H. pylori [56]. In this study, L. reuteri administration was followed by a significant decrease in the Gastrointestinal Symptom Rating Scale (GSRS) as compared to pre-treatment value (7.9 ± 4.1 vs 11.8 ± 8.5; p < .05) that was not observed MCE公司 in patients receiving placebo (9.7 ± 8.7 vs 11.4 ± 9.7; p < NS) [56]. Not all probiotic strains are able do decrease dyspeptic symptoms [53] suggesting that the effect is strain specific. No data are available in the pediatric age. Bacterial resistance and antibiotic’ side-effects represent the most frequent cause for anti-H. pylori treatment failure in clinical practice [9]. Several studies evaluated whether probiotic supplementation might help to prevent or reduce drug-related side effects during H. pylori eradication therapy in adults [61,63,64,66,68,69,72–75,78–80]. All showed that diarrhea, nausea and taste disturbances were significantly reduced by probiotics and overall they were superior to placebo for side effect prevention.

After fixation with 2% paraformaldehyde, cells were stained with

After fixation with 2% paraformaldehyde, cells were stained with horseradish peroxidase [HRP]–goat anti-mouse secondary antibody for 1 hour and developed using 3,3′,5,5′-tetramethylbenzidine liquid substrate for 15 minutes. Endpoint absorbance measurements were taken at 450 nm using a Synergy 2 plate reader (BioTek Instruments, Inc., Winooski, VT). The rate of internalization Enzalutamide chemical structure of the TacCterm chimeras was expressed as a percentage of the decrease in the initial surface binding at 4°C. The background of HEK293T cells

transfected with empty vector was subtracted from each absorbance measurement. All experiments were performed in quadruplicate and repeated at least three times. Surface biotinylation of BSEP was performed as described, with some modifications.30, 31 HEK293T cells were grown on poly-lysine–coated 6-well plates and

transiently transfected using LipofectAMINE 2000 reagent for 48 hours. Cells were cooled to 4°C and washed three times with PBS (Ca2+, Mg2+). The plasma membrane proteins were biotinylated in PBS buffer containing 1 mg/mL sulfo-NHS-SS-biotin Vismodegib (Pierce, Rockford, IL) for 1 hour. After biotinylation, cells were washed with quenching buffer (100 mM glycine in PBS buffer) to remove excess free biotin and then washed twice with PBS. The cells were either lysed immediately with M-PER Mammalian Reagent (Thermo Scientific, Rockford, IL) containing protease inhibitor cocktail or warmed to 37°C and incubated for 0, 2.5, 5, 10, or 20 minutes to allow for endocytosis. After 20 minutes the cells were quickly cooled to 4°C, and the biotinylated protein remaining at the cell surface was stripped with three 10-minute washes in sodium 2-mercaptoethanesulfonate (MESNA) stripping buffer (50 mM 2-mercaptoethanesulfonic acid, 150 mM NaCl, 1 mM EDTA, 0.2% BSA,

and 20 mM Tris, pH 8.6). Excess MESNA was removed with three 5-minute washes in iodoacetamide buffer (50 mM iodoacetamide in PBS). Equal amount of protein in the cell lysates was incubated 上海皓元 overnight at 4°C with streptavidin agarose resin (Thermo Scientific). Biotinylated proteins were eluted in 2X sodium dedecyl sulfate (SDS) buffer, resolved by SDS-polyacrilamide gel electrophoresis (PAGE), transferred to nitrocellulose membrane, and immunoblotted with anti-green fluorescent protein (GFP) antibody (Clontech, Mountain View, CA). A sequence alignment of the C-terminal cytoplasmic tail of BSEP from 10 different species showed the presence of highly conserved consensus Tyr- and Leu-based endocytic sorting signals (Fig. 1A). The C-terminal cytoplasmic tail encompassing residues 1284-1321 contains a putative leucine-based signal (Leu1298-Met) and a tyrosine-based signal (Tyr1310-Try-Lys-Leu-Val).

