Scott A Dulchavsky

Henry Ford Hospital, Detroit, Michigan, United States

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Publications (171)298.97 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate whether providing sonographic (US)/MRI fusion images will enhance the ability of medical students and radiology residents to identify MSK anatomy on sonograms alone. Medical students (n = 31) and radiology residents (n = 23) were each randomly divided into two groups: Group A and Group B. Subjects in Group A were shown 10 MSK sonograms with arrows pointing to a specific anatomic structure or anatomic region. Subjects in Group B were shown the exact same 10 annotated sonograms as Group A as well as an additional fusion image consisting of an MRI of the same anatomy in the same plane fused with the sonogram without arrows. Sonograms and MRI were obtained from adult patients who consented to have their images used. The anatomic regions included the shoulder, hip, and pelvis. Both groups were given the same 10-question multiple choice examination to identify the anatomic structure that the arrow was marking on the sonogram. The transducer's location was given for every question. One minute was allowed to answer each question. The Wilcoxon rank sum test was used to assess if there was a difference between Group A and Group B in both the medical student and the radiology resident cohorts. Medical students: subjects in Group A (n = 16) gave the correct answers in 33.8% of the cases (54/160). Subjects in Group B (n = 15) gave correct answers in 26.0% of the cases (39/150) (p value <0.110). Radiology residents: subjects in Group A (n = 11) gave correct answers in 40.9% of the cases (45/110). Subjects in Group B (n = 12) gave correct answers in 72.5% of the cases (87/120) (p value <0.001). The addition of a fusion MRI/US image enhances radiology residents' ability to identify MSK US anatomy accurately compared with the sonogram alone. The medical students, however, did not show improvement with the addition of the fusion MRI/sonogram. © 2014 Wiley Periodicals, Inc. J Clin Ultrasound, 2014.
    Journal of Clinical Ultrasound 01/2014; · 0.70 Impact Factor
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    ABSTRACT: Ocular changes have been noted during long-duration spaceflight; we studied central retinal artery (CRA) blood flow using Doppler before, during, and after long-term microgravity exposure in astronauts compared with data from a control group of nonastronauts subjected to head-down tilt (HDT). Available Doppler spectra of International Space Station (ISS) crewmembers were obtained from the NASA Lifetime Surveillance of Astronaut Health database, along with 2D ultrasound-derived measurements of the optic nerve sheath diameter (ONSD). CRA Doppler spectra and optic nerve sheath images were also obtained from healthy test subjects in an acute HDT experiment at 20 min of exposure (the ground-based analogue). HDT CRA peak systolic velocity in the ground-based analogue group increased by an average of 3 cm -s(-1) (33%) relative to seated values. ONSD at 300 of HDT increased by 0.5 mm relative to supine values. CRA Doppler spectra obtained on orbit were of excellent quality and demonstrated in-flight changes of +5 cm x s(-1) (50%) compared to preflight. ONSD increased in ISS crewmembers during flight relative to before flight, with some reversal postflight. A significant ONSD response to acute postural change and to spaceflight was demonstrated in this preliminary study. Increases in Doppler peak flow velocities correlated with increases in ONSD. Further investigations are warranted to corroborate the relationship between ONSD, intracranial pressure, and central retinal blood flow for occupational surveillance and research purposes.
