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1.  Noninvasive optical characterization of muscle blood flow, oxygenation, and metabolism in women with fibromyalgia 
Arthritis Research & Therapy  2012;14(6):R236.
Introduction
Women with fibromyalgia (FM) have symptoms of increased muscular fatigue and reduced exercise tolerance, which may be associated with alterations in muscle microcirculation and oxygen metabolism. This study used near-infrared diffuse optical spectroscopies to noninvasively evaluate muscle blood flow, blood oxygenation and oxygen metabolism during leg fatiguing exercise and during arm arterial cuff occlusion in post-menopausal women with and without FM.
Methods
Fourteen women with FM and twenty-three well-matched healthy controls participated in this study. For the fatiguing exercise protocol, the subject was instructed to perform 6 sets of 12 isometric contractions of knee extensor muscles with intensity steadily increasing from 20 to 70% maximal voluntary isometric contraction (MVIC). For the cuff occlusion protocol, forearm arterial blood flow was occluded via a tourniquet on the upper arm for 3 minutes. Leg or arm muscle hemodynamics, including relative blood flow (rBF), oxy- and deoxy-hemoglobin concentration ([HbO2] and [Hb]), total hemoglobin concentration (THC) and blood oxygen saturation (StO2), were continuously monitored throughout protocols using a custom-built hybrid diffuse optical instrument that combined a commercial near-infrared oximeter for tissue oxygenation measurements and a custom-designed diffuse correlation spectroscopy (DCS) flowmeter for tissue blood flow measurements. Relative oxygen extraction fraction (rOEF) and oxygen consumption rate (rVO2) were calculated from the measured blood flow and oxygenation data. Post-manipulation (fatiguing exercise or cuff occlusion) recovery in muscle hemodynamics was characterized by the recovery half-time, a time interval from the end of manipulation to the time that tissue hemodynamics reached a half-maximal value.
Results
Subjects with FM had similar hemodynamic and metabolic response/recovery patterns as healthy controls during exercise and during arterial occlusion. However, tissue rOEF during exercise in subjects with FM was significantly lower than in healthy controls, and the half-times of oxygenation recovery (Δ[HbO2] and Δ[Hb]) were significantly longer following fatiguing exercise and cuff occlusion.
Conclusions
Our results suggest an alteration of muscle oxygen utilization in the FM population. This study demonstrates the potential of using combined diffuse optical spectroscopies (i.e., NIRS/DCS) to comprehensively evaluate tissue oxygen and flow kinetics in skeletal muscle.
doi:10.1186/ar4079
PMCID: PMC3674608  PMID: 23116302
2.  Influences of tissue absorption and scattering on diffuse correlation spectroscopy blood flow measurements 
Biomedical Optics Express  2011;2(7):1969-1985.
In this study we evaluate the influences of optical property assumptions on near-infrared diffuse correlation spectroscopy (DCS) flow index measurements. The optical properties, absorption coefficient (µa) and reduced scattering coefficient (µs′), are independently varied using liquid phantoms and measured concurrently with the flow index using a hybrid optical system combining a dual-wavelength DCS flow device with a commercial frequency-domain tissue-oximeter. DCS flow indices are calculated at two wavelengths (785 and 830 nm) using measured µa and µs′ or assumed constant µa and µs′. Inaccurate µs′ assumptions resulted in much greater flow index errors than inaccurate µa. Underestimated/overestimated µs′ from −35%/+175% lead to flow index errors of +110%/−80%, whereas underestimated/overestimated µa from −40%/+150% lead to −20%/+40%, regardless of the wavelengths used. Examination of a clinical study involving human head and neck tumors indicates up to +280% flow index errors resulted from inter-patient optical property variations. These findings suggest that studies involving significant µa and µs′ changes should concurrently measure flow index and optical properties for accurate extraction of blood flow information.
doi:10.1364/BOE.2.001969
PMCID: PMC3130582  PMID: 21750773
(170.0170) Medical optics and biotechnology; (170.3660) Light propagation in tissues; (170.3880) Medical and biological imaging; (170.6480) Spectroscopy, speckle
3.  Increased Cerebral Blood Flow Velocity in Children with Mild Sleep-Disordered Breathing 
Pediatrics  2006;118(4):e1100-e1108.
Objective
Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits.
Design
Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 PM and 7 PM in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis.
Results
Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation <90%, or respiratory arousals when examined in separate bivariate correlations or in aggregate when entered simultaneously. Similarly, there was no significant association between cerebral blood flow velocities and parental estimation of child’s exposure to sleep-disordered breathing. However, it is important to note that whereas the sleep-disordered breathing group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their sleep-disordered breathing in the past. IQ measures were in the average range and comparable between groups. Measures of processing speed and visual attention were significantly lower in sleep-disordered breathing children compared with controls, although within the average range. There were similar group differences in parental-reported executive function behavior. Although there were no direct correlations, adjusting for cerebral blood flow velocities eliminated significant group differences between processing speed and visual attention and decreased the significance of differences in Behavior Rating Inventory of Executive Function scores, suggesting that cerebral hemodynamic factors contribute to the relationship between mild sleep-disordered breathing and these outcome measures.
Conclusions
Cerebral blood flow velocities measured by noninvasive transcranial Doppler provide evidence for increased cerebral blood flow and/or vascular narrowing in childhood sleep-disordered breathing; the relationship with neuropsychological deficits requires further exploration. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect cerebral blood flow velocities. We were able to explore potential confounding influences of obesity and hypertension, neither of which explained our findings. Second, although cerebral blood flow velocities increase with increasing partial pressure of carbon dioxide and hypoxia, it is unlikely that the observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy, with no cardiorespiratory disease, other than sleep-disordered breathing in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during cerebral blood flow velocity measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the sleep-disordered breathing children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day. Finally, there is an inverse linear relationship between cerebral blood flow and hematocrit in adults, and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study. Preoperative full blood counts were not performed routinely in these children, and, therefore, it was not possible to exclude anemia as a cause of increased cerebral blood flow velocity in the sleep-disordered breathing group. However, hemoglobin levels were obtained in 4 children, 2 of whom had borderline low levels (10.9 and 10.2 g/dL). Although there was no apparent relationship with cerebral blood flow velocity in these children (cerebral blood flow velocity values of 131 and 130 cm/second compared with 130 and 137 cm/second in the 2 children with normal hemoglobin levels), this requires verification. It is of particular interest that our data suggest a relationship among snoring, increased cerebral blood flow velocities and indices of cognition (processing speed and visual attention) and perhaps behavioral (Behavior Rating Inventory of Executive Function) function. This finding is preliminary: a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. Prospective studies that quantify cumulative exposure to the physiologic consequences of sleep-disordered breathing, such as hypoxia, would be informative.
doi:10.1542/peds.2006-0092
PMCID: PMC1995426  PMID: 17015501
sleep disordered breathing; cerebral blood flow; transcranial Doppler; executive function; neuropsychological function
4.  Pulse Oximetry: Evaluation of Accuracy during Outpatient General Anesthesia for Oral Surgery 
Anesthesia Progress  1988;35(2):53-60.
