State of the art review of new technologies in spine deformity surgery-robotics and navigation.

STUDY DESIGN/METHODS: Review article. OBJECTIVES: The goal of this article is to review the available evidence for computerized navigation and robotics as an accuracy improvement tool for spinal deformity surgery, as well as to consider potential complications, impact on clinical outcomes, radiation exposure, and costs. Pedicle screw and rod construct are widely utilized for posterior spinal fixation in spinal deformity correction. Freehand placement of pedicle screws has long been utilized, although there is variable potential for inaccuracy depending on surgeon skill and experience. Malpositioned pedicle screws may have significant clinical implications ranging from nerve root irritation, inadequate fixation, CSF leak, perforation of the great vessels, or spinal cord damage. Computer-based navigation and robotics systems were developed to improve pedicle screw insertion accuracy and consistency, and decrease the risk of malpositioned pedicle fixation. The available evidence suggests that computer-based navigation and robotic-assisted guidance systems for pedicle cannulation are at least equivalent, and in several reports superior, to freehand techniques in terms of accuracy. CT and robotic navigation systems do appear to decrease radiation exposure to the operative team in some reports. Published reports do indicate longer operative times with use of robotic navigation compared with traditional freehand techniques for pedicle screw placement. To date, there is no conclusive evidence that use of CT or robotic navigation has any measurable impact on patient outcomes or overall complication reduction. There are theoretical advantages with robotic and CT navigation in terms of both speed and accuracy for severe spinal deformity or complex revision cases, however, there is a need for studies to investigate this technology in these specific cases. There is no evidence to date demonstrating the cost effectiveness of CT or robotic navigation as compared with traditional pedicle cannulation techniques. CONCLUSIONS: The review of available evidence suggests that computer-based navigation and robotic-assisted guidance systems for pedicle cannulation are at least equivalent, and in several reports superior, to freehand techniques in terms of radiographic accuracy. There is no current clinical evidence that the use of navigation or robotic techniques leads to improved patient outcomes or decreased overall complications or reoperation rates, and the use of these systems may substantially increase surgical costs. LEVEL OF EVIDENCE: V.

Maternal Metabolic Biomarkers are Associated with Obesity and Excess Gestational Weight Gain.

OBJECTIVE: The purpose of this study was to evaluate the independent contribution of maternal obesity and gestational weight gain (GWG) in excess of the Institute of Medicine's guidelines on levels of maternal serum inflammatory and metabolic measures. STUDY DESIGN: Banked maternal serum samples from 120 subjects with documented prepregnancy or first trimester body mass index (BMI) were utilized for analyte analyses. Validated, BMI-specific formulas were utilized to categorize GWG as either insufficient, at goal or excess based on the Institute of Medicine guidelines with gestational age adjustments. Serum was analyzed for known inflammatory or metabolic pathway intermediates using the Luminex xMap system with the MILLIPLEX Human Metabolic Hormone Magnetic Bead Panel. Measured analytes included interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α and metabolic markers amylin, c-peptide, ghrelin, gastric inhibitory polypeptide, glucagon-like peptide-1, glucagon, insulin, leptin, pancreatic polypeptide, and peptide YY. Kruskal-Wallis ANOVA and Pearson's correlation coefficients were calculated for each marker. RESULTS: C-peptide, insulin, and leptin all varied significantly with both obesity and GWG while glucagon-like peptide-1 varied by BMI but not GWG. These analytes covaried with other metabolic analytes, but not with inflammatory analytes. CONCLUSION: Maternal metabolic biomarkers at delivery vary significantly with both obesity and GWG. Taken together, these findings suggest that GWG (with and without comorbid obesity) is an important mediator of measurable metabolites in pregnancy but is not necessarily accompanied by inflammatory measures in serum. These findings are consistent with GWG being an independent risk factor for metabolic disturbances during pregnancy.

Evaluating a Rapid Field Assessment System for Anticoagulant Rodenticide Exposure of Raptors.

