Publications by authors named "Eric R Siegel"

104 Publications

The Alpha-Defensin Prosthetic Joint Infection Test Has Poor Validity for Native Knee Joint Infection.

J Arthroplasty 2021 Aug 25;36(8):2957-2961. Epub 2021 Mar 25.

Departments of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR.

Background: The alpha-defensin test known as Synovaure has been very effective in diagnosis of prosthetic joint infections (PJIs). Being able to easily and accurately differentiate septic and inflammatory arthropathies in native joints would improve diagnostic workup and management. We tested the ability of an alpha-defensin test to distinguish septic from inflammatory or crystalline arthropathy in the native knee.

Methods: 40 native knee joint fluid specimens were tested with cell count, fluid analysis, and culture and alpha-defensin testing. We determined the sensitivity and specificity of the alpha-defensin test using culture-positive fluid as the gold standard for septic arthropathy and positive crystals as the gold standard for crystalline arthropathy.

Results: The Synovasure PJI test had 100% specificity for septic arthritis coupled with a 28% false-positive rate when applied to native knee aspirations. False-positive rate was 5.3 times higher in patients with crystals found in the joint fluid.

Conclusion: Alpha-defensin testing, in the form of the Synovasure PJI test, has a high-false-positive rate when used to distinguish septic and inflammatory arthritis in the native knee joint. Future work will need to determine the sensitivity and specificity of the newer native joint panel. Clinicians should be cognizant of the specific alpha-defensin test used when sampling native knee synovial fluid.
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http://dx.doi.org/10.1016/j.arth.2021.03.020DOI Listing
August 2021

Transfers of pediatric patients with isolated injuries to a rural Level 1 Orthopedic Trauma Center in the United States: are they all necessary?

Arch Orthop Trauma Surg 2021 Jan 4. Epub 2021 Jan 4.

Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR, 72205, USA.

Background: Pediatric fractures are difficult to manage and often result in expensive urgent transfers to a pediatric trauma center. Our study seeks to identify patients transferred with isolated acute orthopedic injuries to a Level 1 center in which no procedure occurred and the patient was discharged home. We sought to examine all patients who are transferred to a Level 1 pediatric trauma center for care of isolated orthopedic injuries, and to determine how often no procedure is performed after transfer. Identification of this group ahead of time could potentially lead to less avoidable transfers.

Methods And Methods: A retrospective chart review of all patients with isolated orthopaedic injuries who were transferred to a Level 1 pediatric trauma center in a rural state within the United States over a 5-year period beginning January, 2011 and ending December, 2015. Demographic factors were collected for each patient as well as diagnosis and treatment at the trauma center. Patients were divided into two groups, those who underwent an operation or fracture reduction after admission and those that had no procedure performed. Patient demographics, fracture types and presentation characteristics were examined to attempt to determine factors related to the potentially avoidable transfers.

Results: 1303 patients were identified who were transferred with isolated orthopedic fractures. Of these, 1113 (85.6%) patients underwent a procedure for their injuries, including 821 treated with surgical intervention and 292 treated with closed reduction of their fracture. 190 of 1303 (14.6%) of the patients transferred with isolated injuries had neither surgery nor a reduction performed. Identifying characteristics of the non-operative group were that they contained a substantially higher percentage of females, transfers by ambulance, fractures involving only the tibia, fracture types classified as other, and fractures from motor-vehicle accidents.

Discussion: Approximately 14.6% of patients transferred to a pediatric Level 1 trauma center for isolated orthopedic injury underwent no surgery or fracture reductions and were discharged directly home. In particular, isolated tibia fractures were more frequently treated without reduction or surgery. In the future, telemedicine consultation for these specific injury types may limit unnecessary and costly transfers to a Level 1 pediatric trauma hospital.
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http://dx.doi.org/10.1007/s00402-020-03679-xDOI Listing
January 2021

Spectroscopic investigation of radiation-induced reoxygenation in radiation-resistant tumors.

Neoplasia 2021 01 18;23(1):49-57. Epub 2020 Nov 18.

Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA. Electronic address:

Fractionated radiation therapy is believed to reoxygenate and subsequently radiosensitize surviving hypoxic cancer cells. Measuring tumor reoxygenation between radiation fractions could conceivably provide an early biomarker of treatment response. However, the relationship between tumor reoxygenation and local control is not well understood. We used noninvasive optical fiber-based diffuse reflectance spectroscopy to monitor radiation-induced changes in hemoglobin oxygen saturation (sO) in tumor xenografts grown from two head and neck squamous cell carcinoma cell lines - UM-SCC-22B and UM-SCC-47. Tumors were treated with 4 doses of 2 Gy over 2 consecutive weeks and diffuse reflectance spectra were acquired every day during the 2-week period. There was a statistically significant increase in sO in the treatment-responsive UM-SCC-22B tumors immediately following radiation. This reoxygenation trend was due to an increase in oxygenated hemoglobin (HbO) and disappeared over the next 48 h as sO returned to preradiation baseline values. Conversely, sO in the relatively radiation-resistant UM-SCC-47 tumors increased after every dose of radiation and was driven by a significant decrease in deoxygenated hemoglobin (dHb). Immunohistochemical analysis revealed significantly elevated expression of hypoxia-inducible factor (HIF-1) in the UM-SCC-47 tumors prior to radiation and up to 48 h postradiation compared with the UM-SCC-22B tumors. Our observation of a decrease in dHb, a corresponding increase in sO, as well as greater HIF-1α expression only in UM-SCC-47 tumors strongly suggests that the reoxygenation within these tumors is due to a decrease in oxygen consumption in the cancer cells, which could potentially play a role in promoting radiation resistance.
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http://dx.doi.org/10.1016/j.neo.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683290PMC
January 2021

Recording and quantifying fetal magnetocardiography signals using a flexible array of optically-pumped magnetometers.

Physiol Meas 2021 01 1;41(12):125003. Epub 2021 Jan 1.

Department of Pediatrics, Division of Neurology, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR, United States of America. Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.

Objective: Fetal magnetocardiography (fMCG) is a non-invasive biomagnetic technique that provides detailed beat-to-beat fetal heart rate analysis, both in normal rhythm as well as in fetal arrhythmias. New cryogenic-free sensors called optically pumped magnetometers (OPMs) have emerged as a less expensive and more geometrically flexible alternative to traditional Superconducting Quantum Interference Device (SQUID) technology for performing fMCG. The objective of the study was to show the ability of OPMs to record fMCG using flexible geometry while seeking to preserve signal quality, and to quantify fetal heart rate variability (FHRV).