    Aviation Space and Environmental Medicine 01/2014; 85(1):3-8. · 0.78 Impact Factor
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    ABSTRACT: Chronic diseases are prevalent in ethnic communities. Churches represent a potent resource for targeted health promotion. A faith-based kiosk was developed as an informational tool and placed in four predominantly (>80%) African-American churches. Congregants were surveyed to describe kiosk-use, kiosk-user characteristics, health status, and self-reported behavior changes attributed to the kiosk. We analyzed 1,573 questionnaires. Mean age of respondents was 46.4 years and >70% were women. "Older" congregations (mean age ≥46.1 years) had more reports of diabetes (p = 0.002) and heart diseases (p = 0.01) than younger churches (mean age ≤44.1), whereas asthma was more prevalent in the latter (p < 0.001). Prevalence of obesity (40%) was similar across churches (p = 0.570). Kiosk-use was reported by 420 (26.7%) respondents. Compared to non-users, kiosk-users were >40 years (p < 0.001), and reported >two health conditions, adjusted Odds Ratio (95% Confidence Interval) = 1.43 (1.0-2.0), p = 0.05. Male kiosk-users preferred to select disease-specific content, aOR = 1.87 (1.10-3.17), p = 0.02, while females tended to select information about supportive community resources, aOR = 0.49 (0.23-1.04), p = 0.062. Knowledge of kiosk-user characteristics and the "health status" of a congregation, provide an opportunity for targeted, church-based health promotion.
    Frontiers in Public Health 01/2014; 2:106.
  • Jennifer Michelle Kufta, Scott A Dulchavsky
    Surgery 11/2013; 154(5):943-5. · 3.37 Impact Factor
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    ABSTRACT: Changes in the lumbar and sacral spine occur with exposure to microgravity in astronauts; monitoring these alterations without radiographic capabilities on the International Space Station (ISS) requires novel diagnostic solutions to be developed. We evaluated the ability of point-of-care ultrasound, performed by nonexpert-operator astronauts, to provide accurate anatomic information about the spine in long-duration crewmembers in space. Astronauts received brief ultrasound instruction on the ground and performed in-flight cervical and lumbosacral ultrasound examinations using just-in-time training and remote expert tele-ultrasound guidance. Ultrasound examinations on the ISS used a portable ultrasound device with real-time communication/guidance with ground experts in Mission Control. The crewmembers were able to obtain diagnostic-quality examinations of the cervical and lumbar spine that would provide essential information about acute or chronic changes to the spine. Spinal ultrasound provides essential anatomic information in the cervical and lumbosacral spine; this technique may be extensible to point-of-care situations in emergency departments or resource-challenged areas without direct access to additional radiologic capabilities.
    Journal of Emergency Medicine 10/2013; · 1.33 Impact Factor
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    ABSTRACT: Abstract Modern medical practice has become extremely dependent upon diagnostic imaging technologies to confirm the results of clinical examination and to guide the response to therapies. Of the various diagnostic imaging techniques, ultrasound is the most portable modality and one that is repeatable, dynamic, relatively cheap, and safe as long as the imaging provided is accurately interpreted. It is, however, the most user-dependent, a characteristic that has prompted the development of remote guidance techniques, wherein remote experts guide distant users through the use of information technologies. Medical mission work often brings specialist physicians to less developed locations, where they wish to provide the highest levels of care but are often bereft of diagnostic imaging resources on which they depend. Furthermore, if these personnel become ill or injured, their own care received may not be to the standard they have left at home. We herein report the utilization of a compact hand-carried remote tele-ultrasound system that allowed real-time diagnosis and follow-up of an acutely torn adductor muscle by a team of ultrasonographers, surgeons, and physicians. The patient was one of the mission surgeons who was guided to self-image. The virtual network of supporting experts was located across North America, whereas the patient was in Lome, Togo, West Africa. The system consisted of a hand-carried ultrasound, the output of which was digitized and streamed to the experts within standard voice-over-Internet-protocol software with an embedded simultaneous videocamera image of the ultrasonographer's hands using a customized graphical user interface. The practical concept of a virtual tele-ultrasound support network was illustrated through the clinical guidance of multiple physicians, including National Aeronautics and Space Administration Medical Operations remote guiders, Olympic team-associated surgeons, and ultrasound-focused emergentologists.
