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1.  Cerebrovascular autoregulation and neurologic injury in neonatal hypoxic-ischemic encephalopathy 
Pediatric research  2013;74(5):525-535.
Neonates with hypoxic-ischemic encephalopathy (HIE) are at risk of cerebral blood flow dysregulation. Our objective was to describe the relationship between autoregulation and neurologic injury in HIE.
Neonates with HIE had autoregulation monitoring with the hemoglobin volume index (HVx) during therapeutic hypothermia, rewarming, and the first 6 h of normothermia. The 5-mmHg range of mean arterial blood pressure (MAP) with best vasoreactivity (MAPOPT) was identified. The percentage of time spent with MAP below MAPOPT and deviation in MAP from MAPOPT were measured. Neonates received brain MRIs 3–7 days after treatment. MRIs were coded as no, mild, or moderate/severe injury in five regions.
HVx identified MAPOPT in 79% (19/24), 77% (17/22), and 86% (18/21) of neonates during hypothermia, rewarming, and normothermia, respectively. Neonates with moderate/severe injury in paracentral gyri, white matter, basal ganglia, and thalamus spent a greater proportion of time with MAP below MAPOPT during rewarming than neonates with no or mild injury. Neonates with moderate/severe injury in paracentral gyri, basal ganglia, and thalamus had greater MAP deviation below MAPOPT during rewarming than neonates without injury.
Maintaining MAP within or above MAPOPT may reduce the risk of neurologic injuries in neonatal HIE.
PMCID: PMC3954983  PMID: 23942555
2.  Noninvasive Autoregulation Monitoring in a Swine Model of Pediatric Cardiac Arrest 
Anesthesia and Analgesia  2012;114(4):825-836.
Cerebrovascular autoregulation after resuscitation has not been well studied in an experimental model of pediatric cardiac arrest. Furthermore, developing noninvasive methods of monitoring autoregulation using near-infrared spectroscopy (NIRS) would be clinically useful in guiding neuroprotective hemodynamic management after pediatric cardiac arrest. We tested the hypotheses that the lower limit of autoregulation (LLA) would shift to a higher arterial blood pressure between 1 and 2 days of recovery after cardiac arrest and that the LLA would be detected by NIRS-derived indices of autoregulation in a swine model of pediatric cardiac arrest. We also tested the hypothesis that autoregulation with hypertension would be impaired after cardiac arrest.
Data on LLA were obtained from neonatal piglets that had undergone hypoxic-asphyxic cardiac arrest and recovery for 1 day (n=8) or 2 days (n=8), or that had undergone sham surgery with 2 days of recovery (n=8). Autoregulation with hypertension was examined in a separate cohort of piglets that underwent hypoxic-asphyxic cardiac arrest (n=5) or sham surgery (n=5) with 2 days of recovery. After the recovery period, piglets were reanesthetized, and autoregulation was monitored by standard laser-Doppler flowmetry and autoregulation indices derived from NIRS (the cerebral oximetry [COx] and hemoglobin volume [HVx] indices). The LLA was determined by decreasing blood pressure through inflation of a balloon catheter in the inferior vena cava. Autoregulation during hypertension was evaluated by inflation of an aortic balloon catheter.
The LLAs were similar between sham-operated piglets and piglets that recovered for 1 or 2 days after arrest. The NIRS-derived indices accurately detected the LLA determined by laser-Doppler flowmetry. The area under the curve of the receiver operator characteristic curve for cerebral oximetry index was 0.91 at 1 day and 0.92 at 2 days after arrest. The area under the curve for hemoglobin volume index was 0.92 and 0.89 at the respective time points. During induced hypertension, the static rate of autoregulation, defined as the percent change in cerebrovascular resistance divided by the percent change in cerebral perfusion pressure, was not different between postarrest and sham-operated piglets. At 2 days recovery from arrest, piglets exhibited neurobehavioral deficits and histologic neuronal injury.
In a swine model of pediatric hypoxic-asphyxic cardiac arrest with confirmed brain damage, the LLA did not differ 1 and 2 days after resuscitation. The NIRS-derived indices accurately detected the LLA compared to laser-Doppler flow measurements at those time points. Autoregulation remained functional during hypertension.