Approach: Biomagnetic measurements were performed with OPMs in 24 healthy pregnant women with uncomplicated singleton pregnancies between 28 and 38 weeks gestation (GA). A total of 96 recordings were analyzed from OPM data that was collected using sensors placed in two different maternal configurations over the abdomen. The fMCG signals were extracted and the quality of the recordings were quantified by peak amplitudes and signal-to-noise ratio (SNR). R peaks were used to perform both time and frequency domain FHRV analysis. FHRV measures obtained from OPMs were compared descriptively to the same measures obtained from GA-matched existing SQUID data.

Main Results: The fMCG derived from OPMs were observed in 21 of the 24 participants. Higher detection rates (85%) of fMCG signals were observed in the data sets recorded at GA >32 weeks. Peak amplitudes and SNR values were similar between two maternal configurations, but peak amplitudes were significantly higher (p = 0.013) in late GA compared to early GA. FHRV indicators were successfully extracted and their values overlapped substantially with those obtained from SQUID recordings.

Significance: Taking advantage of the geometric flexibility of the OPMs, we have demonstrated their ability to record and quantify fMCG in different maternal positions as opposed to rigid SQUID configurations.
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http://dx.doi.org/10.1088/1361-6579/abc353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875519PMC
January 2021

In Vivo Lymphatic Circulating Tumor Cells and Progression of Metastatic Disease.

Cancers (Basel) 2020 Oct 5;12(10). Epub 2020 Oct 5.

Department of Otolaryngology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR 72205, USA.

The dissemination of circulating tumor cells (CTCs) by lymph fluid is one of the key events in the development of tumor metastasis. However, little progress has been made in studying lymphatic CTCs (L-CTCs). Here, we demonstrate the detection of L-CTCs in preclinical mouse models of melanoma and breast cancer using in vivo high-sensitivity photoacoustic and fluorescent flow cytometry. We discovered that L-CTCs are be detected in pre-metastatic disease stage. The smallest primary tumor that shed L-CTCs was measured as 0.094mm×0.094mm, its volume was calculated as 0.0004 mm; and its productivity was estimated as 1 L-CTC per 30 minutes. As the disease progressed, primary tumors continued releasing L-CTCs with certain individual dynamics. The integrated assessment of lymph and blood underlined the parallel dissemination of CTCs at all disease stages. However, the analysis of links between L-CTC counts, blood CTC (B-CTC) counts, primary tumor size and metastasis did not reveal statistically significant correlations, likely due to L-CTC heterogeneity. Altogether, our results showed the feasibility of our diagnostic platform using photoacoustic flow cytometry for preclinical L-CTC research with translational potential. Our findings also demonstrated new insights into lymphatic system involvement in CTC dissemination. They help to lay the scientific foundation for the consideration of L-CTCs as prognostic markers of metastasis and to emphasize the integrative assessment of lymph and blood.
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http://dx.doi.org/10.3390/cancers12102866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650582PMC
October 2020

Lymph Liquid Biopsy for Detection of Cancer Stem Cells.

Cytometry A 2021 May 18;99(5):496-502. Epub 2020 Sep 18.

University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA.

Collection of a blood sample defined by the term "blood liquid biopsy" is commonly used to detect diagnostic, prognostic, and therapeutic decision-making markers of metastatic tumors including circulating tumor cells (CTCs). Many tumors also release CTCs and other markers into lymph fluid, but the utility of lymphatic markers largely remains unexplored. Here, we introduce lymph liquid biopsy through collection of peripheral (afferent) and central (thoracic duct [TD]) lymph samples and demonstrates its feasibility for detection of stem-like CTCs potentially responsible for metastasis development and tumor relapse. Stemness of lymphatic CTCs (L-CTCs) was determined by spheroid-forming assay in vitro. Simultaneously, we tested blood CTCs by conventional blood liquid biopsy, and monitored the primary tumor size, early metastasis in a sentinel lymph node (SLN) and distant metastasis in lungs. Using a mouse model at early melanoma stage with no distant metastasis, we identified stem-like L-CTCs in lymph samples from afferent lymphatic vessels. Since these vessels transport cells from the primary tumor to SLN, our finding emphasizes the significance of the lymphatic pathway in development of SLN metastasis. Surprisingly, in pre-metastatic disease, stem-like L-CTCs were detected in lymph samples from the TD, which directly empties lymph into blood circulation. This suggests a new contribution of the lymphatic system to initiation of distant metastasis. Integration of lymph and blood liquid biopsies demonstrated that all mice with early melanoma had stem-like CTCs in at least one of three samples (afferent lymph, TD lymph, and blood). At the stage of distant metastasis, spheroid-forming L-CTCs were detected in TD lymph, but not in afferent lymph. Altogether, our results demonstrated that lymph liquid biopsy and testing L-CTCs holds promise for diagnosis and prognosis of early metastasis. © 2020 International Society for Advancement of Cytometry.
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http://dx.doi.org/10.1002/cyto.a.24221DOI Listing
May 2021

Narcotic Refills and Patient Satisfaction With Pain Control After Total Joint Arthroplasty.

J Arthroplasty 2021 02 4;36(2):454-461. Epub 2020 Aug 4.

University of Arkansas for Medical Sciences, Department of Orthopaedic Surgery, 4301 West Markham Street, Slot 531 Little Rock, AR 72205.

Background: Patient satisfaction has become an important metric for total joint arthroplasty (TJA) used to reimburse hospitals. Despite ubiquitous narcotic use for post-TJA pain control, there is little understanding regarding patient factors associated with obtaining opioid refills and associations with patient satisfaction.

Methods: Using our state's mandatory opioid prescription monitoring program, we reviewed preoperative and postoperative narcotic prescriptions filled for 438 consecutive TJA patients. Subjects were divided into 3 groups based on the number of post-TJA narcotic refills obtained (0, 1, or >1), and logistic regression analysis was conducted comparing demographics, surgical factors, and satisfaction with pain control.

Results: One hundred twenty-five patients (25.8%) did not consume preoperative opioids and received no postoperative refills. Total hip arthroplasty (THA) patients (P = .0004), subjects ≥65 years (P = .0057), and Medicare patients (P = .0058) had significantly higher rates of 0 postdischarge refills. THA recipients had 268% increased odds of not receiving a refill narcotic (adjusted odds ratio = 0.373; 95% confidence interval, 0.224- 0.622). Every 100-morphine milligram equivalent (MME) increase in presurgery use led to a 16% increase in odds of needing >1 opioid refill (adjusted odds ratio = 1.161; 95% confidence interval, 1.085-1.242). Subjects who noted higher satisfaction consumed less overall opioids when receiving a refill (436 vs 1119 MMEs, P = .021).

Conclusion: Subjects who received fewer narcotic prescriptions and overall MMEs demonstrated higher rates of satisfaction with early pain control. Our results are consistent with other studies in showing that increased preoperative narcotic use portends higher rates of postoperative refills. There appears to be a subset of THA patients >65 years of age who may be candidates for opioid-sparing analgesia.
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http://dx.doi.org/10.1016/j.arth.2020.07.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855659PMC
February 2021

A pilot study: Auditory steady-state responses (ASSR) can be measured in human fetuses using fetal magnetoencephalography (fMEG).