    Telemedicine and e-Health 05/2013; · 1.40 Impact Factor
  • Scott A. Dulchavsky
    Surgery 04/2013; 153(4):443–444. · 3.37 Impact Factor
  • Scott A Dulchavsky
    Surgery 12/2012; · 3.37 Impact Factor
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    ABSTRACT: Xanthohumol (XN), a prenylated chalcone present in hops exhibits anti-inflammatory, antioxidant and anticancer activity. In the present study we show that XN inhibits the proliferation of mouse lymphoma cells and IL-2 induced proliferation and cell cycle progression in mouse splenic T cells. The suppression of T cell proliferation by XN was due to the inhibition of IL-2 induced Janus kinase/signal transducers and activators of transcription (Jak/STAT) and extracellular signal-regulated kinase 1 and 2 (Erk1/2) signaling pathways. XN also inhibited proliferation-related cellular proteins such as c-Myc, c-Fos and NF-kappaB and cyclin D1. Thus, understanding of IL-2 induced cell signaling pathways in normal T cells, which are constitutively turned on in T cell lymphomas may facilitate development of XN for the treatment of hematologic cancers.
    Journal of Experimental Therapeutics and Oncology 01/2012; 10(1):1-8.
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    ABSTRACT: PURPOSE To investigate if medical students and radiology residents will be able to distinguish between regional musculoskeletal (MSK) ultrasound anatomy more accurately if an MRI image is fused with an US image. METHOD AND MATERIALS Medical students with at least 12 hours of ultrasound training and at least 12 hours of MRI/cross-sectional anatomy experience were recruited. Radiology residents with formal MRI and ultrasound training were also enrolled. The medical students (n=31) were randomly divided into Group A or Group B. Radiology residents (n=23) were also randomly assigned to Groups A or B. Group A recruits were shown 10 US images with an arrow pointed to a specific anatomical region or structure of MSK anatomy. Group B were shown the exact same 10 US images with arrows pointed to same anatomy plus a MRI image (with no marker) that had been fused with US using commercially available fusion equipment. Both groups were given the same 10-question multiple choice examination that instructed the examinees to identify what the arrow was marking. The transducer’s location was given for every question. One minute was allowed to answer each question. The Wilcoxon rank sum test was used to assess if there were significant differences between aggregated answers of Groups A and B. RESULTS Among the medical students, Group A (n=16) answered 33.8% of questions correctly and Group B (n=15) answered 26.0% correctly (p-value = 0.110). Among the Radiology Residents, Group A (n=11) answered 40.9% correctly and group B (n=12) answered 72.5% correctly (p-value = 0.001). CONCLUSION MRI fused with an US image enhances radiology residents’ ability to identify MSK ultrasound anatomy. Pattern recognition with respect to musculoskeletal ultrasound did not improve using image fusion for the medical students. CLINICAL RELEVANCE/APPLICATION Fusion US can serve as an excellent teaching method when training residents as knowledge of MRI anatomy helps orient and verify anatomical structures when reading US images
    Radiological Society of North America 2011 Scientific Assembly and Annual Meeting; 11/2011
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    ABSTRACT: Synthetic oleanane triterpenoids are novel agents which have shown strong antitumorigenic activity against a wide range of cancer types in vitro. The objective of the present study was to determine the anticancer activity of methyl-2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oate (CDDO-Me) derived from CDDO, a synthetic analog of oleanolic acid, and its mechanism of action in killing of human ovarian cancer cells. CDDO-Me strongly inhibited the growth of ovarian cancer cells by inducing apoptosis characterized by increased annexin V binding, cleavage of poly (ADP-ribose) polymerase (PARP-1) and procaspases-3, -8 and -9. In addition, CDDO-Me induced mitochondrial depolarization. Western blot analysis showed inhibition of prosurvival (antiapoptotic) phospho-AKT (p-AKT), nuclear factor kappa B (NF-κB) (p65) and phospho-mammalian target of rapamycin (p-mTOR) signaling proteins in cells treated with CDDO-Me. Abrogation of AKT which regulates both NF-κB and mTOR increased the sensitivity of tumor cells to CDDO-Me. Thus, these data showing strong growth-inhibitory and apoptosis-inducing activity of CDDO-Me for ovarian cancer cells through the inhibition of AKT/ NF-κB/mTOR signaling pathway provide basis for evaluation of CDDO-Me for ovarian cancer.