PMCID: PMC3310318  PMID: 22314692
3.  Cerebral Blood Flow and Cerebrovascular Autoregulation in a Swine Model of Pediatric Cardiac Arrest and Hypothermia 
Critical care medicine  2011;39(10):2337-2345.
Knowledge remains limited regarding cerebral blood flow autoregulation after cardiac arrest and during post-resuscitation hypothermia. We determined the relationship of cerebral blood flow to cerebral perfusion pressure in a swine model of pediatric hypoxic-asphyxic cardiac arrest during normothermia and hypothermia and tested novel measures of autoregulation derived from near-infrared spectroscopy.
Prospective, balanced animal study.
Basic physiology laboratory at an academic institution.
Eighty-four neonatal swine.
Piglets underwent hypoxic-asphyhxic cardiac arrest or sham surgery and recovered for 2 hours with normothermia followed by 4 hours of either moderate hypothermia or normothermia. In half of the groups, blood pressure was slowly decreased through inflation of a balloon catheter in the inferior vena cava to identify the lower limit of cerebral autoregulation at 6 hours post-resuscitation. In the remaining groups, blood pressure was gradually increased by inflation of a balloon catheter in the aorta to determine the autoregulatory response to hypertension. Measures of autoregulation obtained from standard laser-Doppler flowmetry and indices derived from near-infrared spectroscopy were compared.
Measurements and Main Results
Laser-Doppler flux was lower in post-arrest animals compared to sham-operated controls during the 2-hour normothermic period after resuscitation. During the subsequent 4-hour recovery, hypothermia decreased laser-Doppler flux in both the sham surgery and post-arrest groups. Autoregulation was intact during hypertension in all groups. With arterial hypotension, post-arrest, hypothermic piglets had a significant decrease in the perfusion pressure lower limit of autoregulation compared to post-arrest, normothermic piglets. The near-infrared spectroscopy-derived measures of autoregulation accurately detected loss of autoregulation during hypotension.
In a pediatric model of cardiac arrest and resuscitation, delayed induction of hypothermia decreased cerebral perfusion and decreased the lower limit of autoregulation. Metrics derived from non-invasive near-infrared spectroscopy accurately identified the lower limit of autoregulation during normothermia and hypothermia in piglets resuscitated from arrest.
PMCID: PMC3178742  PMID: 21705904
pediatrics; heart arrest; cerebrovascular circulation; ischemia; blood pressure; hypothermia
4.  Intraoperative blood pressure and cerebral perfusion: strategies to clarify hemodynamic goals 
Paediatric anaesthesia  2014;24(7):657-667.
Blood pressure can vary considerably during anesthesia. If blood pressure falls outside the limits of cerebrovascular autoregulation, children can become at risk of cerebral ischemic or hyperemic injury. However, the blood pressure limits of autoregulation are unclear in infants and children, and these limits can shift after brain injury. This article will review autoregulation, considerations for the hemodynamic management of children with brain injuries, and research on autoregulation monitoring techniques.
PMCID: PMC4154320  PMID: 24725244
pediatrics; blood pressure; cerebrovascular circulation; brain injuries
5.  Clinical translation of stem cells: insight for cartilage therapies 
The limited regenerative capacity of articular cartilage and deficiencies of current treatments have motivated the investigation of new repair technologies. In vitro cartilage generation using primary cell sources is limited by cell availability and expansion potential. Pluripotent stem cells possess the capacity for chondrocytic differentiation and extended expansion, providing a potential future solution to cell-based cartilage regeneration. However, despite successes in producing cartilage using adult and embryonic stem cells, the translation of these technologies to the clinic has been severely limited. This review discusses recent advances in stem cell-based cartilage tissue engineering and the major current limitations to clinical translation of these products. Concerns regarding appropriate animal models and studies, stem cell manufacturing, and relevant regulatory processes and guidelines will be addressed. Understanding the significant hurdles limiting the clinical use of stem cell-based cartilage may guide future developments in the fields of tissue engineering and regenerative medicine.