Pulse oximetry has been shown to be accurate under steady state conditions. In this study, the accuracy of four pulse oximeters are evaluated and compared during outpatient general anesthesia for third molar extractions. The oximeters evaluated are the Nellcor N-100, the Ohmeda 3700, the Novametrix model 500, and the Bird 4400 portable pulse oximeter.
Ultralight general anesthesia for oral surgery presents a unique challenge for respiratory monitoring in that patients are often not intubated and commonly experience periods of hyper- and hypoventilation. Airway obstruction, apnea, and laryngospasm may occur easily and patients often vocalize and move during surgery. Because hypoxemia is the primary cause of morbidity and mortality during anesthesia, an accurate, continuous, and noninvasive monitor of oxygenation is critical to risk management.
Twenty ASA class I and II patients underwent outpatient general anesthesia for third molar removal using nitrous oxide-oxygen, midazolam, fentanyl, and methohexital. Arterial blood samples were obtained at five-minute intervals during anesthesia, as well as any time a desaturation of >5% occurred, for measurement of arterial SaO2 with an IL282 CO-Oximeter. These values were compared with simultaneously recorded saturations observed for each pulse oximeter. A total of 122 arterial samples were obtained over a range of PaO2 from 52-323 mm Hg and observed saturations of 70-100%.
The Bird 4400 portable pulse oximeter proved to be the most accurate and reliably predicted arterial saturation under these conditions (y = 1.03x - 2.8, r = 0.85). The Novametrix model 500 pulse oximeter also demonstrated a high degree of accuracy by linear regression analysis, but displayed the lowest correlation coefficient (spread of data points) overall (y = 0.97x + 2.8, r = 0.80.) The Nellcor N-100 pulse oximeter also proved to be highly accurate. (y = 1.05x - 4.1, r = 0.84.) In contrast, regression analysis of the observed saturations obtained with the Ohmeda 3700 pulse oximeter revealed that this unit significantly underestimated arterial saturation (y = 1.20x - 19.6, r = 0.83.)
This study demonstrates that despite the rigorous conditions imposed by outpatient general anesthesia for oral surgery, three of the pulse oximeters tested were linearly accurate in predicting arterial oxyhemoglobin saturation over the range of 70-100%. The Ohmeda 3700 was found to significantly underestimate arterial saturation.
Images
PMCID: PMC2148593  PMID: 3166346
5.  Diffuse optical monitoring of hemodynamic changes in piglet brain with closed head injury 
Journal of biomedical optics  2009;14(3):034015.
We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R = 0.89, p < 0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.
doi:10.1117/1.3146814
PMCID: PMC3169814  PMID: 19566308
diffuse correlation spectroscopy (DCS); diffuse reflectance spectroscopy (DRS); cerebral hemodynamics; cerebral blood flow; traumatic brain injury; near—infrared spectroscopy (NIRS)
6.  Use of a Combined SpO2/PtcCO2 Sensor in the Delivery Room 
Sensors (Basel, Switzerland)  2012;12(8):10980-10989.
Arterial oxygen saturation (SaO2) and partial arterial pressure of carbon dioxide (PaCO2) are important respiratory parameters in critically ill neonates. A sensor combining a pulse oximeter with the Stow-Severinghaus electrode, required for the measurement of peripheral oxygen saturation (SpO2) and transcutaneous partial pressure of carbon dioxide (PtcCO2), respectively, has been recently used in neonatal clinical practice (TOSCA500ÒRadiometer). We evaluated TOSCA usability and reliability in the delivery room (DR), throughout three different periods, on term, late-preterm, and preterm neonates. During the first period (period A), 30 healthy term neonates were simultaneously monitored with both TOSCA and a MASIMO pulse oximeter. During the second period (period B), 10 healthy late-preterm neonates were monitored with both TOSCA and a transcutaneous device measuring PtcCO2 (TINAÒ TCM3, Radiometer). During the third period (period C), 15 preterm neonates were monitored with TOSCA and MASIMO after birth, during stabilization, and during transport to the neonatal intensive care unit (NICU). Blood gas analyses were performed to compare transcutaneous and blood gas values. TOSCA resulted easily and safely usable in the DR, allowing reliable noninvasive SaO2 estimation. Since PtcCO2 measurements with TOSCA required at least 10 min to be stable and reliable, this parameter was not useful during the early resuscitation immediately after birth. Moreover, PtcCO2 levels were less precise if compared to the conventional transcutaneous monitoring. However, PtcCO2 measurement by TOSCA was useful as trend-monitoring after stabilization and during transport to NICU.
doi:10.3390/s120810980
PMCID: PMC3472870  PMID: 23112642
oxygen saturation; partial pressure of carbon dioxide; pulse oximeter; delivery room; TOSCA sensor; neonate
7.  Monitoring photodynamic therapy of head and neck malignancies with optical spectroscopies 
In recent years there has been significant developments in photosensitizers (PSs), light sources and light delivery systems that have allowed decreasing the treatment time and skin phototoxicity resulting in more frequent use of photodynamic therapy (PDT) in the clinical settings. Compared to standard treatment approaches such as chemo-radiation and surgery, PDT has much reduced morbidity for head and neck malignancies and is becoming an alternative treatment option. It can be used as an adjunct therapy to other treatment modalities without any additive cumulative side effects. Surface illumination can be an option for pre-malignant and early-stage malignancies while interstitial treatment is for debulking of thick tumors in the head and neck region. PDT can achieve equivalent or greater efficacy in treating head and neck malignancies, suggesting that it may be considered as a first line therapy in the future. Despite progressive development, clinical PDT needs improvement in several topics for wider acceptance including standardization of protocols that involve the same administrated light and PS doses and establishing quantitative tools for PDT dosimetry planning and response monitoring. Quantitative measures such as optical parameters, PS concentration, tissue oxygenation and blood flow are essential for accurate PDT dosimetry as well as PDT response monitoring and assessing therapy outcome. Unlike conventional imaging modalities like magnetic resonance imaging, novel optical imaging techniques can quantify PDT-related parameters without any contrast agent administration and enable real-time assessment during PDT for providing fast feedback to clinicians. Ongoing developments in optical imaging offer the promise of optimization of PDT protocols with improved outcomes.
doi:10.12998/wjcc.v1.i3.96
PMCID: PMC3845916  PMID: 24303476
Head and neck cancer; Photodynamic therapy; Monitoring and predicting response; Blood flow; Oxygenation; Oxygen metabolism; Diffuse optical imaging
8.  Diffuse optical monitoring of repeated cerebral ischemia in mice 
Optics Express  2011;19(21):20301-20315.
