Publications by authors named "Nancy Turner"

93 Publications

Omega-3 Fatty Acid Modulation of Serum and Osteocyte Tumor Necrosis Factor Alpha in Adult Mice Exposed to Ionizing Radiation.

J Appl Physiol (1985) 2021 Jan 7. Epub 2021 Jan 7.

Department of Health and Kinesiology, Texas A&M University, United States.

Chronic inflammation leads to bone loss and fragility. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα) consistently promote bone resorption. Dietary modulation of pro-inflammatory cytokines is an accepted therapeutic approach to treat chronic inflammation, including that induced by space-relevant radiation exposure. As such, these studies were designed to determine whether an anti-inflammatory diet, high in omega-3 fatty acids, could reduce radiation-mediated bone damage via reductions in the levels of inflammatory cytokines in osteocytes and serum. Lgr5-EGFP C57BL/6 mice were randomized to receive diets containing fish oil and pectin (FOP; high in omega-3 fatty acids) or corn oil and cellulose (COC; high in omega-6 fatty acids), then acutely exposed to 0.5 Gy Fe or 2.0 Gy gamma radiation. Mice fed the FOP diet exhibited consistent reductions in serum TNFα in the Fe, but not the gamma, experiment. The percentage osteocytes (%Ot) positive for TNFα increased in gamma exposed COC, but not FOP, mice. Minimal changes in %Ot positive for sclerostin were observed. FOP mice exhibited modest improvements in several measures of cancellous microarchitecture and volumetric bone mineral density (vBMD) post-exposure to Fe and gamma radiation. Reduced serum TNFα in FOP mice exposed to Fe was associated with either neutral or modestly positive changes in bone structural integrity. Collectively, these data are generally consistent with previous findings that dietary intake of omega-3 fatty acids may effectively mitigate systemic inflammation after acute radiation exposure and facilitate maintenance of BMD during spaceflight in humans.
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http://dx.doi.org/10.1152/japplphysiol.00848.2020DOI Listing
January 2021

Outcomes of interfacility helicopter transportation in acute stroke care.

Neurol Clin Pract 2020 Oct;10(5):422-427

Department of Neurology (EA, NT, ED, CAH), Medical University of South Carolina, Charleston; Departments of Neurology, Epidemiology and Neurosurgery (SAK, ECL), University of Iowa Carver College of Medicine; Department of Neurology (MN, JC, D-VG, JAS), Augusta University, GA; and Department of Healthcare Leadership and Management (JBH), College of Health Professions, Medical University of South Carolina, Charleston.

Objective: To evaluate the long-term functional outcome of interhospital transfer of patients with stroke with suspected large vessel occlusion (LVO) using Helicopter Emergency Medical Services (HEMS).

Methods: Records of consecutive patients evaluated through 2 telestroke networks and transferred to thrombectomy-capable stroke centers between March 2017 and March 2018 were reviewed. Inverse probability of treatment weighting (IPTW) using the propensity score was performed to address confounding factors. Multivariate logistic regression analysis with IPTW was used to determine whether HEMS were associated with good long-term functional outcome (modified Rankin scale score ≤ 2).

Results: A total of 199 patients were included; median age was 67 years (interquartile range [IQR] 55-79 years), 90 (45.2%) were female, 120 (60.3%) were white, and 100 (50.3%) were transferred by HEMS. No significant differences between the 2 groups were found in mean age, sex, race, IV tissue plasminogen activator (tPA) receipt, and thrombectomy receipt. The median baseline NIH Stroke Scale score was 14 (IQR 9-18) in the helicopter group vs 11 (IQR 6-18) for patients transferred by ground ( = 0.039). The median transportation time was 60 minutes (IQR 49-70 minutes) by HEMS and 84 minutes (IQR 25-102 minutes) by ground ( < 0.001). After weighting baseline characteristics, the use of HEMS was associated with higher odds of good long-term outcome (OR 4.738, 95% CI 2.15-10.444, < 0.001) controlling for transportation time, door-in-door-out time, and thrombectomy and tPA receipt. The magnitude of the HEMS effect was larger in thrombectomy patients who had successful recanalization (OR 1.758, 95% CI 1.178-2.512, = 0.027).

Conclusions: HEMS use was associated with better long-term functional outcome in patients with suspected LVO, independently of transportation time.
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http://dx.doi.org/10.1212/CPJ.0000000000000737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717633PMC
October 2020

Production and control of coagulation proteins for factor X activation in human endothelial cells and fibroblasts.

Sci Rep 2020 02 6;10(1):2005. Epub 2020 Feb 6.

Department of Bioengineering, Rice University, Houston, TX, USA.