PMCID: PMC4314285  PMID: 24083452
regenerative medicine; osteoarthritis; cartilage tissue engineering; clinical trials; stem cell treatments
6.  Thyroid hormones enhance the biomechanical functionality of scaffold-free neocartilage 
The aim of this study was to investigate the effects of thyroid hormones tri-iodothyronine (T3), thyroxine (T4), and parathyroid hormone (PTH) from the parathyroid glands, known to regulate the developing limb and growth plate, on articular cartilage tissue regeneration using a scaffold-free in vitro model.
In Phase 1, T3, T4, or PTH was applied during weeks 1 or 3 of a 4-week neocartilage culture. Phase 2 employed T3 during week 1, followed by PTH during week 2, 3, or weeks 2 to 4, to further enhance tissue properties. Resultant neotissues were evaluated biochemically, mechanically, and histologically.
In Phase 1, T3 and T4 treatment during week 1 resulted in significantly enhanced collagen production; 1.4- and 1.3-times untreated neocartilage. Compressive and tensile properties were also significantly increased, as compared to untreated and PTH groups. PTH treatment did not result in notable tissue changes. As T3 induces hypertrophy, in Phase 2, PTH (known to suppress hypertrophy) was applied sequentially after T3. Excitingly, sequential treatment with T3 and PTH reduced expression of hypertrophic marker collagen X, while yielding neocartilage with significantly enhanced functional properties. Specifically, in comparison to no hormone application, these hormones increased compressive and tensile moduli 4.0-fold and 3.1-fold, respectively.
This study demonstrated that T3, together with PTH, when applied in a scaffold-free model of cartilage formation, significantly enhanced functional properties. The novel use of these thyroid hormones generates mechanically robust neocartilage via the use of a scaffold-free tissue engineering model.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0541-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4355350  PMID: 25884593
7.  Cerebral Blood Flow Autoregulation Is Preserved After Hypothermic Circulatory Arrest 
Patients undergoing aortic surgery with hypothermic circulatory arrest (HCA) may require prolonged rewarming, a maneuver associated with impaired cerebral blood flow (CBF) autoregulation. The purpose of this study was to determine the effects of HCA on CBF autoregulation with validated method based on near-infrared spectroscopy.
Regional cerebral oxygen saturation (rScO2) was monitored in 25 patients undergoing aortic reconstructive surgery. HCA was used in 13 patients. Autoregulation was measured continuously during surgery by calculating the linear correlation coefficient between lowfrequency changes in rScO2 and mean arterial pressure (MAP), generating the variable cerebral oximetry index (COx). When CBF autoregulation is functional, COx is near zero, as CBF and MAP are not correlated, but it approaches 1 when autoregulation is impaired (i.e., CBF is pressure passive). Based on prior studies, impaired autoregulation was defined as COx > 0.3.
COx did not differ between HCA and non-HCA groups before cardiopulmonary bypass or during the cooling phase of surgery, although the lower limit of autoregulation tended to be lower in patients before HCA (p=0.053). During patient rewarming, COx was lower in the HCA group (p=0.045) and abnormal COx was less frequent ( 31% vs 75%, p=0.047) compared with the non-HCA group.
During aortic reconstructive surgery, CBF autoregulation is preserved during the cooling phase of surgery in patients undergoing HCA. Perfusion maneuvers associated with HCA may be protective against impaired autoregulation during rewarming compared with the non-HCA group.
PMCID: PMC3972490  PMID: 24446562
Aorta operations; cerebral autoregulation
8.  Cerebrovascular Autoregulation in Pediatric Moyamoya Disease 
Paediatric anaesthesia  2013;23(6):547-556.
Moyamoya syndrome carries a high risk of cerebral ischemia, and impaired cerebrovascular autoregulation may play a critical role. Autoregulation indices derived from near-infrared spectroscopy (NIRS) may clarify hemodynamic goals that conform to the limits of autoregulation.
The aims of this pilot study were to determine whether the NIRS-derived indices could identify blood pressure ranges that optimize autoregulation and whether autoregulatory function differs between anatomic sides in patients with unilateral vasculopathy.
Pediatric patients undergoing indirect surgical revascularization for moyamoya were enrolled sequentially. NIRS-derived autoregulation indices, the cerebral oximetry index (COx) and the hemoglobin volume index (HVx), were calculated intraoperatively and postoperatively to measure autoregulatory function. The 5-mmHg ranges of optimal mean arterial blood pressure (MAPOPT) with best autoregulation and the lower limit of autoregulation (LLA) were identified.