    Anticancer research 11/2011; 31(11):3673-81. · 1.71 Impact Factor
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    ABSTRACT: The transition to microgravity eliminates the hydrostatic gradients in the vascular system. The resulting fluid redistribution commonly manifests as facial edema, engorgement of the external neck veins, nasal congestion, and headache. This experiment examined the responses to modified Valsalva and Mueller maneuvers measured by cardiac and vascular ultrasound (ECHO) in a baseline steady state and under the influence of thigh occlusion cuffs available as a countermeasure device (Braslet cuffs). Nine International Space Station crewmember subjects (expeditions 16-20) were examined in 15 experiment sessions 101 ± 46 days after launch (mean ± SD; 33-185). Twenty-seven cardiac and vascular parameters were obtained with/without respiratory maneuvers before and after tightening of the Braslet cuffs (162 parameter states/session). Quality of cardiac and vascular ultrasound examinations was assured through remote monitoring and guidance by investigators from the NASA Telescience Center in Houston, TX, and the Mission Control Center in Korolyov, Moscow region, Russia. 14 of 81 conditions (27 parameters measured at baseline, Valsalva, and Mueller maneuver) were significantly different when the Braslet was applied. Seven of 27 parameters were found to respond differently to respiratory maneuvers depending on the presence or absence of thigh compression. Acute application of Braslet occlusion cuffs causes lower extremity fluid sequestration and exerts commensurate measurable effects on cardiac performance in microgravity. Ultrasound techniques to measure the hemodynamic effects of thigh cuffs in combination with respiratory maneuvers may serve as an effective tool in determining the volume status of a cardiac or hemodynamically compromised patient at the "microgravity bedside."
    Journal of Applied Physiology 09/2011; 112(3):454-62. · 3.48 Impact Factor
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    ABSTRACT: This study investigated whether it is feasible to use sonography to monitor changes in the optic nerve sheath diameter in a porcine model. A fiber-optic intracranial pressure transducer was surgically placed through the frontal sinus directly into the brain parenchyma of adult Yorkshire pigs (n = 5). A second bolt was placed on the contralateral side for intraparenchymal fluid infusion. Optic nerve sheath diameter measurements were acquired by each of 2 ultrasound operators around the leading edge of the nerve, 3 to 5 mm distal from the origin of the optic nerve. To induce a change in diameter, intracranial pressure was manipulated by injecting normal saline into the intraparenchymal infusion catheter located in the symmetric contralateral position as the pressure-monitoring probe. Data from 1 pig were unusable because of a cerebrospinal fluid leak into the sinus and orbital fissure. Saline aliquots of 1 to 10 mL were able to generate intracranial pressures typically starting from 10 to 15 mm Hg and increasing to 75 to 90 mm Hg, which eventually evoked a Cushing response. Fluid injection was controlled to increase pressures by 60 mm Hg over a 15- to 20-minute period. Regression analysis of all animals showed that the optic nerve sheath diameter increased by 0.0034 mm/mm Hg of intracranial pressure; however, this slope ranged from 0.0025 to 0.0046, depending on the animal measured. There was no discernible effect of the ultrasound operator on the slope; however, measurements made by 1 operator were consistently higher than the others by about 8% of the overall diameter range. These results suggest that the use of the optic nerve sheath diameter to noninvasively confirm acute changes in intracranial pressure over 1 hour is feasible in a porcine model. We recommend that this method be validated in humans using direct intracranial pressure measurement where possible to confirm it as a screening tool for acute and chronically increased diameters secondary to elevated pressure in clinical settings.
    Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine 05/2011; 30(5):651-9. · 1.40 Impact Factor
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    ABSTRACT: A prospective trial of echocardiography was conducted on six crew members onboard the International Space Station. The main objective was to determine the efficacy of remotely guided tele-echocardiography, including just-in-time e-training methods and determine what is "space normal" echocardiographic data. Each crew member operator (n = 6) had 2-hour preflight training. Baseline echocardiographic data were collected 55-167 days preflight. Similar equipment was used in each 60-minute in-flight session (mean microgravity exposure--114 days [34--190]). On-orbit ultrasound (US) operators used an e-learning system within 24 hours of these sessions. Expert assistance was provided using US video downlink and two-way voice. Testing was repeated 5-16 days after landing. Separate ANOVA was used on each echocardiographic variable (n = 33). Within each ANOVA, three tests were made: (a) effect of mission phase (preflight, in-flight, postflight); (b) effect of echo technician (two technicians independently analyzed the data); (c) interaction between mission phase and technician. Eleven rejections of the null hypothesis (mission phase or technician or both had no effect) were found that could be considered for possible follow up. Of these, eight rejections were for significant technician effects, not space flight. Three rejections of the null hypothesis (aortic valve time velocity integral, mitral E-wave velocity, and heart rate) were attributable to space flight but determine to not be clinically significant. No rejections were due to the interaction between technician and space flight. Thus, we found no consistent clinically significant effects of long-duration space flight on echocardiographic variables of the given group of subjects.
    Echocardiography 05/2011; 28(5):491-501. · 1.26 Impact Factor
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    ABSTRACT: In an extension of our previous studies showing potent antitumorigenic activity of synthetic triterpenoids of oleanolic acid against prostate cancer cell lines, we examined the efficacy of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) in preventing the development and/or progression of prostate cancer in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Data show that oral gavage with CDDO (10 μmol/kg) for 20 weeks resulted in inhibition of the progression of preneoplastic lesions in the dorsolateral prostate and ventral prostate to adenocarcinoma without toxicity. CDDO also inhibited metastasis of tumor to the distant organs. Treatment with CDDO significantly inhibited cell proliferation, reduced the density of blood vessels and promoted apoptosis in the prostatic tissue. Further, Akt, NF-κB and NF-κB regulated Bcl-2, Bcl-xL, survivin and cIAP1 appear to be the molecular targets of CDDO for inhibiting the progression of prostate cancer in TRAMP mice. Thus, these studies show for the first time the potential of CDDO for chemoprevention of human prostate cancer.
    Carcinogenesis 02/2011; 32(5):757-64. · 5.64 Impact Factor
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    ABSTRACT: CDDO-Me, an oleanane synthetic triterpenoid has shown strong antitumorigeic activity towards diverse cancer cell types including colorectal cancer cells. In the present study, we investigated the role of free radicals in the growth inhibitory and apoptosis-inducing activity of CDDO-Me in colorectal cancer cells lines. Results demonstrated that CDDO-Me potently inhibited the growth of colorectal cancer cells and pretreatment of cancer cells with small-molecule antioxidant N-acetylcysteine (NAC) completely blocked the growth inhibitory activity of CDDO-Me. CDDO-Me caused the generation of reactive oxygen species, which was inhibited by NAC and mitochondrial chain 1 complex inhibitors DPI and rotenone. CDDO-Me induced apoptosis as demonstrated by the cleavage of PARP-1, activation of procaspases -3, -8, and -9 and mitochondrial depolarization and NAC blocked the activation of these apoptosis related processes. Furthermore, induction of apoptosis by CDDO-Me was associated with the inhibition of antiapoptotic/ prosurvival Akt, mTOR and NF-kappaB signaling proteins and the inhibition of these signaling molecules was blocked by NAG. Together these studies provided evidence that CDDO-Me is a potent anticancer agent, which imparts growth inhibition and apoptosis in colorectal cancer cells through the generation of free radicals.
    Journal of Experimental Therapeutics and Oncology 01/2011; 9(2):119-27.
