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Background: Progression rates from initial HIV-1 infection to advanced AIDS vary significantly among infected individuals. A distinct subgroup of HIV-1-infected individuals--termed viremic non-progressors (VNP) or controllers--do not seem to progress to AIDS, maintaining high CD4+ T cell counts despite high levels of viremia for many years. Several studies have evaluated multiple host factors, including immune activation, trying to elucidate the atypical HIV-1 disease progression in these patients; however, limited work has been done to characterize viral factors in viremic controllers. Methods: We analyzed HIV-1 isolates from three VNP individuals and compared the replicative fitness, near full-length HIV-1 genomes and intra-patient HIV-1 genetic diversity with viruses from three typical (TP) and one rapid (RP) progressor individuals. Results: Viremic non-progressors and typical patients were infected for >10 years (range 10-17 years), with a mean CD4+ T-cell count of 472 cells/mm³ (442-529) and 400 cells/mm³ (126-789), respectively. VNP individuals had a less marked decline in CD4+ cells (mean -0.56, range -0.4 to -0.7 CD4+/month) than TP patients (mean -10.3, -8.2 to -13.1 CD4+/month). Interestingly, VNP individuals carried viruses with impaired replicative itness, compared to HIV-1 isolates from the TP and RP patients (p < 0.05, 95% CI). Although analyses of the near full-length HIV-1 genomes showed no clear patterns of single-nucleotide polymorphisms (SNP) that could explain the decrease in replicative fitness, both the number of SNPs and HIV-1 population diversity correlated inversely with the replication capacity of the viruses (r = -0.956 and r = -0.878, p < 0.01, respectively). Conclusion: It is likely that complex multifactorial parameters govern HIV-1 disease progression in each individual, starting with the infecting virus (phenotype, load, and quasispecies diversity) and the intrinsic ability of the host to respond to the infection. Here we analyzed a subset of viremic controller patients and demonstrated that similar to the phenomenon observed in patients with a discordant response to antiretroviral therapy (i.e., high CD4+ cell counts with detectable plasma HIV-1 RNA load), reduced viral replicative fitness seems to be linked to slow disease progression in these antiretroviral-naïve individuals. [ABSTRACT FROM AUTHOR]

Why do regimes delegate authority over a territory to nonstate militias, in effect voluntarily sacrificing their monopoly over the use of violence? This article argues that two factors increase the probability of states delegating control to a proxy militia, namely, military purges and armed conflict. Military purges disrupt intelligence-gathering structures and the organizational capacity of the military. To counteract this disruption, military leaders subcontract the task of control and repression to allied militias that have the local intelligence skills necessary to manage the civilian population. This argument is conditioned by whether the state faces an armed insurgency in a given region since intelligence, control, and repression are needed most where the state is being challenged. This hypothesis is tested on unique data for all subnational regions within Myanmar during the period 1962 to 2010 and finds that proxy militias are more likely to be raised in conflict areas after military purges. [ABSTRACT FROM AUTHOR]

Summary Chemotherapy-induced mucositis is characterized by damage of mucous membranes throughout the alimentary tract (AT). Extracellular matrix (ECM) components play a vital role in maintaining mucosal barrier integrity by regulating cellular apoptosis, proliferation and differentiation of overlying epithelial cells. The aims of this study were to characterize the changes in epithelial cell kinetics and to investigate the expression of the ECM components in the gastrointestinal tract following irinotecan administration. Female dark agouti rats were treated with single 200 mg/kg dose irinotecan and killed at various time points (1, 6, 24, 48, 72, 96 and 144 h) after treatment. Ki67 immunostaining and TUNEL were used to assess proliferation and apoptosis, respectively, in the jejunum and colon. Masson trichrome staining and picro-sirius red staining were used to determine the level of collagen, and immunohistochemistry was used to further assess collagen IV, fibronectin and laminin 1 and 2 expression in these tissues. Irinotecan halved cellular proliferation in the jejunum and colon at 48 and 24 h, respectively, while apoptosis peaked at 6 h ( P < 0.05). There was a substantial increase in total collagen deposits around crypts from 24 h in both regions. However, collagen IV expression decreased significantly in the crypt region in a delayed fashion ( P < 0.05). Fibronectin expression decreased significantly in jejunum and colon from 6 to 24 h following treatment ( P < 0.05). Irinotecan induced a significant alteration in epithelial cell kinetics in both the jejunum and colon, and this correlated with changes in ECM component expression. Changes in ECM expression may have a direct impact on the loss of mucosal layer integrity evident in chemotherapy-induced mucositis. [ABSTRACT FROM AUTHOR]