Human endothelial cells (ECs) synthesize, store, and secrete von Willebrand factor multimeric strings and coagulation factor (F) VIII. It is not currently known if ECs produce other coagulation factors for active participation in coagulation. We found that 3 different types of human ECs in primary culture produce clotting factors necessary for FX activation via the intrinsic (FVIII-FIX) and extrinsic (tissue factor [TF]-FVII) coagulation pathways, as well as prothrombin. Human dermal fibroblasts were used as comparator cells. TF, FVII, FIX, FX, and prothrombin were detected in ECs, and TF, FVII, FIX, and FX were detected in fibroblasts. In addition, FVII, FIX, FX, and prothrombin were detected by fluorescent microscopy in EC cytoplasm (associated with endoplasmic reticulum and Golgi proteins). FX activation occurred on human umbilical vein EC surfaces without the addition of external coagulation proteins, proteolytic enzymes, or phospholipids. Tumour necrosis factor, which suppresses the generation of activated protein C and increases TF, augmented FX activation. Fibroblasts also produced TF, but (in contrast to ECs) were incapable of activating FX without the exogenous addition of FX and had a marked increase in FX activation following the addition of both FX and FVII. We conclude that human ECs produce their own coagulation factors that can activate cell surface FX without the addition of exogenous proteins or phospholipids.
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http://dx.doi.org/10.1038/s41598-020-59058-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005260PMC
February 2020

Racial/Ethnic Disparities in Acute Ischemic Stroke Treatment Within a Telestroke Network.

Telemed J E Health 2020 Oct 22;26(10):1221-1225. Epub 2019 Nov 22.

Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA.

The growth of telestroke services expanded the reach of acute stroke treatment. However, ethnic disparities in receiving such treatment have not been fully assessed. We reviewed prospectively maintained data on patients evaluated through the Medical University of South Carolina telestroke program between January 2016 and November 2018. Outcomes included odds of receiving intravenous recombinant tissue plasminogen activator (tPA), receiving mechanical thrombectomy (MT), and achieving door-to-needle (DTN) time ≤60 and ≤45 min among patients receiving tPA. We used logistic regression to analyze the contribution of race/ethnicity. We included 2,977 patients, of whom 1,093 (36.7%) identified as nonwhite; of these, 1,048 patients (95.9%) identified as black or African American. Significantly more nonwhite patients were seen at a primary stroke center (PSC) (68.4% vs. 52.3% in whites, p < 0.001). However, white patients had significantly higher odds of receiving tPA (odds ratio [OR] 1.47, confidence interval [95% CI] 1.17-1.84). There was no significant difference in receiving MT between races. Among patients receiving tPA, whites had higher odds of DTN ≤45 min (OR 1.76, 1.20-2.57) and ≤60 min (OR 1.87, 95% CI 1.31-2.66). White patients had better odds achieving DTN ≤45 min and DTN ≤60 min if receiving tPA within a telestroke setting, as well as higher odds of receiving tPA, even after adjustment for comorbidities. This was noted despite white patients having less access to PSCs. However, larger scale studies are needed to further study the impact of ethnic disparities.
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http://dx.doi.org/10.1089/tmj.2019.0127DOI Listing
October 2020

The Relationship Between Admission Systolic Blood Pressure and Mortality in Telestroke Patients.

Telemed J E Health 2020 Jul 10;26(7):941-944. Epub 2019 Oct 10.

Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA.

A "U-shaped" relationship between admission blood pressure (BP) and mortality (wherein patients within a middle range have better outcomes than patients at higher or lower extremes) in patients receiving intravenous recombinant tissue-plasminogen activator (tPA) has been previously described. We aim to determine if this U-shaped relationship persists for patients in a telestroke setting regardless of tPA administration. We conducted a retrospective chart review of the prospectively collected registry data for all patients seen through the Medical University of South Carolina (MUSC) telestroke network. Admission systolic BP (SBP) was divided into quartiles with thresholds based on the 25th, 50th, and 75th percentiles as cut points separately by tPA status. The primary outcomes of this study were odds of 90-day modified Rankin scale ≤2 and 90-day mortality. Logistic regression analyses were used to analyze associations between BP quartiles and these outcomes, adjusted for relevant clinical covariates. Our sample comprised 1,232 patients evaluated for telestroke, 616 of whom received tPA. Patients in the second (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.15-0.77 in the tPA group, OR 0.27, 95% CI 01.0-0.78 in the non-tPA group) and third (OR 0.26, 95% CI 0.11-0.64 in the tPA group, OR 0.36, 95% CI 0.14-0.92 in the non-tPA group) quartiles of admission SBP had lower adjusted odds of 90-day mortality. Our findings support a U-shaped relationship between admission SBP and 90-day mortality in acute stroke patients regardless of tPA administration, after adjustment for relevant covariates. Further research into interventions regarding BP management poststroke is warranted.
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http://dx.doi.org/10.1089/tmj.2019.0151DOI Listing
July 2020

Beyond acute stroke: Rate of stroke transfers to a tertiary centre following the implementation of a dedicated inpatient teleneurology network.

J Telemed Telecare 2019 Aug 28:1357633X19868097. Epub 2019 Aug 28.

Department of Neurology, Medical University of South Carolina, USA.

Introduction: This study evaluated the impact of establishing an inpatient teleneurology consultation service alongside an already established telestroke network on the stroke transfers to the hub. The study also aimed to assess the financial impact of establishing this network.

Methods: Prospectively collected data on all stroke patients evaluated through our telestroke and teleneurology networks between January 2008 and March 2018 were interrogated. For all spokes (eight sites) that had both teleneurology and telestroke services, we compared the rate of transfers to the hub before and after the establishment of the teleneurology network in August 2014. The cost reduction was estimated using the Medicare 5% standard analytic files.