Anticoagulant rodenticides (ARs) are commonly used to control rodent pests. However, worldwide, their use is associated with secondary and tertiary poisoning of nontarget species, especially predatory and scavenging birds. No medical device can rapidly test for AR exposure of avian wildlife. Prothrombin time (PT) is a useful biomarker for AR exposure, and multiple commercially available point-of-care (POC) devices measure PT of humans, and domestic and companion mammals. We evaluated the potential of one commercially available POC device, the Coag-Sense® PT/INR Monitoring System, to rapidly detect AR exposure of living birds of prey. The Coag-Sense device delivered repeatable PT measurements on avian blood samples collected from four species of raptors trapped during migration (Intraclass Correlation Coefficient > 0.9; overall intra-sample variation CV: 5.7%). However, PT measurements reported by the Coag-Sense system from 81 ferruginous hawk (Buteo regalis) nestlings were not correlated to those measured by a one-stage laboratory avian PT assay (r = - 0.017, p = 0.88). Although precise, the lack of agreement in PT estimates from the Coag-Sense device and the laboratory assay indicates that this device is not suitable for detecting potential AR exposure of birds of prey. The lack of suitability may be related to the use of a mammalian reagent in the clotting reaction, suggesting that the device may perform better in testing mammalian wildlife.

Center of Biomedical Research Excellence in Matrix Biology: Building Research Infrastructure, Supporting Young Researchers, and Fostering Collaboration.

The Center of Biomedical Research Excellence in Matrix Biology strives to improve our understanding of extracellular matrix at molecular, cellular, tissue, and organismal levels to generate new knowledge about pathophysiology, normal development, and regenerative medicine. The primary goals of the Center are to i) support junior investigators, ii) enhance the productivity of established scientists, iii) facilitate collaboration between both junior and established researchers, and iv) build biomedical research infrastructure that will support research relevant to cell-matrix interactions in disease progression, tissue repair and regeneration, and v) provide access to instrumentation and technical support. A Pilot Project program provides funding to investigators who propose applying their expertise to matrix biology questions. Support from the National Institute of General Medical Sciences at the National Institutes of Health that established the Center of Biomedical Research Excellence in Matrix Biology has significantly enhanced the infrastructure and the capabilities of researchers at Boise State University, leading to new approaches that address disease diagnosis, prevention, and treatment. New multidisciplinary collaborations have been formed with investigators who may not have previously considered how their biomedical research programs addressed fundamental and applied questions involving the extracellular matrix. Collaborations with the broader matrix biology community are encouraged.

Characterization of 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidases from Borrelia burgdorferi: Antibiotic targets for Lyme disease.

BACKGROUND: Borrelia burgdorferi causes Lyme disease, the most common tick-borne illness in the United States. The Center for Disease Control and Prevention estimates that the occurrence of Lyme disease in the U.S. has now reached approximately 300,000 cases annually. Early stage Borrelia burgdorferi infections are generally treatable with oral antibiotics, but late stage disease is more difficult to treat and more likely to lead to post-treatment Lyme disease syndrome. METHODS: Here we examine three unique 5'-methylthioadenosine/S-adenosylhomocysteine (MTA/SAH) nucleosidases (MTNs or MTANs, EC 3.2.2.9) responsible for salvage of adenine and methionine in B. burgdorferi and explore their potential as antibiotic targets to treat Lyme disease. Recombinant Borrelia MTNs were expressed and purified from E. coli. The enzymes were extensively characterized for activity, specificity, and inhibition using a UV spectrophotometric assay. In vitro antibiotic activities of MTN inhibitors were assessed using a bioluminescent BacTiter-Glo™ assay. RESULTS: The three Borrelia MTNs showed unique activities against the native substrates MTA, SAH, and 5'-deoxyadenosine. Analysis of substrate analogs revealed that specific activity rapidly dropped as the length of the 5'-alkylthio substitution increased. Non-hydrolysable nucleoside transition state analogs demonstrated sub-nanomolar enzyme inhibition constants. Lastly, two late stage transition state analogs exerted in vitro IC50 values of 0.3-0.4 µg/mL against cultured B. burgdorferi cells. CONCLUSION: B. burgdorferi is unusual in that it expresses three distinct MTNs (cytoplasmic, membrane bound, and secreted) that are effectively inactivated by nucleoside analogs. GENERAL SIGNIFICANCE: The Borrelia MTNs appear to be promising targets for developing new antibiotics to treat Lyme disease.