PLoS One 2020 22;15(7):e0235310. Epub 2020 Jul 22.

Ob/Gynecology Department, SARA Research Center, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.

Background: Auditory steady-state responses (ASSRs) are ongoing evoked brain responses to continuous auditory stimuli that play a role for auditory processing of complex sounds and speech perception. Transient auditory event-related responses (AERRs) have previously been recorded using fetal magnetoencephalography (fMEG) but involve different neurological pathways. Previous studies in children and adults demonstrated that the cortical components of the ASSR are significantly affected by state of consciousness and by maturational changes in neonates and young infants. To our knowledge, this is the first study to investigate ASSRs in human fetuses.

Methods: 47 fMEG sessions were conducted with 24 healthy pregnant women in three gestational age groups (30-32 weeks, 33-35 weeks and 36-39 weeks). The stimulation consisted of amplitude-modulated (AM) tones with a duration of one second, a carrier frequency (CF) of 500 Hz and a modulation frequency (MF) of 27 Hz or 42 Hz. Both tones were presented in a random order with equal probability adding up to 80-100 repetitions per tone. The ASSR across trials was quantified by assessing phase synchrony in the cortical signals at the stimulation frequency.

Results And Conclusion: Ten out of 47 recordings were excluded due to technical problems or maternal movements. Analysis of the included 37 fetal recordings revealed a statistically significant response for the phase coherence between trials for the MF of 27 Hz but not for 42 Hz. An exploratory subgroup analysis moreover suggested an advantage in detectability for fetal behavioral state 2F (active asleep) compared to 1F (quiet asleep) detected using fetal heart rate. In conclusion, this pilot study is the first description of a method to detect human ASSRs in fetuses. The findings warrant further investigations of the developing fetal brain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235310PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375519PMC
September 2020

Tracking evoked responses to auditory and visual stimuli in fetuses exposed to maternal high-risk conditions.

Dev Psychobiol 2021 Jan 11;63(1):5-15. Epub 2020 Jul 11.

Department of Obstetrics and Gynecology, SARA Fetal MEG Research Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Magnetoencephalography (MEG) has been successfully applied to record fetal auditory (auditory evoked response [AER]) and visual evoked responses (VER). In this study, we report the AER and VER development trajectory by tracking the evoked response detectability and latency from recordings starting at 27 weeks of gestation in pregnancies classified as high risk. Fetal MEG and ultrasound recordings were performed on 158 pregnant women, and the total number of fetal auditory and visual tests conducted was 321 and 237, respectively. The overall evoked response analysis showed 237 AER (73.8%) and 164 VER detections (69.2%). The mean AER latency was 290.7 (SD 125.5) ms and the mean VER latency was 293.7 (SD 114.5) ms. The rate of decrease (95% confidence limits) in average AER and VER first-peak latency between 100-350 ms was 1.97 (-1.86, +5.81) ms/week and 1.35 (-3.83, +6.53) ms/week, respectively. This trend in high-risk fetuses conforms to the general trajectory of decrease in latency with gestational age progression, even though this decrease was non-significant, as reported in the case of normal growing fetuses. Although there was a significant difference in detection rates between male and female fetuses, this was not reflected in either latency values or the sensory modality applied. Furthermore, the main factors that had the most significant effect on response detectability included the presence of intervening layers of adipose tissue between the fetal head and stimulus source and an increase in the maternal body mass index.
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http://dx.doi.org/10.1002/dev.22008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875520PMC
January 2021

Impact of Myc in HIV-associated non-Hodgkin lymphomas treated with EPOCH and outcomes with vorinostat (AMC-075 trial).

Blood 2020 09;136(11):1284-1297

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; and.

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count <200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs, resulted in more frequent grade 4 neutropenia and thrombocytopenia, and did not affect survival. Overall, patients with Myc+ DLBCL had a significantly lower EFS. A low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, whereas preprotocol therapy had no negative impact. In summary, EPOCH had broad efficacy against highly aggressive HIV-NHLs, whereas vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting preprotocol therapy facilitated accruals without compromising outcomes. This trial was registered at www.clinicaltrials.gov as #NCT0119384.
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http://dx.doi.org/10.1182/blood.2019003959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483436PMC
September 2020

Carbohydrate (Chondroitin 4) Sulfotransferase-11-Mediated Induction of Epithelial-Mesenchymal Transition and Generation of Cancer Stem Cells.

Pharmacology 2020 28;105(5-6):246-259. Epub 2020 Apr 28.

Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA,

Introduction: We have previously shown that the expression of carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) is elevated in human breast cancer tissues, and that its expression in human breast cancer cell lines is associated with aggressive behavior of cells. The clinical significance of CHST11 expression is unknown, and its function in breast cancer cells is not fully understood.

Objective: The current study was performed to define the clinical significance of this gene and address its biological function in promoting the aggressive behavior of breast cancer cells.

Methods: Publicly available datasets were analyzed to determine the correlation of CHST11 expression with breast cancer survival. MCF-7 cells were transfected with the human CHST11 gene, and MCF-7-CHST11 cells with stable expression of the gene were established. Morphology and metastatic capacity of transfected cells were monitored in vitro. E-cadherin and β-catenin expression was compared by immunofluorescence. The expression of genes involved in epithelial-mesenchymal transition (EMT) and pluripotency was determined using real-time PCR. The Wnt inhibitor, Wnt-C59, was used to examine the involvement of Wnt in CHST11-mediated morphology.

Results: The elevated expression of CHST11 in breast tumor specimens was significantly associated with poor survival among patients. MCF-7-CHST11 cells displayed morphological characteristics consistent with EMT, together with a significantly higher proliferation rate, enhanced migratory potential, and more robust anchorage-independent growth. MCF-7-CHST11 cells showed decreased expression of E-cadherin and increased accumulation of β-catenin, as assessed by immunofluorescence. Consistently, increased expression of CHST11 resulted in upregulation of key EMT and stem cell markers. Morphological transition in MCF-7-CHST11 cells was partially reversed by co-incubation with an inhibitor of the Wnt pathway.

Conclusions: Our findings support a role for CHST11 in induction of EMT and stem cell-like properties. Our data also associate the expression levels of CHST11 in breast tumor specimens with patients' survival. The results have a significant implication for CHST11 expression level as a novel molecular signature for predictive and prognostic purposes in breast cancer. Moreover, with a possible role in driving tumor cell aggressiveness, CHST11 expression might be further considered as a potential therapeutic target for breast cancer.
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http://dx.doi.org/10.1159/000506710DOI Listing
February 2021

Genome-wide DNA methylation signatures to predict pathologic complete response from combined neoadjuvant chemotherapy with bevacizumab in breast cancer.

