Estimating racial health disparities among adverse birth outcomes as deviations from the population rates.

BACKGROUND: Despite significant research, the reasons for racial health disparities among adverse birth outcomes (ABO) remain largely unknown. The bulk of research into racial health disparities among ABO in the United States has concentrated on the risk of race and ethnic groups relative to the specific sub-population of non-Hispanic white women and their children. The objective of this study was to estimate the racial and ethnic risks among a set of neonatal and maternal health disparities while minimizing bias attributable to how the baseline risk was established. METHODS: All birth records were obtained from the United States Natality database for the years 2014 to 2017. A Bayesian modeling approach was used to estimate the risk disparity for disorders by race. The estimation of the race-specific risks used a sum-to-zero constraint for the race regression coefficients. RESULTS: Estimating racial health disparities relative to the overall population rate yielded novel results and identified perinatal health disparities for all the race groups studied. CONCLUSIONS: Unbiased risk estimates for racial disparities among ABO are now available for stimulating and initiating more complex causal modeling that can lead to understanding how racial health disparities for ABO are mediated and how they can be prevented.

The risks of advancing parental age on neonatal morbidity and mortality are U- or J-shaped for both maternal and paternal ages.

BACKGROUND: The biologic implications of delayed parenthood have been blamed for a major public health crisis in the United States, that includes high rates of neonatal morbidity and mortality (NMM). The objective of this study was to evaluate the risk of parent age on NMM and to provide results that can serve as a starting point for more specific mediation modeling. METHODS: Data containing approximately 15,000,000 birth records were obtained from the United States Natality database for the years 2014 to 2018. A Bayesian modeling approach was used to estimate the both the total effect and the risk adjusted for confounding between parent ages and for mediation by chromosomal disorders including Down syndrome. Outcomes included intra-hospital death and nine measures of neonatal morbidity. RESULTS: For paternal age, seven NMM (preterm birth, very preterm birth, low Apgar score, treatment with antibiotics, treatment with surfactant, prolonged ventilation, intra-hospital death) had U-shaped risk patterns, two NMM (small for gestational age, admission to neonatal intensive care) had J-shaped risk patterns, one NMM (seizures) was not significantly related to paternal age. For maternal age, three NMM (low Apgar score, treatment with antibiotics and intra-hospital death) had U-shaped risk patterns, four NMM (preterm delivery, very preterm delivery, admission to neonatal intensive care, treatment with surfactant) had J-shaped risk patterns, one NMM (small for gestational age) had a risk declining with age, one NMM (prolonged ventilation) had a risk increasing with age and one NMM (seizures) was not significantly related to maternal age. CONCLUSIONS: Both advancing maternal and paternal ages had U- or J-shaped risk patterns for neonatal morbidity and mortality.

Disentangling the roles of maternal and paternal age on birth prevalence of down syndrome and other chromosomal disorders using a Bayesian modeling approach.

BACKGROUND: Multiple neonatal and pediatric disorders have been linked to older paternal ages. Combining these findings with the evidence that many men are having children at much later ages generates considerable public health concern. The risk of paternal age has been difficult to estimate and interpret because children often have parents whose ages are similar and likely to be confounded. Epidemiologic studies often model the conditional effects of paternal age using regression models that typically treat maternal age as linear, curvilinear or as age-band categories. Each of these approaches has limitations. As an alternative, the current study measures age to the nearest year, and fits a Bayesian model in which each parent's age is given a conditional autoregressive prior (CAR). METHODS: Data containing approximately 12,000,000 birth records were obtained from the United States Natality database for the years 2014 to 2016. Date were cross-tabulated for maternal ages 15-49 years and for paternal ages 15-65 years. A Bayesian logistic model was implemented using conditional autoregressive priors for both maternal and paternal ages modeled separately and jointly for both Down syndrome and chromosomal disorders other than Down syndrome. RESULTS: Models with maternal and paternal ages given CAR priors were judged to be better fitting than traditional models. For Down syndrome, the approach attributed a very large risk to advancing maternal age with the effect of advancing paternal age having a very small sparing effect on birth prevalence. Maternal age was also related to the birth prevalence of chromosomal disorders other than Down syndrome while paternal age was not. CONCLUSIONS: Advancing paternal age was not associated with an increase in risk for either Down syndrome or chromosomal disorders other than Down syndrome.