Of seven enrolled patients (aged 2–16 years), six had intraoperative and postoperative autoregulation monitoring and one had only intraoperative monitoring. Intraoperative MAPOPT was identified in six (86%) of seven patients with median values of 60–80 mmHg. Intraoperative LLA was identified in three (43%) patients at 55–65 mmHg. Postoperative MAPOPT was identified in six (100%) of six patients with median values of 70–90 mmHg. Patients with unilateral disease had higher intraoperative HVx (p=0.012) on the side with vasculopathy.
NIRS-derived indices may identify hemodynamic goals that optimize autoregulation in pediatric moyamoya.
PMCID: PMC3648623  PMID: 23506446
Pediatric; neurosurgery; moyamoya; cerebrovascular; autoregulation
9.  Efficacy of Chest Compressions Directed by End‐Tidal CO2 Feedback in a Pediatric Resuscitation Model of Basic Life Support 
End‐tidal carbon dioxide (ETCO2) correlates with systemic blood flow and resuscitation rate during cardiopulmonary resuscitation (CPR) and may potentially direct chest compression performance. We compared ETCO2‐directed chest compressions with chest compressions optimized to pediatric basic life support guidelines in an infant swine model to determine the effect on rate of return of spontaneous circulation (ROSC).
Methods and Results
Forty 2‐kg piglets underwent general anesthesia, tracheostomy, placement of vascular catheters, ventricular fibrillation, and 90 seconds of no‐flow before receiving 10 or 12 minutes of pediatric basic life support. In the optimized group, chest compressions were optimized by marker, video, and verbal feedback to obtain American Heart Association‐recommended depth and rate. In the ETCO2‐directed group, compression depth, rate, and hand position were modified to obtain a maximal ETCO2 without video or verbal feedback. After the interval of pediatric basic life support, external defibrillation and intravenous epinephrine were administered for another 10 minutes of CPR or until ROSC. Mean ETCO2 at 10 minutes of CPR was 22.7±7.8 mm Hg in the optimized group (n=20) and 28.5±7.0 mm Hg in the ETCO2‐directed group (n=20; P=0.02). Despite higher ETCO2 and mean arterial pressure in the latter group, ROSC rates were similar: 13 of 20 (65%; optimized) and 14 of 20 (70%; ETCO2 directed). The best predictor of ROSC was systemic perfusion pressure. Defibrillation attempts, epinephrine doses required, and CPR‐related injuries were similar between groups.
The use of ETCO2‐directed chest compressions is a novel guided approach to resuscitation that can be as effective as standard CPR optimized with marker, video, and verbal feedback.
PMCID: PMC4187472  PMID: 24732917
CPR; end‐tidal carbon dioxide; pediatrics; resuscitation
10.  Cost-effective therapeutic hypothermia treatment device for hypoxic ischemic encephalopathy 
Despite recent advances in neonatal care and monitoring, asphyxia globally accounts for 23% of the 4 million annual deaths of newborns, and leads to hypoxic-ischemic encephalopathy (HIE). Occurring in five of 1000 live-born infants globally and even more in developing countries, HIE is a serious problem that causes death in 25%–50% of affected neonates and neurological disability to at least 25% of survivors. In order to prevent the damage caused by HIE, our invention provides an effective whole-body cooling of the neonates by utilizing evaporation and an endothermic reaction. Our device is composed of basic electronics, clay pots, sand, and urea-based instant cold pack powder. A larger clay pot, lined with nearly 5 cm of sand, contains a smaller pot, where the neonate will be placed for therapeutic treatment. When the sand is mixed with instant cold pack urea powder and wetted with water, the device can extract heat from inside to outside and maintain the inner pot at 17°C for more than 24 hours with monitoring by LED lights and thermistors. Using a piglet model, we confirmed that our device fits the specific parameters of therapeutic hypothermia, lowering the body temperature to 33.5°C with a 1°C margin of error. After the therapeutic hypothermia treatment, warming is regulated by adjusting the amount of water added and the location of baby inside the device. Our invention uniquely limits the amount of electricity required to power and operate the device compared with current expensive and high-tech devices available in the United States. Our device costs a maximum of 40 dollars and is simple enough to be used in neonatal intensive care units in developing countries.