Occlusions of bilateral common carotid arteries (bi-CCA) in mice are popular models for the investigation of transient forebrain ischemia. Currently available technologies for assessing cerebral blood flow (CBF) and oxygenation in ischemic mice have limitations. This study tests a novel near-infrared diffuse correlation spectroscopy (DCS) flow-oximeter for monitoring both CBF and cerebral oxygenation in mice undergoing repeated transient forebrain ischemia. Concurrent flow measurements in a mouse brain were first conducted for validation purposes; DCS measurement was found highly correlated with laser Doppler measurement (R2 = 0.94) and less susceptible to motion artifacts. With unique designs in experimental protocols and fiber-optic probes, we have demonstrated high sensitivities of DCS flow-oximeter in detecting the regional heterogeneity of CBF responses in different hemispheres and global changes of both CBF and cerebral oxygenation across two hemispheres in mice undergoing repeated 2-minute bi-CCA occlusions over 5 days. More than 75% CBF reductions were found during bi-CCA occlusions in mice, which may be considered as a threshold to determine a successful bi-CCA occlusion. With the progress of repeated 2-minute bi-CCA occlusions over days, a longitudinal decline in the magnitudes of CBF reduction was observed, indicating the brain adaptation to cerebral ischemia through the repeated preconditioning.
doi:10.1364/OE.19.020301
PMCID: PMC3495871  PMID: 21997041
(170.0170) Medical optics and biotechnology; (170.3660) Light propagation in tissues; (170.3880) Medical and biological imaging; (170.6480) Spectroscopy, speckle
9.  Avoiding hyperoxemia during neonatal resuscitation: time to response of different SpO2 monitors 
Aim
To assess the time to obtain reliable oxygen saturation readings by different pulse oximeters during neonatal resuscitation in the delivery room or NICU.
Methods
Prospective study comparing three different pulse oximeters: Masimo Radical-7 compared simultaneously with Ohmeda Biox 3700 or with Nellcor N395, in newborn infants who required resuscitation. Members of the research team placed the sensors for each of the pulse oximeters being compared simultaneously, one sensor on each foot of the same baby. Care provided routinely, without interference by the research team. The time elapsed until a reliable SpO2 was obtained was recorded using a digital chronometer. Statistical comparisons included chi-square and student's T-test.
Results
Thirty-two infants were enrolled; median gestational age 32 weeks. Seventeen paired measurements were made with the Radical-7 and Biox 3700; mean time to a stable reading was 20.2 ± 7 sec for the Radical-7 and 74.2 ± 12 sec for the Biox 3700 (p = 0.02). The Radical-7 and the N- 395 were paired on 15 infants; the times to obtain a stable reading were 20.9 ± 4 sec and 67.3 ± 12 sec, respectively (p = 0.03).
Conclusion
The time to a reliable reading obtained simultaneously in neonatal critical situations differs by the type of the pulse oximeter used, being significantly faster with Masimo Signal Extraction Technology. This may permit for better adjustments of inspired oxygen, aiding in the prevention of damage caused by unnecessary exposure to high or low oxygen.
doi:10.1111/j.1651-2227.2010.02097.x
PMCID: PMC3085071  PMID: 21091987
Neonatal Resuscitation; Newborn; Oxygen saturation
10.  Trends in survival among extremely-low-birth-weight infants (less than 1000 g) without significant bronchopulmonary dysplasia 
BMC Pediatrics  2012;12:63.
Objective
The aim of this study was to analyze the evolution from 1997 to 2009 of survival without significant (moderate and severe) bronchopulmonary dysplasia (SWsBPD) in extremely-low-birth-weight (ELBW) infants and to determine the influence of changes in resuscitation, nutrition and mechanical ventilation on the survival rate.
Study design
In this study, 415 premature infants with birth weights below 1000 g (ELBW) were divided into three chronological subgroups: 1997 to 2000 (n = 65), 2001 to 2005 (n = 178) and 2006 to 2009 (n = 172).
Between 1997 and 2000, respiratory resuscitation in the delivery room was performed via a bag and mask (Ambu®, Ballerup, Sweden) with 40-50% oxygen. If this procedure was not effective, oral endotracheal intubation was always performed. Pulse oximetry was never used. Starting on January 1, 2001, a change in the delivery room respiratory policy was established for ELBW infants. Oxygenation and heart rate were monitored using a pulse oximeter (Nellcor®) attached to the newborn’s right hand. If resuscitation was required, ventilation was performed using a face mask, and intermittent positive pressure was controlled via a ventilator (Babylog2, Drägger). In 2001, a policy of aggressive nutrition was also initiated with the early provision of parenteral amino acids. We used standardized parenteral nutrition to feed ELBW infants during the first 12–24 hours of life. Lipids were given on the first day. The glucose concentration administered was increased by 1 mg/kg/minute each day until levels reached 8 mg/kg/minute. Enteral nutrition was started with trophic feeding of milk. In 2006, volume guarantee treatment was instituted and administered together with synchronized intermittent mandatory ventilation (SIMV + VG). The complications of prematurity were treated similarly throughout the study period. Patent ductus arteriosus was only treated when hemodynamically significant. Surgical closure of the patent ductus arteriosus was performed when two courses of indomethacin or ibuprofen were not sufficient to close it.
