HFE gene mutations increase the risk of coronary heart disease in women

The purpose of the present study is to examine HFE gene mutations in relation to newly diagnosed (incident) coronary heart disease (CHD). In a population-based follow-up study of 7,983 individuals aged 55 years and older, we compared the risk of incident CHD between HFE carriers and non-carriers, overall and stratified by sex and smoking status. HFE mutations were significantly associated with an increased risk of incident CHD in women but not in men (hazard ratio [HR] for women = 1.7, 95% confidence interval [CI] 1.2–2.4 versus HR for men = 0.9, 95% CI 0.7–1.2). This increased CHD risk associated with HFE mutations in women was statistically significant in never smokers (HR = 1.8, 95% CI 1.1–2.8) and current smokers (HR = 3.1, 95% CI 1.4–7.1), but not in former smokers (HR = 1.3, 95% CI 0.7–2.4). HFE mutations are associated with increased risk of incident CHD in women

Role of endogenous interferon and LPS in the immunomodulatory effects of bovine lactoferrin in murine peritoneal macrophages

Lactoferrin (Lf) plays an important role in host defense against infection and excessive inflammation. Although the mechanisms underlying its immunomodulatory properties have not been fully elucidated yet, recent evidence suggests that some of these effects may be related to its capacity to form complexes with LPS. We report that the culture of resting mouse peritoneal macrophages (PM) with bovine Lf (bLf), prior to infection with the vesicular stomatitis virus (VSV), resulted in a significant reduction of virus yield with respect to control cultures. The antiviral activity of bLF was related to its capacity of inducing IFN-α/β expression, which in turn inhibited VSV replication. Indeed, the accumulation of IFN-β but not of IFNα 1-2 transcripts was up-modulated markedly early after bLf addition. Furthermore, bLf did not exert any antiviral activity in the presence of neutralizing antibodies to IFN-α/β in PM from wildtype mice, as well as in PM from mice genetically defective for the response to IFN. The antiviral activity of bLf relied on its intrinsic capacity to bind LPS, as this protein did not induce IFN expression in PM from LPS-hyporesponsive mice. It is interesting that this LPS-binding property was dispensable for the production of TNF-α, which also occurred in LPS-hyporesponsive mice. Overall, these results indicate that some of the immunomodulatory effects ascribed to Lf may be related to its capacity to favor Type I IFN expression and argue in favor of an important role of the LPS-binding feature and TLR4 in some of the effects ascribed to this molecule. © Society for Leukocyte Biology

Aged garlic extract therapy for sickle cell anemia patients

BACKGROUND: Sickle cell anemia is one of the most prevalent hereditary disorders with prominent morbidity and mortality. With this disorder oxidative, phenomena play a significant role in its pathophysiology. One of the garlic (Allium sativum L.) formulations, aged garlic extract (AGE), has been reported to exert an anti-oxidant effect in vitro, we have evaluated the anti-oxidant effect of AGE on sickle red blood cells (RBC). METHODS: Five patients (two men and three women, mean age 40 ± 15 years, range 24–58 years) with sickle cell anemia participated in the study. AGE was administered at a dose of 5 ml a day. Whole blood samples were obtained at baseline and at 4 weeks for primarily Heinz body analysis. RESULTS: The data were consistent with our hypothesis. In all patients, the number of Heinz bodies decreased over the 4 week period (58.9 ± 20.0% at baseline to 29.8 ± 15.3% at follow-up, p = 0.03). CONCLUSIONS: These data suggest that there is a significant anti-oxidant activity of AGE on sickle RBC. AGE may be further evaluated as a potential therapeutic agent to ameliorate complications of sickle cell anemia

Assessment of the Red Cell Proteome of Young Patients with Unexplained Hemolytic Anemia by Two-Dimensional Differential In-Gel Electrophoresis (DIGE)

Erythrocyte cytosolic protein expression profiles of children with unexplained hemolytic anemia were compared with profiles of close relatives and controls by two-dimensional differential in-gel electrophoresis (2D-DIGE). The severity of anemia in the patients varied from compensated (i.e., no medical intervention required) to chronic transfusion dependence. Common characteristics of all patients included chronic elevation of reticulocyte count and a negative workup for anemia focusing on hemoglobinopathies, morphologic abnormalities that would suggest a membrane defect, immune-mediated red cell destruction, and evaluation of the most common red cell enzyme defects, glucose-6-phosphate dehydrogenase and pyruvate kinase deficiency. Based upon this initial workup and presentation during infancy or early childhood, four patients classified as hereditary nonspherocytic hemolytic anemia (HNSHA) of unknown etiology were selected for proteomic analysis. DIGE analysis of red cell cytosolic proteins clearly discriminated each anemic patient from both familial and unrelated controls, revealing both patient-specific and shared patterns of differential protein expression. Changes in expression pattern shared among the four patients were identified in several protein classes including chaperons, cytoskeletal and proteasome proteins. Elevated expression in patient samples of some proteins correlated with high reticulocyte count, likely identifying a subset of proteins that are normally lost during erythroid maturation, including proteins involved in mitochondrial metabolism and protein synthesis. Proteins identified with patient-specific decreased expression included components of the glutathione synthetic pathway, antioxidant pathways, and proteins involved in signal transduction and nucleotide metabolism. Among the more than 200 proteins identified in this study are 21 proteins not previously described as part of the erythrocyte proteome. These results demonstrate the feasibility of applying a global proteomic approach to aid characterization of red cells from patients with hereditary anemia of unknown cause, including the identification of differentially expressed proteins as potential candidates with a role in disease pathogenesis

Prevalence of anaemia in older persons: systematic review

<p>Abstract</p> <p>Background</p> <p>Ageing populations will impact on healthcare provision, especially since extra years are not necessarily spent in good health. It is important to identify and understand the significance of common medical problems in older people. Anaemia may be one such problem. We report on the prevalence of anaemia in cohorts of elderly people in the general population. The presence of anaemia is associated with a worse prognosis for both morbidity and mortality.</p> <p>Methods</p> <p>Electronic searching and reference lists of published reports were used to identify studies that reported on prevalence of anaemia in cohorts of at least 100 individuals predominantly aged 65 years and over living in developed countries, together with criteria used to define anaemia. Studies of anaemia prevalence in specific disease groups or published before 1980 were excluded. Prevalence data for the entire cohort, for men and women separately and for different age bands were extracted.</p> <p>Results</p> <p>Forty-five studies contributed data. Thirty-four studies (n = 85,409) used WHO criteria to define anaemia. The weighted mean prevalence was 17% (3–50%) overall, and 12% (3–25%) in studies based in the community (27, n = 69,975), 47% (31–50%) in nursing homes (3, n = 1481), and 40% (40–72%) in hospital admissions (4, n = 13,953). Anaemia prevalence increased with age, was slightly higher in men than women, and was higher in black people than white. Most individuals classified as anaemic using WHO criteria were only mildly anaemic.</p> <p>Conclusion</p> <p>Anaemia, as defined by WHO criteria, is common in older people living in the community and particularly common in nursing home residents and hospital admissions. Predicted demographic changes underline the need to understand more about anaemia in older people.</p

Differential cell reaction upon Toll-like receptor 4 and 9 activation in human alveolar and lung interstitial macrophages

BACKGROUND: Investigations on pulmonary macrophages (M&#934;) mostly focus on alveolar M&#934; (AM) as a well-defined cell population. Characteristics of M&#934; in the interstitium, referred to as lung interstitial M&#934; (IM), are rather ill-defined. In this study we therefore aimed to elucidate differences between AM and IM obtained from human lung tissue. METHODS: Human AM and IM were isolated from human non-tumor lung tissue from patients undergoing lung resection. Cell morphology was visualized using either light, electron or confocal microscopy. Phagocytic activity was analyzed by flow cytometry as well as confocal microscopy. Surface marker expression was measured by flow cytometry. Toll-like receptor (TLR) expression patterns as well as cytokine expression upon TLR4 or TLR9 stimulation were assessed by real time RT-PCR and cytokine protein production was measured using a fluorescent bead-based immunoassay. RESULTS: IM were found to be smaller and morphologically more heterogeneous than AM, whereas phagocytic activity was similar in both cell types. HLA-DR expression was markedly higher in IM compared to AM. Although analysis of TLR expression profiles revealed no differences between the two cell populations, AM and IM clearly varied in cell reaction upon activation. Both M&#934; populations were markedly activated by LPS as well as DNA isolated from attenuated mycobacterial strains (M. bovis H37Ra and BCG). Whereas AM expressed higher amounts of inflammatory cytokines upon activation, IM were more efficient in producing immunoregulatory cytokines, such as IL10, IL1ra, and IL6.CONCLUSION: AM appear to be more effective as a non-specific first line of defence against inhaled pathogens, whereas IM show a more pronounced regulatory function. These dissimilarities should be taken into consideration in future studies on the role of human lung M&#934; in the inflammatory response

The Herpes Simplex Virus-1 Transactivator Infected Cell Protein-4 Drives VEGF-A Dependent Neovascularization

Herpes simplex virus-1 (HSV-1) causes lifelong infection affecting between 50 and 90% of the global population. In addition to causing dermal lesions, HSV-1 is a leading cause of blindness resulting from recurrent corneal infection. Corneal disease is characterized by loss of corneal immunologic privilege and extensive neovascularization driven by vascular endothelial growth factor-A (VEGF-A). In the current study, we identify HSV-1 infected cells as the dominant source of VEGF-A during acute infection, and VEGF-A transcription did not require TLR signaling or MAP kinase activation. Rather than being an innate response to the pathogen, VEGF-A transcription was directly activated by the HSV-1 encoded immediate early transcription factor, ICP4. ICP4 bound the proximal human VEGF-A promoter and was sufficient to promote transcription. Transcriptional activation also required cis GC-box elements common to the VEGF-A promoter and HSV-1 early genes. Our results suggest that the neovascularization characteristic of ocular HSV-1 disease is a direct result of HSV-1's major transcriptional regulator, ICP4, and similarities between the VEGF-A promoter and those of HSV-1 early genes

Glucuronidation by UGT1A1 Is the Dominant Pathway of the Metabolic Disposition of Belinostat in Liver Cancer Patients

10.1371/journal.pone.0054522PLoS ONE81