Peptide motif analysis predicts alphaviruses as triggers for rheumatoid arthritis.

Rheumatoid arthritis (RA) develops in response to both genetic and environmental factors. The strongest genetic determinant is HLA-DR, where polymorphisms within the P4 and P6 binding pockets confer elevated risk. However, low disease concordance across monozygotic twin pairs underscores the importance of an environmental factor, probably infectious. The goal of this investigation was to predict the microorganism most likely to interact with HLA-DR to trigger RA under the molecular mimicry hypothesis. A set of 185 structural proteins from viruses or intracellular bacteria was scanned for regions of sequence homology with a collagen peptide that binds preferentially to DR4; candidates were then evaluated against a motif required for T cell cross-reactivity. The plausibility of the predicted agent was evaluated by comparison of microbial prevalence patterns to epidemiological characteristics of RA. Peptides from alphavirus capsid proteins provided the closest fit. Variations in the P6 position suggest that the HLA binding preference may vary by species, with Ross River virus, Chikungunya virus, and Mayaro virus peptides binding preferentially to DR4, and peptides from Sindbis/Ockelbo virus showing stronger affinity to DR1. The predicted HLA preference is supported by epidemiological studies of post-infection chronic arthralgia. Parallels between the cytokine profiles of RA and chronic alphavirus infection are discussed.

Peptide motif analysis predicts lymphocytic choriomeningitis virus as trigger for multiple sclerosis.

The etiology of multiple sclerosis (MS) involves both genetic and environmental factors. Genetically, the strongest link is with HLA DRB1*1501, but the environmental trigger, probably a virus, remains uncertain. This investigation scans a panel of proteins from encephalitogenic viruses for peptides homologous to the primary autoantigen from myelin basic protein (MBP), then evaluates candidate peptides against a motif required for T cell cross-reactivity and compares viral prevalence patterns to epidemiological characteristics of MS. The only peptide meeting criteria for cross-reactivity with MBP was one from lymphocytic choriomeningitis virus (LCMV), a zoonotic agent. In contrast to current candidates such as Epstein-Barr virus, the distribution of LCMV is consistent with epidemiological features of MS, including concentration in the temperate zone, higher prevalence farther from the equator, and increased prevalence in proximity to regions of peak MS incidence, while lack of person-to-person transmission is consistent with low MS concordance across monozygotic twins. Further, LCMV blocks induction of type I interferon (IFN). Hypothetically this would dysregulate immune processes in favor of proinflammatory pathways as well as upregulating HLA class II and providing more binding sites for autoantigen. The combination of molecular mimicry with virally-induced immune dysregulation has the potential to explain aspects of autoimmunity not addressed by either mechanism alone.

Efficacy of acupuncture for chronic low back pain: protocol for a randomized controlled trial.

BACKGROUND: Chronic back pain is a major public health problem and the primary reason patients seek acupuncture treatment. Therefore, an objective assessment of acupuncture efficacy is critical for making informed decisions about its appropriate role for patients with this common condition. This study addresses methodological shortcomings that have plagued previous studies evaluating acupuncture for chronic low back pain. METHODS AND DESIGN: A total of 640 participants (160 in each of four arms) between the ages of 18 and 70 years of age who have low back pain lasting at least 3 months will be recruited from integrated health care delivery systems in Seattle and Oakland. They will be randomized to one of two forms of Traditional Chinese Medical (TCM) acupuncture needling (individualized or standardized), a "control" group (simulated acupuncture), or to continued usual medical care. Ten treatments will be provided over 7 weeks. Study participants and the "Diagnostician" acupuncturists who evaluate participants and propose individualized treatments will be masked to the acupuncture treatment actually assigned each participant. The "Therapist" acupuncturists providing the treatments will not be masked but will have limited verbal interaction with participants. The primary outcomes, standard measures of dysfunction and bothersomeness of low back pain, will be assessed at baseline, and after 8, 26, and 52 weeks by telephone interviewers masked to treatment assignment. General health status, satisfaction with back care, days of back-related disability, and use and costs of healthcare services for back pain will also be measured. The primary analysis comparing outcomes by randomized treatment assignment will be analysis of covariance adjusted for baseline value. For both primary outcome measures, this trial will have 99% power to detect the presence of a minimal clinically significant difference among all four treatment groups and over 80% power for most pairwise comparisons. Secondary analyses will compare the proportions of participants in each group that improve by a clinically meaningful amount. CONCLUSION: Results of this trial will help clarify the value of acupuncture needling as a treatment for chronic low back pain. TRIAL REGISTRATION: Clinical Trials.gov NCT00065585.

Increased risk of high-grade anal neoplasia associated with a human papillomavirus type 16 E6 sequence variant.

Expression of the E6 and E7 genes of human papillomavirus (HPV) type 16 have been implicated in the etiology of anogenital premalignant and malignant lesions. To evaluate whether variations in the HPV-16 E6 sequence were related to the incidence of high-grade anal neoplasia, 628 HPV-16-positive anal specimens from 193 human immunodeficiency virus (HIV)-positive and 59 HIV-negative participants were typed for variations in 15 E6 nucleotide positions. Although most participants were infected with a prototype strain, 15 (6%) carried the G131 variant, and 12 (5%) were infected with the Af1a variant. Two new variants not previously reported were identified as well. An elevated risk for high-grade anal squamous intraepithelial lesions was associated with infection by G131 variants, compared with the prototype strain (odds ratio, 3.4; 95% confidence interval, 1.1-10), after controlling for HIV status. These data provide further evidence for HPV strain variation as a factor in determining the natural history of anogenital neoplasia.

Description and validation of a noninvasive placebo acupuncture procedure.

OBJECTIVE: To evaluate a simulated acupuncture technique for use in randomized controlled trials assessing the efficacy of acupuncture for low-back pain. SETTING: The clinic of an accredited acupuncture college in Seattle, Washington. SUBJECTS: Acupuncture-naïve enrollees of Group Health Cooperative who had visited their primary care provider with a complaint of back pain that persisted for at least 3 months. EXPERIMENTAL DESIGN: In the first experiment, subjects received six insertions of real needles and six pokes with a toothpick in a guidetube in a two-period crossover design. In the second experiment, subjects were randomly assigned to receive either a complete treatment with real acupuncture needles or a simulated treatment using a toothpick in a guidetube. OUTCOMES: In the first experiment, we compared subjects' perceptions about which implement was used for each "insertion" while in the second, we compared the perceptions (e.g., acupuncturist's warmth and caring, the reasonableness of acupuncture as a treatment) and pain relief of those who received an acupuncture treatment using needles to those receiving simulated acupuncture. RESULTS: In the first experiment, the toothpick insertions were perceived as slightly more like real needling than the real needling (mean ratings of 2.8 and 2.1, respectively; p = 0.08). In the second experiment, 52% percent of those receiving the simulated needling versus 65% of those receiving real acupuncture believed they were "definitely" or "probably" receiving real acupuncture (p = 0.33). Perceptions of acupuncture, as measured by a credibility questionnaire, were similar in the two groups. Those receiving real acupuncture were more likely to report immediate pain relief, and this was the factor most predictive of the subject's belief about which treatment they had received (p = 0.02). CONCLUSIONS: The simulated acupuncture procedure evaluated in this study represents a reasonable control treatment for acupuncture-naïve individuals in randomized controlled trials assessing the efficacy of acupuncture for low-back pain.