Results: A total of 4296 stroke patients were evaluated during the study period. Of these, 2493 were seen before and 1803 were seen after the implementation of the teleneurology network at the included sites. Patients in the pre-teleneurology group were older (66.4 years ( = 14.7 years) vs. 67.8 years ( = 15.1 years);  = 0.002). Otherwise, there were no differences in baseline characteristics. Patients in the pre-teleneurology group were more likely to be transferred to the telestroke hub (29.4% vs. 20.2%;  < 0.001). The estimated mean cost reduction for each one minus the cost of transfer was estimated to be US$4997.

Discussion: The implementation of an inpatient teleneurology network was associated with a significant reduction in the transfer rate of stroke patients to hospitals with a higher level of care and could lead to a significant cost reduction.
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http://dx.doi.org/10.1177/1357633X19868097DOI Listing
August 2019

Door in door out and transportation times in 2 telestroke networks.

Neurol Clin Pract 2019 Feb;9(1):41-47

Department of Neurology (SAK), University of Iowa; Department of Neurology (EA, NT, ED, CAH), Medical University of South Carolina, Charleston; Department of Healthcare Leadership and Management (JH), College of Health Professions, Medical University of South Carolina, Charleston; and Department of Neurology (JC, JAS), Augusta University.

Background: Inter-hospital transfer is important in the treatment of acute stroke. We sought to assess door in to door out (DIDO) time at spoke sites, and transportation time between spoke sites and thrombectomy-capable stroke center (TSC) in 2 large, rural telestroke networks.

Methods: Records of patients treated with tissue plasminogen activator through 2 telestroke networks between March 2017 and December 2017 were reviewed. Mann-Whitney test was used to compare median times, and a generalized linear regression model was used to predict the total time of care controlling for transportation distance.

Results: Eighty-five patients were included with median NIH stroke scale on presentation of 13 (interquartile range [IQR] 7-17), median door to needle time 49 minutes (IQR 40-62), and median DIDO 111 minutes (IQR 92-157). Eighteen patients (21%) underwent computed tomography angiography (CTA) at spoke prior to transportation. Median DIDO was 169 minutes for patients who received CTA before transfer, compared with 107 minutes for patients who did not ( = 0.0004). Median door-to-groin time at TSC was 68 minutes for the CTA group and 85 minutes in the non-CTA group ( = 0.832). Controlling for distance, the predicted time of care from spoke door in time to groin puncture at TSC (sDTG) is 93.68 minutes longer for patients who receive CTA prior to transport ( = 0.034).

Conclusion: In the included telestroke networks, the sDTG time is longer when CTA is conducted at spoke site prior to transportation to TSC. New strategies are urgently needed to decrease sDTG when CTA is done prior to transfer to TSC.
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http://dx.doi.org/10.1212/CPJ.0000000000000570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382383PMC
February 2019

Functional Outcomes of Intravenous Thrombolysis in Octogenarians and Nonagenarians Through Telestroke: Single-Center Experience.

Telemed J E Health 2020 01 26;26(1):18-23. Epub 2019 Feb 26.

Department of Neurology, Medical University of South Carolina, Charleston, South Carolina.

Patients aged ≥80 years are often underrepresented in stroke trials. Observational studies have shown that older patients have worse outcomes compared with younger patients, but outcomes in patients aged ≥80 years treated with intravenous (IV)-alteplase specifically through telestroke (TS) have not been studied. To compare clinical and safety outcomes in stroke patients aged ≥80 and 60-79 years treated with IV-alteplase via TS. The Medical University of South Carolina TS database was analyzed to identify IV-alteplase-treated patients aged 60-79 and ≥80 years between January 2015 and March 2018. Baseline demographics and TS-specific variables were compared. Clinical outcomes were assessed using the 90-day modified Rankin Scale (mRS). Safety outcomes were evaluated by comparing symptomatic intracranial hemorrhage (sICH). Multivariate logistic regression analysis was performed to determine odds ratio (OR) for good outcome (mRS 0-2) in the older age group at 90 days. IV-alteplase was used in 151 patients in ≥80 years age group and 273 patients in 60-79 years age group. The older age group had more women and a higher National Institutes of Health Stroke Scale. The mean "ED-door-to-TS-consultant-login" time was shorter (21.6 min vs. 25.6 min; p = 0.048), but "TS-consultant-login-to-alteplase" time was longer (22.1 min vs. 19.3 min; p = 0.01) in the older age group. No difference was noted in eventual "door-to-needle" time. The older age group had fewer good outcomes (39.1% vs. 74%; p = 0.001) and more deaths (38% vs. 14%; p = 0.001) at 90 days. The sICH rates were similar in the two groups. The OR for good outcome in ≥80 years age group was 0.20 (95% CI: 0.12-0.34) after controlling for baseline variables. Stroke patients aged ≥80 years treated via TS have similar post-thrombolysis hemorrhage rates but worse clinical outcomes compared with patients aged 60-79 years.
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http://dx.doi.org/10.1089/tmj.2018.0305DOI Listing
January 2020

Teleneurology Network to Improve Access to Neurologists for Patients in Rural Areas: A Real-World Experience.

Telemed J E Health 2020 01 14;26(1):110-113. Epub 2019 Feb 14.

Department of Neurology, Medical University of South Carolina, Charleston, South Carolina.