PLoS One 2020 16;15(4):e0230248. Epub 2020 Apr 16.

Department of Internal Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.

Trial Registration: ClinicalTrials.gov Identifier: NCT00203502.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230248PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162481PMC
June 2020

Studying the Effect of Maternal Pregestational Diabetes on Fetal Neurodevelopment Using Magnetoencephalography.

Clin EEG Neurosci 2020 Sep 11;51(5):331-338. Epub 2020 Mar 11.

Department of Obstetrics and Gynecology, SARA Fetal MEG Research Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Developmental origin of health and disease states that an adverse intrauterine environment can lead to different diseases in later life. In this study, we aimed to explore the effect of maternal pregestational diabetes on the fetal brain activity using magnetoencephalography (MEG). Forty participants were included in an observational study with 9 type 1 and 19 type 2 diabetic pregnant women compared with data from 12 nondiabetic participants. Spontaneous fetal MEG signals were recorded and power spectral density was computed in 4 standard frequency bands. Group differences were investigated using analysis of covariance. . Our results showed that type 1 group was significantly different ( < .05) from the reference group for 3 of the 4 brain activity frequency bands, while in type 2 group, 2 bands exhibited this trend. When dichotomized based on the maternal glycemic control, significant differences in all bands were observed between the poor-control and reference groups. . The fetal background brain activity parameters appear to be altered in diabetic pregnancy in comparison with the reference low-risk group. The study showed that maternal pregestational diabetes could potentially influence in utero neurodevelopment.
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http://dx.doi.org/10.1177/1550059420909658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232045PMC
September 2020

Streamlining Hospital Treatment of Prosthetic Joint Infection.

J Arthroplasty 2020 03;35(3S):S63-S68

Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR.

Background: Prosthetic joint infection (PJI) is associated with significant morbidity, mortality, and costs. We developed a fast-track PJI care system using an infectious disease physician to work directly with the TJA service and coordinate in the treatment of PJI patients. We hypothesized that streamlined care of patients with hip and knee PJI decreases the length of the acute hospital stay without increasing the risk of complication or incorrect antibiotic selection.

Methods: A single-center retrospective chart review was performed for all patients treated operatively for PJI. A cohort of 78 fast-track patients was compared to 68 control patients treated before the implementation of the program. Hospital length of stay (LOS) and cases of antibiotic mismatch were primary outcomes. Secondary outcomes, including 90-day readmissions, reoperations, mortality, rate of reimplantation, and 12-month reimplant survival, were compared. Cox regressions were analyzed to assess the effects on LOS of patient demographics and the type of surgery performed.

Results: Average hospital LOS from infection surgery to discharge was significantly lower in the fast-track cohort (3.8 vs 5.7 days; P = .012). There were no episodes of antibiotic mismatch in the fast-track group vs 1 recorded episode in the control group. No significant differences were noted comparing 90-day complications, reimplantation rate, or 12-month reimplant survival rates.

Conclusion: Through the utilization of an orthopedic-specific infectious disease physician, a fast-track PJI protocol can significantly shorten hospital LOS while remaining safe. Streamlining care pathways may help decrease the overall healthcare costs associated with treating PJI.
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http://dx.doi.org/10.1016/j.arth.2019.10.056DOI Listing
March 2020

Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells.

Reprod Sci 2020 01 1;27(1):267-277. Epub 2020 Jan 1.

Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Metformin (MET) is increasingly implicated in reducing the incidence of multiple cancer types in patients with diabetes. However, similar effects of MET in non-diabetic women with endometrial cancer (EC) remain unknown. In a pilot study, obese non-diabetic women diagnosed with type 1, grade 1/2 EC, and consenting to participate were randomly assigned to receive MET or no MET (control (CON)) during the pre-surgical window between diagnosis and hysterectomy. Endometrial tumors obtained at surgery (MET, n = 4; CON, n = 4) were analyzed for proliferation (Ki67), apoptosis (TUNEL), and nuclear expression of ERα, PGR, PTEN, and KLF9 proteins in tumor glandular epithelial (GE) and stromal (ST) cells. The percentages of immunopositive cells for PGR and for KLF9 in GE and for PTEN in ST were higher while those for ERα in GE but not ST were lower, in tumors of MET vs. CON patients. The numbers of Ki67- and TUNEL-positive cells in tumor GE and ST did not differ between groups. In human Ishikawa endometrial cancer cells, MET treatment (60 μM) decreased cell numbers and elicited distinct temporal changes in ESR1, KLF9, PGR, PGR-B, KLF4, DKK1, and other tumor biomarker mRNA levels. In the context of reduced KLF9 expression (by siRNA targeting), MET rapidly amplified PGR, PGR-B, and KLF4 transcript levels. Our findings suggest that MET acts directly in EC cells to modify steroid receptor expression and signaling network and may constitute a preventative strategy against EC in high-risk non-diabetic women.
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http://dx.doi.org/10.1007/s43032-019-00019-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077930PMC
January 2020

The Atypical Patient With Slipped Capital Femoral Epiphyses May Be at Increased Risk for a Missed Contralateral Slip.

Orthopedics 2020 Mar 13;43(2):e114-e118. Epub 2020 Jan 13.

Slipped capital femoral epiphysis (SCFE) is a commonly encountered hip disorder. The goal of this study was to describe the incidence of missed contra-lateral SCFE as well as to identify risk factors. The authors hypothesized that contralateral slips are more often missed in patients with severe involvement of the treated side. After institutional review board approval was obtained, a retrospective chart review was performed of all pediatric patients who were treated for sequential and bilateral SCFE at a single institution during an 18-year period. Medical records were reviewed for demographic features and attending surgeon. Radiographs were reviewed for skeletal maturity, Klein's line, and severity of the treated slip. All radiographs were reviewed by 3 pediatric orthopedists. Contralateral SCFE was deemed present when consensus was achieved. Comparisons were made with Fisher's exact test, and P<.05 was considered significant. Of the records that were reviewed, 56 patients met the study criteria. Of these, 19 patients had bilateral involvement and 5 missed slips were identified (8.9%). The patients with missed disease tended to be younger (mean age, 10.8 vs 11.4 years), with a lower body mass index. Fellowship-trained pediatric surgeons were more likely to identify bilateral disease compared with orthopedists without pediatric training (P=.0065). A contralateral slip was more likely to be present in patients who had a positive finding for Klein's line (P<.0001). Severity of the treated slip did not increase the likelihood of missing a contralateral slip. Although Klein's line is a useful tool in the diagnosis of SCFE, a false-negative rate of 40% was observed. The authors recommend increased vigilance when an "atypical" patient with SCFE presents with unilateral disease. [Orthopedics. 2020;43(2):e114-e118.].
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http://dx.doi.org/10.3928/01477447-20200107-04DOI Listing
March 2020

Dual antivascular function of human fibulin-3 variant, a potential new drug discovery strategy for glioblastoma.