Mild BPD were defined by a supplemental oxygen requirement at 28 days of life and moderate BPD if breathing room air or a need for <30% oxygen at 36 weeks postmenstrual age or discharge from the NICU, whichever came first. Severe BPD was defined by a supplemental oxygen requirement at 28 days of life and a need for greater than or equal to 30% oxygen use and/or positive pressure support (IPPV or nCPAP) at 36 weeks postmenstrual age or discharge, whichever came first. Moderate and severe BPD have been considered together as “significant BPD”. The goal of pulse oximetry was to maintain a hemoglobin saturation of between 88% and 93%. Patients were considered to not need oxygen supplementation when it could be permanently withdrawn. The distribution of the variables was not normal based on a Kolmogorov-Smirnov test (p < 0.05 in all cases). Therefore, quantitative variables were expressed as the median and interquartile range (IQR; 25th-75th percentile). Statistical analysis of the data was performed using nonparametric techniques (Kruskal-Wallis test and Mann–Whitney U test). A chi-square analysis was used to analyze qualitative variables. Potential confounding variables were those possibly related to BPD in survivors (p between 0.05 and 0.3 in univariate analysis). Logistic regression analysis was performed with variables related to BPD in survivors (p < 0.05) and potential confounding variables. The forward stepwise method adjusted for confounding factors was used to select the variables, and the enter method using selected variables was used to obtain the odds ratios.
Results and conclusion
There was an increase in the rate of SWsBPD (1997 to 2000: 58.5%; 2001 to 2005: 74.2%; and 2006 to 2009: 75.0%; p = 0.032). In survivors, the occurrence of significant BPD decreased after 2001 (9.5% vs. 2.3%; p = 0.013). The factors associated with improved SWsBPD were delivery by caesarean section, a reduced endotracheal intubation rate and a reduced duration of mechanical ventilation.While the mortality of ELBW infants has not changed since 2001, the frequency of SWsBPD has significantly increased (75.0%) in association with increased caesarean sections and reductions in the endotracheal intubation rate, as well as the duration of mechanical ventilation.
doi:10.1186/1471-2431-12-63
PMCID: PMC3507706  PMID: 22682000
Bronchopulmonary dysplasia; Chronic lung disease; Extremely low birth weight infants; Preterm infants
11.  Tumor Blood Flow Differs between Mouse Strains: Consequences for Vasoresponse to Photodynamic Therapy 
PLoS ONE  2012;7(5):e37322.
Fluctuations in tumor blood flow are common and attributed to factors such as vasomotion or local vascular structure, yet, because vessel structure and physiology are host-derived, animal strain of tumor propagation may further determine blood flow characteristics. In the present report, baseline and stress-altered tumor hemodynamics as a function of murine strain were studied using radiation-induced fibrosacomas (RIF) grown in C3H or nude mice. Fluctuations in tumor blood flow during one hour of baseline monitoring or during vascular stress induced by photodynamic therapy (PDT) were measured by diffuse correlation spectroscopy. Baseline monitoring revealed fluctuating tumor blood flow highly correlated with heart rate and with similar median periods (i.e., ∼9 and 14 min in C3H and nudes, respectively). However, tumor blood flow in C3H animals was more sensitive to physiologic or stress-induced perturbations. Specifically, PDT-induced vascular insults produced greater decreases in blood flow in the tumors of C3H versus nude mice; similarly, during baseline monitoring, fluctuations in blood flow were more regular and more prevalent within the tumors of C3H mice versus nude mice; finally, the vasoconstrictor L-NNA reduced tumor blood flow in C3H mice but did not affect tumor blood flow in nudes. Underlying differences in vascular structure, such as smaller tumor blood vessels in C3H versus nude animals, may contribute to strain-dependent variation in vascular function. These data thus identify clear effects of mouse strain on tumor hemodynamics with consequences to PDT and potentially other vascular-mediated therapies.
doi:10.1371/journal.pone.0037322
PMCID: PMC3356280  PMID: 22624014
12.  Monitoring photobleaching and hemodynamic responses to HPPH-mediated photodynamic therapy of head and neck cancer: a case report 
Optics express  2010;18(14):14969-14978.
We present initial results obtained during the course of a Phase I clinical trial of 2-1[hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH)-mediated photo-dynamic therapy (PDT) in a head and neck cancer patient. We quantified blood flow, oxygenation and HPPH drug photobleaching before and after therapeutic light treatment by utilizing fast, non-invasive diffuse optical methods. Our results showed that HPPH-PDT induced significant drug photobleaching, and reduction in blood flow and oxygenation suggesting significant vascular and cellular reaction. These changes were accompanied by cross-linking of the signal transducer and activator of transcription 3 (STAT3), a molecular measure for the oxidative photoreaction. These preliminary results suggest diffuse optical spectroscopies permit non-invasive monitoring of PDT in clinical settings of head and neck cancer patients.
PMCID: PMC2964147  PMID: 20639983
13.  Hemodynamic Parameters in Blood Vessels in Choroidal Melanoma Xenografts and Rat Choroid 
Purpose
Choroidal melanoma is the most common primary ocular cancer among the adult population. To avoid enucleation, there has been a concerted effort to develop therapies that spare the affected eye and the patient’s vision. Blood flow helps shape the tumor’s microenvironment, plays a key role in the tumor’s response to many different types of therapy, and is necessary for delivery of chemotherapeutic agents. To rationally design new therapies and optimize existing treatments, it is essential to learn as much as possible about blood flow and the microcirculation in this tumor. In recent years, much has been discovered about the anatomy of the microvasculature and the dynamics of overall blood flow in choroidal melanoma, but little is known about the factors that determine microvascular blood flow. In this study hemodynamic parameters in individual microvessels of a human choroidal melanoma xenograft were compared with those same parameters in a normal rat choroid.
Methods
Nude, athymic WAG/RijHs-rnu rats were used in this study. The human choroidal melanoma cell line OCM-1 was used to grow solid tumors subcutaneously in the flanks of donor rats. Small pieces of these tumors were then implanted into the choroidal space of recipient rats. After 6 to 8 weeks, the rats were anesthetized with a subcutaneous injection of urethane, and the sclera was exposed. Rhodamine-labeled li-posomes and red blood cells (RBCs) labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) were injected intravenously. Epifluorescent, intravital microscopy was used to visualize the flow of fluorescent RBCs through individual vessels in the choroid or tumor. Flow through multiple vessels was recorded on videotape for later analysis. From the recordings, RBC flux, RBC velocity (Vc), and microvascular hematocrit (HCTm) were determined. Similar experiments were performed in rats with no tumor growth, and these same parameters were calculated in normal choroidal vessels. RBC flow was characterized in 55 vessels in six OCM-1 tumors and in 153 choroidal vessels in five non–tumor-bearing rats.
Results
RBC flux was higher in larger tumor vessels (>30 μm in diameter) compared with similarly sized choroidal vessels. There were no differences in the velocities of RBCs through the two types of vessels. HCTm was significantly higher in medium-sized (>20 μm in diameter) and larger tumor vessels compared with normal choroidal vessels.