Selenium in buoyant marine debris biofilm.

Marine debris is widespread in all the world's oceans. Currently little is understood about how marine debris affects the chemistry of the surface oceans, particularly trace elements that can adsorb to the surface of marine debris, especially plastic debris, or be taken up by biofilms and algae growing on the surface of marine debris. Selenium (Se) is a micronutrient that is essential to all living organisms. Average seawater Se concentrations in the modern ocean are <1 nM. Here we measure the concentration of Se in surface water and one deep water sample and the concentration of Se found in algae/biofilms growing on the surface of macro-debris collected in October of 2012. Concentrations of Se in biofilm varied more according to the type of biofilm rather than the type of plastic. However, further Se measurements are needed for more conclusive results.

Electronic cigarette liquid exposure induces flavor-dependent osteotoxicity and increases expression of a key bone marker, collagen type I.

Electronic cigarettes (e-cigarettes) are nicotine delivery devices advertised as a healthier alternative to conventional tobacco products, but their rapid rise in popularity outpaces research on potential health consequences. As conventional tobacco use is a risk factor for osteoporosis, this study examines whether exposure to electronic liquid (e-liquid) used in e-cigarettes affects bone-forming osteoblasts. Human MG-63 and Saos-2 osteoblast-like cells were treated for 48 hours with 0.004%-4.0% dilutions of commercially available e-liquids of various flavors with or without nicotine. Changes in cell viability and key osteoblast markers, runt-related transcription factor 2 and Col1a1, were assessed. With all e-liquids tested, cell viability decreased in a dose-dependent manner, which was least pronounced in flavorless e-liquids, most pronounced in cinnamon-flavored e-liquids and occurred independently of nicotine. Col1a1, but not runt-related transcription factor 2, mRNA expression was upregulated in response to coffee-flavored and fruit-flavored e-liquids. Cells treated with a non-cytotoxic concentration of fruit-flavored Mango Blast e-liquid with or without nicotine showed significantly increased collagen type I protein expression compared to culture medium only. We conclude that the degree of osteotoxicity is flavor-dependent and occurs independently of nicotine and that flavored e-liquids reveal collagen type I as a potential target in osteoblasts. This study elucidates potential consequences of e-cigarette use in bone.

SOD1A4V aggregation alters ubiquitin homeostasis in a cell model of ALS.

A hallmark of amyotrophic lateral sclerosis (ALS) pathology is the accumulation of ubiquitylated protein inclusions within motor neurons. Recent studies suggest the sequestration of ubiquitin (Ub) into inclusions reduces the availability of free Ub, which is essential for cellular function and survival. However, the dynamics of the Ub landscape in ALS have not yet been described. Here, we show that Ub homeostasis is altered in a cell model of ALS induced by expressing mutant SOD1 (SOD1A4V). By monitoring the distribution of Ub in cells expressing SOD1A4V, we show that Ub is present at the earliest stages of SOD1A4V aggregation, and that cells containing SOD1A4V aggregates have greater ubiquitin-proteasome system (UPS) dysfunction. Furthermore, SOD1A4V aggregation is associated with the redistribution of Ub and depletion of the free Ub pool. Ubiquitomics analysis indicates that expression of SOD1A4V is associated with a shift of Ub to a pool of supersaturated proteins, including those associated with oxidative phosphorylation and metabolism, corresponding with altered mitochondrial morphology and function. Taken together, these results suggest that misfolded SOD1 contributes to UPS dysfunction and that Ub homeostasis is an important target for monitoring pathological changes in ALS.This article has an associated First Person interview with the first author of the paper.

PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation: A Randomized Phase II Study: BrUOG 244.