PMCID: PMC3540914  PMID: 23319871
therapeutic hypothermia; evaporative cooling; hypoxic ischemic encephalopathy; birth asphyxia; neuroprotection
11.  CPAF: A Chlamydial Protease in Search of an Authentic Substrate 
PLoS Pathogens  2012;8(8):e1002842.
Bacteria in the genus Chlamydia are major human pathogens that cause an intracellular infection. A chlamydial protease, CPAF, has been proposed as an important virulence factor that cleaves or degrades at least 16 host proteins, thereby altering multiple cellular processes. We examined 11 published CPAF substrates and found that there was no detectable proteolysis when CPAF activity was inhibited during cell processing. We show that the reported proteolysis of these putative CPAF substrates was due to enzymatic activity in cell lysates rather than in intact cells. Nevertheless, Chlamydia-infected cells displayed Chlamydia-host interactions, such as Golgi reorganization, apoptosis resistance, and host cytoskeletal remodeling, that have been attributed to CPAF-dependent proteolysis of host proteins. Our findings suggest that other mechanisms may be responsible for these Chlamydia-host interactions, and raise concerns about all published CPAF substrates and the proposed roles of CPAF in chlamydial pathogenesis.
Author Summary
Chlamydia are bacteria that invade eukaryotic host cells and live within a membrane-bound compartment called the chlamydial inclusion. Growth and survival of these important human and animal pathogens depends on extensive interactions with the host cell, which allow chlamydiae to acquire critical nutrients and to avoid host anti-microbial defenses. Chlamydiae are proposed to cause many of these host-pathogen interactions through the cleavage or degradation of host proteins by the chlamydial protease CPAF, which is secreted into the host cytoplasm. Here, we raise questions about the proposed roles of this virulence factor during infection, as well as its published substrates. We found that there was no detectable cleavage or degradation of 11 previously reported CPAF substrates in Chlamydia-infected cells and that CPAF-mediated proteolysis of these host proteins occurs during cell harvest and lysis. However, we still observed host-pathogen interactions previously attributed to CPAF proteolysis of these proteins, suggesting that Chlamydia is likely to cause these effects on the host cell through other mechanisms. Our findings call for a re-evaluation of all published CPAF substrates as well as the proposed roles of this protease in chlamydial pathogenesis.
PMCID: PMC3410858  PMID: 22876181
12.  Current state of the art in laparoscopic colorectal surgery for cancer: Update on the multi-centric international trials 
Laparoscopic colectomy is now widely applied to cases of malignancy, supported by early data from several large randomized controlled trials. Long-term follow-up is now available from those trials, supporting equivalency of cancer-free and overall survival for open and laparoscopic resections. This promising data has inspired further exploration of other applications of laparoscopic techniques, including use of single incision laparoscopy. This article reviews recent reports of long-term data for colorectal cancer resection from four randomized, prospective international trials.
PMCID: PMC3444362  PMID: 22846394
Laparoscopy; Colorectal cancer; Cost; Classic; Color
13.  Radiographic and Endoscopic Diagnosis and Treatment of Enterocutaneous Fistulas 
The management of enterocutaneous fistulas continues to be a challenging postoperative complication. Understanding the anatomy of the fistula optimizes its evaluation and management. Diagnostic radiology has always played an important role in this task. The use of plain radiography with contrasted studies and fistulograms is well documented in the earliest investigations of fistulas and they continue to be helpful techniques. The imaging techniques have evolved rapidly over the past 15 years with the introduction of cross-sectional imaging, ultrasound and endoscopy. The purpose of this chapter is to review both the diagnostic and therapeutic roles of fistulograms, small bowel follow-through, computed tomography, magnetic resonance imaging, ultrasound, and endoscopy in the setting of acquired enterocutaneous fistulas.
PMCID: PMC2967314  PMID: 21886464
Enterocutaneous fistula; fistulogram; small bowel follow-through; computed tomography; magnetic resonance imaging
14.  Continuous Measurement of Autoregulation by Spontaneous Fluctuations in Cerebral Perfusion Pressure Comparison of 3 Methods 
Background and Purpose
Clinical application of continuous autoregulation monitoring would benefit from a comparison of curves generated by online monitoring with standard autoregulation curves in animal models. We characterized the accuracy of 3 continuous monitors of autoregulation in a piglet model of hypotension.