Cancer Sci 2020 Mar 8;111(3):940-950. Epub 2020 Feb 8.

Department of Neurological Surgery, Brain Tumor Research Laboratory, University of California, Irvine, CA, USA.

The ECM protein EFEMP1 (fibulin-3) is associated with all types of solid tumor through its cell context-dependent dual function. A variant of fibulin-3 was engineered by truncation and mutation to alleviate its oncogenic function, specifically the proinvasive role in glioblastoma multiforme (GBM) cells at stem-like state. ZR30 is an in vitro synthesized 39-kDa protein of human fibulin-3 variant. It has a therapeutic effect in intracranial xenograft models of human GBM, through suppression of epidermal growth factor receptor/AKT and NOTCH1/AKT signaling in GBM cells and extracellular MMP2 activation. Glioblastoma multiforme is highly vascular, with leaky blood vessels formed by tumor cells expressing endothelial cell markers, including CD31. Here we studied GBM intracranial xenografts, 2 weeks after intratumoral injection of ZR30 or PBS, by CD31 immunohistochemistry. We found a 70% reduction of blood vessel density in ZR30-treated xenografts compared with that of PBS-treated ones. Matrigel plug assays showed the effect of ZR30 on suppressing angiogenesis. We further studied the effect of ZR30 on genes involved in endothelial transdifferentiation (ETD), in 7 primary cultures derived from 3 GBMs under different culture conditions. Two GBM cultures formed mesh structures with upregulation of ETD genes shortly after culture in Matrigel Matrix, and ZR30 suppressed both. ZR30 also downregulated ETD genes in two GBM cultures with high expression of these genes. In conclusion, multifaceted tumor suppression effects of human fibulin-3 variant include both suppression of angiogenesis and vasculogenic mimicry in GBM.
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http://dx.doi.org/10.1111/cas.14300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060460PMC
March 2020

Dantrolene Attenuates Cardiotoxicity of Doxorubicin Without Reducing its Antitumor Efficacy in a Breast Cancer Model.

Transl Oncol 2020 Feb 7;13(2):471-480. Epub 2020 Jan 7.

Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, USA.

Dysregulation of calcium homeostasis is a major mechanism of doxorubicin (DOX)-induced cardiotoxicity. Treatment with DOX causes activation of sarcoplasmic reticulum (SR) ryanodine receptor (RYR) and rapid release of Ca in the cytoplasm resulting in depression of myocardial function. The aim of this study was to examine the effect of dantrolene (DNT) a RYR blocker on both the cardiotoxicity and antitumor activity of DOX in a rat model of breast cancer. Female F344 rats with implanted MAT B III breast cancer cells were randomized to receive intraperitoneal DOX twice per week (12 mg/kg total dose), 5 mg/kg/day oral DNT or a combination of DOX + DNT for 3 weeks. Echocardiography and blood troponin I levels were used to measure myocardial injury. Hearts and tumors were evaluated for histopathological alterations. Blood glutathione was assessed as a measure of oxidative stress. The results showed that DNT improved DOX-induced alterations in the echocardiographic parameters by 50%. Histopathologic analysis of hearts showed reduced DOX induced cardiotoxicity in the group treated with DOX + DNT as shown by reduced interstitial edema, cytoplasmic vacuolization, and myofibrillar disruption, compared with DOX-only-treated hearts. Rats treated with DNT lost less body weight, had higher blood GSH levels and lower troponin I levels than DOX-treated rats. These data indicate that DNT is able to provide protection against DOX cardiotoxicity without reducing its antitumor activity. Further studies are needed to determine the optimal dosing of DNT and DOX in a tumor-bearing host.
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http://dx.doi.org/10.1016/j.tranon.2019.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031101PMC
February 2020

Gastrointestinal Tract Dysbiosis Enhances Distal Tumor Progression through Suppression of Leukocyte Trafficking.

Cancer Res 2019 12 7;79(23):5999-6009. Epub 2019 Oct 7.

Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

The overall use of antibiotics has increased significantly in recent years. Besides fighting infections, antibiotics also alter the gut microbiota. Commensal bacteria in the gastrointestinal tract are crucial to maintain immune homeostasis, and microbial imbalance or dysbiosis affects disease susceptibility and progression. We hypothesized that antibiotic-induced dysbiosis of the gut microbiota would suppress cytokine profiles in the host, thereby leading to changes in the tumor microenvironment. The induced dysbiosis was characterized by alterations in bacterial abundance, composition, and diversity in our animal models. On the host side, antibiotic-induced dysbiosis caused elongated small intestines and ceca, and B16-F10 melanoma and Lewis lung carcinoma progressed more quickly than in control mice. Mechanistic studies revealed that this progression was mediated by suppressed TNFα levels, both locally and systemically, resulting in reduced expression of tumor endothelial adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1) and a subsequent decrease in the number of activated and effector CD8 T cells in the tumor. However, suppression of ICAM-1 or its binding site, the alpha subunit of lymphocyte function-associated antigen-1, was not seen in the spleen or thymus during dysbiosis. TNFα supplementation in dysbiotic mice was able to increase ICAM-1 expression and leukocyte trafficking into the tumor. Overall, these results demonstrate the importance of commensal bacteria in supporting anticancer immune surveillance, define an important role of tumor endothelial cells within this process, and suggest adverse consequences of antibiotics on cancer control. SIGNIFICANCE: Antibiotic-induced dysbiosis enhances distal tumor progression by altering host cytokine levels, resulting in suppression of tumor endothelial adhesion molecules and activated and effector CD8 T cells in the tumor.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-4108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891208PMC
December 2019

Use of electronic nicotine delivery systems by pregnant women II: Hair biomarkers for exposures to nicotine and tobacco-specific nitrosamines.

Tob Induc Dis 2019 6;17:50. Epub 2019 Jun 6.

Department of Environmental and Occupational Health, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, United States.

Introduction: Public awareness of electronic nicotine delivery systems (ENDS) has increased over time, and the perception that ENDS offer a safer alternative to cigarettes may lead some pregnant women to use them to reduce cigarette smoking during pregnancy. No previous studies have used metabolite levels in hair to measure nicotine exposure for ENDS users during pregnancy. We aimed to measure and compare levels of nicotine, cotinine, and tobacco-specific nitrosamines (TSNAs) in hair samples from pregnant women who were current ENDS users, current smokers, and current non-smokers. We also aimed to estimate the association between ENDS use/smoking and smallness for gestational age (SGA).

