The Role of HIV Infectivity and Composition of Factor VIII Concentrates on the Immunity of Haemophiliacs Positive for HIV Antibodies

Forty-six subjects (44 HIV antibody-positive) with some degree of immune deficiency (at least TH/TS ratio below 1) were randomly distributed into 4 treatment groups. Each group was assigned to 1 of 4 products to be used exclusively for a 1-year period: 1 concentrate was of intermediate purity and not heat-treated, and 3 were heat-treated in order to inactivate HIV, 2 of them being of higher purity. At 4-6-month intervals, check-ups, including as markers clinical examination, platelet, lymphocyte and T cell subset counts, IgG levels and delayed hypersensitivity test, were carried out. At entry as well as at the end of the study, groups were not statistically distinguishable. No intra- nor inter-group differences were demonstrable for any of the markers. In contrast, using a scoring system for each marker and the results of check-up at entry as reference, significant differences between groups appeared on subsequent check-ups. Patients receiving intermediate-purity factor VIII, whether heat-treated or not, were mostly steady, while groups receiving heat-treated concentrates of a higher purity significantly worsened. This surprising outcome was no related to differences in anti-HIV titers or specificities. From this study, the potential long-term predictive value of this scoring system could not be established.     

Churg‐Strauss syndrome with poor‐prognosis factors: A prospective multicenter trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in forty‐eight patients

Objective

To compare long and short durations of adjunctive cyclophosphamide for the treatment of severe Churg‐Strauss syndrome (CSS).

Methods

In this prospective multicenter therapeutic trial, 48 patients with CSS with at least 1 poor‐prognosis factor at baseline were treated with glucocorticoids and either 12 or 6 intravenous cyclophosphamide pulses.

Results

At 8 years, complete remission rates and severe side effects of therapy were comparable for both groups. The overall difference in relapses was not significant between the 12‐pulse and the 6‐pulse regimens (P = 0.07), but when considering only the number of mild relapses this difference became statistically significant (P < 0.02). Although the total number of inclusions was not reached, the study was stopped prematurely in response to the superiority of the 12‐pulse regimen.

Conclusion

We concluded that 12 cyclophosphamide pulses were better able to control severe CSS than a 6‐pulse regimen. The optimal duration of therapy remains to be determined.     

Slowed ST segment recovery despite early infarct artery patency in patients with Q waves at presentation with a first acute myocardial infarction. Implications of initial Q waves on myocyte reperfusion.

BACKGROUND: The presence of Q waves at presentation with a first acute myocardial infarction reflects a more advanced stage of the infarction process. When infarct-related artery patency (Thrombolysis in Myocardial Infarction 2 or 3 flow) is restored, resolution of ST segment elevation indicating successful myocyte reperfusion may differ according to how far the infarction process has progressed. METHODS AND RESULTS: In 144 patients with a first acute myocardial infarction treated with streptokinase in the first Hirulog Early Reperfusion Occlusion trial, information was obtained from continuous ST segment monitoring, the presenting electrocardiogram and early angiography performed at a median time of 99 min after the commencement of streptokinase (interquartile range 89-108 min). We determined how many patients had 50% ST recovery within 120 min and in how many cases it was sustained over 4h. In the 109 patients with patent infarct-related arteries, 50% ST recovery occurred in 95% of patients without vs 80% of those with initial Q waves (P=0.03), and sustained ST recovery occurred in 67% of patients without vs 47% of those with initial Q waves (P=0.03). On multivariate analysis including the time from symptom onset to streptokinase therapy, the presence of Q waves at presentation was the only predictor of failure to achieve 50% ST recovery (odds ratio 5.08, 95% confidence interval 1.29-20.01, P=0.02). TIMI 2 flow, as opposed to TIMI 3 flow, was the only predictor of failure to achieve stable ST recovery (odds ratio 2.63, 95% confidence interval 1.15-5.88,P =0.02). CONCLUSION: The presence of initial Q waves predicts slower and less complete ST recovery, reflecting reduced myocyte reperfusion, even in those with early infarct artery patency. These patients may be targeted for new therapeutic strategies to improve microvascular reperfusion.     

Risk Factors for Campylobacteriosis in Two Washington State Counties with High Numbers of Dairy Farms

Campylobacteriosis is a frequently reported, food-borne, human bacterial disease that can be associated with ruminant reservoirs, although public health messages primarily focus on poultry. In Washington State, the two counties with the highest concentrations of dairy cattle also report the highest incidences of campylobacteriosis. Conditional logistic regression analysis of case-control data from both counties found living or working on a dairy farm (odds ratio [OR], 6.7 [95% confidence interval [CI], 1.7 to 26.4]) and Hispanic ethnicity (OR, 6.4 [95% CI, 3.1 to 13.1]) to have the strongest significant positive associations with campylobacteriosis. When the analysis was restricted to residents of one county, Hispanic ethnicity (OR, 9.3 [95% CI, 3.9 to 22.2]), contact with cattle (OR, 5.0 [95% CI, 1.3 to 19.5]), and pet ownership (OR, 2.6 [95% CI, 1.1 to 6.3]) were found to be independent risk factors for disease. Campylobacter jejuni isolates from human (n = 65), bovine (n = 28), and retail poultry (n = 27) sources from the same counties were compared using multilocus sequence typing. These results indicated that sequence types commonly found in human isolates were also commonly found in bovine isolates. These findings suggest that, in areas with high concentrations of dairy cattle, exposure to dairy cattle may be more important than food-borne exposure to poultry products as a risk for campylobacteriosis.     