PURPOSE: Efficacy signals but substantial myelosuppression were demonstrated in a single arm phase II study of paclitaxel poliglumex (PPX) in combination with temozolomide (TMZ) and radiation therapy (RT) for first-line treatment of glioblastoma. The objective of this randomized phase II trial was to assess the efficacy and safety of single-agent PPX with RT (PPX/RT) versus TMZ with RT (TMZ/RT) for glioblastoma without O-methylguanine-DNA methyltransferase (MGMT) methylation. MATERIALS AND METHODS: Patients with glioblastoma with unmethylated MGMT without prior chemotherapy or RT were eligible. Patients were randomly assigned 2:1 to PPX, 50 mg/m/wk for 6 weeks, or standard TMZ, with concurrent 60.0 Gy RT. One month after completion of chemoradiation all patients received standard maintenance TMZ. The primary endpoint was progression-free survival (PFS). RESULTS: Of the 164 patients enrolled, 86 were MGMT unmethylated. Of these, 63 patients were randomized (42 to PPX/RT and 21 to TMZ/RT). Fifty-nine patients could be analyzed. The median PFS was 9 months in the PPX/RT group and 9.5 months in the TMZ/RT group (hazard ratio in the PPX/RT group, 1.10; 95% confidence interval, 0.79-2.08; P=0.75). Median overall survival was 16 versus 14.8 months for PPX/RT and TMZ/RT groups, respectively (hazard ratio, 1.44; 95% confidence interval, 0.75-2.77; P=0.27). In the PPX and TMZ groups 44% versus 22% of patients, respectively, experienced one or more grade 3 or higher toxicities during chemoradiation. CONCLUSIONS: PPX/RT did not improve PFS or overall survival. This study provides an effective trial design for screening RT sensitizers in glioblastoma.

Informed consent in oncology clinical trials: A Brown University Oncology Research Group prospective cross-sectional pilot study.

BACKGROUND: Informed consent forms (ICFs) for oncology clinical trials have grown increasingly longer and more complex. We evaluated objective understanding of critical components of informed consent among patients enrolling in contemporary trials of conventional or novel biologic/targeted therapies. METHODS: We evaluated ICFs for cancer clinical trials for length and readability, and patients registered on those studies were asked to complete a validated 14-question survey assessing their understanding of key characteristics of the trial. Mean scores were compared in groups defined by trial and patient characteristics. RESULTS: Fifty patients, of whom half participated in trials of immunotherapy or biologic/targeted agents and half in trials of conventional therapy, completed the survey. On average, ICFs for industry-originated trials (N = 9 trials) were significantly longer (P < .0001) and had lower Flesch ease-of-reading scores (P = .003) than investigator-initiated trials (N = 11). At least 80% of patients incorrectly responded to three key questions which addressed the experimental nature of their trial therapy, its purported efficacy and potential risks relative to alternative treatments. The mean objective understanding score was 76.9±8.8, but it was statistically significantly lower for patients who had not completed high school (P = .011). The scores did not differ significantly by type of cancer therapy (P = .12) or trial sponsor (P = .38). CONCLUSIONS: Many participants enrolled on cancer trials had poor understanding of essential elements of their trial. In order to ensure true informed consent, innovative approaches, such as expanded in-person counseling adapted to the patient's education level or cultural characteristics should be evaluated across socio-demographic groups. TRIAL REGISTRATION: Clinicaltrials.gov NCT01772511.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) increases necroinflammation and hepatic stellate cell activation but does not exacerbate experimental liver fibrosis in mice.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant and high-affinity ligand for the aryl hydrocarbon receptor (AhR). Increasing evidence indicates that AhR signaling contributes to wound healing, which involves the coordinated deposition and remodeling of the extracellular matrix. In the liver, wound healing is attributed to the activation of hepatic stellate cells (HSCs), which mediate fibrogenesis through the production of soluble mediators and collagen type I. We recently reported that TCDD treatment increases the activation of human HSCs in vitro. The goal of this study was to determine how TCDD impacts HSC activation in vivo using a mouse model of experimental liver fibrosis. To elicit fibrosis, C57BL6/male mice were treated twice weekly for 8weeks with 0.5ml/kg carbon tetrachloride (CCl4). TCDD (20µg/kg) or peanut oil (vehicle) was administered once a week during the last 2weeks. Results indicate that TCDD increased liver-body-weight ratios, serum alanine aminotransferase activity, and hepatic necroinflammation in CCl4-treated mice. Likewise, TCDD treatment increased mRNA expression of HSC activation and fibrogenesis genes, namely α-smooth muscle actin, desmin, delta-like homolog-1, TGF-ß1, and collagen type I. However, TCDD treatment did not exacerbate fibrosis, nor did it increase the collagen content of the liver. Instead, TCDD increased hepatic collagenase activity and increased expression of matrix metalloproteinase (MMP)-13 and the matrix regulatory proteins, TIMP-1 and PAI-1. These results support the conclusion that TCDD increases CCl4-induced liver damage and exacerbates HSC activation, yet collagen deposition and the development of fibrosis may be limited by TCDD-mediated changes in extracellular matrix remodeling.