An evaluation of whether a gestational weight gain of 5 to 9 kg for obese women optimizes maternal and neonatal health risks.

BACKGROUND: Maternal obesity has a wide range of health effects on both the pregnant woman and developing fetus. The clinical significance of these disorders, combined with a dramatically increasing prevalence of obesity among pregnant women has precipitated a major health crisis in the United States. The most commonly used recommendations for gestational weight gain were established by the Institute of Medicine (IOM) in 2009 and have become well known and often adopted. The authors of the IOM report acknowledged that the recommended gestational weight gain of 5 to 9 kg for obese women whose body mass index was greater than 30 kg/m2 was based on very little empirical evidence. The objective of this study was to evaluate whether a 5 to 9 kg weight gain, for obese women, optimized a set of maternal and neonatal health outcomes. METHODS: Data containing approximately 12,000,000 birth records were obtained from the United States Natality database for the years 2014 to 2016. A Bayesian modeling approach was used to estimate the controlled direct effects of pre-pregnancy body mass index and gestational weight gain. RESULTS: Obese women gaining less than 5 kg during pregnancy had reduced maternal risks for gestational hypertension, eclampsia, induction of labor and Caesarian section. In contrast, maternal gestational weight gain of less than 5 kg was associated with increased risks for multiple adverse neonatal outcomes with macrosomia the exception. Obese women who gained more than 9 kg during pregnancy had increased risk for multiple maternal and neonatal adverse outcomes. CONCLUSIONS: Obese women who were observed to gain less than 5 kg during gestation had reduced odds of several peripartum disorders. However, this lower gestational weight gain was associated with an increase in multiple risks for the neonate.

Effect of intra-ovarian injection of mesenchymal stem cells in aged mares.

PURPOSE: This study aims to determine if intra-ovarian injection of bone marrow-derived mesenchymal stem cells (MSCs) improves or restores ovarian function in aged females. METHODS: Prospective randomized study of eight aged mares and six young mares receiving intra-ovarian injection of MSCs or vehicle. Main outcome measures were antral follicle count and serum anti-Müllerian hormone (AMH) (aged and young mares), and for aged mares, oocyte meiotic and developmental competence; gross and histological ovarian assessment; evaluation of presence of chimerism in recovered granulosa cells and in ovarian tissue samples; and gene expression in ovarian tissue as assessed by RNA sequencing. RESULTS: Injection of MSCs was not associated with significant changes in follicle number, oocyte recovery rate on follicle aspiration, oocyte maturation rate, or blastocyst rate after ICSI in aged mares, or in changes in follicle number in young mares. There were no significant changes in peripheral AMH concentrations, indicating a lack of effect on growing follicles. MSC donor DNA was not recovered in granulosa cells or in ovarian tissue, indicating lack of persistence of injected MSC. RNA sequencing revealed significant differences in gene expression between MSC- and vehicle-injected ovaries. CONCLUSIONS: Intra-ovarian injection of bone marrow-derived MSCs altered gene expression but did not improve ovarian function in aged mares.

Metronidazole for the treatment of Tritrichomonas foetus in bulls.

