Clarifying the Ethics and Oversight of Chimeric Research.

This article is the lead piece in a special report that presents the results of a bioethical investigation into chimeric research, which involves the insertion of human cells into nonhuman animals and nonhuman animal embryos, including into their brains. Rapid scientific developments in this field may advance knowledge and could lead to new therapies for humans. They also reveal the conceptual, ethical, and procedural limitations of existing ethics guidance for human-nonhuman chimeric research. Led by bioethics researchers working closely with an interdisciplinary work group, the investigation focused on generating conceptual clarity and identifying improvements to governance approaches, with the goal of helping scholars, funders, scientists, institutional leaders, and oversight bodies (embryonic stem cell research oversight [ESCRO] committees and institutional animal care and use committees [IACUCs]) deliver principled and trustworthy oversight of this area of science. The article, which focuses on human-nonhuman animal chimeric research that is stem cell based, identifies key ethical issues in and offers ten recommendations regarding the ethics and oversight of this research. Turning from bioethics' previous focus on human-centered questions about the ethics of "humanization" and this research's potential impact on concepts like human dignity, this article emphasizes the importance of nonhuman animal welfare concerns in chimeric research and argues for less-siloed governance and oversight and more-comprehensive public communication.

The tampon test for vulvodynia treatment outcomes research: reliability, construct validity, and responsiveness.

OBJECTIVE: A standardized tampon insertion and removal test, the Tampon Test provides an alternative to sexual intercourse pain as an outcome measure for vulvodynia research. We report upon the reliability, validity, and responsiveness to change of the Tampon Test as an outcome measure for vulvodynia clinical trials. METHODS: Outcome measures were assessed in women enrolled in the Vulvar Vestibulitis Clinical Trial, a randomized clinical trial of oral desipramine and topical lidocaine effectiveness. Reliability estimates of the Tampon Test using the Kappa statistic evaluated week-to-week measures at baseline. Tampon Test construct and discriminant validity were assessed through correlation with other outcome measures. Patients' ability to regularly perform the Tampon Test was compared with regularity of reporting intercourse pain. RESULTS: During the 2-week baseline phase, women with vulvodynia reported stable mean Tampon Test scores 4.6+/-2.6 (week -2); 4.6+/-2.7 (week -1); and 4.7+/-2.8 (week 0) with moderate week-to-week reliability (weighted Kappa 0.52). Over an 8-week phase of trial intervention, change in the Tampon Test measure significantly correlated to a number of outcome measures, including daily pain (r=0.42), intercourse pain (r=0.35), cotton swab vestibular pain (r=0.38), and the Brief Pain Inventory (r=0.49). Women with vulvodynia study participants performed the Tampon Test 96.3% of the requested time, which was twofold higher adherence than intercourse pain measurement (49.7%). CONCLUSION: The Tampon Test reflects a real life experience that is reliable, with good construct validity as shown by the breadth of correlated outcome measures. The Tampon Test is an appropriate outcome measure for vulvodynia research that can be considered for use as the primary efficacy endpoint in clinical trials of treatments for vulvodynia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00276068 LEVEL OF EVIDENCE: II.

Site-specific mesenchymal control of inflammatory pain to yeast challenge in vulvodynia-afflicted and pain-free women.

Fibroblast strains were derived from 2 regions of the lower genital tract of localized provoked vulvodynia (LPV) cases and pain-free controls. Sixteen strains were derived from 4 cases and 4 controls, age and race matched, after presampling mechanical pain threshold assessments. Strains were challenged with 6 separate stimuli: live yeast species (Candida albicans, Candida glabrata, Candida tropicalis, and Saccharomyces cerevisiae), yeast extract (zymosan), or inactive vehicle. Production of prostaglandin E2 (PGE2) and interleukin 6 (IL-6) were proinflammatory response measures. Highest IL-6 and PGE2 occurred with vestibular strains after C albicans, C glabrata, and zymosan challenges, resulting in the ability to significantly predict IL-6 and PGE2 production by genital tract location. After C albicans and C glabrata challenge of all 16 fibroblast strains, adjusting for dual sampling of subjects, PGE2 and IL-6 production significantly predicted the presampling pain threshold from the genital tract site of sampling. At the same location of pain assessment and fibroblast sampling, in situ immunohistochemical (IHC)(+) fibroblasts for IL-6 and Cox-2 were quantified microscopically. The correlation between IL-6 production and IL-6 IHC(+) was statistically significant; however, biological significance is unknown because of the small number of IHC(+) IL-6 fibroblasts identified. A low fibroblast IL-6 IHC(+) count may result from most IL-6 produced by fibroblasts existing in a secreted extracellular state. Enhanced, site-specific, innate immune responsiveness to yeast pathogens by fibroblasts may be an early step in LPV pathogenesis. Fibroblast strain testing may offer an attractive and objective marker of LPV pathology in women with vulvodynia of inflammatory origin.

Oral desipramine and topical lidocaine for vulvodynia: a randomized controlled trial.

OBJECTIVE: To estimate the efficacy of common treatments for vulvodynia: topical lidocaine monotherapy, oral desipramine monotherapy, and lidocaine-desipramine combined therapy. METHODS: A 12-week randomized, double-blinded, placebo-controlled trial was conducted on 133 vulvodynia-afflicted women assigned to four treatment arms: placebo tablets-placebo cream, desipramine tablets-placebo cream, placebo tablets-lidocaine cream, and desipramine tablets-lidocaine cream. The tampon test was selected as primary end point using a modified intention-to-treat analysis. Twelve secondary end points were also examined. At completion of the 12-week randomized phase, women were examined "open label" through 52 weeks postrandomization. RESULTS: All treatment arms reported substantial tampon-test pain reduction: 33% reduction placebo cream-placebo tablet, 20% reduction lidocaine cream-placebo tablet, 24% reduction placebo cream-desipramine tablet, and 36% reduction lidocaine cream-desipramine tablet. Compared with placebo, we found no significant difference in tampon-test pain reduction with desipramine (t=0.90; P=.37) or lidocaine (t=1.27; P=.21). Of the remaining 12 outcome measures, only the Index of Sexual Satisfaction, improved with desipramine compared with placebo (t=-2.81; P=.006). During the open-label phase, women undergoing vestibulectomy surgery reported significantly improved pain as measured by cotton swab test and the McGill Pain Scale compared with nonsurgical alternatives. CONCLUSION: Oral desipramine and topical lidocaine, as monotherapy or in combination, failed to reduce vulvodynia pain more than placebo. Placebo or placebo-independent effects are behind the substantial pain improvement seen in all treatment allocations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00276068. LEVEL OF EVIDENCE: I.

Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network.

A recent study by Persico et al. [2001: Mol Psychiatry 6:150-159] suggests alleles of a CGG polymorphism, just 5' of the reelin gene (RELN) initiator codon, confer liability for autism, especially alleles bearing 11 or more CGG repeats (long alleles). The association is consistent across both a case-control and family-based sample. We attempted to replicate their finding using a larger, independent family-based sample from the NIH Collaborative Programs of Excellence in Autism (CPEA) Network. In our data, allele transmissions to individuals with autism versus unaffected individuals are unbiased, both when alleles are classified by repeat length and when they are classified into long/short categories. Because of the apparent linkage of autism to chromosome 7q, particularly related to the development of language, we also evaluate the relationship between Reelin alleles and the age at which autism subjects use their first word or first phrase. Neither is significantly associated with Reelin alleles. Our results are not consistent with a major role for Reelin alleles in liability to autism.