The need for neurologists has been steadily increasing over the past few years. The implementation of teleneurology networks could serve as a potential solution to this need. A retrospective review of the Medical University of South Carolina (MUSC) Teleneurology records for all consults performed between August 2014 and July 2018 was conducted. Collected data included number of consults, baseline characteristics, final diagnosis, and number of providers and hospitals over the study period. A total of 4,542 Teleneurology consults were performed during the study period. The most common diagnosis was cerebrovascular disease, followed by seizure disorders. The number of consults per month increased throughout the study period from three in August 2014 to 257 in July 2018. The number of community hospitals covered has increased from 3 hospitals in August 2014 to 14 hospitals throughout the state of South Carolina in July 2018. Over 4 years, the MUSC teleneurology program has evolved into a robust partnership with 14 partner hospitals, and is now delivering more than 250 expert neurology consultations monthly to patients throughout the state of South Carolina.
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http://dx.doi.org/10.1089/tmj.2018.0290DOI Listing
January 2020

Deficiency of complement factor H-related proteins and autoantibody-positive hemolytic uremic syndrome in an infant with combined partial deficiencies and autoantibodies to complement factor H and ADAMTS13.

Clin Kidney J 2018 Dec 7;11(6):791-796. Epub 2018 Mar 7.

Baylor College of Medicine, Houston, TX, USA.

A 3-month-old male infant developed an extremely severe episode of atypical hemolytic uremic syndrome (aHUS) associated with partial deficiencies of full-length complement factor H (FH; ∼15% of infant normal) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) (39% of normal) and autoantibodies reactive with both proteins. His FH and ADAMTS13 genes were normal, indicating that the partial deficiencies were acquired, probably as the result of autoantibodies against full-length FH and ADAMTS13. The child also had a homozygous deletion of the complement factor H-related (CFHR)3-CFHR1 portion in the complement factor H () gene cluster. He therefore had deficiency of CFHR proteins and autoantibody-positive hemolytic uremic syndrome (DEAP-HUS) with an unusual early onset associated with a partial deficiency of ADAMTS13 and an anti-ADAMTS13 autoantibody. His clinical episode of aHUS responded to plasma infusion and subsequent treatment with mycophenolate and rituximab. We believe that this is the first report of DEAP-HUS in an infant with partial deficiencies in both ADAMTS13 and full-length FH acquired in association with autoantibodies to both proteins.
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http://dx.doi.org/10.1093/ckj/sfy010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275444PMC
December 2018

Establishment of a multicomponent dietary bioactive human equivalent dose to delete damaged Lgr5+ stem cells using a mouse colon tumor initiation model.

Eur J Cancer Prev 2019 09;28(5):383-389

Program in Integrative Nutrition and Complex Diseases.

Multicomponent therapy has gained interest for its potential to synergize and subsequently lower the effective dose of each constituent required to reduce colon cancer risk. We have previously showed that rapidly cycling Lgr5 stem cells are exquisitely sensitive to extrinsic dietary factors that modulate colon cancer risk. In the present study, we quantified the dose-dependent synergistic properties of dietary n-3 polyunsaturated fatty acids (PUFA) and curcumin (Cur) to promote targeted apoptotic deletion of damaged colonic Lgr5 stem cells. For this purpose, both heterogeneous bulk colonocytes and Lgr5 stem cells were isolated from Lgr5-EGFP-IRES-CreER knock-in mice injected with azoxymethane (AOM). Isolated cells were analyzed for DNA damage (γH2AX), apoptosis (cleaved caspase-3), and targeted apoptosis (both γH2AX and cleaved caspase-3) at 12 h post-AOM injection. Comparison of the percentage of targeted apoptosis in Lgr5 stem cells (GFP) across a broad bioactive dose-range revealed an ED50 of 16.0 mg/day n-3 PUFA + 15.9 mg/day Cur. This corresponded to a human equivalent dose of 3.0 g n-3 PUFA + 3.0 g Cur. In summary, our results provide evidence that a low dose (n-3 PUFA + Cur) combination diet reduces AOM-induced DNA damage in Lgr5 stem cells and enhances targeted apoptosis of DNA-damaged cells, implying that a lower human equivalent dose can be utilized in future human clinical trials.
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http://dx.doi.org/10.1097/CEJ.0000000000000465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422758PMC
September 2019

Protected land: Many factors shape success.

Science 2018 08;361(6402):561

School of Environmental Studies, University of Victoria, Victoria, BC V8W 2Y2, Canada.

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http://dx.doi.org/10.1126/science.aau5168DOI Listing
August 2018

"Stop the Bleed": A U.S. Military Installation's Model for Implementation of a Rapid Hemorrhage Control Program.

Mil Med 2019 03;184(3-4):67-71

11 MDOS Squadron Readiness Liaison, 1050W. Perimeter Road Joint Base Andrews, MD.

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http://dx.doi.org/10.1093/milmed/usy185DOI Listing
March 2019

Door to needle time and functional outcome for mild ischemic stroke over telestroke.

J Telemed Telecare 2019 Jul 12;25(6):365-369. Epub 2018 May 12.

3 Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA.

Introduction: Faster intravenous alteplase (tPA) administration from time of symptom onset is associated with better functional outcome. Lack of recognition of mild ischemic stroke (MIS) might result in delay in treatment with tPA. We hypothesise that patients with MIS have a longer door to needle (DTN) time when compared to patients with severe stroke symptoms.