BACKGROUND: Tritrichomonas foetus is a sexually transmitted protozoon that causes reproductive failure, among cattle, so disruptive that many western US states have initiated control programs. Current control programs are based on the testing and exclusion of individual bulls. Unfortunately, these programs are utilizing screening tests that are lacking in sensitivity. Blanket treatment of all the exposed bulls and adequate sexual rest for the exposed cows could provide a more viable disease control option. The objectives of this study were twofold. The first objective was to demonstrate effectiveness for metronidazole treatment of a bull under ideal conditions and with an optimized treatment regime. This type of study with a single subject is often referred to as an n-of-1 or single subject clinical trial. The second objective of the current study was to review the scientific basis for the banning of metronidazole for use in Food Animals by the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA). RESULTS: Results from an antimicrobial assay indicated that metronidazole at a concentration of 0.5 µg/mL successfully eliminated in vitro protozoal growth of bovine Tritrichomonas foetus. The estimated effective intravenous dose was two treatments with 60 mg/kg metronidazole, 24 h apart. A bull that had tested positive for Tritrichomonas foetus culture at weekly intervals for 5 weeks prior to treatment was negative for Tritrichomonas foetus culture at weekly intervals for five consecutive weeks following this treatment regimen. An objective evaluation of the published evidence on the potential public health significance of using metronidazole to treat Tritrichomonas foetus in bulls provides encouragement for veterinarians and regulators to consider approaches that might lead to permitting the legal use of metronidazole in bulls. CONCLUSION: The study demonstrated successful inhibition of Tritrichomonas foetus both in vitro and in vivo with metronidazole. The current status of metronidazole is that the Animal Medicinal Drug Use Clarification Act of 1994 prohibits its extra-label use in food-producing animals. Veterinarians and regulators should consider approaches that might lead to permitting the legal use of metronidazole in bulls.

Evaluating geostatistical modeling of exceedance probability as the first step in disease cluster investigations: very low birth weights near toxic Texas sites.

BACKGROUND: The first step in evaluating potential geographic clusters of disease calls for an evaluation of the disease risk comparing the risk in a defined location to the risk in neighboring locations. Environmental exposures, however, represent continuous exposure levels across space not an exposure with a distinct boundary. The objectives of the current study were to adapt, apply and evaluate a geostatistical approach for identifying disease clusters. METHODS: The exceedance probability for very low birth weight (VLBW; < 1.5 kg) infants was mapped using an Intrinsic Conditional Autoregressive model. The data were applied to a 20 by 20 grid of 1 km2 pixels centered on each of the 13 National Priority List Superfund Sites in Harris County, Texas. RESULTS: Large clusters of VLBW were identified in close proximity to four of the 13 Superfund Sites. Three of the Superfund Sites, associated with disease clusters, were located close together in central Houston and these sites may have been surrounded by a single, confluent disease cluster. CONCLUSIONS: Geostatistical modeling of the exceedance probability for very low birth weights identified disease clusters of varying size, shape and statistical certainty near Superfund Sites in Harris County, Texas. The approach offers considerable potential as the first step for investigating potential disease clusters.

Ultrasonographic characteristics of lipiduria in clinically normal cats.

Echoes are frequently seen in the urinary bladder of cats during abdominal ultrasound. These have been attributed to hematuria, pyuria, crystalluria, and lipid. However, sonographic findings have not been previously correlated with urinalysis. We prospectively evaluated 40 clinically normal cats via ultrasound, serum chemistry, and urinalysis. Thin layer chromatography was performed on the urine to determine the amount (mg) of lipid subfractions including diacylglycerol, triglyceride, phospholipid, free fatty acid, cholesterol, and cholesterol ester. Ninety percent (36/40) of the cats in our population had sonographic echoes suspended in the urinary bladder, with most having a subjective score of mild echoes (n = 20). None of the sonographic echoes were gravity dependent or caused distal acoustic shadowing, reverberation, or twinkle artifact. Of the cats with sonographic echoes in the urine, 66% (24/36) had no significant findings on urinalysis other than the presence of lipid. The total amount of subjective sonographic echoes was not significantly related to the total amount of fat measured on thin layer chromatography or the number of lipid droplets seen on urinalysis. An increased amount of urine diacylglycerol was significantly associated with clumping of echoes (P = 0.02) and the amount of lipid droplets seen on urinalysis (P = 0.04). An association between increased amounts of urine diacylglycerol and the amount of echoes seen on ultrasound approached significance (P = 0.05). Findings from this study support previously published theories that sonographic echoes within the urinary bladder of clinically normal cats may be due to urine lipid.

Evaluation of the WARP-turbo spin echo sequence for 3 Tesla magnetic resonance imaging of stifle joints in dogs with stainless steel tibial plateau leveling osteotomy implants.