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    ABSTRACT: Management of health problems in limited resource environments, including spaceflight, faces challenges in both available equipment and personnel. The medical support for spaceflight outside Low Earth Orbit is still being defined; ultrasound (US) imaging is a candidate since trials on the International Space Station (ISS) prove that this highly informative modality performs very well in spaceflight. Considering existing estimates, authors find that US could be useful in most potential medical problems, as a powerful factor to mitigate risks and protect mission. Using outcome-oriented approach, an intuitive and adaptive US image catalog is being developed that can couple with just-in-time training methods already in use, to allow non-expert crew to autonomously acquire and interpret US data for research or diagnosis.The first objective of this work is to summarize the experience in providing imaging expertise from a central location in real time, enabling data collection by a minimally trained operator onsite. In previous investigations, just-in-time training was combined with real-time expert guidance to allow non-physician astronauts to perform over 80 h of complex US examinations on ISS, including abdominal, cardiovascular, ocular, musculoskeletal, dental/sinus, and thoracic exams. The analysis of these events shows that non-physician crew-members, after minimal training, can perform complex, quality US examinations. These training and guidance methods were also adapted for terrestrial use in professional sporting venues, the Olympic Games, and for austere locations including Mt. Everest.The second objective is to introduce a new imaging support system under development that is based on a digital catalog of existing sample images, complete with image recognition and acquisition logic and technique, and interactive multimedia reference tools, to guide and support autonomous acquisition, and possibly interpretation, of images without real-time link with a human expert. In other words, we are attempting to replace, to the extent possible, expert guidance by guidance from a digital information resource. This is a next logical phase of the authors’ sustained effort to make US imaging available to sites lacking proper expertise. This effort will benefit NASA as the agency plans to develop future human exploration programs requiring increased medical autonomy. The new system will be readily adaptable to terrestrial medicine including emergency, rural, and military applications.
    Acta Astronautica 01/2011; · 0.70 Impact Factor
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    ABSTRACT: 2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), a synthetic analog of oleanolic acid, and its C28 methyl ester derivative (CDDO-Me), have shown potent antitumorigenic activity against a wide range of cancer cell lines, including prostate cancer cells in vitro, and inhibited the development of liver and lung cancer in vivo. In the present study, we examined the efficacy of CDDO-Me in preventing the development and progression of prostate cancer in the transgenic adenocarinoma of the mouse prostate (TRAMP) model. CDDO-Me inhibited the growth of murine TRAMPC-1 prostate cancer cells by inducing apoptosis through the inhibition of antiapoptotic p-Akt, p-mTOR and NF-κB. Early intervention with CDDO-Me (7.5 mg/kg) initiated at five weeks of age for 20 wk inhibited the progression of the preneoplastic lesions (low-grade PIN and high-grade-PIN) to adenocarcinoma in the dorsolateral prostate (DLP) and ventral prostate (VP) lobes of TRAMP mice. Even delayed administration of CDDO-Me started at 12 wk of age for 12 wk inhibited the development of adenocarcimona of the prostate. Both early and late treatment with CDDO-Me inhibited the metastasis of tumor to the distant organs. Treatment with CDDO-Me inhibited the expression of prosurvival p-Akt and NF-κB in the prostate and knocking-down Akt in TRAMPC-1 tumor cells sensitized them to CDDO-Me. These findings indicated that Akt is a target for apoptoxicity in TRAMPC-1 cells in vitro and potentially a target of CDDO-Me for inhibition of prostate cancer in vivo.
    Cancers. 01/2011; 3(3):3353-3369.
