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Retroviral integration site targeting is not random and plays a critical role in expression and long-term survival of the integrated provirus. To better understand the genomic environment surrounding retroviral integration sites, we performed a meta-analysis of previously published integration site data from evolutionarily diverse retroviruses, including new experimental data from HIV-1 subtypes A, B, C and D. We show here that evolutionarily divergent retroviruses exhibit distinct integration site profiles with strong preferences for integration near non-canonical B-form DNA (non-B DNA). We also show that in vivo-derived HIV-1 integration sites are significantly more enriched in transcriptionally silent regions and transcription-silencing non-B DNA features of the genome compared to in vitro-derived HIV-1 integration sites. Integration sites from individuals infected with HIV-1 subtype A, B, C or D viruses exhibited different preferences for common genomic and non-B DNA features. In addition, we identified several integration site hotspots shared between different HIV-1 subtypes, all of which were located in the non-B DNA feature slipped DNA. Together, these data show that although evolutionarily divergent retroviruses exhibit distinct integration site profiles, they all target non-B DNA for integration. These findings provide new insight into how retroviruses integrate into genomes for long-term survival. [ABSTRACT FROM AUTHOR]

Background: Increasing first-line treatment failures in low- and middle-income countries (LMICs) have led to increased use of integrase strand transfer inhibitors (INSTIs) such as dolutegravir. However, HIV-1 susceptibility to INSTIs in LMICs, especially with previous raltegravir exposure, is poorly understood due to infrequent reporting of INSTI failures and testing for INSTI drug resistance mutations (DRMs).Methods: A total of 51 non-subtype B HIV-1 infected patients failing third-line (raltegravir-based) therapy in Uganda were initially selected for the study. DRMs were detected using Sanger and deep sequencing. HIV integrase genes of 13 patients were cloned and replication capacities (RCs) and phenotypic susceptibilities to dolutegravir, raltegravir and elvitegravir were determined with TZM-bl cells. Spearman's correlation coefficient was used to determine cross-resistance between INSTIs.Results: INSTI DRMs were detected in 47% of patients. HIV integrase-recombinant virus carrying one primary INSTI DRM (N155H or Y143R/S) was susceptible to dolutegravir but highly resistant to raltegravir and elvitegravir (>50-fold change). Two patients, one with E138A/G140A/Q148R/G163R and one with E138K/G140A/S147G/Q148K, displayed the highest reported resistance to raltegravir, elvitegravir and even dolutegravir. The former multi-DRM virus had WT RC whereas the latter had lower RCs than WT.Conclusions: In HIV-1 subtype A- and D-infected patients failing raltegravir and harbouring INSTI DRMs, there is high-level resistance to elvitegravir and raltegravir. More routine monitoring of INSTI treatment may be advised in LMICs, considering that multiple INSTI DRMs may have accumulated during prolonged exposure to raltegravir during virological failure, leading to high-level INSTI resistance, including dolutegravir resistance. [ABSTRACT FROM AUTHOR]

Background: Thymidine analogs, namely AZT (Zidovudine or Retrovir™) and d4T (Stavudine or Zerit™) are antiretroviral drugs still employed in over 75% of first line combination antiretroviral therapy (cART) in Kampala, Uganda despite aversion to prescribing these drugs for cART in high income countries due in part to adverse events. For this study, we explored how the continued use of these thymidine analogs in cART could impact emergence of drug resistance and impact on future treatment success in Uganda, a low-income country. Methods: We examined the drug resistance genotypes by Sanger sequencing of 262 HIV-infected patients failing a first line combined antiretroviral treatment containing either AZT or d4T, which represents approximately 5% of the patients at the Joint Clinical Research Center receiving a AZT or d4T containing treatment. Next generation sequencing (DEEPGEN™HIV) and multiplex oligonucleotide ligation assays (AfriPOLA) were then performed on a subset of patient samples to detect low frequency drug resistant mutations. CD4 cell counts, viral RNA loads, and treatment changes were analyzed in a cohort of treatment success and failures. Results: Over 80% of patients failing first line AZT/d4T-containing cART had predicted drug resistance to 3TC (Lamivudine) and non-nucleoside RT inhibitors (NNRTIs) in the treatment regimen but only 45% had resistance AZT/d4T associated resistance mutations (TAMs). TAMs were however detected at low frequency within the patients HIV quasispecies (1-20%) in 21 of 34 individuals who were failing first-line AZT-containing cART and lacked TAMs by Sanger. Due to lack of TAMs by Sanger, AZT was typically maintained in second-line therapies and these patients had a low frequency of subsequent virologic success. Conclusions: Our findings suggest that continued use of AZT and d4T in first-line treatment in low-to-middle income countries may lead to misdiagnosis of HIV-1 drug resistance and possibly enhance a succession of second- and third-line treatment failures. [ABSTRACT FROM AUTHOR]