Methods: We used hair specimens from pregnant women who were dual users (ENDS and cigarettes), smokers, and non-smokers from a prospective cohort study to estimate exposure to nicotine, cotinine, and TSNAs. The exposure biomarkers and self-reports of smoking and ENDS use were used in log-binomial regression models to estimate risk ratios (RRs) for SGA among offspring.

Results: Nicotine concentrations for pregnant dual users were not significantly different from those for smokers (11.0 and 10.6 ng/mg hair, respectively; p=0.58). Similarly, levels of cotinine, and TSNAs for pregnant dual users were not lower than those for smokers. The RR for SGA was similar for dual users and smokers relative to nonsmokers, (RR=3.5, 95% CI: 0.8-14.8) and (RR=3.3, 95% CI: 0.9-11.6), respectively. Using self-reports confirmed by hair nicotine, the RR values for dual ENDS users and smokers were 8.3 (95% CI: 1.0-69.1) and 7.3 (95% CI:1.0-59.0), respectively.

Conclusions: We did not observe lower levels of nicotine, cotinine, and TSNAs for current dual users compared to smokers during pregnancy. The risk of SGA for offspring of pregnant dual users was similar to that for offspring of pregnant smokers. Future studies are needed to further estimate the magnitude of the association between ENDS use and smallness for gestational age.
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http://dx.doi.org/10.18332/tid/105387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662780PMC
June 2019

Magnetocardiographic identification of prolonged fetal corrected QT interval in women receiving treatment for opioid use disorder.

J Obstet Gynaecol Res 2019 Oct 11;45(10):1989-1996. Epub 2019 Jul 11.

Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.

Aim: Pregnant women undergoing treatment for opioid use disorder (OUD) may be exposed to multiple QT prolonging agents. We used magnetocardiography to measure fetal QT intervals in mothers with OUD on buprenorphine therapy.

Methods: Fetal and maternal magnetocardiography was performed in pregnant women receiving buprenorphine-assisted treatment (Disorder group); these were matched by gestational age to pregnant women who were opiate naïve (Reference group). Corrected QT intervals were determined using Bazett's formula and compared between groups.

Results: A total of eight women in the Disorder group matched to eight in the Reference group. Seven of the mothers (88%) in the Disorder group were smokers; there were no smokers in the Reference group. The average fetal corrected QT was significantly longer (P = 0.022) in the Disorder group than that in the Reference group (505 milliseconds [ms] ± 68.6 [standard deviation] vs 383 ms ± 70.3 [standard deviation]).

Conclusion: Novel data from this small sample demonstrate prolongation of fetal corrected QT in women with OUD participating in buprenorphine assisted therapy. Additional investigation from a larger sample is needed to clarify if fetal buprenorphine and/or tobacco exposure is associated with changes in fetal QT which would warrant further prenatal and postnatal testing.
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http://dx.doi.org/10.1111/jog.14055DOI Listing
October 2019

In vivo liquid biopsy using Cytophone platform for photoacoustic detection of circulating tumor cells in patients with melanoma.

Sci Transl Med 2019 06;11(496)

Arkansas Nanomedicine Center, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.

Most cancer deaths arise from metastases as a result of circulating tumor cells (CTCs) spreading from the primary tumor to vital organs. Despite progress in cancer prognosis, the role of CTCs in early disease diagnosis is unclear because of the low sensitivity of CTC assays. We demonstrate the high sensitivity of the Cytophone technology using an in vivo photoacoustic flow cytometry platform with a high pulse rate laser and focused ultrasound transducers for label-free detection of melanin-bearing CTCs in patients with melanoma. The transcutaneous delivery of laser pulses via intact skin to a blood vessel results in the generation of acoustic waves from CTCs, which are amplified by vapor nanobubbles around intrinsic melanin nanoclusters. The time-resolved detection of acoustic waves using fast signal processing algorithms makes photoacoustic data tolerant to skin pigmentation and motion. No CTC-associated signals within established thresholds were identified in 19 healthy volunteers, but 27 of 28 patients with melanoma displayed signals consistent with single, clustered, and likely rolling CTCs. The detection limit ranged down to 1 CTC/liter of blood, which is ~1000 times better than in preexisting assays. The Cytophone could detect individual CTCs at a concentration of ≥1 CTC/ml in 20 s and could also identify clots and CTC-clot emboli. The in vivo results were verified with six ex vivo methods. These data suggest the potential of in vivo blood testing with the Cytophone for early melanoma screening, assessment of disease recurrence, and monitoring of the physical destruction of CTCs through real-time CTC counting.
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http://dx.doi.org/10.1126/scitranslmed.aat5857DOI Listing
June 2019

Glutaminase inhibitor CB-839 increases radiation sensitivity of lung tumor cells and human lung tumor xenografts in mice.

Int J Radiat Biol 2019 04 15;95(4):436-442. Epub 2019 Jan 15.

b The Winthrop P. Rockefeller Cancer Institute , University of Arkansas for Medical Sciences , Little Rock , AR , USA.

Purpose: The purpose of this study was to translate our in vitro therapy approach to an in vivo model. Increased glutamine uptake is known to drive cancer cell proliferation, making tumor cells glutamine-dependent. Studying lymph-node aspirates containing malignant lung tumor cells showed a strong correlation between glutamine consumption and glutathione (GSH) excretion. Subsequent experiments with A549 and H460 lung tumor cell lines provided additional evidence for glutamine's role in driving synthesis and excretion of GSH. Using stable-isotope-labeled glutamine as a tracer metabolite, we demonstrated that the glutamate group in GSH is directly derived from glutamine, linking glutamine utilization intimately to GSH syntheses.

Materials And Methods: To understand the possible mechanistic link between glutamine consumption and GSH excretion, we studied GSH metabolism in more detail. Inhibition of glutaminase (GLS) with BPTES, a GLS-specific inhibitor, effectively abolished GSH synthesis and excretion. Since our previous work, several novel GLS inhibitors became available and we report herein effects of CB-839 in A427, H460 and A549 lung tumor cells and human lungtumor xenografts in mice.

Results: Inhibition of GLS markedly reduced cell viability, producing ED values for inhibition of colony formation of 9, 27 and 217 nM in A427, A549 and H460, respectively. Inhibition of GLS is accompanied by ∼30% increased response to radiation, suggesting an important role of glutamine-derived GSH in protecting tumor cells against radiation-induced injury. In subsequent mouse xenografts, short-term CB-839 treatments reduced serum GSH by >50% and increased response to radiotherapy of H460-derived tumor xenografts by 30%.

Conclusion: The results support the proposed mechanistic link between GLS activity and GSH synthesis and suggest that GLS inhibitors are effective radiosensitizers.
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http://dx.doi.org/10.1080/09553002.2018.1558299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6622448PMC
April 2019

Characterizing pelvic floor muscles activities using magnetomyography.