Susceptibility artifacts caused by ferromagnetic implants compromise magnetic resonance imaging (MRI) of the canine stifle after tibial plateau leveling osteotomy (TPLO) procedures. The WARP-turbo spin echo sequence is being developed to mitigate artifacts and utilizes slice encoding for metal artifact reduction. The aim of the current study was to evaluate the WARP-turbo spin echo sequence for imaging post TPLO canine stifle joints. Proton density weighted images of 19 canine cadaver limbs were made post TPLO using a 3 Tesla MRI scanner. Susceptibility artifact sizes were recorded and compared for WARP vs. conventional turbo spin echo sequences. Three evaluators graded depiction quality for the tibial tuberosity, medial and lateral menisci, tibial osteotomy, and caudal cruciate ligament as sufficient or insufficient to make a diagnosis. Artifacts were subjectively smaller and local structures were better depicted in WARP-turbo spin echo images. Signal void area was also reduced by 75% (sagittal) and 49% (dorsal) in WARP vs. conventional turbo spin echo images. Evaluators were significantly more likely to grade local anatomy depiction as adequate for making a diagnosis in WARP-turbo spin echo images in the sagittal but not dorsal plane. The proportion of image sets with anatomic structure depiction graded adequate to make a diagnosis ranged from 28 to 68% in sagittal WARP-turbo spin echo images compared to 0-19% in turbo spin echo images. Findings indicated that the WARP-turbo spin echo sequence reduces the severity of susceptibility artifacts in canine stifle joints post TPLO. However, variable depiction of local anatomy warrants further refinement of the technique.

Autologous regulatory T cells for the treatment of type 1 diabetes.

The immune system is tasked with defending the host from a wide array of pathogens and environmental insults. When uncontrolled, this endeavor may lead to off-target reactivity to self-tissues resulting in multiple autoimmune diseases including type 1 diabetes (T1D). This multifactorial disease process involves over 40 susceptibility genes and is influenced by poorly characterized environmental factors. While many questions regarding the pathogenesis of the disease process remain, it has become increasingly clear that the progression to disease results from a breakdown in the processes that maintain peripheral immune tolerance. The end result of this process is localized tissue inflammation, islet dysfunction, and ultimately the destruction of pancreatic ß cells due to concomitant defects in innate and adaptive immune responses. A number of immunomodulatory intervention trials have now been conducted in patients at risk for or with recent onset T1D, often with the goal of restoring immune tolerance by inducing regulatory T cells (Tregs). Unfortunately, many of these trials have fallen short of inducing persistent immune regulation. This shortfall has led to additional efforts to more directly shift the balance from destructive effector T cell (Teff) responses to favor Tregs, including the use of autologous Treg cell therapy. In this review we will discuss key concepts related to the use of autologous Treg cell therapy for the treatment of T1D. Among these topics, we will discuss the notions of genetic control of Treg activity, Treg cellular plasticity, and requirements for antigen-specificity.

Identification of acidic pH-dependent ligands of pentameric C-reactive protein.

C-reactive protein (CRP) is a phylogenetically conserved protein; in humans, it is present in the plasma and at sites of inflammation. At physiological pH, native pentameric CRP exhibits calcium-dependent binding specificity for phosphocholine. In this study, we determined the binding specificities of CRP at acidic pH, a characteristic of inflammatory sites. We investigated the binding of fluid-phase CRP to six immobilized proteins: complement factor H, oxidized low-density lipoprotein, complement C3b, IgG, amyloid ß, and BSA immobilized on microtiter plates. At pH 7.0, CRP did not bind to any of these proteins, but, at pH ranging from 5.2 to 4.6, CRP bound to all six proteins. Acidic pH did not monomerize CRP but modified the pentameric structure, as determined by gel filtration, 1-anilinonaphthalene-8-sulfonic acid-binding fluorescence, and phosphocholine-binding assays. Some modifications in CRP were reversible at pH 7.0, for example, the phosphocholine-binding activity of CRP, which was reduced at acidic pH, was restored after pH neutralization. For efficient binding of acidic pH-treated CRP to immobilized proteins, it was necessary that the immobilized proteins, except factor H, were also exposed to acidic pH. Because immobilization of proteins on microtiter plates and exposure of immobilized proteins to acidic pH alter the conformation of immobilized proteins, our findings suggest that conformationally altered proteins form a CRP-ligand in acidic environment, regardless of the identity of the protein. This ligand binding specificity of CRP in its acidic pH-induced pentameric state has implications for toxic conditions involving protein misfolding in acidic environments and favors the conservation of CRP throughout evolution.

