Chronic Viral Infection and Primary Central Nervous System Malignancy

Primary central nervous system (CNS) tumors cause significant morbidity and mortality in both adults and children. While some of the genetic and molecular mechanisms of neuro-oncogenesis are known, much less is known about possible epigenetic contributions to disease pathophysiology. Over the last several decades, chronic viral infections have been associated with a number of human malignancies. In primary CNS malignancies, two families of viruses, namely polyomavirus and herpesvirus, have been detected with varied frequencies in a number of pediatric and adult histological tumor subtypes. However, establishing a link between chronic viral infection and primary CNS malignancy has been an area of considerable controversy, due in part to variations in detection frequencies and methodologies used among researchers. Since a latent viral neurotropism can be seen with a variety of viruses and a widespread seropositivity exists among the population, it has been difficult to establish an association between viral infection and CNS malignancy based on epidemiology alone. While direct evidence of a role of viruses in neuro-oncogenesis in humans is lacking, a more plausible hypothesis of neuro-oncomodulation has been proposed. The overall goals of this review are to summarize the many human investigations that have studied viral infection in primary CNS tumors, discuss potential neuro-oncomodulatory mechanisms of viral-associated CNS disease and propose future research directions to establish a more firm association between chronic viral infections and primary CNS malignancies

An intron polymorphism of the fibronectin gene is associated with end-stage knee osteoarthritis in a Han Chinese population: two independent case-control studies

BACKGROUND: Knee osteoarthritis (OA) is a complex disease involving both biomechanical and metabolic factors that alter the tissue homeostasis of articular cartilage and subchondral bone. The catabolic activities of extracellular matrix degradation products, especially fibronectin (FN), have been implicated in mediating cartilage degradation. Chondrocytes express several members of the integrin family which can serve as receptors for FN including integrins α5β1, αvβ3, and αvβ5. The purpose of this study was to determine whether polymorphisms in the FN (FN-1) and integrin genes are markers of susceptibility to, or severity of, knee OA in a Han Chinese population. METHODS: Two independent case–control studies were conducted on 928 patients with knee OA and 693 healthy controls. Ten single nucleotide polymorphisms (SNPs) of FN-1 and the integrin αV gene (ITGAV) were detected using the ABI 7500 real-time PCR system. RESULTS: The AT heterozygote in FN-1 (rs940739A/T) was found to be significantly associated with knee OA (adjusted OR = 1.44; 95% CI = 1.16–1.80) in both stages of the study. FN-1 rs6725958C/A and ITGAV rs10174098A/G SNPs were only associated with knee OA when both study groups were combined. Stratifying the participants by Kellgren-Lawrence (KL) score identified significant differences in the FN-1 rs6725958C/A and rs940739 A/T genotypes between patients with grade 4 OA and controls. Haplotype analyses revealed that TGA and TAA were associated with a higher risk of OA, and that TAG conferred a lower risk of knee OA in the combined population. CONCLUSIONS: Our study suggests that the FN-1 rs940739A/T polymorphism may be an important risk factor of genetic susceptibility to knee OA in the Han Chinese population

Evaluation of a novel assessment form for observing medical residents: a randomised, controlled trial.

CONTEXT: Teaching faculty cannot reliably distinguish between satisfactory and unsatisfactory resident performances and give non-specific feedback. OBJECTIVES: This study aimed to test whether a novel rating form can improve faculty accuracy in detecting unsatisfactory performances, generate more rater observations and improve feedback quality. METHODS: Participants included two groups of 40 internal medicine residency faculty staff. Both groups received 1-hour training on how to rate trainees in the mini-clinical evaluation exercise (mini-CEX) format. The intervention group was given a new rating form structured with prompts, space for free-text comments, behavioural anchors and fewer scoring levels, whereas the control group used the current American Board of Internal Medicine Mini-CEX form. Participants watched and scored six scripted videotapes of resident performances 2-3 weeks after the training session. RESULTS: Intervention group participants were more accurate in discriminating satisfactory from unsatisfactory performances (85% versus 73% correct; odds ratio [OR] 2.13, 95% confidence interval [CI] 1.16-3.14, P = 0.02) and yielded more correctly identified unsatisfactory performances (96% versus 52% correct; OR 25.35, 95% CI 9.12-70.46), but were less accurate in identifying satisfactory performances (73% versus 95% correct; OR 0.15, 95% CI 0.05-0.39). Intervention group participants averaged one fewer declared intended feedback item (4.7 versus 5.7) and showed no difference in the amount of feedback that was above minimal in quality. Intervention group participants generated more written evaluative observations (10.8 versus 5.7). Inter-rater agreement improved with the new form (Fleiss\u27 kappa, 0.52 versus 0.30). CONCLUSIONS: Modifying the currently used direct observations process may produce more recorded observations, increase inter-rater agreement and improve overall rater accuracy, but it may also increase severity error

Mad-1 Is the Exclusive JC Virus Strain Present in the Human Colon, and Its Transcriptional Control Region Has a Deleted 98-Base-Pair Sequence in Colon Cancer Tissues

JC virus (JCV), along with other members of the polyomavirus family, encodes a class of highly conserved proteins, T antigens, that are capable of inducing aneuploidy in cultured cells. We have previously isolated T-antigen DNA variants of JCV from both colon cancer tissues and the corresponding nonneoplastic gastrointestinal tissues, raising new questions about the role of JCV in the development of chromosomal instability of the colon. Based on the sequence of the transcriptional control region (TCR), JCV can be classified as archetype or tandem repeat variants. Among the latter, Mad-1, the prototype virus first isolated from a patient with progressive multifocal leukoencephalopathy, is characterized by lacking the 23- and 66-bp sequences that are present in the archetype and by duplication of a 98-bp sequence. In this study, we evaluated differences in the TCR of JCV isolated from colon cancer tissues and nonneoplastic epithelium. To characterize JCV variants, we first treated eight pairs of DNA samples from colon cancers and noncancerous tissue with topoisomerase I and then amplified and cloned the JCV TCR. We obtained 285 recombinant clones from the JCV TCR, 157 from nonneoplastic samples, and 128 from colon cancer tissues. Of these clones, 262 spanned the length of the JCV Mad-1 TCR: 99.3% from nonneoplastic samples and 82.8% from colon cancer tissues. In sequencing 54 clones in both directions, we did not find archetype JCV either in the nonneoplastic tissue or in the cancer samples. From all colon cancer tissues, 18 clones had a deletion of one 98-bp tandem repeat. This deleted strain was not detected in any of the nonneoplastic tissues (14 versus 0% [χ(2) = 23.6; P < 0.001]). Our study demonstrates that the only JCV strain present in the human colon is Mad-1, and the variant with a single 98-bp sequence is found exclusively in the cancer tissues. This strain may be involved in the development of chromosomal instability