CHOP‐mediated hepcidin suppression modulates hepatic iron load

The liver is the central regulator of iron metabolism and accordingly, chronic liver diseases often lead to systemic iron overload due to diminished expression of the iron‐regulatory hormone hepcidin. To study the largely unknown regulation of iron metabolism in the context of hepatic disease, we used two established models of chronic liver injury, ie repeated carbon tetrachloride (CCl₄) or thioacetamide (TAA) injections. To determine the impact of CCAAT/enhancer‐binding protein (C/EBP)‐homologous protein (CHOP) on hepcidin production, the effect of a single TAA injection was determined in wild‐type and CHOP knockout mice. Furthermore, CHOP and hepcidin expression was assessed in control subjects and patients with alcoholic liver disease. Both chronic injury models developed a distinct iron overload in macrophages. TAA‐, but not CCl₄‐ injected mice displayed additional iron accumulation in hepatocytes, resulting in a significant hepatic and systemic iron overload which was due to suppressed hepcidin levels. C/EBPα signalling, a known hepcidin inducer, was markedly inhibited in TAA mice, due to lower C/EBPα levels and overexpression of CHOP, a C/EBPα inhibitor. A single TAA injection resulted in a long‐lasting (> 6 days) suppression of hepcidin levels and CHOP knockouts (compared to wild‐types) displayed significantly attenuated hepcidin down‐regulation in response to acute TAA administration. CHOP mRNA levels increased 5‐fold in alcoholic liver disease patients versus controls (p < 0.005) and negatively correlated with hepcidin expression. Our results establish CHOP as an important regulator of hepatic hepcidin expression in chronic liver disease. The differences in iron metabolism between the two widely used fibrosis models likely reflect the differential regulation of hepcidin expression in human liver disease. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Socioeconomic inequalities in health dynamics: A comparison of Britain and the United States

Drawing on theory and research on the fundamental causes of health, the life course, and the welfare state, we investigate social inequalities in dynamic self-rated health for working-aged Britons and Americans. We use data from the British Household Panel Survey and Panel Study of Income Dynamics (1990–2004) and a mixture latent Markov model to test a theoretical model of health as a discrete state that may remain stable or change over time. Our contributions are threefold. First, our finding of three distinctive types of health processes (stable good health, stable poor health, and a “mover” health trajectory) represents a more differentiated profile of long-term health than previously shown. Second, we characterize health trajectories in structural terms by suggesting who was more likely to experience what type of health trajectory. Third, our more differentiated picture of dynamic health leads to a more nuanced understanding of comparative health: Although the health advantage of Britons was confirmed, our results also indicate that they were more likely to experience health change. Moreover, the socioeconomic gradient in long-term health was steeper in the US, raising provocative questions about how state policies and practices may affect population health.     

Osteoporosis assessment strategies for male nursing home residents

OBJECTIVES: Twenty-five to thirty percent of hip fractures occur in men, and nursing home residents have a 5-10-fold greater fracture risk than community-dwellers. Osteoporosis prevalence in men in long-term care, however, is poorly defined. Our objectives were to determine the prevalence of osteoporosis, as assessed by peripheral bone mineral density (BMD), in a group of institutionalized veterans, and to determine how many men with low BMD had received a prior diagnosis of osteoporosis. METHODS: Subjects were residents in a 740-bed skilled nursing facility (78% men). Male residents (n = 103) competent to give informed consent underwent bilateral calcaneal and forearm BMD by dual-energy X-ray absorptiometry (DXA). Prior osteoporosis documentation was sought in medical records. RESULTS: Twenty percent of veterans (95% confidence interval (CI) 12-28%) exhibited calcaneal osteoporosis (T-score < -2.5), and 62% (CI 52-72%) were osteoporotic at the forearm. Forearm and calcaneal BMD were correlated (r = 0.678, P < 0.001). BMD of the left and right forearm, and of left and right calcaneus, were highly correlated (r = 0.880, P < 0.001 and r = 0.931, P < 0.001, respectively). Documentation of osteoporosis existed for one of 20 men with calcaneal osteoporosis and four of 59 men with forearm osteoporosis. CONCLUSIONS: Osteoporosis was prevalent but poorly documented in institutionalized veterans. Discordance in T-scores between forearm and heel was similar to that reported in other studies. The broad range of T-scores among subjects suggests that peripheral BMD measurement may be useful for clinical fracture risk stratification. Correlation among skeletal sites indicates that measuring a single site may be practical.     