Class II-associated invariant chain peptide down-modulation enhances the immunogenicity of myeloid leukemic blasts resulting in increased CD4+ T-cell responses.

BACKGROUND: Disease recurrence in patients with acute myeloid leukemia may be partially explained by the escape of leukemic blasts from CD4(+) T-cell recognition. The current study investigates the role of aberrant HLA class II antigen presentation on leukemic blasts by determining both the clinical and functional impact of the class II-associated invariant chain peptide (CLIP). DESIGN AND METHODS: The levels of expression of CLIP and HLA-DR on blood and bone marrow samples from 207 patients with acute myeloid leukemia were correlated with clinical outcome. Irradiated CLIP(-) and CLIP(+) leukemic blasts were compared for their ability to induce CD4(+) T cells during mixed leukocyte reactions. To discriminate between these blasts, we down-modulated CLIP expression on myeloid leukemic cell lines by RNA interference of the invariant chain, a chaperone protein critically involved in HLA-DR processing, and performed flow cytometric sorting for their isolation from primary acute myeloid leukemia samples. RESULTS: We found that patients with leukemic blasts characterized by a high amount of HLA-DR occupied by CLIP (relative amount of CLIP) had a significantly shortened disease-free survival. The clear reductions in amount of HLA-DR occupied by CLIP on blasts of the THP-1 and Kasumi-1 myeloid leukemic cell lines after treatment with invariant chain short interfering RNA resulted in enhanced rates of allogeneic CD4(+) T-cell proliferation. Similar findings were obtained in an autologous setting, in which there were strong increases in proliferation of remission CD4(+) T cells stimulated with CLIP(-)-sorted leukemic blasts from HLA-DR(+) acute myeloid leukemia patients, in contrast to CLIP(+)-sorted leukemic blasts from the same patients. CONCLUSIONS: These data highlight the relevance of CLIP expression on leukemic blasts and the potential of CLIP as a target for immunomodulatory strategies to enhance HLA class II antigen presentation and CD4(+) T-cell reactivity in acute myeloid leukemia.

Risks of childhood cancer among Texas watersheds, based on mothers' living locations at the time of birth.

Cancer is the most common fatal disease among US children. The fetus has reduced resistance to toxic injury and is especially prone to mutagenic injury because of the high rate of cell division. A fetus can be exposed to environmental toxins through maternal consumption of contaminated water. The objective of this study was to estimate the incidence risk for childhood cancers within each watershed in Texas. The approach modeled risk for 19 cancer histotypes incorporating correlations among the cancer types and spatial correlation. Several watersheds in a very large area known as the Central Great Plains of North Texas were associated with increased risk for astrocytoma. Two watersheds near Houston, Buffalo-San Jacinto and West Galveston Bay, had increased risk for renal cancer and acute lymphoid leukemia, respectively. A watershed in South Texas, the South Laguna Madre, had increased risk for atypical leukemias. The possibility that waterborne toxins cause these childhood cancers should be investigated further.

Massive pulmonary embolism and acute limb ischaemia in a patient of hereditary spherocytosis and patent foramen ovale.

Paradoxical embolism accounts for 2% of patients who present with acute arterial embolism of extremities. We report a case of a 41 year-old male with hereditary spherocytosis who presented to the emergency department with acute limb ischaemia and pulmonary embolism. On further evaluation, he was found to have patent foramen ovale (PFO) and deep vein thrombosis (DVT), leading to paradoxical embolism. The purpose of this report is to emphasise that in a patient presenting with acute limb ischaemia without an obvious systemic arterial embolic source, an evaluation for a right-to-left shunting lesion, especially PFO, should be performed.

The Effects of Parent Ages on Birth Defects.