Piglets 5 to10 days old with intracranial pressure (ICP) at naïve or elevated (20 mm Hg) levels had gradual arterial hypotension induced by a balloon catheter in the inferior vena cava. Elevated ICP was maintained by a continuous infusion of artificial cerebrospinal fluid. Three indices of autoregulation were simultaneously and continuously calculated. A moving, linear Pearson's coefficient between spontaneous slow waves of cerebral perfusion pressure and slow waves of laser-Doppler flux or cortical oxygenation rendered the laser-Doppler index and cerebral-oximetry index, respectively. Similar correlation between slow waves of arterial blood pressure and ICP rendered the pressure-reactivity index. The lower limit of autoregulation was determined directly for each animal by plotting laser-Doppler cortical red blood cell flux as a function of cerebral perfusion pressure. Receiver-operator characteristics were determined for the 3 indices.
The areas under the receiver-operator characteristics curves for discriminating the individual lower limit of autoregulation at low and high ICP were 0.89 and 0.85 for the laser-Doppler index, 0.89 and 0.84 for the cerebral-oximetry index, and 0.79 and 0.79 for the pressure-reactivity index. The pressure-reactivity index performed equally well at low and high ICPs.
Continuous monitoring of autoregulation by spontaneous slow waves of cerebral perfusion pressure can accurately detect loss of autoregulation due to hypotension in piglets by all 3 modalities.
PMCID: PMC2566962  PMID: 18669896
autoregulation; cerebral blood flow; hypotension; neonates; oxygenation; piglets
15.  Neurocognitive Monitoring and Care During Pediatric Cardiopulmonary Bypass—Current and Future Directions 
Current Cardiology Reviews  2008;4(2):123-139.
Neurologic injury in patients with congenital heart disease remains an important source of morbidity and mortality. Advances in surgical repair and perioperative management have resulted in longer life expectancies for these patients. Current practice and research must focus on identifying treatable risk factors for neurocognitive dysfunction, advancing methods for perioperative neuromonitoring, and refining treatment and care of the congenital heart patient with potential neurologic injury. Techniques for neuromonitoring and future directions will be discussed.
PMCID: PMC2779352  PMID: 19936287
16.  Continuous Time-Domain Analysis of Cerebrovascular Autoregulation Using Near-Infrared Spectroscopy 
Background and Purpose
Assessment of autoregulation in the time domain is a promising monitoring method for actively optimizating cerebral perfusion pressure (CPP) in critically ill patients. The ability to detect loss of autoregulatory vasoreactivity to spontaneous fluctuations in CPP was tested with a new time-domain method that used near-infrared spectroscopic measurements of tissue oxyhemoglobin saturation in an infant animal model.
Piglets were made progressively hypotensive over 4 to 5 hours by inflation of a balloon catheter in the inferior vena cava, and the breakpoint of autoregulation was determined using laser-Doppler flowmetry. The cerebral oximetry index (COx) was determined as a moving linear correlation coefficient between CPP and INVOS cerebral oximeter waveforms during 300-second periods. A laser-Doppler derived time-domain analysis of spontaneous autoregulation with the same parameters (LDx) was also determined.
An increase in the correlation coefficient between cerebral oximetry values and dynamic CPP fluctuations, indicative of a pressure-passive relationship, occurred when CPP was below the steady state autoregulatory breakpoint. This COx had 92% sensitivity (73% to 99%) and 63% specificity (48% to 76%) for detecting loss of autoregulation attributable to hypotension when COx was above a threshold of 0.36. The area under the receiver-operator characteristics curve for the COx was 0.89. COx correlated with LDx when values were sorted and averaged according to the CPP at which they were obtained (r=0.67).
The COx is sensitive for loss of autoregulation attributable to hypotension and is a promising monitoring tool for determining optimal CPP for patients with acute brain injury.
PMCID: PMC2377358  PMID: 17761921
autoregulation; cerebral blood flow; hypotension; neonate; oxygenation; piglet

Results 1-16 (16)