Archeological and Bioarcheological Investigations at Campbell’s Bayou Cemetery Galveston County, Texas

This report documents the removal of individuals buried within Campbell’s Bayou Cemetery (41GV171) to avoid potential impact to the remains during implementation of remediation activities at the Malone Service Company Superfund Site (Site) in Texas City, TX. An oil recovery and waste processing facility had operated at the Site for more than 30 years, ending in the mid1990s. The facility had stored, processed, and disposed of industrial solid wastes and hazardous wastes. In July 2012, a group of companies known as the Malone Cooperating Parties (MCP) entered into a Consent Decree with the U.S. Government, the U.S. Environmental Protection Agency, and the State of Texas to implement a remedial design and remedial action at the Site. It was determined that if the remains in the cemetery were not relocated, there was the potential that remediation activities could impact the cemetery. Archival research, review of historic maps and aerial photographs, and reconnaissance survey revealed the extent of potential remains at the cemetery, and, given the location of the cemetery and the scope of the planned remediation activities, it was deemed impractical for the environmental remediation contractors to work around the cemetery. (41GV171). The MCP consulted with EPA, Campbell family descendants, the Galveston County Historical Commission, and the Texas Historical Commission and developed a plan to relocate the remains to a perpetual care cemetery in accordance with Texas state law and associated rules and procedures. In accordance with Texas Health and Safety Code §711.004, the landowner Land Navigator, Ltd., on behalf of the MCP, petitioned the Galveston County Judicial District Court for removal of the dedication of the cemetery and the transfer of the human remains to the perpetual care cemetery operated by Forest Park East Funeral Home and Cemetery (FPE), 21620 Gulf Freeway, Webster, TX 77598. On February 11, 2014, Land Navigator was granted a Summary Judgment allowing Land Navigator to disinter and relocate the remains to FPE. Versar, Inc. (formerly Geo-Marine, Inc.), on behalf of the MCP, provided all archeological and human osteological expertise for the disinterment and analysis of the human remains. Disinterment permits from the State Registrar of the Vital Statistics Unit of the Department of State Health Services, as required by Texas Administrative Code, Title 13, Chapter 22 (Texas Historical Commission, Cemeteries), were obtained for each burial. The disinterment excavations at Campbell’s Bayou Cemetery revealed 34 burials from which 35 individuals were excavated. No graves were marked by headstones. It is the professional judgment of Versar that, of the 35 individual sets of remains identified, 11 were determined to be adults (5 male and 3 female; 3 of indeterminate sex), and 24 were determined to be children. The majority of children at Campbell’s Bayou Cemetery (n=18) are under 5 years of age and six are premature infants aged 30–40 weeks. Burials could not be associated conclusively with any individuals identified by the descendants; however, the combination of bioarcheological analysis, coffin hardware analysis, census data, and descendant identifications resulted in a list of individuals that may have been interred in certain graves. Some of the interments include James and Mary Campbell, Charlie Meyers, Benjamin Ninnie Dick, Phoebe Rutlage, and Shelby McNeil, Jr. Children were difficult to identify; however, there is good potential the graves of Frank Campbell, Mary Jane Campbell, Charles Munson, and Grace Dick were identified. Data are conclusive that the children Levi and Joseph (Joe) Parr were both interred together in Burial 6, the concrete crypt with brick covering. Grace Dick was the last individual interred at the cemetery in 1904

The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington's disease

<p>Abstract</p> <p>Background</p> <p>Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion within the huntingtin gene. Mutant huntingtin protein misfolds and accumulates within neurons where it mediates its toxic effects. Promoting mutant huntingtin clearance by activating macroautophagy is one approach for treating Huntington's disease (HD). In this study, we evaluated the mTOR kinase inhibitor and macroautophagy promoting drug everolimus in the R6/2 mouse model of HD.</p> <p>Results</p> <p>Everolimus decreased phosphorylation of the mTOR target protein S6 kinase indicating brain penetration. However, everolimus did not activate brain macroautophagy as measured by LC3B Western blot analysis. Everolimus protected against early declines in motor performance; however, we found no evidence for neuroprotection as determined by brain pathology. In muscle but not brain, everolimus significantly decreased soluble mutant huntingtin levels.</p> <p>Conclusions</p> <p>Our data suggests that beneficial behavioral effects of everolimus in R6/2 mice result primarily from effects on muscle. Even though everolimus significantly modulated its target brain S6 kinase, this did not decrease mutant huntingtin levels or provide neuroprotection.</p

Unexplained Gaps and Oaxaca-Blinder Decompositions

We analyze four methods to measure unexplained gaps in mean outcomes: three decompositions based on the seminal work of Oaxaca (1973) and Blinder (1973) and an approach involving a seemingly naive regression that includes a group indicator variable. Our analysis yields two principal findings. We show that the coefficient on a group indicator variable from an OLS regression is an attractive approach for obtaining a single measure of the unexplained gap. We also show that a commonly-used pooling decomposition systematically overstates the contribution of observable characteristics to mean outcome differences when compared to OLS regression, therefore understating unexplained differences. We then provide three empirical examples that explore the practical importance of our analytic results

KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients

The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology

Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1α, has been reported to be a significant modifier of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these findings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p < 0.001), suggesting population-dependent phenotype stratification. When the generalized estimating equations models were adjusted for ancestry, the effect of the rs7665116 genotype on AO decreased dramatically. Our results do not support rs7665116 as a modifier of AO of motor symptoms, as we found evidence for a dramatic effect of phenotypic (AO) and genotypic (MAF) stratification among European cohorts that was not considered in previously reported association studies. A significantly older AO in Southern Europe may reflect population differences in genetic or environmental factors that warrant further investigation

Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington’s disease motor onset

Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3′ UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington\u27s Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington\u27s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington\u27s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression