Allopregnanolone Levels Are Inversely Associated with Self-Reported Pain Symptoms in U.S. Iraq and Afghanistan-Era Veterans: Implications for Biomarkers and Therapeutics.

BACKGROUND AND OBJECTIVES: Pain symptoms are common among Iraq/Afghanistan-era veterans, many of whom continue to experience persistent pain symptoms despite multiple pharmacological interventions. Preclinical data suggest that neurosteroids such as allopregnanolone demonstrate pronounced analgesic properties, and thus represent logical biomarker candidates and therapeutic targets for pain. Allopregnanolone is also a positive GABAA receptor modulator with anxiolytic, anticonvulsant, and neuroprotective actions in rodent models. We previously reported inverse associations between serum allopregnanolone levels and self-reported pain symptom severity in a pilot study of 82 male veterans. METHODS: The current study investigates allopregnanolone levels in a larger cohort of 485 male Iraq/Afghanistan-era veterans to attempt to replicate these initial findings. Pain symptoms were assessed by items from the Symptom Checklist-90-R (SCL-90-R) querying headache, chest pain, muscle soreness, and low back pain over the past 7 days. Allopregnanolone levels were quantified by gas chromatography/mass spectrometry. RESULTS: Associations between pain ratings and allopregnanolone levels were examined with Poisson regression analyses, controlling for age and smoking. Bivariate nonparametric Mann–Whitney analyses examining allopregnanolone levels across high and low levels of pain were also conducted. Allopregnanolone levels were inversely associated with muscle soreness [P = 0.0028], chest pain [P = 0.032], and aggregate total pain (sum of all four pain items) [P = 0.0001]. In the bivariate analyses, allopregnanolone levels were lower in the group reporting high levels of muscle soreness [P = 0.001]. CONCLUSIONS: These findings are generally consistent with our prior pilot study and suggest that allopregnanolone may function as an endogenous analgesic. Thus, exogenous supplementation with allopregnanolone could have therapeutic potential. The characterization of neurosteroid profiles may also have biomarker utility.

Developing drugs for developing countries.

Infectious and parasitic diseases create enormous health burdens, but because most of the people suffering from these diseases are poor, little is invested in developing treatments. We propose that developers of treatments for neglected diseases receive a "priority review voucher." The voucher could save an average of one year of U.S. Food and Drug Administration (FDA) review and be sold by the developer to the manufacturer of a blockbuster drug. In a well-functioning market, the voucher would speed access to highly valued treatments. Thus, the voucher could benefit consumers in both developing and developed countries at relatively low cost to the taxpayer.

In Whose Image: The Emergence, Development, and Challenge of African-American Evangelicalism

The current era of American Christianity marks the transition from a Western, white-dominated U.S. Evangelicalism to an ethnically diverse demographic for evangelicalism. Despite this increasing diversity, U.S. Evangelicalism has demonstrated a stubborn inability to address the entrenched assumption of white supremacy. The 1970s witnessed the rise in prominence of Evangelicalism in the United States. At the same time, the era witnessed a burgeoning movement of African-American evangelicals, who often experienced marginalization from the larger movement. What factors prevented the integration between two seemingly theologically compatible movements? How do these factors impact the challenge of integration and reconciliation in the changing demographic reality of early twenty-first Evangelicalism?

The question is examined through the unpacking of the diseased theological imagination rooted in U.S. Evangelicalism. The theological categories of Creation, Anthropology, Christology, Soteriology, and Ecclesiology are discussed to determine specific deficiencies that lead to assumptions of white supremacy. The larger history of U.S. Evangelicalism and the larger story of the African-American church are explored to provide a context for the unique expression of African-American evangelicalism in the last third of the twentieth century. Through the use of primary sources — personal interviews, archival documents, writings by principals, and private collection documents — the specific history of African-American evangelicals in the 1960s and 1970s is described. The stories of the National Black Evangelical Association, Tom Skinner, John Perkins, and Circle Church provide historical snapshots that illuminate the relationship between the larger U.S. Evangelical movement and African-American evangelicals.

Various attempts at integration and shared leadership were made in the 1970s as African-American evangelicals engaged with white Evangelical institutions. However, the failure of these attempts point to the challenges to diversity for U.S. Evangelicalism and the failure of the Evangelical theological imagination. The diseased theological imagination of U.S. Evangelical Christianity prevented engagement with the needed challenge of African American evangelicalism, resulting in dysfunctional racial dynamics evident in twenty-first century Evangelical Christianity. The historical problem of situating African American evangelicals reveals the theological problem of white supremacy in U.S. Evangelicalism.

Electrostatic Energetics of Bacillus subtilis Ribonuclease P Protein Determined by Nuclear Magnetic Resonance-Based Histidine pKa Measurements.

The pKa values of ionizable groups in proteins report the free energy of site-specific proton binding and provide a direct means of studying pH-dependent stability. We measured histidine pKa values (H3, H22, and H105) in the unfolded (U), intermediate (I), and sulfate-bound folded (F) states of RNase P protein, using an efficient and accurate nuclear magnetic resonance-monitored titration approach that utilizes internal reference compounds and a parametric fitting method. The three histidines in the sulfate-bound folded protein have pKa values depressed by 0.21 ± 0.01, 0.49 ± 0.01, and 1.00 ± 0.01 units, respectively, relative to that of the model compound N-acetyl-l-histidine methylamide. In the unliganded and unfolded protein, the pKa values are depressed relative to that of the model compound by 0.73 ± 0.02, 0.45 ± 0.02, and 0.68 ± 0.02 units, respectively. Above pH 5.5, H22 displays a separate resonance, which we have assigned to I, whose apparent pKa value is depressed by 1.03 ± 0.25 units, which is ∼0.5 units more than in either U or F. The depressed pKa values we observe are consistent with repulsive interactions between protonated histidine side chains and the net positive charge of the protein. However, the pKa differences between F and U are small for all three histidines, and they have little ionic strength dependence in F. Taken together, these observations suggest that unfavorable electrostatics alone do not account for the fact that RNase P protein is intrinsically unfolded in the absence of ligand. Multiple factors encoded in the P protein sequence account for its IUP property, which may play an important role in its function.