Aryl Hydrocarbon Receptor Activation by TCDD Modulates Expression of Extracellular Matrix Remodeling Genes during Experimental Liver Fibrosis.

The aryl hydrocarbon receptor (AhR) is a soluble, ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence implicates the AhR in regulating extracellular matrix (ECM) homeostasis. We recently reported that TCDD increased necroinflammation and myofibroblast activation during liver injury elicited by carbon tetrachloride (CCl4). However, TCDD did not increase collagen deposition or exacerbate fibrosis in CCl4-treated mice, which raises the possibility that TCDD may enhance ECM turnover. The goal of this study was to determine how TCDD impacts ECM remodeling gene expression in the liver. Male C57BL/6 mice were treated for 8 weeks with 0.5 mL/kg CCl4, and TCDD (20 µg/kg) was administered during the last two weeks. Results indicate that TCDD increased mRNA levels of procollagen types I, III, IV, and VI and the collagen processing molecules HSP47 and lysyl oxidase. TCDD also increased gelatinase activity and mRNA levels of matrix metalloproteinase- (MMP-) 3, MMP-8, MMP-9, and MMP-13. Furthermore, TCDD modulated expression of genes in the plasminogen activator/plasmin system, which regulates MMP activation, and it also increased TIMP1 gene expression. These findings support the notion that AhR activation by TCDD dysregulates ECM remodeling gene expression and may facilitate ECM metabolism despite increased liver injury.

Monocyte chemoattractant protein-1 is not required for liver regeneration after partial hepatectomy.

BACKGROUND: Liver regeneration following 70 % partial hepatectomy (PH) requires the coordinated expression of soluble mediators produced by macrophages. Monocyte chemoattractant protein-1 (MCP-1) is a potent stimulus of monocyte recruitment and macrophage activation. The goal of this study was to determine how MCP-1 contributes to liver regeneration. METHODS: PH was performed on anesthetized C57Bl/6 (wild type) and MCP-1 knockout mice, and macrophage-produced cytokines and hepatocyte proliferation were measured. RESULTS: In wild type mice, hepatic MCP-1 protein levels increased 4-6 h after PH, and elevated plasma MCP-1 levels were detected 12 h after PH. Hepatocyte proliferation was comparable in MCP-1 knockout and wild type mice, as was the expression of macrophage-derived cytokines, TNFα and IL-6, and levels of phosphorylated STAT3. The number of CCR2(+) cells in the liver was similar in MCP-1 knockout and wild type mice, which suggests that other chemokines may recruit CCR2(+) cells in the absence of MCP-1. Studies with CCR2 knockout mice revealed that hepatocyte proliferation was suppressed ~40 % compared to wild type mice 36 h after PH, but proliferation and liver-body-weight ratios were similar at 48 h. CONCLUSION: These findings suggest that MCP-1 is not required for PH-induced liver regeneration, yet the role of CCR2 warrants further study.

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases human hepatic stellate cell activation.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a halogenated aromatic hydrocarbon that elicits toxicity through the aryl hydrocarbon receptor (AhR). In the liver, gross markers of TCDD toxicity are attributed to AhR activation in parenchymal hepatocytes. However, less is known regarding the consequences of TCDD treatment on non-parenchymal cells in the liver. Hepatic stellate cells (HSCs) are non-parenchymal cells that store vitamin A when quiescent. Upon liver injury, activated HSCs lose this storage ability and instead function in the development and maintenance of inflammation and fibrosis through the production of pro-inflammatory mediators and collagen type I. Reports that TCDD exposure disrupts hepatic retinoid homeostasis and dysregulates extracellular matrix remodeling in the liver led us to speculate that TCDD treatment may disrupt HSC activity. The human HSC line LX-2 was used to test the hypothesis that TCDD treatment directly activates HSCs. Results indicate that exposure to 10nM TCDD almost completely inhibited lipid droplet storage in LX-2 cells cultured with retinol and palmitic acid. TCDD treatment also increased LX-2 cell proliferation, expression of α-smooth muscle actin, and production of monocyte chemoattractant protein-1 (MCP-1), all of which are characteristics of activated HSCs. However, TCDD treatment had no effect on Col1a1 mRNA levels in LX-2 cells stimulated with the potent profibrogenic mediator, transforming growth factor-ß. The TCDD-mediated increase in LX-2 cell proliferation, but not MCP-1 production, was abolished when phosphoinositide 3-kinase was inhibited. These results indicate that HSCs are susceptible to direct modulation by TCDD and that TCDD likely increases HSC activation through a multi-faceted mechanism.