Methods: Data on all patients who received tPA at spoke hospitals through the Medical University of South Carolina (MUSC) telestroke network were analysed. Collected data included baseline characteristics, stroke severity on presentation measured by the National Institute of Health Stroke Scale (NIHSS), the rate of symptomatic intracerebral haemorrhage, discharge location, and discharge functional outcome measured by the modified Rankin scale.

Results And Discussion: Of the 454 patients treated with tPA through the MUSC telestroke network in the period from January 2013 to April 2017, 98 (22%) had MIS defined as NIHSS ≤ 5 on presentation; the remaining 356 (78%) patients were found to have severe stroke defined as NIHSS > 5 on presentation. Patients presenting with MIS were found to have a delay in receiving intravenous tPA by ∼10 min ( = 0.007) and approximately 15% of them had poor functional outcome at discharge. Patients with a MIS on presentation have significantly more prolonged DTN time. Nearly 15% of low severity strokes had poor outcome even after receiving tPA.
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http://dx.doi.org/10.1177/1357633X18774460DOI Listing
July 2019

Brain microvascular endothelial cells exhibit lower activation of the alternative complement pathway than glomerular microvascular endothelial cells.

J Biol Chem 2018 05 19;293(19):7195-7208. Epub 2018 Mar 19.

the Department of Bioengineering, Rice University, Houston, Texas 77005.

Atypical hemolytic uremic syndrome (aHUS) and bone marrow transplantation-associated thrombotic microangiopathy (TA-TMA) are associated with excessive activation of the alternative complement pathway (AP) and with severe renal, but rarely cerebral, microvascular damage. Here, we compared AP activation and regulation in human glomerular and brain microvascular endothelial cells (GMVECs and BMVECs, respectively) unstimulated or stimulated by the proinflammatory cytokine, tumor necrosis factor (TNF). Compared with GMVECs and under both experimental conditions, BMVECs had increased gene expression of the AP-related genes , , and and decreased expression of This was associated with increased expression in BMVECs (relative to GMVECs) of the genes for surface and soluble regulatory molecules (, , , , and ) suppressing formation of the AP C3 and C5 convertases. Of note, unlike GMVECs, BMVECs generated extremely low levels of C3a and C5a and displayed decreased activation of the AP (as measured by a lower percentage of Ba generation than GMVECs). Moreover, BMVECs exhibited increased function of CD141, mediating activation of the natural anticoagulant protein C, compared with GMVECs. We also found that the C3a receptor (C3aR) is present on both cell types and that TNF greatly increases expression in GMVECs, but only slightly in BMVECs. Higher AP activation and C3a generation in GMVECs than in BMVECs, coupled with an increase in C3aR production in TNF-stimulated GMVECs, provides a possible explanation for the predominance of renal damage, and the absence of cerebral injury, in individuals with episodes of aHUS and TA-TMA.
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http://dx.doi.org/10.1074/jbc.RA118.002639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949983PMC
May 2018

Rate of Symptomatic Intracerebral Hemorrhage Related to Intravenous tPA Administered Over Telestroke Within 4.5-Hour Window.

Telemed J E Health 2018 10 25;24(10):749-752. Epub 2018 Jan 25.

1 Department of Neurology, Medical University of South Carolina , Charleston, South Carolina.

Background: Intravenous tissue plasminogen activator (tPA) remains the cornerstone medical treatment for acute ischemic stroke. The establishment of telestroke technology has allowed patients presenting to hospitals that lack expert stroke care to be evaluated and receive tPA. The safety of tPA administered through telestroke has been evaluated only when tPA is given within the 3-h window of last known normal. The purpose of this study is to evaluate the safety of tPA when administered through telestroke within a 4.5-h window.

Methods: A retrospective analysis on the prospectively collected database for all patients who received tPA at the Medical University of South Carolina Comprehensive Stroke Center (MUSC) (hub), as well as the MUSC telestroke network partner hospitals (spokes), was performed. Collected data included demographics, baseline characteristics, time from last known well to tPA administration, and symptomatic intracerebral hemorrhage (sICH) rates. Logistic regression was used to examine the odds of a sICH in patients at spoke sites compared with the hub controlling for patient stroke severity, gender, age, and race.

Results: A total of 830 patients were identified. Median National Institute of Health Stroke Scale was significantly higher among patients treated at the hub (9 vs. 8, p = 0.013), and the hub treated a higher percentage of nonwhite patients (p = 0.039). sICH occurred in 27 (4.8%) in the spoke group and 10 (3.8%) in the hub group (p = 0.523). Logistic regression results found no significant difference in the odds of sICH if tPA is given in a spoke site.

Conclusions: Our study shows similar rates of sICH when intravenous tPA is administered at spokes through telestroke network compared with the hub.
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http://dx.doi.org/10.1089/tmj.2017.0248DOI Listing
October 2018

Optimization of novel monobactams with activity against carbapenem-resistant Enterobacteriaceae - Identification of LYS228.

Bioorg Med Chem Lett 2018 02 4;28(4):748-755. Epub 2018 Jan 4.

Novartis Institutes for BioMedical Research, Emeryville, CA, USA.

