Objective To delineate the risk factors, symptom patterns, and longitudinal course of prolonged illnesses after a variety of acute infections.
Background: Chronic fatigue syndrome (CFS) is defined by symptoms and disability, has no confirmatory physical signs or characteristic laboratory abnormalities, and the etiology and pathophysiology remain unknown. Difficulties with accurate case ascertainment contribute to this ignorance.
SummaryThe human cytokine interferon-inducible protein 10 (IP-10) is a small glycoprotein secreted by activated T cells, monocytes, endothelial cells, and keratinocytes, and is structurally related to a family of chemotactic cytokines called chemokines. Although this protein is present in sites of delayed-type hypersensitivity reactions and lepromatous leprosy lesions, the biological activity of IP-10 remains unknown. We report here that recombinant human IP-10 stimulated significant in vitro chemotaxis of human peripheral blood monocytes but not neutrophils. Recombinant human IP-10 also stimulated chemotaxis of stimulated, but not unstimulated, human peripheral blood T lymphocytes. Phenotypic analysis of the stimulated T cell population responsive to IP-10 demonstrated that stimulated CD4 + and CD29 + T cells migrated in response to IP-10. This resembles the biological activity of the previously described T cell chemoattractant R.ANTES. Using an endothelial cell adhesion assay, we demonstrated that stimulated T cells pretreated with optimal doses of IP-10 exhibited a greatly enhanced ability to bind to an interleukin 1-treated endothelial cell monolayer. These results demonstrate that the IP-10 gene encodes for an inflammatory mediator that specifically stimulates the directional migration of T cells and monocytes as well as potentiates T cell adhesion to endothelium.
To gain a clearer understanding of the rate of progression to cirrhosis and its determinants in chronic hepatitis C virus (HCV) infection, a systematic review of published epidemiologic studies that incorporated assessment for cirrhosis has been undertaken. Inclusion criteria were more than 20 cases of chronic HCV infection, and information on either age of subjects or duration of infection. Of 145 studies examined, 57 fulfilled the inclusion criteria. Least-squares linear regression was employed to estimate rates of progression to cirrhosis, and to examine for factors associated with more rapid disease progression in 4 broad study categories: 1) liver clinic series (number of studies ؍ 33); 2) posttransfusion cohorts (n ؍ 5); 3) blood donor series (n ؍ 10); and 4) community-based cohorts (n ؍ 9). Estimates of progression to cirrhosis after 20 years of chronic HCV infection were 22% (95% CI, 18%-26%) for liver clinic series, 24% (11%-37%) for posttransfusion cohorts, 4% (1%-7%) for blood donor series, and 7% (4%-10%) for community-based cohorts. Factors that were associated with more rapid disease progression included older age at HCV infection, male gender, and heavy alcohol intake. Even after accounting for these factors, progression estimates were much higher for cross-sectional liver clinic series. Selection biases probably explain the higher estimates of disease progression in this group of studies. Community-based cohort studies are likely to provide a more representative basis for estimating disease progression at a population level. These suggest that for persons who acquire HCV infection in young adulthood, less than 10% are estimated to develop cirrhosis within 20 years. (HEPATOLOGY 2001;34:809-816.)The majority of persons with hepatitis C virus (HCV) infection progress to chronic infection, which can lead to liver fibrosis and the subsequent occurrence of cirrhosis, liver failure, and hepatocellular carcinoma. 1 However, it is unclear what proportion of persons will develop HCV-related hepatic complications and who is most at risk of progression. The likelihood of progression can influence choice about therapy for the individual, and is a fundamental factor in predicting disease burden at a population level.Because chronic HCV infection is largely asymptomatic and runs a protracted and highly variable course, it has been difficult to reliably measure disease progression in epidemiologic studies. 2 Early studies in blood-transfusion recipients and liver clinic patients seemed to indicate that cirrhosis would develop in 20% to 50% within 20 years of acquiring HCV infection. 3,4 Then, several more recent studies suggested progression rates that were much lower, of the order of 2% to 10%. 5-9 Some interpreted these discrepancies as being caused by different distributions of factors associated with more rapid disease progression, such as age at HCV infection, gender, and source of HCV infection, between the study populations. The higher estimates, however, continue to be used to project disease bur...