FOLFOX+Nab-Paclitaxel (FOLFOX-A) for Advanced Pancreatic Cancer: A Brown University Oncology Research Group Phase I Study.

BACKGROUND: The Brown University Oncology Research Group performed a phase I study to remove irinotecan from FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) and substitute nab-paclitaxel. METHODS: Patients with newly diagnosed advanced pancreatic adenocarcinoma were eligible. Patients received oxaliplatin 85 mg/m, leucovorin 400 mg/m, and 5-fluorouracil 2400 mg/m with 3 dose levels of nab-paclitaxel (125, 150, and 175 mg/m) every 2 weeks. Dose-limiting toxicities were assessed in the first 2 cycles of treatment. The final dose level was expanded to assess cumulative neurotoxicity. RESULTS: Thirty-five patients were entered; 24 with metastatic and 11 with locally advanced pancreatic cancer. The maximum tolerated dose of nab-paclitaxel was 150 mg/m every 2 weeks with FOLFOX. Cumulative neuropathy was the most important toxicity. Grade 3 neuropathy developed in 2 of the first 6 patients at 10 and 11 cycles of FOLFOX-A. Following an amendment to reduce oxaliplatin to 65 mg/m if grade 2 neuropathy developed, no additional patients developed grade 3 neurotoxicity. Twenty-one of 35 patients (60%) had a partial response. The median survival for patients with metastatic disease was 15 months. CONCLUSIONS: The maximum tolerated dose of nab-paclitaxel is 150 mg/m every 2 weeks with FOLFOX. The regimen of FOLFOX-A represents a promising treatment for pancreatic cancer.

The preterm placental microbiome varies in association with excess maternal gestational weight gain.

OBJECTIVE: Although a higher maternal body mass index is associated with preterm birth, it is unclear whether excess gestational weight gain (GWG) or obesity drives increased risk. We and others have shown that the placenta harbors microbiota, which is significantly different among preterm births. Our aim in this study was to investigate whether the preterm placental microbiome varies by virtue of obesity or alternately by excess GWG. STUDY DESIGN: Placentas (n=320) were collected from term and preterm pregnancies. Genomic DNA was extracted and subjected to metagenomic sequencing. Data were analyzed by clinical covariates that included the 2009 Institute of Medicine's GWG guideline and obesity. RESULTS: Analysis of 16S recombinant RNA-based metagenomics revealed no clustering of the microbiome by virtue of obesity (P=.161). Among women who spontaneously delivered preterm, there was again no clustering by obesity (P=.480), but there was significant clustering by excess GWG (P=.022). Moreover, among preterm births, detailed analysis identified microbial genera (family and genus level) and bacterial metabolic gene pathways that varied among pregnancies with excess GWG. Notably, excess GWG was associated with decreased microbial folate biosynthesis pathways and decreased butanoate metabolism (linear discriminate analysis, >3.0-fold). CONCLUSION: Although there were no significant alterations in the microbiome by virtue of obesity per se, excess GWG was associated with an altered microbiome and its metabolic profile among those women who experienced a preterm birth.

Ah receptor-mediated suppression of liver regeneration through NC-XRE-driven p21Cip1 expression.