Metallo-β-lactamases (MBLs), such as New Delhi metallo-β-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of β-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine β-lactamases (SBLs), which are often co-expressed in clinical isolates. Here, we optimized novel monobactams for stability against SBLs, which led to the identification of LYS228 (compound 31). LYS228 is potent in the presence of all classes of β-lactamases and shows potent activity against carbapenem-resistant isolates of Enterobacteriaceae (CRE).
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http://dx.doi.org/10.1016/j.bmcl.2018.01.006DOI Listing
February 2018

Case report of transient mcr-1-haboring Escherichia coli with concurrent Staphylococcus aureus bacteremia in Long Beach, California.

Diagn Microbiol Infect Dis 2017 Dec 14;89(4):303-304. Epub 2017 Jul 14.

JMI Laboratories, North Liberty, IA, USA. Electronic address:

A 55-year-old man with history of chronic hepatitis B cirrhosis presented to an emergency department in California with abdominal pain, constipation, and jaundice. The patient developed methicillin-susceptible S. aureus bacteremia with a concurrent transient E. coli. This organism carried mcr-1 in a plasmid similar to other mcr-1-carrying plasmids from the USA. The spread of mcr-1 into carbapenem-resistant isolates is of great concern and monitoring of this resistance mechanism is important.
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http://dx.doi.org/10.1016/j.diagmicrobio.2017.07.005DOI Listing
December 2017

Door to Needle Time over Telestroke-A Comprehensive Stroke Center Experience.

Telemed J E Health 2018 02 28;24(2):111-115. Epub 2017 Jul 28.

1 Department of Neurology, Medical University of South Carolina , Charleston, South Carolina.

Background: The implementation of telestroke programs has allowed patients living in rural areas suffering from acute ischemic stroke to receive expert acute stroke consultation and intravenous Alteplase (tPA). The purpose of this study is to compare door to needle (DTN) time when tPA is administered at telestroke sites (spokes) through telestroke consultations compared to tPA administration at the comprehensive stroke center (hub).

Methods: Data on all patients who received intravenous tPA at the hub and spoke hospitals through a large telestroke program between May 2008 and December 2016 were collected. Baseline characteristics were compared between the two groups, and the percentage of patients meeting DTN guidelines was compared between the hub and spoke hospitals during the study period. Comparison of DTN before and after the implementation of a quality improvement project was performed.

Results: A total of 1,665 patients received tPA at either the spoke (n = 1,323) or the hub (n = 342) during the study period. Baseline characteristics were comparable in both treatment groups. Before the intervention, DTN time <60 min was achieved in 88% of the hub patients versus 38% of the spoke patients. This difference between the two groups decreased by 35 percentage points, controlling for year (p = 0.0018) after the interventions.

Conclusion: Overall, DTN is longer at the spoke hospitals compared to the hub hospital. This can be improved by various interventions that target quality, training, education, and improving the comfort level of the staff at partner hospitals when treating acute stroke patients.
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http://dx.doi.org/10.1089/tmj.2017.0067DOI Listing
February 2018

Shaping functional gut microbiota using dietary bioactives to reduce colon cancer risk.

Semin Cancer Biol 2017 Oct 1;46:191-204. Epub 2017 Jul 1.

Nutrition and Food Science Department, and Faculty of Genetics, Texas A&M University, College Station, TX 77843-2253, USA. Electronic address:

Colon cancer is a multifactorial disease associated with a variety of lifestyle factors. Alterations in the gut microbiota and the intestinal metabolome are noted during colon carcinogenesis, implicating them as critical contributors or results of the disease process. Diet is a known determinant of health, and as a modifier of the gut microbiota and its metabolism, a critical element in maintenance of intestinal health. This review summarizes recent evidence demonstrating the role and responses of the intestinal microbiota during colon tumorigenesis and the ability of dietary bioactive compounds and probiotics to impact colon health from the intestinal lumen to the epithelium and systemically. We first describe changes to the intestinal microbiome, metabolome, and epithelium associated with colon carcinogenesis. This is followed by a discussion of recent evidence indicating how specific classes of dietary bioactives, prebiotics, or probiotics affect colon carcinogenesis. Lastly, we briefly address the prospects of using multiple 'omics' techniques to integrate the effects of diet, host, and microbiota on colon tumorigenesis with the goal of more fully appreciating the interconnectedness of these systems and thus, how these approaches can be used to advance personalized nutrition strategies and nutrition research.
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http://dx.doi.org/10.1016/j.semcancer.2017.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626600PMC
October 2017

Impact of Novel Sorghum Bran Diets on DSS-Induced Colitis.

Nutrients 2017 Mar 27;9(4). Epub 2017 Mar 27.

Intercollegiate Faculty of Genetics, Texas A&M University, College Station, TX 77843, USA.

We have demonstrated that polyphenol-rich sorghum bran diets alter fecal microbiota; however, little is known regarding their effect on colon inflammation. Our aim was to characterize the effect of sorghum bran diets on intestinal homeostasis during dextran sodium sulfate (DSS)-induced colitis. Male Sprague-Dawley rats ( = 20/diet) were provided diets containing 6% fiber from cellulose, or Black (3-deoxyanthocyanins), Sumac (condensed tannins) or Hi Tannin Black (both) sorghum bran. Colitis was induced ( = 10/diet) with three separate 48-h exposures to 3% DSS, and feces were collected. On Day 82, animals were euthanized and the colon resected. Only discrete mucosal lesions, with no diarrhea or bloody stools, were observed in DSS rats. Only bran diets upregulated proliferation and , and short chain fatty acids (SCFA) transporter expression after a DSS challenge. DSS did not significantly affect fecal SCFA concentrations. Bran diets alone upregulated repair mechanisms and SCFA transporter expression, which suggests these polyphenol-rich sorghum brans may suppress some consequences of colitis.
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http://dx.doi.org/10.3390/nu9040330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409669PMC
March 2017

Association between red meat consumption and colon cancer: A systematic review of experimental results.