Neurourol Urodyn 2019 01 2;38(1):151-157. Epub 2018 Nov 2.

Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Aims: To characterize levator ani muscle (LAM) activity in nulligravidas using magnetomyography (MMG) and define MMG characteristics associated with LAM activity with and without accessory muscle contributions.

Methods: MMG data were collected from eight nulligravidas during rest and voluntary LAM contractions (Kegels) of varying intensity. We utilized simultaneous vaginal manometry and surface electromyography (sEMG) to evaluate for accessory muscle recruitment. Moderate Kegel (MK) MMG trials were sub-selected based on the presence or absence of accessory muscle interaction. Amplitude and spectral-related indicators were calculated across MK epochs: root-mean square (RMS) amplitude, percentage amplitude relative to rest, and relative power spectrum density (rPSD) in three frequency bands (low, middle, high). Ternary diagram characterized rPSD from selected Kegels and ROC analysis was performed to identify cut-points to differentiate MKs from interacting MKs.

Results: Nineteen MMG recordings were obtained. Amplitude and spectral parameters were significantly different between isolated and interacting MK epochs. Mean RMS and power values of the isolated MK were, respectively, 120.66 ± 43.8 fT and 1.72 ± 1.44 (T /Hz)*10 . Amplitudes of MK were 64% and 117 higher than baseline activities for the isolated and interacting epochs, respectively. ROC curves reveled cut-off points on low and middle frequency bands that achieved perfect separation (ROC-AUC = 1.0) between isolated and interacting MK.

Conclusions: Our study demonstrates that MMG, a novel biomagnetic technique, allows precise detection and characterization of normal female pelvic floor function. Results show that isolated moderate voluntary contraction of the LAMs produces distinct MMG amplitude and spectral characteristics compared with Kegels involving co-activation of other muscle groups.
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http://dx.doi.org/10.1002/nau.23870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232046PMC
January 2019

The effect of radial head prosthesis diameter on posterolateral rotatory instability of the elbow.

Clin Biomech (Bristol, Avon) 2018 12 4;60:89-94. Epub 2018 Oct 4.

University of Arkansas of for Medical Sciences, Department of Orthopaedic Surgery, Little Rock, AR, United States.

Background: The purpose of this study is to investigate how different diameters of radial head replacement affect posterolateral translation with a valgus and supination force. We hypothesized that there would be less posterolateral rotatory translation with larger implant diameter.

Methods: Eleven cadaveric arms were stressed at 30 and 60° of flexion with a consistent supination and valgus stress force under five conditions: native radial head, radial head excision, and with 3 sizes of radial head prosthesis. Displacement of the radial head posteriorly in relation to the capitellum on radiographs was measured. Displacement was expressed as a percentage relative to the average of the maximum and minimum native radial head diameters.

Findings: The native radial heads had average minimum and maximum diameters of 23.3 mm and 25.2 mm, respectively. The angle of testing did not significantly change translation of the radial head. There was increased posterior translation relative to native head as the radial head sizes decreased from 24 mm to 20 mm and with excision of the radial head. Compared to the native head, the differences in displacement were statistically significant for the 20 mm radial head, but not for the 22 mm or 24 mm replacements. Radial head translation significantly increased after radial head excision.

Interpretations: This cadaveric study illustrates that patients treated with radial head excision and radial head prosthesis with undersized diameters have increased posterior translation with a valgus and supination stress. The larger the radial head prosthesis (closer to native radial head), the more closely it approximated the amount of translation of the native radial head.
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http://dx.doi.org/10.1016/j.clinbiomech.2018.10.005DOI Listing
December 2018

Patients With Hip or Knee Arthritis Underreport Narcotic Usage.

J Arthroplasty 2018 10 29;33(10):3113-3117. Epub 2018 May 29.

Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Background: Patients taking narcotics chronically are more likely to have worse outcomes after total joint arthroplasty. These negative outcomes may be avoided when modifiable risk factors such as narcotic use are identified and improved before elective joint replacement. An accurate assessment of narcotic use is needed to identify patients before surgery. This study examines the amount of reported narcotic use in patients with hip or knee osteoarthritis and compares this with the narcotic prescriptions recorded in our state's drug prescription monitoring database.

Methods: All new patients seen during a 1-year period by our adult reconstruction practice were identified. Patients' electronic health records were reviewed to determine whether narcotic use was reported. A subsequent search was performed using the Arkansas Prescription Drug Monitoring Program to determine if the patient had been previously prescribed a narcotic.

Results: A total of 502 patients were included in the study. One hundred seventy patients (34%) were prescribed a narcotic within 3 months of the clinic visit according to the Arkansas Prescription Drug Monitoring Program, but only 111 (22%) reported narcotic use in their electronic health record (P < .0001). Moreover, only 92 patients (54% of 170) prescribed a narcotic within 3 months reported it. Narcotic recipients were more likely to be under the age of 65 years (P = .0081), smokers (P < .0001), and current benzodiazepine users (P < .0001).

Conclusion: This study demonstrates that patients significantly underreport their narcotic use to their physician. The availability of a state prescription drug monitoring program allows physicians to check the frequency of filled narcotic prescriptions by their patients.
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http://dx.doi.org/10.1016/j.arth.2018.05.032DOI Listing
October 2018

Fetal assessment in buprenorphine-maintained women using fetal magnetoencephalography: a pilot study.

Addiction 2018 10 13;113(10):1895-1904. Epub 2018 Jun 13.

Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Background And Aims: In-utero exposure to opioids including buprenorphine (BUP) has been shown to affect fetal activity, specifically heart-rate variability (FHRV) and fetal movement (FM). Our objective was to extract simultaneous recordings of fetal cardiac and brain-related activity in BUP-maintained and non-opioid exposed pregnant women using a novel non-invasive biomagnetic technique.

Design: A pilot study was conducted, recording and analyzing biomagnetic data from fetuses of BUP-maintained and non-opioid exposed pregnant women. Signals were acquired with the non-invasive 151-channel SARA (SQUID-Array for Reproductive Assessment) system. Advanced signal-processing techniques were applied to extract fetal heart and brain activity.

Setting: University of Arkansas for Medical Sciences (UAMS, Little Rock, Arkansas, USA).

Participants: Eight BUP-maintained pregnant women from UAMS Women's Mental Health Program between gestational ages (GA) of 29-37 weeks who were treated with 8-24 mg of BUP daily. Sixteen pregnant women with no known opioid exposure in the same GA range were also included.

Measurements: Outcome measures from the fetal heart and brain signals included: heart rate (FHR), FM, FHR accelerations, FHR-FM coupling, FHRV, fetal behavioral states (FBS) and power spectral density (PSD) of spontaneous brain activity. These measures were analyzed at three GA intervals.