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    ABSTRACT: Introduction: This joint US–Russian work aims to establish a methodology for assessing cardiac function in microgravity in association with manipulation of central circulating volume. Russian Braslet-M (Braslet) occlusion cuffs were used to temporarily increase the volume of blood in the lower extremities, effectively reducing the volume in central circulation. The methodology was tested at the International Space Station (ISS) to assess the volume status of crewmembers by evaluating the responses to application and release of the cuffs, as well as to modified Valsalva and Mueller maneuvers. This case study examines the use of tissue Doppler (TD) of the right ventricular (RV) free wall. Results: Baseline TD of the RV free wall without Braslet showed early diastolic E′ (16 cm/s), late diastolic A′ (14 cm/s), and systolic S′ (12 cm/s) velocities comparable with those in normal subjects on Earth. Braslet application caused 50% decrease of E′ (8 cm/s), 45% increase of A′, and no change to S′. Approximately 8 beats after the Braslet release, TD showed E′ of 8 cm/s, A′ of 12 cm/s, and S′ of 13 cm/s. At this point after release, E′ did not recover to baseline values while l A′ and S′ did recover. The pre-systolic cross-sectional area of the internal jugular vein without Braslet was 1.07 cm2, and 1.13 cm2 10 min after the Braslet was applied. The respective cross-sectional areas of the femoral vein were 0.50 and 0.54 cm2. The RV myocardial performance Tei index was calculated by dividing the sum of the isovolumic contraction time and isovolumic relaxation time by the ejection time ((IVCT+IVRT)/ET); baseline and Braslet-on values for Tei index were 0.25 and 0.22, respectively. Braslet Tei indices are within normal ranges found in healthy terrestrial subjects and temporarily become greater than 0.4 during the dynamic Braslet release portion of the study. Conclusions: TD modality was successfully implemented in space flight for the first time. TD of RV revealed that the Braslet influenced cardiac preload and that fluid was sequestered in the lower extremity interstitial and vascular space after only 10 min of application. This report demonstrates that Braslet application has an effect on RV physiology in long-duration space flight based on TD, and that this effect is in part due to venous hemodynamics.
    Acta Astronautica 01/2011; · 0.70 Impact Factor
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancy with dismal prognosis and few effective therapeutic options. Novel agents that are safe and effective are urgently needed. Oleanolic acid-derived synthetic triterpenoids are potent antitumorigenic agents, but their efficacy or the mechanism of action for pancreatic cancer has not been adequately investigated. In this study, we evaluated the antitumor activity and the mechanism of action of methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me), a oleanane-derived synthetic triterpenoid for human pancreatic cancer cell lines. CDDO-Me inhibited the growth of both K-ras mutated (MiaPaca2, Panc1 and Capan2) and wild-type K-ras (BxPC3) pancreatic cancer cells at very low concentrations. The growth inhibitory activity of CDDO-Me was attributed to the induction of apoptosis characterized by increased annexin-V-FITC binding and cleavage of PARP-1 and procaspases-3, -8 and-9. In addition, CDDO-Me induced the loss of mitochondrial membrane potential and release of cytochrome C. The antitumor activity of CDDO-Me was associated with the inhibition of prosurvival p-Akt, NF-κB and mammalian target of rapamycin (mTOR) signaling proteins and the downstream targets of Akt and mTOR, such as p-Foxo3a (Akt) and p-S6K1, p-eIF-4E and p-4E-BP1 (mTOR). Silencing of Akt or mTOR with gene specific-siRNA sensitized the pancreatic cancer cells to CDDO-Me, demonstrating Akt and mTOR as molecular targets of CDDO-Me for its growth inhibitory and apoptosis-inducing activity.
    Cancers. 12/2010; 2(4):1779-1793.

Publication Stats

3k Citations
298.97 Total Impact Points

Institutions

  • 2004–2014
    • Henry Ford Hospital
      • Surgery
      Detroit, Michigan, United States
    • Henry Ford Health System
      • Department of Surgery
      Detroit, Michigan, United States
  • 2013
    • Children's Hospital of Michigan
      Detroit, Michigan, United States
  • 2011
    • NASA
      Washington, West Virginia, United States
  • 2009–2010
    • University of Ottawa
      • Department of Emergency Medicine
      Ottawa, Ontario, Canada
  • 2008
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 1988–2007
    • Wayne State University
      • Department of Surgery
      Detroit, Michigan, United States
  • 1987–2005
    • Detroit Medical Center
      • Division of Surgery
      Detroit, Michigan, United States
  • 1996
    • Harper University Hospital
      Detroit, Michigan, United States
  • 1990–1993
    • Stony Brook University
      • • Department of Surgery
      • • Department of Medicine
      Stony Brook, NY, United States