Molecular subtypes of glioma identified by genome‐wide methylation profiling

Recent studies have indicated a prognostic role for genome‐wide methylation in gliomas: Tumors that show an overall increase in DNA methylation at CpG sites (CIMP+; CpG island methylator phenotype) have a more favorable prognosis than CIMP? gliomas. Here, we have determined whether methylation profiling can identify more and clinically relevant molecular subtypes of glioma by performing genome‐wide methylation profiling on 138 glial brain tumors of all histological diagnosis. Hopach (Hierarchical ordered partitioning and collapsing hybrid) clustering using the 1,000 most variable CpGs identified three distinct glioma subtypes (C+_1p19q, C+_wt, and C?) and one adult brain subtype. All “C+_1p19q” and “C+_wt” tumors were CIMP+ whereas most (50/54) “C?” tumors were CIMP?. The C? subtype gliomas contained many glioblastomas and all pilocytic astrocytomas. 1p19q LOH was frequent in the C+_1p19q subtype. Other genetic changes (IDH1 mutation and EGFR amplification) and gene‐expression based molecular subtypes also segregated in distinct methylation subtypes, demonstrating that these subtypes are also genetically distinct. Each subtype was associated with its own prognosis: median survival for C?, C+_1p19q, and C+_wt tumors was 1.18, 5.00, and 2.62 years, respectively. The prognostic value of these methylation subtypes was validated on an external dataset from the TCGA. Analysis of recurrences of 14 primary tumors samples indicates that shifts between some C+_wt and C+_1p/19q tumors can occur between the primary and recurrent tumor, but CIMP status remained stable. Our data demonstrate that methylation profiling identifies at least three prognostically relevant subtypes of glioma that can aid diagnosis and potentially guide treatment for patients. © 2013 Wiley Periodicals, Inc.     

Immune activation in patients infected with HIV type 1 and maintaining suppression of viral replication by highly active antiretroviral therapy

Immune activation associated with HIV infection declines after highly active antiretroviral therapy (HAART), but may persist or recur in some patients. It is not clear whether this reflects a resurgence of HIV replication or another cause of immune activation, such as inflammatory reactions to opportunistic pathogens (immune restoration disease [IRD]). Here, we studied plasma and cellular immune activation markers in adult HIV-1 patients who had received HAART for >12 months and maintained plasma HIV RNA levels of <400 copies/ml for >6 months. Plasma interleukin 1 receptor antagonist and tumor necrosis factor receptor I levels were similar in patients and HIV-negative control subjects, but the highest levels occurred mainly in patients with a history of IRD. In contrast, expression of HLA-DR and CD38 on monocytes and of HLA-DR on CD8(+) T cells was higher in patients than in control subjects. Thus, cellular markers of immune activation are abnormal in some patients with a good virological response to HAART, and abnormalities of plasma immune activation markers correlate with a history of IRD.     

Restoration of CD4 T-cell responses to cytomegalovirus is short-lived in severely immunodeficient HIV-infected patients responding to highly active antiretroviral therapy

OBJECTIVES: To define the level of pathogen-specific immune reconstitution persisting over 3 to 5 years of highly active antiretroviral therapy (HAART) in HIV-infected patients who began therapy with CD4 T-cell counts below 50 cells/microL. METHODS: Cytomegalovirus (CMV)-specific T-cell responses were analysed in adult HIV-1-infected patients with nadir CD4 T-cell counts below 50 cells/microL before HAART. CMV-specific CD4 T-cell responses were measured by interferon-gamma enzyme-linked immunospot assay (ELISpot assay), lymphoproliferation and interferon-gamma levels in cell culture supernatants. RESULTS: CD4 T-cell responses to CMV were low in untreated patients and remained low during the first year on HAART, but increased progressively to levels similar to those found in HIV-seronegative CMV-seropositive controls at 3 years. Responses then declined markedly and at 5 years were lower than controls. This could not be explained by changes in CD4 or CD8 T-cell counts or plasma HIV RNA levels. Interferon-gamma and interleukin-5 responses to a mitogen were maintained or elevated. CONCLUSIONS: CMV-specific CD4 T-cell responses were found to decline after 3-5 years on HAART and may provide inadequate long-term protection against CMV disease in patients who are severely immunodeficient prior to treatment.