Exp Biol Med (Maywood) 2017 Apr 1;242(8):813-839. Epub 2017 Jan 1.

1 Nutrition & Food Science Department, Texas A&M University, TX 77843-2253, USA.

A role for red and processed meat in the development of colorectal cancer has been proposed based largely on evidence from observational studies in humans, especially in those populations consuming a westernized diet. Determination of causation specifically by red or processed meat is contingent upon identification of plausible mechanisms that lead to colorectal cancer. We conducted a systematic review of the available evidence to determine the availability of plausible mechanistic data linking red and processed meat consumption to colorectal cancer risk. Forty studies using animal models or cell cultures met specified inclusion criteria, most of which were designed to examine the role of heme iron or heterocyclic amines in relation to colon carcinogenesis. Most studies used levels of meat or meat components well in excess of those found in human diets. Although many of the experiments used semi-purified diets designed to mimic the nutrient loads in current westernized diets, most did not include potential biologically active protective compounds present in whole foods. Because of these limitations in the existing literature, there is currently insufficient evidence to confirm a mechanistic link between the intake of red meat as part of a healthy dietary pattern and colorectal cancer risk. Impact statement Current recommendations to reduce colon cancer include the reduction or elimination of red or processed meats. These recommendations are based on data from epidemiological studies conducted among cultures where meat consumption is elevated and consumption of fruits, vegetables, and whole grains are reduced. This review evaluated experimental data exploring the putative mechanisms whereby red or processed meats may contribute to colon cancer. Most studies used levels of meat or meat-derived compounds that were in excess of those in human diets, even in cultures where meat intake is elevated. Experiments where protective dietary compounds were used to mitigate the extreme levels of meat and meat-derived compounds showed protection against colon cancer, with some essentially negating the impact of meat in the diet. It is essential that better-designed studies be conducted that use relevant concentrations of meat or meat-derived compounds in complex diets representative of the foods consumed by humans.
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http://dx.doi.org/10.1177/1535370217693117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407540PMC
April 2017

Plum polyphenols inhibit colorectal aberrant crypt foci formation in rats: potential role of the miR-143/protein kinase B/mammalian target of rapamycin axis.

Nutr Res 2016 10 14;36(10):1105-1113. Epub 2016 Jun 14.

Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA; Department of Veterinary Physiology & Pharmacology, Texas A&M University, College Station, TX 77843, USA. Electronic address:

The nutritional prevention of aberrant crypt foci by polyphenols may be a crucial step to dietary cancer prevention. The objective of this study was to determine the underlying mechanisms that contribute to the anti-inflammatory and antitumorigenic properties of plum (Prunus salicina L.) polyphenols, including chlorogenic acid and neochlorogenic acid, in azoxymethane (AOM)-treated rats. The hypothesis was that plum polyphenolics suppress AOM-induced aberrant crypt foci formation through alterations in the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and relative micro-RNA expressions. Sprague-Dawley rats (n=10/group) received plum beverage (1346mg gallic acid equivalents/L) or a control beverage ad libitum for 10 weeks with subcutaneous injections of AOM (15mg/kg) at weeks 2 and 3. Results show that the consumption of the plum beverage decreased the number of dysplastic aberrant crypt foci by 48% (P<.05) and lowered proliferation of mucosal cells by 24% (P<.05). The plum beverage decreased the activity of glutathione peroxidase, superoxide dismutase, and catalase in mucosal scrapings, as well as the superoxide dismutase activity in serum. The results were accompanied by a down-regulation of proinflammatory enzymes nuclear factor κB, nitric oxide synthase, cyclooxygenase-2, and vascular cell adhesion molecule 1 messenger RNA. Plum inhibited the expression of AKT and mTOR messenger RNA, phosphorylated AKT, mTOR, and hypoxia-inducible factor-1α protein levels, and the ratio of the phosphorylated/total protein expression of mTOR. Also, the plum beverage increased the expression of miR-143, which is involved in the regulation of AKT. These results suggest that plum polyphenols may exhibit a chemopreventive potential against colon carcinogenesis by impacting the AKT/mTOR pathway and miR-143.
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http://dx.doi.org/10.1016/j.nutres.2016.06.008DOI Listing
October 2016

Rapidly cycling Lgr5 stem cells are exquisitely sensitive to extrinsic dietary factors that modulate colon cancer risk.

Cell Death Dis 2016 11 10;7(11):e2460. Epub 2016 Nov 10.

Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, USA.