The role of Bruton’s tyrosine kinase in autoimmunity and implications for therapy

Bruton’s tyrosine kinase (BTK) mediates B cell signaling and is also present in innate immune cells but not T cells. BTK propagates B cell receptor (BCR) responses to antigen-engagement as well as to stimulation via CD40, toll-like receptors (TLRs), Fc receptors (FCRs) and chemokine receptors. Importantly, BTK can modulate signaling, acting as a “rheostat” rather than an “on-off” switch; thus, overexpression leads to autoimmunity while decreased levels improve autoimmune disease outcomes. Autoreactive B cells depend upon BTK for survival to a greater degree than normal B cells, reflected as loss of autoantibodies with maintenance of total antibody levels when BTK is absent. This review describes contributions of BTK to immune tolerance, including studies testing BTK-inhibitors for treatment of autoimmune diseases.     

Brief report: cognitive functioning in children with Tourette's syndrome with and without comorbid ADHD

OBJECTIVE: To examine whether patients with Tourette's syndrome (TS) with and without comorbid attention deficit and hyperactivity disorder (ADHD) differ in cognitive functioning and whether a higher level of cognitive functioning is associated with severity of TS symptoms and psychosocial functioning. METHODS: Cognitive functioning, symptom severity, and psychosocial functioning were examined in 40 patients (33 boys, 7 girls; age range 6-18 years) with TS, of whom 17 had the comorbid diagnosis of ADHD. RESULTS: Patients with a comorbid ADHD diagnosis evidenced poorer performance than those with TS alone with respect to severity of TS symptoms, psychosocial functioning, verbal and performance intelligence, and word fluency, but not on tests of cognitive flexibility. Psychosocial functioning was predicted by symptom severity, but not by intelligence or fluency. CONCLUSIONS: Results confirm prior findings that comorbid ADHD is associated with more TS symptoms and worse psychosocial and cognitive functioning, and motivate whether cognitive flexibility plays a role in moderating the deleterious psychosocial effects of Tourette's syndrome and ADHD.     

Relationship between all-cause mortality and cumulative working life course psychosocial and physical exposures in the United States labor market from 1968 to 1992

OBJECTIVE: To examine the relationship between cumulative exposures to psychosocial and physical work conditions and mortality in a nationally representative sample. METHODS: A working cohort was created using the U.S. Panel Study of Income Dynamics. Information on psychosocial and physical work conditions were imputed using the Job Characteristics Scoring System exposure matrix for the period 1968 through 1991 to construct working life courses. Deaths were ascertained from 1970 through 1992. RESULTS: Working in low-control jobs for a working life was associated with a 43% increase in the chance of death (OR, 1.43, 1.13-1.81) assuming a 10-year time lag. No significant effect was found for high-strain work (ie, high psychosocial job demands and low job control), but a relationship was found between passive work (ie, low psychosocial job demands and low job control) and mortality (OR, 1.35, 1.06-1.72). No significant risk of death was found for psychosocial or physical job demands, job security, or work-related social support. Retirement (OR, 2.85, 1.59-5.11) and unemployment (OR, 2.26, 1.65-3.10) transitions and baseline disability (OR, 1.38, 1.06-1.79) predicted mortality. CONCLUSIONS: The results support the importance of job control to health. The passive work effect suggests that job content may be important in shaping a worker's health over the life course. Future research should focus on modeling stressors over the life course to capture the dynamic interplay of life transitions, stressor intensity and duration and the role of health in the interplay.     