Previous studies in hepatocyte-derived cell lines and the whole liver established that the aryl hydrocarbon receptor (AhR) can disrupt G1-phase cell cycle progression following exposure to persistent AhR agonists, such as TCDD (dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin). Growth arrest was attributed to inhibition of G1-phase cyclin-dependent kinase 2 (CDK2) activity. The present study examined the effect of TCDD exposure on liver regeneration following 70% partial hepatectomy in mice lacking the Cip/Kip inhibitors p21(Cip1) or p27(Kip1) responsible for regulating CDK2 activity. Assessment of the regenerative process in wild-type, p21(Cip1) knockout, and p27(Kip1) knockout mice confirmed that TCDD-induced inhibition of liver regeneration is entirely dependent on p21(Cip1) expression. Compared with wild-type mice, the absence of p21(Cip1) expression completely abrogated the TCDD inhibition, and accelerated hepatocyte progression through G1 phase during the regenerative process. Analysis of the transcriptional response determined that increased p21(Cip1) expression during liver regeneration involved an AhR-dependent mechanism. Chromatin immunoprecipitation studies revealed that p21(Cip1) induction required AhR binding to the newly characterized nonconsensus xenobiotic response element, in conjunction with the tumor suppressor protein Kruppel-like factor 6 functioning as an AhR binding partner. The evidence also suggests that AhR functionality following partial hepatectomy is dependent on a p21(Cip1)-regulated signaling process, intimately linking AhR biology to the G1-phase cell cycle program.

Predictors of exclusive breastfeeding at least 8 weeks among Asian and Native Hawaiian or other Pacific Islander race subgroups in Hawaii, 2004-2008.

Breastfeeding is nurturing, cost-effective, and beneficial for the health of mother and child. Babies receiving formula are sick more often and are at higher risk for childhood obesity, diabetes, asthma, and other conditions compared with breastfed children. National and international organizations recommend exclusive breastfeeding for 6 months. Exclusive breastfeeding in Asian and Native Hawaiian or Other Pacific Islander (NHOPI) subgroups is not well characterized. Data from the 2004-2008 Hawaii Pregnancy Risk Assessment Monitoring System, a population-based surveillance system on maternal behaviors and experiences before, during, and after pregnancy, were analyzed for 8,508 mothers with a recent live birth. We examined exclusive breastfeeding status for at least 8 weeks. We calculated prevalence risk ratios across maternal race groups accounting for maternal and socio-demographic characteristics. The overall estimate of exclusive breastfeeding for at least 8 weeks was 36.3%. After adjusting for maternal age, pre-pregnancy weight, cesarean delivery, return to work/school, and self-reported postpartum depressive symptoms, the racial differences in prevalence ratios for exclusive breastfeeding for each ethnic group compared to Whites were: Samoan (aPR = 0.54; 95% CI 0.43-0.69), Filipino (aPR = 0.58; 95% CI 0.53-0.63), Japanese (aPR = 0.58; 95% CI 0.52-0.65), Chinese (aPR = 0.64; 95% CI 0.58-0.70), Native Hawaiian (aPR = 0.67; 95% CI 0.61-0.72), Korean (aPR = 0.72; 95% CI 0.64-0.82), and Black (aPR = 0.79; 95% CI 0.65-0.96) compared to white mothers. Providers and community groups should be aware that just over one-third of mothers breastfeed exclusively at least 8 weeks with lower rates among Asian, NHOPI, and Black mothers. Culturally appropriate efforts to promote exclusive breastfeeding are recommended particularly among Asian subgroups that have high breastfeeding initiation rates that do not translate into high exclusivity rates.

Conducting Ethical Research with Correctional Populations: Do Researchers and IRB Members Know the Federal Regulations?

Conducting or overseeing research in correctional settings requires knowledge of specific federal rules and regulations designed to protect the rights of individuals in incarceration. To investigate the extent to which relevant groups possess this knowledge, using a 10-item questionnaire, we surveyed 885 IRB prisoner representatives, IRB members and chairs with and without experience reviewing HIV/AIDS correctional protocols, and researchers with and without correctional HIV/AIDS research experience. Across all groups, respondents answered 4.5 of the items correctly. Individuals who have overseen or conducted correctional research had the highest scores; however, even these groups responded correctly only to slightly more than half of the items. These findings emphasize the need for ongoing training in federal guidelines governing correctional research, particularly for those individuals who are embarking on this type of research.