Conclusions
These experiments demonstrate differences between hemodynamic parameters in normal choroidal microvessels and microvessels in choroidal melanoma in this animal model. Because HCTm is a key determinant of apparent viscosity, abnormally high HCTm in the tumor vessels would increase vascular resistance and decrease flow. This could have a negative impact on the tumor oxygen levels and on the ability to deliver drugs effectively. On the contrary, higher local HCTm has also been shown to increase oxygen delivery. The impact and interplay of these two effects on tumor oxygenation remain to be determined.
PMCID: PMC1945177  PMID: 12202528
14.  Simultaneous measurement of deep tissue blood flow and oxygenation using noncontact diffuse correlation spectroscopy flow-oximeter 
Scientific Reports  2013;3:1358.
We report a novel noncontact diffuse correlation spectroscopy flow-oximeter for simultaneous quantification of relative changes in tissue blood flow (rBF) and oxygenation (Δ[oxygenation]). The noncontact probe was compared against a contact probe in tissue-like phantoms and forearm muscles (n = 10), and the dynamic trends in both rBF and Δ[oxygenation] were found to be highly correlated. However, the magnitudes of Δ[oxygenation] measured by the two probes were significantly different. Monte Carlo simulations and phantom experiments revealed that the arm curvature resulted in a significant underestimation (~−20%) for the noncontact measurements in Δ[oxygenation], but not in rBF. Other factors that may cause the residual discrepancies between the contact and noncontact measurements were discussed, and further comparisons with other established technologies are needed to identify/quantify these factors. Our research paves the way for noncontact and simultaneous monitoring of blood flow and oxygenation in soft and vulnerable tissues without distorting tissue hemodynamics.
doi:10.1038/srep01358
PMCID: PMC3584314  PMID: 23446991
15.  Normothermic cardiopulmonary bypass increases cerebral tissue oxygenation during combined valve surgery: a single-centre, randomized trial 
OBJECTIVES
In cardiac surgery, the choice of temperature regimen during cardiopulmonary bypass (CPB) remains a subject of debate. Hypothermia reduces tissue metabolic demands, but may impair the autoregulation of cerebral blood flow and contribute to neurological morbidity. The aim of this study was to evaluate the effect of two different temperature regimens during CPB on the systemic oxygen transport and the cerebral oxygenation during surgical correction of acquired heart diseases.
METHODS
In a prospective study, we randomized 40 adult patients with combined valvular disorders requiring surgical correction of two or more valves into two groups: (i) a normothermic (NMTH) group (n = 20), in which the body core temperature was maintained at 36.6°C during CPB and (ii) a hypothermic (HPTH) group (n = 20), in which the body was cooled to a core temperature of 32°C maintained throughout the period of CPB. The systemic oxygen transport and the cerebral oxygen saturation (SctO2) were assessed by means of a PiCCO2 haemodynamic monitor and a cerebral oximeter, respectively. All the patients received standard perioperative monitoring. We assessed haemodynamic and oxygen transport parameters, the duration of mechanical ventilation and the length of the ICU and the hospital stays.
RESULTS
During CPB, central venous oxygen saturation was significantly higher in the HPTH group but SctO2 was increased in the NMTH group (P < 0.05). Cardiac index, systemic oxygen delivery and consumption increased postoperatively in both groups. However, oxygen delivery and consumption were significantly higher in the NMTH group (P < 0.05). The duration of respiratory support and the length of ICU and hospital stays did not differ between the groups.
CONCLUSIONS
During combined valve surgery, normothermic CPB provides lower central venous oxygen saturation, but increases cerebral tissue oxygenation when compared with the hypothermic regimen.
TRIAL REGISTRATION NUMBER
NCT01685554.
doi:10.1093/icvts/ivt016
PMCID: PMC3630427  PMID: 23407696
Oxygen transport; Cerebral oximetry; Cardiac surgery; Normothermia; Hypothermia; Cardiopulmonary bypass
16.  Prediction of clinical toxicity in locally advanced head and neck cancer patients by radio-induced apoptosis in peripheral blood lymphocytes (PBLs) 
Head and neck cancer is treated mainly by surgery and radiotherapy. Normal tissue toxicity due to x-ray exposure is a limiting factor for treatment success. Many efforts have been employed to develop predictive tests applied to clinical practice. Determination of lymphocyte radio-sensitivity by radio-induced apoptosis arises as a possible method to predict tissue toxicity due to radiotherapy. The aim of the present study was to analyze radio-induced apoptosis of peripheral blood lymphocytes in head and neck cancer patients and to explore their role in predicting radiation induced toxicity. Seventy nine consecutive patients suffering from head and neck cancer, diagnosed and treated in our institution, were included in the study. Toxicity was evaluated using the Radiation Therapy Oncology Group scale. Peripheral blood lymphocytes were isolated and irradiated at 0, 1, 2 and 8 Gy during 24 hours. Apoptosis was measured by flow cytometry using annexin V/propidium iodide. Lymphocytes were marked with CD45 APC-conjugated monoclonal antibody. Radiation-induced apoptosis increased in order to radiation dose and fitted to a semi logarithmic model defined by two constants: α and β. α, as the origin of the curve in the Y axis determining the percentage of spontaneous cell death, and β, as the slope of the curve determining the percentage of cell death induced at a determined radiation dose, were obtained. β value was statistically associated to normal tissue toxicity in terms of severe xerostomia, as higher levels of apoptosis were observed in patients with low toxicity (p = 0.035; Exp(B) 0.224, I.C.95% (0.060-0.904)). These data agree with our previous results and suggest that it is possible to estimate the radiosensitivity of peripheral blood lymphocytes from patients determining the radiation induced apoptosis with annexin V/propidium iodide staining. β values observed define an individual radiosensitivity profile that could predict late toxicity due to radiotherapy in locally advanced head and neck cancer patients. Anyhow, prospective studies with different cancer types and higher number of patients are needed to validate these results.
doi:10.1186/1748-717X-5-4
PMCID: PMC2827476  PMID: 20109191
17.  Structural Adaptation and Heterogeneity of Normal and Tumor Microvascular Networks 
PLoS Computational Biology  2009;5(5):e1000394.
Relative to normal tissues, tumor microcirculation exhibits high structural and functional heterogeneity leading to hypoxic regions and impairing treatment efficacy. Here, computational simulations of blood vessel structural adaptation are used to explore the hypothesis that abnormal adaptive responses to local hemodynamic and metabolic stimuli contribute to aberrant morphological and hemodynamic characteristics of tumor microcirculation. Topology, vascular diameter, length, and red blood cell velocity of normal mesenteric and tumor vascular networks were recorded by intravital microscopy. Computational models were used to estimate hemodynamics and oxygen distribution and to simulate vascular diameter adaptation in response to hemodynamic, metabolic and conducted stimuli. The assumed sensitivity to hemodynamic and conducted signals, the vascular growth tendency, and the random variability of vascular responses were altered to simulate ‘normal’ and ‘tumor’ adaptation modes. The heterogeneous properties of vascular networks were characterized by diameter mismatch at vascular branch points (d3var) and deficit of oxygen delivery relative to demand (O2def). In the tumor, d3var and O2def were higher (0.404 and 0.182) than in normal networks (0.278 and 0.099). Simulated remodeling of the tumor network with ‘normal’ parameters gave low values (0.288 and 0.099). Conversely, normal networks attained tumor-like characteristics (0.41 and 0.179) upon adaptation with ‘tumor’ parameters, including low conducted sensitivity, increased growth tendency, and elevated random biological variability. It is concluded that the deviant properties of tumor microcirculation may result largely from defective structural adaptation, including strongly reduced responses to conducted stimuli.
Author Summary
Blood vessels of tumors have abnormal structures, being irregular and tortuous. Oxygen supply to tumors is heterogeneous, with regions of low oxygen that resist radiation treatment and some types of chemotherapy. Blood vessels undergo continual structural change (adaptation) in response to blood flow and metabolite levels. Our hypothesis is that abnormal adaptation of tumor microvessels causes their heterogeneous structure and impaired function. We used computational models to estimate blood flow and oxygen delivery and to simulate diameter adaptation in networks of microvessels, using network structures derived from microscopic observations of living normal and tumor tissues. The simulation of adaptation depends on several parameters that describe vessel sensitivity to fluid shear stress, to blood pressure, to oxygen levels, and to signals propagated along vessel walls (conducted response). We found that structural adaptation of a tumor network using parameters derived from normal tissues could ‘normalize’ the network, giving it properties similar to a normal tissue. Conversely, adaptation of normal networks using parameters derived from the tumor network, including reduced conducted response, gave tumor-like properties. We conclude that the deviant properties of tumor microcirculation may result largely from defective structural adaptation, including reduced conducted responses.
doi:10.1371/journal.pcbi.1000394
PMCID: PMC2682204  PMID: 19478883
18.  A comparative study between the imaging system and the optical tracking system in proton therapy at CNAO 
Journal of Radiation Research  2013;54(Suppl 1):i129-i135.
The synergy between in-room imaging and optical tracking, in co-operation with highly accurate robotic patient handling represents a concept for patient-set-up which has been implemented at CNAO (Centro Nazionale di Adroterapia Oncologica). In-room imaging is based on a double oblique X-ray projection system; optical tracking consists of the detection of the position of spherical markers placed directly on the patient's skin or on the immobilization devices. These markers are used as external fiducials during patient positioning and dose delivery. This study reports the results of a comparative analysis between in-room imaging and optical tracking data for patient positioning within the framework of high-precision particle therapy. Differences between the optical tracking system (OTS) and the imaging system (IS) were on average within the expected localization accuracy. On the first 633 fractions for head and neck (H&N) set-up procedures, the corrections applied by the IS, after patient positioning using the OTS only, were for the mostly sub-millimetric regarding the translations (0.4±1.1 mm) and sub-gradual regarding the rotations (0.0°±0.8°). On the first 236 fractions for pelvis localizations the amplitude of the corrections applied by the IS after preliminary optical set-up correction were moderately higher and more dispersed (translations: 1.3±2.9 mm, rotations 0.1±0.9°). Although the indication of the OTS cannot replace information provided by in-room imaging devices and 2D-3D image registration, the reported data show that OTS preliminary correction might greatly support image-based patient set-up refinement and also provide a secondary, independent verification system for patient positioning.
doi:10.1093/jrr/rrt043
PMCID: PMC3700512  PMID: 23824116
IGRT; patient positioning; optical tracking system; particle therapy; head and neck; pelvis localizations
19.  Recombinant AAV9-TLK1B Administration Ameliorates Fractionated Radiation-Induced Xerostomia 
Human Gene Therapy  2013;24(6):604-612.
Abstract
Salivary glands are highly susceptible to radiation, and patients with head and neck cancer treated with radiotherapy invariably suffer from its distressing side effect, salivary hypofunction. The reduction in saliva disrupts oral functions, and significantly impairs oral health. Previously, we demonstrated that adenoviral-mediated expression of Tousled-like kinase 1B (TLK1B) in rat submandibular glands preserves salivary function after single-dose ionizing radiation. To achieve long-term transgene expression for protection of salivary gland function against fractionated radiation, this study examines the usefulness of recombinant adeno-associated viral vector for TLK1B delivery. Lactated Ringers or AAV2/9 with either TLK1B or GFP expression cassette were retroductally delivered to rat submandibular salivary glands (1011 vg/gland), and animals were exposed, or not, to 20 Gy in eight fractions of 2.5 Gy/day. AAV2/9 transduced predominantly the ductal cells, including the convoluted granular tubules of the submandibular glands. Transgene expression after virus delivery could be detected within 5 weeks, and stable gene expression was observed till the end of study. Pilocarpine-stimulated saliva output measured at 8 weeks after completion of radiation demonstrated >10-fold reduction in salivary flow in saline- and AAV2/9-GFP-treated animals compared with the respective nonirradiated groups (90.8% and 92.5% reduction in salivary flow, respectively). Importantly, there was no decrease in stimulated salivary output after irradiation in animals that were pretreated with AAV2/9-TLK1B (121.5% increase in salivary flow; p<0.01). Salivary gland histology was better preserved after irradiation in TLK1B-treated group, though not significantly, compared with control groups. Single preemptive delivery of AAV2/9-TLK1B averts salivary dysfunction resulting from fractionated radiation. Although AAV2/9 transduces mostly the ductal cells of the gland, their protection against radiation assists in preserving submandibular gland function. AAV2/9-TLK1B treatment could prove beneficial in attenuating xerostomia in patients with head and neck cancer undergoing radiotherapy.