The majority of colon tumors are driven by aberrant Wnt signaling in intestinal stem cells, which mediates an efficient route toward initiating intestinal cancer. Natural lipophilic polyphenols and long-chain polyunsaturated fatty acids (PUFAs) generally suppress Wnt- and NF-κB- (nuclear factor-κ light-chain enhancer of activated B-cell) related pathways. However, the effects of these extrinsic agents on colonic leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5) stem cells, the cells of origin of colon cancer, have not been documented to date. Therefore, we examined the effect of n-3 PUFA and polyphenol (curcumin) combination on Lgr5 stem cells during tumor initiation and progression in the colon compared with an n-6 PUFA-enriched control diet. Lgr5-EGFP-IRES- knock-in mice were fed diets containing n-6 PUFA (control), n-3 PUFA, n-6 PUFA+curcumin or n-3 PUFA+curcumin for 3 weeks, followed by 6 azoxymethane (AOM) injections, and terminated 17 weeks after the last injection. To further elucidate the effects of the dietary bioactives at the tumor initiation stage, Lgr5 stem cells were also assessed at 12 and 24 h post AOM injection. Only n-3 PUFA+curcumin feeding reduced nuclear β-catenin in aberrant crypt foci (by threefold) compared with control at the progression time point. n-3 PUFA+curcumin synergistically increased targeted apoptosis in DNA-damaged Lgr5 stem cells by 4.5-fold compared with control at 12 h and maximally reduced damaged Lgr5 stem cells at 24 h, down to the level observed in saline-treated mice. Finally, RNAseq analysis indicated that p53 signaling in Lgr5 stem cells from mice exposed to AOM was uniquely upregulated only following n-3 PUFA+curcumin cotreatment. These novel findings demonstrate that Lgr5 stem cells are uniquely responsive to external dietary cues following the induction of DNA damage, providing a therapeutic strategy for eliminating damaged Lgr5 stem cells to reduce colon cancer initiation.
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http://dx.doi.org/10.1038/cddis.2016.269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5260883PMC
November 2016

Homeostatic responses of colonic LGR5+ stem cells following acute in vivo exposure to a genotoxic carcinogen.

Carcinogenesis 2016 Feb 30;37(2):206-14. Epub 2015 Dec 30.

Program in Integrative Nutrition and Complex Diseases, Department of Nutrition and Food Science, Vegetable Crop Improvement Center, Texas A&M University, College Station, TX, USA

Perturbations in DNA damage, DNA repair, apoptosis and cell proliferation in the base of the crypt where stem cells reside are associated with colorectal cancer (CRC) initiation and progression. Although the transformation of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)(+) cells is an extremely efficient route towards initiating small intestinal adenomas, the role of Lgr5(+) cells in CRC pathogenesis has not been well investigated. Therefore, we further characterized the properties of colonic Lgr5(+) cells compared to differentiated cells in Lgr5-EGFP-IRES-creER(T2) knock-in mice at the initiation stage of carcinogen azoxymethane (AOM)-induced tumorigenesis using a quantitative immunofluorescence microscopy approach. At 12 and 24h post-AOM treatment, colonic Lgr5(+) stem cells (GFP(high)) were preferentially damaged by carcinogen, exhibiting a 4.7-fold induction of apoptosis compared to differentiated (GFP(neg)) cells. Furthermore, with respect to DNA repair, O(6)-methylguanine DNA methyltransferase (MGMT) expression was preferentially induced (by 18.5-fold) in GFP(high) cells at 24h post-AOM treatment compared to GFP(neg) differentiated cells. This corresponded with a 4.3-fold increase in cell proliferation in GFP(high) cells. These data suggest that Lgr5(+) stem cells uniquely respond to alkylation-induced DNA damage by upregulating DNA damage repair, apoptosis and cell proliferation compared to differentiated cells in order to maintain genomic integrity. These findings highlight the mechanisms by which colonic Lgr5(+) stem cells respond to cancer-causing environmental factors.
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http://dx.doi.org/10.1093/carcin/bgv250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804129PMC
February 2016

TNF Regulates Essential Alternative Complement Pathway Components and Impairs Activation of Protein C in Human Glomerular Endothelial Cells.

J Immunol 2016 Jan 16;196(2):832-45. Epub 2015 Dec 16.

Department of Bioengineering, Rice University, Houston, TX 77005.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy with severe renal injury secondary to an overactive alternative complement pathway (AP). aHUS episodes are often initiated or recur during inflammation. We investigated gene expression of the surface complement regulatory proteins (CD55, CD59, CD46, and CD141 [thrombomodulin]) and AP components in human glomerular microvascular endothelial cells (GMVECs) and in HUVECs, a frequently used investigational model of endothelial cells. Surface complement regulatory proteins were also quantified by flow cytometry. All experiments were done with and without exposure to IL-1β or TNF. Without cytokine stimulation, we found that GMVECs had greater AP activation than did HUVECs. With TNF stimulation, THBD gene expression and corresponding CD141 surface presence in HUVECs and GMVECs were reduced, and gene expression of complement components C3 (C3) and factor B (CFB) was increased. Consequently, AP activation, measured by Ba production, was increased, and conversion of protein C (PC) to activated PC by CD141-bound thrombin was decreased, in GMVECs and HUVECs exposed to TNF. IL-1β had similar, albeit lesser, effects on HUVEC gene expression, and it only slightly affected GMVEC gene expression. To our knowledge, this is the first detailed study of the expression/display of AP components and surface regulatory proteins in GMVECs with and without cytokine stimulation. In aHUS patients with an underlying overactive AP, additional stimulation of the AP and inhibition of activated PC-mediated anticoagulation in GMVECs by the inflammatory cytokine TNF are likely to provoke episodes of renal failure.
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http://dx.doi.org/10.4049/jimmunol.1500960DOI Listing
January 2016