Findings: Fetal heart and brain activity parameters were extracted and quantified successfully from 18 non-opioid and 16 BUP recordings. Overall analysis in both groups show that: FHR and FM ranged from 131 to 141 beats per minute (b.p.m.) and 5 to 11 counts, respectively. In the 35-37 weeks GA, the coupling duration (~9 s) was the shortest, while three of the FHRV parameters were the highest. The PSD of brain activity revealed highest power in 0.5-4 Hz bandwidth. Transitions in FBS from quiet to active sleep were > 50% of sessions.

Conclusions: This pilot study showed that a novel biomagnetic technique allows simultaneous quantification of cardiac and brain activities of a group of buprenorphine-exposed and non-exposed fetuses in the third trimester.
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http://dx.doi.org/10.1111/add.14266DOI Listing
October 2018

A novel multiple biomarker panel for the early detection of high-grade serous ovarian carcinoma.

Gynecol Oncol 2018 06 21;149(3):585-591. Epub 2018 Mar 21.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:

Introduction: Since the majority of patients are diagnosed at an advanced stage, ovarian cancer remains the most lethal gynecologic malignancy. There is no single biomarker with the sensitivity and specificity required for effective cancer screening; therefore, we investigated a panel of novel biomarkers for the early detection of high-grade serous ovarian carcinoma.

Methods: Twelve serum biomarkers with high differential gene expression and validated antibodies were selected: IL-1Ra, IL-6, Dkk-1, uPA, E-CAD, ErbB2, SLPI, HE4, CA125, LCN2, MSLN, and OPN. They were tested using Simple Plex™, a multi-analyte immunoassay platform, in samples collected from 172 patients who were either healthy, had benign gynecologic pathologies, or had high-grade serous ovarian adenocarcinomas. The receiver operating characteristic (ROC) curve, ROC area under the curve (AUC), and standard error (SE) of the AUC were obtained. Univariate ROC analyses and multivariate ROC analyses with the combination of multiple biomarkers were performed.

Results: The 4-marker panel consisting of CA125, HE4, E-CAD, and IL-6 had the highest ROC AUC. When evaluated for the ability to distinguish early stage ovarian cancer from a non-cancer control, not only did this 4-marker panel (AUC=0.961) performed better than CA 125 alone (AUC=0.851; P=0.0150) and HE4 alone (AUC=0.870; P=0.0220), but also performed significantly better than the 2- marker combination of CA125+HE4 (AUC=0.922; P=0.0278). The 4-marker panel had the highest average sensitivity under the region of its ROC curve corresponding to specificity ranging from 100% down to ~95%.

Conclusion: The four-marker panel, CA125, HE4, E-CAD, and IL-6, shows potential in detecting serous ovarian cancer at earlier stages. Additional validation studies using the biomarker combination in ovarian cancer patients are warranted.
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http://dx.doi.org/10.1016/j.ygyno.2018.03.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986604PMC
June 2018

Evaluation of Quantra Hologic Volumetric Computerized Breast Density Software in Comparison With Manual Interpretation in a Diverse Population.

Breast Cancer (Auckl) 2018 22;12:1178223418759296. Epub 2018 Feb 22.

Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Objective: Increased mammographic breast density is a well-established risk factor for breast cancer development, regardless of age or ethnic background. The current gold standard for categorizing breast density consists of a radiologist estimation of percent density according to the American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) criteria. This study compares paired qualitative interpretations of breast density on digital mammograms with quantitative measurement of density using Hologic's Food and Drug Administration-approved R2 Quantra volumetric breast density assessment tool. Our goal was to find the best cutoff value of Quantra-calculated breast density for stratifying patients accurately into high-risk and low-risk breast density categories.

Methods: Screening digital mammograms from 385 subjects, aged 18 to 64 years, were evaluated. These mammograms were interpreted by a radiologist using the ACR's BI-RADS density method, and had quantitative density measured using the R2 Quantra breast density assessment tool. The appropriate cutoff for breast density-based risk stratification using Quantra software was calculated using manually determined BI-RADS scores as a gold standard, in which scores of D3/D4 denoted high-risk densities and D1/D2 denoted low-risk densities.

Results: The best cutoff value for risk stratification using Quantra-calculated breast density was found to be 14.0%, yielding a sensitivity of 65%, specificity of 77%, and positive and negative predictive values of 75% and 69%, respectively. Under bootstrap analysis, the best cutoff value had a mean ± SD of 13.70% ± 0.89%.

Conclusions: Our study is the first to publish on a North American population that assesses the accuracy of the R2 Quantra system at breast density stratification. Quantitative breast density measures will improve accuracy and reliability of density determination, assisting future researchers to accurately calculate breast cancer risks associated with density increase.
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http://dx.doi.org/10.1177/1178223418759296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826095PMC
February 2018

Human fibulin-3 protein variant expresses anti-cancer effects in the malignant glioma extracellular compartment in intracranial xenograft models.

Oncotarget 2017 Dec 9;8(63):106311-106323. Epub 2017 Nov 9.

Neurosurgery & Brain and Nerve Research Laboratory.

Background: Decades of cytotoxic and more recently immunotherapy treatments for malignant glioma have had limited success due to dynamic intra-tumoral heterogeneity. The dynamic interplay of cancer cell subpopulations has been found to be under the control of proteins in the cancer microenvironment. EGF-containing fibulin-like extracellular matrix protein (EFEMP1) (also fibulin-3) has the multiple functions of suppressing cancer growth and angiogenesis, while promoting cancer cell invasion. EFEMP1-derived tumor suppressor protein (ETSP) retains EFEMP1's anti-growth and anti-angiogenic functions while actually inhibiting cancer cell invasion.

Methods: In this study, we examined the therapeutic effect on glioblastoma multiforme (GBM) of an synthesized protein, ZR30, which is based on the sequence of ETSP, excluding the signaling peptide.

Results: ZR30 showed the same effects as ETSP in blocking EGFR/NOTCH/AKT signaling pathways, when applied to cultures of multiple GBM cell lines and primary cultures. ZR30's inhibition of MMP2 activation was shown not only for GBM cells, but also for other types of cancer cells having overexpression of MMP2. A significant improvement in survival of mice with orthotopic human GBM xenografts was observed after a single, intra-tumoral injection of ZR30. Using a model mimicking the intra-tumoral heterogeneity of GBM with cell subpopulations carrying different invasive and proliferative phenotypes, we demonstrated an equal and simultaneous tumor suppressive effect of ZR30 on both tumor cell subpopulations, with suppression of and activation of expressions in the xenografts.

Conclusion: Overall, the data support a complementary pleiotrophic therapeutic effect of ZR30 acting in the extracellular compartment of GBM.
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http://dx.doi.org/10.18632/oncotarget.22344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739735PMC
December 2017
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