Background: Men and women, in the United States, are having children at considerably older ages. This changing demographic has been associated with multiple neonatal adverse birth outcomes that are currently considered to constitute a major public health crisis. The objective of this study was to evaluate the risk of parent age on birth defects and to provide results that can serve as a starting point for more specific mediation modeling. The modeling estimated the effects of parent age on birth defects controlling for confounding between maternal and paternal age and separated the mediating effect of chromosomal disorders, including Down syndrome. Methods: Data containing approximately 15,000,000 birth records were obtained from the United States Natality database for the years 2014 to 2018. A Bayesian modeling approach was used to estimate adjusted risks of parent ages both unadjusted and adjusted for the other parent's age and for the mediational effect of chromosomal disorders, including Down syndrome. Results: Increasing maternal age was associated with increased risks for hypospadias and cyanotic congenital heart disease. Increasing maternal and paternal ages were associated with decreasing risks for gastroschisis. For limb reduction defect, cleft lip and all defects combined, the risk of maternal age was U-shaped with the lowest risks observed at approximately age 35y. Paternal age was not associated with an increase in the birth prevalence of birth defects. Conclusion: Advancing maternal age was associated with increased birth prevalence of hypospadias and cyanotic congenital heart disease and associated with a lower birth prevalence for gastroschisis. Both older and younger maternal ages were related to limb reduction defect and cleft lip. Advancing paternal age was not associated with an increased birth prevalence of birth defects but was associated with a decreased birth prevalence of gastroschisis.

Assessment of dissolved organic carbon and iron effects on water color between a forest and pasture-dominated fine-scale catchment in a Central Appalachian region, West Virginia.

Dissolved organic carbon (DOC) and iron (Fe) have been observed to be the important contributors to surface water brownification. Additionally, the DOC quality influences water color by forming Fe-DOC complexes that provide additive effects and is influenced by dominant land use type within watersheds. However, the influence of quantity and quality of DOC on Fe and water color is poorly understood in headwater streams. The aim of this study was to investigate the effects of DOC and Fe on water color in forest (FC) and pasture (GFC) fine-scale watersheds to remove the confounding effects of climate and soil parent material. Significant differences of DOC, Fe, and water absorbance at 420 nm (a420) between FC and GFC were found (p < 0.05). A dominant contribution to water color was from DOC (95.5 - 63.7%) with a decreasing trend when Fe increased from 0.011 to 0.258 mg L-1. There were no significant interactions between FC and GFC and Fe on either a420/DOC (p = 0.06) or specific ultraviolet absorbance at 254 nm (SUVA254) (p = 0.30). Increasing values of a420/DOC and SUVA254 were significantly associated with increasing Fe concentration (p < 0.01). Significant interactions were found between FC and GFC and Fe on spectral slope ratio (S ratio) (p < 0.01). The response rate of S ratio with increasing Fe per unit was 0.235 for GFC while it was - 11.043 for FC. These differences indicate that land use may change the quality of DOC, influence Fe-DOC interactions, and thus affect water color. Linking the effects of soil Fe and DOC and headwater Fe and DOC may help identify optimal management practice to mitigate surface water brownification.

Effects of transrectal palpation with the fetal membrane slip technique for early pregnancy diagnosis on the proportion and type of associated pregnancy loss in dairy cattle.

OBJECTIVE: To assess the effect of transrectal palpation (TRP) performed with the fetal membrane slip (FMS) technique for early pregnancy diagnosis on the proportion and type of associated pregnancy losses (PLs) in dairy cattle. ANIMALS: 580 healthy pregnant cattle. PROCEDURES: Data for artificially inseminated females with 1 or 2 viable embryos detected by transrectal ultrasonography (TRUS) at approximately 30 days of gestation were retrospectively assessed. Cattle were assigned to 1 of 2 groups on the basis of whether they did or did not undergo TRP once between 34 and 41 days of gestation (palpation and control group, respectively). At approximately 45 and 60 days of gestation, all cattle were reevaluated by TRUS; PL was categorized as type I (FMS detectable by TRP and TRUS-confirmed evidence of embryo or fetus degeneration and a functional corpus luteum) or type II (FMS undetectable by TRP and no TRUS-confirmed evidence of an embryo or fetus or of a functional corpus luteum). RESULTS: Of the 580 healthy pregnant cattle, 271 underwent TRP and 309 did not. In the palpation and control groups, PL occurred in 40 (14.8%) and 47 (15.2%) cattle, respectively. Among the palpation group's PLs, 17 (43%) were type I and 23 (58%) were type II. Among the control group's PLs, 27 (57%) were type I and 20 (43%) were type II. The prevalance and type of PL did not differ between groups. CONCLUSIONS AND CLINICAL RELEVANCE: TRP with the FMS technique for early pregnancy diagnosis did not increase the prevalence of PL in dairy cattle or alert the proportion of type I versus type II PL.