Recombinant human macrophage inflammatory protein-1 alpha (rhMIP-1 alpha) and rhMIP-1 beta were potent chemoattractants of human T lymphocytes. These rhMIP-1 cytokines attracted only T cells activated by monoclonal antibody to CD3 and did not attract unstimulated lymphocytes. Phenotypic analysis revealed that CD4+ T cells were capable of migrating in response to rhMIP-1 beta, whereas rhMIP-1 alpha induced chemotaxis of predominantly CD8+ T lymphocytes. Activated naïve and memory T cells also migrated in response to rhMIP-1 cytokines. Furthermore, these cytokines enhanced the ability of T cells to bind to an endothelial cell monolayer. These results suggest that rhMIP-1 cytokines preferentially recruit specific T cell subsets during the evolution of the immune response.
SummarySerum amyloid A (SAA) is an acute phase protein that in the blood is bound to high density lipoproteins; SAA is secreted mainly by hepatocytes, and its concentration increases in the blood up to 1000 times during an inflammatory response. At present, its biological function is unclear. Since some forms of secondary amyloidosis are caused by deposition in tissues of peptides derived from the SAA and leukocytes seem to be involved in this process, we investigated the effect of human SAA on human monocytes and polymorphonuclear cells (PMN). When recombinant human SAA (rSAA) was used at concentrations corresponding to those found during the acute phase (>0.8 /zM), it induced directional migration of monocytes and polymorphonuclear leukocytes. Preincubation of rSAA with high density lipoproteins blocked this chemoattractant activity for both monocytes and PMN. rSAA also regulated the expression of the adhesion proteins CD11b and leukocyte cell adhesion molecule I and induced the adhesion of PMN and monocytes to umbilical cord vein endothelial cell monolayers. When subcutaneously injected into mice, rSAA recruited PMN and monocytes at the injection site. On the basis of these data, we suggest that SAA may participate in enhancing the migration ofmonocytes and PMN to inflamed tissues during an acute phase response.
Although 20–40% of persons with acute HCV infection demonstrate spontaneous clearance, the time-course and factors associated with clearance remain poorly understood. We investigated the time to spontaneous clearance and predictors among participants with acute HCV using Cox proportional hazards analyses. Data for this analysis were drawn from an international collaboration of nine prospective cohorts evaluating outcomes following acute HCV infection. Among 632 participants with acute HCV, 35% were female, 82% were Caucasian, 49% had IL28B CC genotype (rs12979860), 96% had injected drugs ever, 47% were infected with HCV genotype 1 and 5% had HIV co-infection. Twenty-eight percent were HCV antibody negative/RNA positive at the time of acute HCV detection (early acute HCV). During follow-up, spontaneous clearance occurred in 173 of 632 and at one year following infection, 25% (95%CI: 21%, 29%) had cleared virus. Among those with clearance, the median time to clearance was 16.5 weeks (IQR: 10.5, 33.4 weeks), with 34%, 67% and 83% demonstrating clearance at three, six and twelve months. Adjusting for age, factors independently associated with time to spontaneous clearance included female sex [adjusted hazards ratio (AHR) 2.16; 95%CI 1.48, 3.18], IL28B CC genotype (vs. CT/TT, AHR 2.26; 95%CI 1.52, 3.34), and HCV genotype 1 (vs. non-genotype 1, AHR 1.56; 95%CI 1.06, 2.30). The effect of IL28B genotype and HCV genotype on spontaneous clearance was greater among females compared to males. Conclusions Female sex, favorable IL28B genotype and HCV genotype 1 are independent predictors of spontaneous clearance. Further research is required to elucidate the observed sex-based differences in HCV control.
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