Human thyroglobulin peptide p2340 induces autoimmune thyroiditis in HLA-DR3 transgenic mice

In a previous study we demonstrated that the human thyroglobulin (hTg) peptide p2340 (aa 2340-2359) can stimulate a T cell response and elicit experimental autoimmune thyroiditis (EAT) in AKR/J (H-2(k)) mice. In the present study we examined whether p2340 can induce EAT in single HLA class II DR3 transgenic mice. This peptide was found to be immunogenic at the T cell level in DR3 mice, since it induced specific proliferative responses, as well as IL-2 and IFN-gamma secretion in secondary cultures of peptide-primed lymph node cells (LNC). Immunization of HLA-DR3 mice with p2340 in CFA elicited EAT (infiltration index of 1 to 2) in eight of nine mice. Peptide-primed LNC responded to intact hTg, whereas, hTg-primed LNC did not respond to p2340 in culture, suggesting that p2340 contains subdominant T cell epitope(s). P2340 was also found to be immunogenic at the B cell level, since strong p2340-specific IgG response was detected in all transgenic mice tested. Thus, we provide evidence for a pathogenic role of an hTg peptide in HLA-DR3 transgenic mice. Therefore, p2340 could be presented by DR3 molecule in patients with Hashimoto's thyroiditis and participate in the development of the disease.     

Characterization of the filamentous hemagglutinin-like protein FhaS in Bordetella bronchiseptica

Filamentous hemagglutinin (FHA) is a large (>200 kDa), rod-shaped protein expressed by bordetellae that is both surface-associated and secreted. FHA mediates bacterial adherence to epithelial cells and macrophages in vitro and is absolutely required for tracheal colonization in vivo. The recently sequenced Bordetella bronchiseptica genome revealed the presence of a gene, fhaS, that is nearly identical to fhaB, the FHA structural gene. We show that although fhaS expression requires the BvgAS virulence control system, it is maximal only under a subset of conditions in which BvgAS is active, suggesting an additional level of regulation. We also show that, like FHA, FhaS undergoes a C-terminal proteolytic processing event and is both surface-associated and secreted and that export across the outer membrane requires the channel-forming protein FhaC. Unlike FHA, however, FhaS was unable to mediate adherence of B. bronchiseptica to epithelial cell lines in vitro and was not required for respiratory tract colonization in vivo. In a coinfection experiment, a DeltafhaS strain was out-competed by wild-type B. bronchiseptica, indicating that fhaS is expressed in vivo and that FhaS contributes to bacterial fitness in a manner revealed when the mutant must compete with wild-type bacteria. These data suggest that FHA and FhaS perform distinct functions during the Bordetella infectious cycle. A survey of various Bordetella strains revealed two distinct fhaS alleles that segregate according to pathogen host range and that B. parapertussis(hu) most likely acquired its fhaS allele from B. pertussis horizontally, suggesting fhaS may contribute to host-species specificity.     

LSECtin interacts with filovirus glycoproteins and the spike protein of SARS coronavirus

Cellular attachment factors like the C-type lectins DC-SIGN and DC-SIGNR (collectively referred to as DC-SIGN/R) can augment viral infection and might promote viral dissemination in and between hosts. The lectin LSECtin is encoded in the same chromosomal locus as DC-SIGN/R and is coexpressed with DC-SIGNR on sinusoidal endothelial cells in liver and lymphnodes. Here, we show that LSECtin enhances infection driven by filovirus glycoproteins (GP) and the S protein of SARS coronavirus, but does not interact with human immunodeficiency virus type-1 and hepatitis C virus envelope proteins. Ligand binding to LSECtin was inhibited by EGTA but not by mannan, suggesting that LSECtin unlike DC-SIGN/R does not recognize high-mannose glycans on viral GPs. Finally, we demonstrate that LSECtin is N-linked glycosylated and that glycosylation is required for cell surface expression. In summary, we identified LSECtin as an attachment factor that in conjunction with DC-SIGNR might concentrate viral pathogens in liver and lymph nodes.