Shanmugam and colleagues demonstrate that a single instillation of recombinant AAV9 encoding Tousled-like kinase 1B (TLK1B) in rat submandibular glands leads to a complete amelioration of salivary dysfunction caused by fractionated radiation. They suggest that this treatment modality may be beneficial in attenuating xerostomia in headand-neck cancer patients undergoing radiotherapy.
doi:10.1089/hum.2012.235
PMCID: PMC3689188  PMID: 23614651
20.  High-Precision Radiosurgical Dose Delivery by Interlaced Microbeam Arrays of High-Flux Low-Energy Synchrotron X-Rays 
PLoS ONE  2010;5(2):e9028.
Microbeam Radiation Therapy (MRT) is a preclinical form of radiosurgery dedicated to brain tumor treatment. It uses micrometer-wide synchrotron-generated X-ray beams on the basis of spatial beam fractionation. Due to the radioresistance of normal brain vasculature to MRT, a continuous blood supply can be maintained which would in part explain the surprising tolerance of normal tissues to very high radiation doses (hundreds of Gy). Based on this well described normal tissue sparing effect of microplanar beams, we developed a new irradiation geometry which allows the delivery of a high uniform dose deposition at a given brain target whereas surrounding normal tissues are irradiated by well tolerated parallel microbeams only. Normal rat brains were exposed to 4 focally interlaced arrays of 10 microplanar beams (52 µm wide, spaced 200 µm on-center, 50 to 350 keV in energy range), targeted from 4 different ports, with a peak entrance dose of 200Gy each, to deliver an homogenous dose to a target volume of 7 mm3 in the caudate nucleus. Magnetic resonance imaging follow-up of rats showed a highly localized increase in blood vessel permeability, starting 1 week after irradiation. Contrast agent diffusion was confined to the target volume and was still observed 1 month after irradiation, along with histopathological changes, including damaged blood vessels. No changes in vessel permeability were detected in the normal brain tissue surrounding the target. The interlacing radiation-induced reduction of spontaneous seizures of epileptic rats illustrated the potential pre-clinical applications of this new irradiation geometry. Finally, Monte Carlo simulations performed on a human-sized head phantom suggested that synchrotron photons can be used for human radiosurgical applications. Our data show that interlaced microbeam irradiation allows a high homogeneous dose deposition in a brain target and leads to a confined tissue necrosis while sparing surrounding tissues. The use of synchrotron-generated X-rays enables delivery of high doses for destruction of small focal regions in human brains, with sharper dose fall-offs than those described in any other conventional radiation therapy.
doi:10.1371/journal.pone.0009028
PMCID: PMC2815784  PMID: 20140254
21.  Optical Monitoring and Detection of Spinal Cord Ischemia 
PLoS ONE  2013;8(12):e83370.
Spinal cord ischemia can lead to paralysis or paraparesis, but if detected early it may be amenable to treatment. Current methods use evoked potentials for detection of spinal cord ischemia, a decades old technology whose warning signs are indirect and significantly delayed from the onset of ischemia. Here we introduce and demonstrate a prototype fiber optic device that directly measures spinal cord blood flow and oxygenation. This technical advance in neurological monitoring promises a new standard of care for detection of spinal cord ischemia and the opportunity for early intervention. We demonstrate the probe in an adult Dorset sheep model. Both open and percutaneous approaches were evaluated during pharmacologic, physiological, and mechanical interventions designed to induce variations in spinal cord blood flow and oxygenation. The induced variations were rapidly and reproducibly detected, demonstrating direct measurement of spinal cord ischemia in real-time. In the future, this form of hemodynamic spinal cord diagnosis could significantly improve monitoring and management in a broad range of patients, including those undergoing thoracic and abdominal aortic revascularization, spine stabilization procedures for scoliosis and trauma, spinal cord tumor resection, and those requiring management of spinal cord injury in intensive care settings.
doi:10.1371/journal.pone.0083370
PMCID: PMC3865183  PMID: 24358279
22.  Stereotactic Radiotherapy of Central Nervous System and Head and Neck Lesions, Using a Conformal Intensity-Modulated Radiotherapy System (Peacock™ System) 
Skull Base  2001;11(2):109-119.
The objective of this article is to evaluate single-fraction or fractionated stereotactic radiotherapy of central nervous system (CNS) and head and neck lesions using intensity-modulated radiotherapy (IMRT) with a commercially available system (Peacock™, Nomos Corporation, Sewickley, PA). This system allows tomotherapeutic delivery of intensity-modulated radiation, that is, the slice-by-slice treatment of the volume of interest with an intensity-modulated beam, making the delivery of highly conformal radiation to the target possible in both single or multiple fractions mode. During an 18-month period, 43 (21 males and 22 females) patients were treated, using a removable cranial screw-fixation device. Ages ranged from 10 to 77 years (mean, 52.2; median, 53.5). Intra- and extra-axial lesions, including head and neck malignancies and spine metastases, were treated. Clinical target volume ranged from 0.77 to 195 cm3 (mean, 47.8; median, 29.90). The dose distribution was normalized to the maximum and was prescribed, in most cases, at the 80% or 90% isodose line (range, 65 to 96%; median, 85%; mean, 83.4%) and ranged from 14 to 80 Gy (mean, 48; median, 50). The number of fractions ranged from 1 to 40 (mean, 23; median, 25). In all but one patient, 90% of the prescription isodose line covered 100% of the clinical target volume. The heterogeneity index (the ratio between the maximum radiation dose and the prescribed dose) ranged between 1.0 and 1.50, whereas the conformity index (the ratio between the volume encompassed by the prescription isodose line and the clinical target volume) ranged between 1.0 and 4.5. There were no complications related to the radiation treatment. With a median follow-up of 6 months, more than 70% of our patients showed decreased lesion size. Stereotactic IMRT of CNS and head and neck lesions can be delivered safely and accurately. The Peacock system delivers stereotactic radiation in single or multiple fractions and has no volume limitations. It has been used to treat intracranial, head and neck, and spinal lesions. The option of fractionation, the lack of volume constraint, and the capability of treating intracranial, head and neck, and spinal pathology make stereotactic IMRT a valuable adjunct to established stereotactic radiotherapy systems delivering convergent-beam irradiation using the Linac or Gamma Knife. In a clinical setting that offers Linac, Gamma Knife radiosurgery, and conformal stereotactic radiotherapy, the latter may have advantages for treating large (> 25-cm3) and irregular lesions, especially when fractionation is considered useful.
Images
PMCID: PMC1656797  PMID: 17167610
Intensity-modulated radiotherapy; intracranial lesions; linear accelerator; stereotactic radiotherapy
23.  Hemodynamic and metabolic diffuse optical monitoring in a mouse model of hindlimb ischemia 
Biomedical Optics Express  2010;1(4):1173-1187.
Murine hindlimb ischemia is a useful model for investigation of the mechanisms of peripheral arterial disease and for understanding the role of endothelial cells and generic factors affecting vascular regeneration or angiogenesis. To date, important research with these models has explored tissue reperfusion following ischemia with Laser Doppler methods, methods which provide information about superficial (~mm) vascular regeneration. In this work, we employ diffuse correlation spectroscopy (DCS) and diffuse optical spectroscopy (DOS) in mice after hindlimb ischemia. We hypothesize that vascular re-growth is not uniform in tissue, and therefore, since diffuse optical methods are capable of probing deep tissues, that the diffuse optics approach will provide a more complete picture of the angiogenesis process throughout the whole depth profile of the limb. Besides increased depth penetration, the combined measurements of DCS and DOS enable all-optical, noninvasive, longitudinal monitoring of tissue perfusion and oxygenation that reveals the interplay between these hemodynamic parameters during angiogenesis. Control mice were found to reestablish 90% of perfusion and oxygen consumption during this period, but oxygen saturation in the limb only partially recovered to about 30% of its initial value. The vascular recovery of mice with endothelial cell-specific deletion of HIF-2α was found to be significantly impaired relative to control mice, indicating that HIF-2α is important for endothelial cell functions in angiogenesis. Comparison of DOS/DCS measurements to parallel measurements in the murine models using Laser Doppler Flowmetry reveal differences in the reperfusion achieved by superficial versus deep tissue during neoangiogenesis; findings from histological analysis of blood vessel development were further correlated with these differences. In general, the combination of DCS and DOS enables experimenters to obtain useful information about oxygenation, metabolism, and perfusion throughout the limb. The results establish diffuse optics as a practical noninvasive method to evaluate the role of transcription factors, such as the endothelial cell-specific HIF-2α, in genetic ally modified mice.
doi:10.1364/BOE.1.001173
PMCID: PMC3018079  PMID: 21258539
(170.3880) Medical and biological imaging; (170.1420) Biology; (170.3660) Light propagation in tissues; (170.5380) Physiology
24.  Modulating the tumor microenvironment to increase radiation responsiveness 
Cancer biology & therapy  2009;8(21):1994-2001.
Radiosensitivity can be influenced both by factors intrinsic and extrinsic to the cancer cell. One of the factors in the tumor microenvironment (TME) extrinsic to the cancer cell that can affect radiosensitivity is oxygenation. Severely hypoxic cells require a 2–3 fold higher dose of radiation to achieve the same level of cell killing as do well-oxygenated cells. Other elements in the microenvironment that may influence tumor radiosensitivity are the response of stromal cells to radiation and the expression of factors such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 (HIF-1). There are currently several classes of agents that may increase tumor radiosensitivity by modulating the TME. Pre-clinical evidence indicates that inhibition of VEGF may increase local control after radiation. Several mechanisms have been postulated to explain this including radiosensitization of tumor endothelial cells, prevention of the establishment of new vasculature post-radiation, and increased oxygenation secondary to vascular normalization. Agents targeting HIF-1 also increase local control after radiation in pre-clinical models. This may occur via indirect inhibition of VEGF, which is a downstream target of HIF-1, or by VEGF-independent means. When combined with radiation, the EGFR inhibitor cetuximab improves local control and survival in patients with head and neck cancer. Pre-clinical data indicate that EGFR inhibitors can increase the intrinsic radiosensitivity of cancer cells. They can also improve tumor blood flow and oxygenation, which may increase extrinsic radiosensitivity. One of the pathways downstream of EGFR that may contribute to this effect is the PI3K/Akt pathway. Agents that directly inhibit this pathway improve blood flow and increase tumor oxygenation in pre-clinical models. The challenge remains to obtain clinical data from patients showing that modulation of the TME is an important mechanism by which biological agents can radiosensitize tumors and then to utilize this information to optimize therapy.
PMCID: PMC3965173  PMID: 19823031
radiation; radiosensitization; vascular normalization; EGFR; VEGF; HIF; PI3 kinase; Akt; tumor microenvironment
25.  Noninvasive Measurement of Cerebral Blood Flow and Blood Oxygenation Using Near-Infrared and Diffuse Correlation Spectroscopies in Critically Brain-Injured Adults 
Neurocritical care  2010;12(2):173-180.
Background
This study assesses the utility of a hybrid optical instrument for noninvasive transcranial monitoring in the neurointensive care unit. The instrument is based on diffuse correlation spectroscopy (DCS) for measurement of cerebral blood flow (CBF), and near-infrared spectroscopy (NIRS) for measurement of oxy- and deoxy-hemoglobin concentration. DCS/NIRS measurements of CBF and oxygenation from frontal lobes are compared with concurrent xenon-enhanced computed tomography (XeCT) in patients during induced blood pressure changes and carbon dioxide arterial partial pressure variation.
Methods
Seven neurocritical care patients were included in the study. Relative CBF measured by DCS (rCBFDCS), and changes in oxy-hemoglobin (ΔHbO2), deoxy-hemoglobin (ΔHb), and total hemoglobin concentration (ΔTHC), measured by NIRS, were continuously monitored throughout XeCT during a baseline scan and a scan after intervention. CBF from XeCT regions-of-interest (ROIs) under the optical probes were used to calculate relative XeCT CBF (rCBFXeCT) and were then compared to rCBFDCS. Spearman’s rank coefficients were employed to test for associations between rCBFDCS and rCBFXeCT, as well as between rCBF from both modalities and NIRS parameters.
Results
rCBFDCS and rCBFXeCT showed good correlation (rs = 0.73, P = 0.010) across the patient cohort. Moderate correlations between rCBFDCS and ΔHbO2/ΔTHC were also observed. Both NIRS and DCS distinguished the effects of xenon inhalation on CBF, which varied among the patients.
Conclusions
DCS measurements of CBF and NIRS measurements of tissue blood oxygenation were successfully obtained in neurocritical care patients. The potential for DCS to provide continuous, noninvasive bedside monitoring for the purpose of CBF management and individualized care is demonstrated.
doi:10.1007/s12028-009-9305-x
PMCID: PMC2844468  PMID: 19908166
Near-infrared spectroscopy; Diffuse correlation spectroscopy; Cerebral blood flow; Xenon CT; Neurocritical care

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