64Cu PET Imaging of the CXCR4 Chemokine Receptor Using a Cross-Bridged Cyclam Bis-Tetraazamacrocyclic Antagonist.

Expression of the chemokine receptor chemokine C-X-C motif receptor 4 (CXCR4) plays an important role in cancer metastasis, in autoimmune diseases, and during stem cell-based repair processes after stroke and myocardial infarction. Previously reported PET imaging agents targeting CXCR4 suffer from either high nonspecific uptake or bind only to the human form of the receptor. The objective of this study was to develop a high-stability 64Cu-labeled small-molecule PET agent for imaging both human and murine CXCR4 chemokine receptors. Methods: Synthesis, radiochemistry, stability and radioligand binding assays were performed for the novel tracer 64Cu-CuCB-bicyclam. In vivo dynamic PET studies were performed on mice bearing U87 (CXCR4 low-expressing) and U87.CXCR4 (human-CXCR4 high-expressing) tumors. Biodistribution and receptor blocking studies were performed on CD1-IGS immunocompetent mice. CXCR4 expression on tumor and liver disaggregates was confirmed using a combination of immunohistochemistry, quantitative polymerase chain reaction, and Western blot. Results:64Cu-CuCB-bicyclam has a high affinity for both the human and the murine variants of the CXCR4 receptor (half-maximal inhibitory concentration, 8 nM [human]/2 nM [murine]) and can be obtained from the parent chelator that has low affinity. In vitro and in vivo studies demonstrate specific uptake in CXCR4-expressing cells that can be blocked by more than 90% using a higher-affinity antagonist, with limited uptake in non-CXCR4-expressing organs and high in vivo stability. The tracer was also able to selectively displace the CXCR4 antagonists AMD3100 and AMD3465 from the liver. Conclusion: The tetraazamacrocyclic small molecule 64Cu-CuCB-bicyclam has been shown to be an imaging agent for the CXCR4 receptor that is likely to be applicable across a range of species. It has high affinity and stability and is suitable for preclinical research in immunocompetent murine models.

Geostatistical analysis of DNA damage in oysters, Crassostrea virginica, in Lavaca Bay, Texas.

This study evaluated the health of the marine ecosystem in Lavaca Bay, Texas using the Eastern oyster (Crassostrea virginica) as the sentinel species. Lavaca Bay has a history of having gradients of concentrations of pollutants present with some areas containing concentrations high enough to pose a threat to marine ecosystem health. The Comet assay was used to evaluate for the presence of genotoxic response in oyster hematocytes. Bayesian geostatistical analysis was then used to determine if the DNA damage in oyster hematocytes was spatially oriented and to develop continuous surface maps of the risk of DNA damage in this sentinel species. Results indicated that proximity to industrial facilities increased the locational risk of genotoxicity in this species.

Geostatistical analysis of biomarkers of genotoxicity in cattle, Bos taurus and Bos taurus x Bos indicus, sentinels near industrial facilities.

This study, performed at the behest of ranchers living and working down-prevailing wind from industrial facilities located in Calhoun County, Texas investigated locational risks to ecosystem health associated with proximity to specific industrial complexes. Concerns expressed were for potential genotoxicity in cattle resulting from the release of complex chemical mixtures. The Comet Assay and flow cytometric evaluation of variations in DNA content were utilized to evaluate DNA damage. Bayesian geo-statistical analysis revealed the presence of important spatial processes. The Comet assay's optical density provided a strong indication of increased damage down-prevailing wind from the industrial complexes. Results indicated that proximity to and location down-prevailing winds from industrial facilities increased the locational risk of genotoxicity in this sentinel species.