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]

Glioblastoma (GBM) is an aggressive, malignant brain tumor typically resulting in death of the patient within one year following diagnosis; and those who survive beyond this point usually present with tumor recurrence within two years (5-year survival is 5%). The genetic heterogeneity of GBM has made the molecular characterization of these tumors an area of great interest and has led to identification of molecular subtypes in GBM. The availability of sequencing platforms that are both fast and economical can further the adoption of tumor sequencing in the clinical environment, potentially leading to identification of clinically actionable genetic targets. In this pilot study, comprised of triplet samples of normal blood, primary tumor, and recurrent tumor samples from three patients; we compared the ability of Illumina whole exome sequencing (ExomeSeq) and the Ion AmpliSeq Comprehensive Cancer Panel (CCP) to identify somatic variants in patient-paired primary and recurrent tumor samples. Thirteen genes were found to harbor variants, the majority of which were exclusive to the ExomeSeq data. Surprisingly, only two variants were identified by both platforms and they were located within the PTCH1 and NF1 genes. Although preliminary in nature, this work highlights major differences in variant identification in data generated from the two platforms. Additional studies with larger samples sizes are needed to further explore the differences between these technologies and to enhance our understanding of the clinical utility of panel based platforms in genomic profiling of brain tumors. [ABSTRACT FROM AUTHOR]

The role of HIV-1 minority variants on transmission, pathogenesis, and virologic failure to antiretroviral regimens has been explored; however, most studies of low-level HIV-1 drug-resistant variants have focused in single target regions. Here we used a novel HIV-1 genotypic assay based on deep sequencing, DEEPGEN (Gibson et al 2014 Antimicrob Agents Chemother 58∶2167) to simultaneously analyze the presence of minority variants carrying mutations associated with reduced susceptibility to protease (PR), reverse transcriptase (RT), and integrase strand transfer integrase inhibitors (INSTIs), as well as HIV-1 coreceptor tropism. gag-p2/NCp7/p1/p6/pol-PR/RT/INT and env/C2V3 PCR products were obtained from twelve heavily treatment-experienced patients experiencing virologic failure while participating in a 48-week dose-ranging study of elvitegravir (GS-US-183-0105). Deep sequencing results were compared with (i) virological response to treatment, (ii) genotyping based on population sequencing, (iii) phenotyping data using PhenoSense and VIRALARTS, and (iv) HIV-1 coreceptor tropism based on the phenotypic test VERITROP. Most patients failed the antiretroviral regimen with numerous pre-existing mutations in the PR and RT, and additionally newly acquired INSTI-resistance mutations as determined by population sequencing (mean 9.4, 5.3, and 1.4 PI- RTI-, and INSTI-resistance mutations, respectively). Interestingly, since DEEPGEN allows the accurate detection of amino acid substitutions at frequencies as low as 1% of the population, a series of additional drug resistance mutations were detected by deep sequencing (mean 2.5, 1.5, and 0.9, respectively). The presence of these low-abundance HIV-1 variants was associated with drug susceptibility, replicative fitness, and coreceptor tropism determined using sensitive phenotypic assays, enhancing the overall burden of resistance to all four antiretroviral drug classes. Further longitudinal studies based on deep sequencing tests will help to clarify (i) the potential impact of minority HIV-1 drug resistant variants in response to antiretroviral therapy and (ii) the importance of the detection of HIV minority variants in the clinical practice. [ABSTRACT FROM AUTHOR]

Aims: To assess differences between articles published in the Journal of Orthodontics (JO) and European Journal of Orthodontics (EJO) from 1999 to 2008 and compare longitudinal publication profiles. Design: Retrospeclive, observational Methods: The main study examined articles from the American Journal of Orthodontics and Den tofacial Orthopedics and Angle Orthodontist alongside the JO and EJO. All journals were hand-searched to identify eligible articles. A random sample from these articles was obtained to provide 80% power to detect a 100% increase in the number of randomized controlled trials (RCTs) at the 5% level of significance. Each article was classified according to pre-determined criteria by one author (RG). Variations between journals were assessed using the chi-squared test or odds ratio (OR) and 95% confidence intervals (95% Results: A random sample of 425 articles was obtained from 4301 eligible articles, of which 113 were from the JO or EJO. About 34.5% of articles were from the JO and 66.5% the EJO. Statistically significant differences were found between the type (P<0.00l), subject (P=0.049), method/direction (P=0.038) and controls (P=0.006) of articles published in the two journals. When compared longitudinally the proportion of RCTs published between 1989 and 1993 (2.8%) and 1999-2008 (18.5%) was statistically significant (OR=8.0, 95% CI 2.8, 23.1). Statistically significant differences were seen over time in all aspects investigated. Conclusions: Statistically significant differences were found in the publication profiles of the two orthodontic journals during the period examined and longitudinally. A piece of clinical research was 8 times more likely to be an RCT during 1999-2008, compared to 1989-1993. [ABSTRACT FROM AUTHOR]

The problem of narcotics trafficking (and more recently, methamphetamine production and trafficking) in Myanmar has been a regional and international problem for decades. The issue must be approached as an economic and social problem rather than a political or military one. The approaches must be multinational and multi-discipline, taking into account the economic, commercial, political, and social issues that force the cultivation of the opium poppy and the production of illegal drugs in the Shan State. This multi-dimensional approach is preferable whether the present military government or a democratic alternative holds power in Yangon. The problems include the lack of viable alternative crops, nonexistent transportation, the problem of armed gangs (whether ethnic or economic in nature), the lack of government presence, and the historical inability of the Myanmar armed forces to control the region. [ABSTRACT FROM AUTHOR]

In this paper, we examine the demographic and socioeconomic characteristics of migration streams between metropolitan and nonmetropolitan areas for four different wears over the period 1975-1993. During this period, there have been three shifts in the direction of net metro-nonmetro migration. Through nonmetro net in-migration, the " nonmetropolitan turnaround" of the 1970s revered historical patterns of nonmetro loss of human resources, with gains and increased retention of the young and better-educated. The 1980s, however, again saw nei-migration loss, including large shifts from gain one of nonmetro net-migration gain or reduced loss, with the greatest increases among those higher status groups which experienced the greatest declines during the 1980s. The latest patterns is due largely to increased population retention, whereas previous research has shown the migration turnaround of the 1970s was due about equally to increasing retention and in-migration. [ABSTRACT FROM AUTHOR]

The twin processes of population concentration and deconcentration, working at the regional, metropolitan-nonmetropolitan and local levels, have defined the redistribution of the American people in the twentieth century. Over most of this period, there was a massive concentration of population into cities, with a multiplication of places as urbanization spread and larger centers captured ever greater numbers. Although growth generally was at the periphery of such places, with the widespread use of the automobile there was in addition a spread of population into formerly rural nearby areas. The recognition of this led to the adoption of the metropolitan area concept in 1950, and on this basis one may generalize that at least until 1970 the twentieth century settlement process could be described as concentration into metropolitan areas and deconcentration within these areas. The analysis of population redistribution by size of place within nonmetropolitan areas has shown that since the 1950s patterns of growth have supported a more deconcentrated settlement pattern.

Neurotoxicity is a common side effect of chemotherapy treatment, with unclear molecular mechanisms. Clinical studies suggest that the most frequent neurotoxic adverse events affect memory and learning, attention, concentration, processing speeds and executive function. Emerging preclinical research points toward direct cellular toxicity and induction of neuroinflammation as key drivers of neurotoxicity and subsequent cognitive impairment. Emerging data now show detectable levels of some chemotherapeutic agents within the CNS, indicating potential disruption of blood brain barrier integrity or transport mechanisms. Blood brain barrier disruption is a key aspect of many neurocognitive disorders, particularly those characterized by a proinflammatory state. Importantly, many proinflammatory mediators able to modulate the blood brain barrier are generated by tissues and organs that are targets for chemotherapy-associated toxicities. This review therefore aims to explore the hypothesis that peripherally derived inflammatory cytokines disrupt blood brain barrier permeability, thereby increasing direct access of chemotherapeutic agents into the CNS to facilitate neuroinflammation and central neurotoxicity. [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]

Existing empirical research suggests that human resource officials, managers, and in-house counsel influence the meaning of antidiscrimination law by communicating an altered ideology of what civil rights laws mean that is colored with managerial values. This article explores how insurance companies play a critical and, as yet, unrecognized role in mediating the meaning of antidiscrimination law through Employment Practice Liability Insurance ( EPLI). My analysis draws from, links, and contributes to two literatures that examine organizational behavior in different ways: new institutional organizational sociology studies of how organizations respond to legal regulation and sociolegal insurance scholars' research on how institutions govern through risk. Through participant observation at EPLI conferences, interviews, and content analysis of insurance loss prevention manuals, my study bridges these two literatures and highlights how the insurance field uses a risk-based logic to construct the threat of employment law and influence the form of compliance from employers. Faced with uncertain legal risk concerning potential discrimination violations, insurance institutions elevate the risk and threat in the legal environment and offer EPLI and a series of risk-management services that build discretion into legal rules and mediate the nature of civil rights compliance. My data suggest that insurance risk-management services may sometimes be compatible with civil rights goals of improving equality, due process, and fair governance in workplace settings, but at other times may simply make discrimination claims against employers more defensible. [ABSTRACT FROM AUTHOR]

Background: Considerable progress has been made in our understanding of the biological basis for cancer therapy-induced mucosal barrier injury (mucositis). The last formal review of the subject by MASCC/ISOO was published in 2007; consequently, an update is timely. Methods: Panel members reviewed the biomedical literature on mucositis pathobiology published between January 2005 and December 2011. Results: Recent research has provided data on the contribution of tissue structure changes, inflammation and microbiome changes to the development of mucositis. Additional research has focused on targeted therapy-induced toxicity, toxicity clustering and the investigation of genetic polymorphisms in toxicity prediction. This review paper summarizes the recent evidence on these aspects of mucositis pathobiology. Conclusion: The ultimate goal of mucositis researchers is to identify the most appropriate targets for therapeutic interventions and to be able to predict toxicity risk and personalize interventions to genetically suitable patients. Continuing research efforts are needed to further our understanding of mucositis pathobiology and the pharmacogenomics of toxicity. [ABSTRACT FROM AUTHOR]

Background: Considerable progress has been made in our understanding of the biological basis for cancer therapy-induced mucosal barrier injury (mucositis). The last formal review of the subject by MASCC/ISOO was published in 2007; consequently, an update is timely. Methods: Panel members reviewed the biomedical literature on mucositis pathobiology published between January 2005 and December 2011. Results: Recent research has provided data on the contribution of tissue structure changes, inflammation and microbiome changes to the development of mucositis. Additional research has focused on targeted therapy-induced toxicity, toxicity clustering and the investigation of genetic polymorphisms in toxicity prediction. This review paper summarizes the recent evidence on these aspects of mucositis pathobiology. Conclusion: The ultimate goal of mucositis researchers is to identify the most appropriate targets for therapeutic interventions and to be able to predict toxicity risk and personalize interventions to genetically suitable patients. Continuing research efforts are needed to further our understanding of mucositis pathobiology and the pharmacogenomics of toxicity. [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]

Mucositis is a major oncological problem, caused by the cytotoxic effects of cancer chemotherapy and radiotherapy. Irinotecan is used to treat a variety of solid tumours, through the inhibition of DNA topoisomerase I and is linked with severe mucositis and diarrhoea. Mucus production appears to be increased, which may contribute to the development of diarrhoea. Dark agouti rats were treated with irinotecan, and tissues collected at several time points up to 72 h. Goblet cells and mucin secretion were investigated, as well as mucin expression (Muc2 and Muc4) and kruppel-like factor (Klf) 4 using immunohistochemistry in the gastrointestinal tract. Both goblet cells and cells positive for Muc expression were counted, and analysed statistically using the Mann–Whitney U test with Bonferroni correction. Goblet cells decreased significantly after irinotecan treatment. However, mucin secretion increased. Mucin expression changed significantly after treatment. Muc2 and Muc4 decreased significantly in the villi of the jejunum after treatment, Muc2 and Muc4 decreased significantly in the crypts. Muc2 decreased significantly in the colon. Irinotecan causes an increase in mucin secretion and a net decrease in mucin-producing goblet cells, and the expression of Muc2 and Muc4 in the gastrointestinal tract is altered following treatment. Increased mucin secretion is likely to be related to altered mucin expression, and may contribute to chemotherapy-induced diarrhoea. [ABSTRACT FROM AUTHOR]

Rural America's economy, culture, and landscape have entered a period of sustained and dramatic change. Patterns of land use and the context of development are increasingly driven by natural resource-based amenity values. Planners face a new breed of economic, social, and environmental issues brought about by this rapid change in land use; driven, in large part, by demands for rural residential developments and recreationally-oriented land uses. This annotated bibliography has been compiled as a primer to the academic literature that relates to this phenomenon. [ABSTRACT FROM AUTHOR]

In this article the author comments on the study by Richard M. Gibson and Jayne E. Harrison on the changes of the content of articles published in two orthodontic journals since 1999-2008. He says that the authors of the study show the rise of publication for reviews and the reduction on publication of articles related to education. He mentions the need to maintain research related to education as it is critical to ensure the use of the most suitable methods in the next generation.