Liver injury (serum ALT) and steatosis (H&E and oil red staining)

Liver injury (serum ALT) and steatosis (H&E and oil red staining) were significantly greater in ETOH+Chol and ETOH+Chol+Coil compared to ETOH and ETOH+Coil groups. M1 proinflammatory macrophage markers, MCP-1, Ly6c, TNFα, NOS2 and F4/80, were higher in EtOH+Chol and EtOH+Chol+Coil groups. However,

M2 anti-inflammatory markers, CD163 and Arg-1, were reduced in EtOH+Chol or EtOH+Chol+Coil fed groups. Furthermore, the inflammatory markers IL-6 and ICAM-1 were more elevated in EtOH+Chol and EtOH+Chol+Coil groups. Additionally, fribrosis examined by Sirius red staining and fibrotic markers, collagen, αSMA, osteopontin, desmin and hydroxyproline levels were highly increased in EtOH+Chol and EtOH+Chol+Coil groups. Alcohol GDC-0068 molecular weight binge drinking caused more injury (serum ALT and H&E) and inflammation Trametinib in HC than in LD pretreated mice despite similar degree of steatosis. Conclusion: cholesterol intake has a synergic effect with alcohol aggravating liver injury and progression to alcoholic hepatitis, pointing that targeting cholesterol may be a valuable approach for future therapeutic interventions in ALD. Disclosures: The following people have nothing to disclose: Laura Conde de la Rosa, Carmen Garcia-Ruiz, Jose Fernandez-Checa

Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepati-tis (NASH) are the most frequent conditions leading to medchemexpress elevated liver enzymes and liver cirrhosis, respectively, in the Western world. However, despite strong epidemiological evidence for combined effects on the progression of liver injury, the mutual interaction of the pathophysiological mechanisms is incompletely understood. The aim of this study was to establish an in vitro model for joint effects of alcohol and lipids on hepatic steatosis and inflammation. Methods and Results: Initially, we established the dose

range in which neither alcohol nor incubation with the free fatty acid oleate affected viability or mito-chondrial activity in primary human hepatocytes (PHH). Subsequently, we assessed the combined effect of alcohol (1%ndash;2%) and oleate (0.2mM) on hepatocellular lipid accumulation in PHH. Under these conditions, alcohol significantly enhanced oleate induced expression of genes regulating lipogenesis (FASN, SCD-1) and lipid peroxidation (CPT-1) as well as cellular triglyceride content and free fatty acid (FFA) levels, while alcohol alone had only a minimal effect. Analysis of heme oxy-genase-1 (HMOX-1) expression and malondialdehyde levels revealed that the combination of alcohol and oleate caused significantly higher oxidative stress and lipid peroxidation than either of the two substances alone. Further, we observed a syn-ergistic effect of alcohol and FFA on JNK-activation and pro-inflammatory (IL-8 and ICAM-1) gene expression.

Relative risk of occupational disability within the first 3 years

Relative risk of occupational disability within the first 3 years of follow-up was even more strongly associated with γ-GT than within the entire follow-up period. After exclusion of the first 3 years of follow-up, the results did not materially change compared to the analysis without left truncation. Again, risk of occupational disability was significantly increased at all γ-GT levels compared to the lowest group. The monotonically increasing

association of γ-GT with disability pension could also be observed in dose-response analyses using γ-GT as a continuous variable (Fig. 1). The increase in hazard ratios was steeper at lower AZD1208 γ-GT concentrations than at higher levels. Additional analyses with stratification by the presence or absence of cardiovascular http://www.selleckchem.com/products/bmn-673.html diseases, diabetes mellitus, and diseases of the liver, bile, and pancreas, which all might cause elevations of γ-GT levels, did not indicate any relevant confounding or interaction by these conditions (data not shown). Information on cause of disability could be obtained for 2,713

out of 2,998 (90.5%) cases of disability pension. With 1,244 (45.9%) cases, musculoskeletal disorders represented the most common cause of disability pension, with half of them being due to dorsopathies. The second most common cause was cardiovascular diseases (17.3%), followed by mental disorders (8.9%), and cancer (8.0%). Frequencies and hazard ratios (multiple adjusted) of cause-specific disability pension are shown in Table 3. Risk of disability monotonically increased with γ-GT activity for cardiovascular diseases, respiratory diseases, as well as musculoskeletal disorders, with significant increased risks for the two highest γ-GT categories. For the latter, the relative MCE risk was even significantly elevated at all γ-GT categories compared with the reference group. This pattern did not change

when separately considering disability pension due to dorsopathy as well as due to osteoarthritis, the two most predominant musculoskeletal causes of disability in our cohort (data not shown). Increased risks of occupational disability due to all of the assessed causes were observed in the highest quartile of γ-GT concentration. With an age-adjusted hazard ratio of 9.86 (95% confidence limits: 3.10; 30.21), the strongest risk elevation was observed for occupational disability due to diseases of the digestive system, which were predominantly diseases of the liver, bile, and pancreas. The significant increase of occupational disability due to other causes among men with γ-GT concentrations in the highest quartile was mainly due to diabetes. Serum γ-GT is not merely a sensitive marker for liver and bile disorders, but also a risk marker for a multiplicity of other chronic diseases.