New Hemodynamic Parameters in Peri-Operative and Critical Care-Challenges in Translation.

Hemodynamic monitoring technologies are evolving continuously-a large number of bedside monitoring options are becoming available in the clinic. Methods such as echocardiography, electrical bioimpedance, and calibrated/uncalibrated analysis of pulse contours are becoming increasingly common. This is leading to a decline in the use of highly invasive monitoring and allowing for safer, more accurate, and continuous measurements. The new devices mainly aim to monitor the well-known hemodynamic variables (e.g., novel pulse contour, bioreactance methods are aimed at measuring widely-used variables such as blood pressure, cardiac output). Even though hemodynamic monitoring is now safer and more accurate, a number of issues remain due to the limited amount of information available for diagnosis and treatment. Extensive work is being carried out in order to allow for more hemodynamic parameters to be measured in the clinic. In this review, we identify and discuss the main sensing strategies aimed at obtaining a more complete picture of the hemodynamic status of a patient, namely: (i) measurement of the circulatory system response to a defined stimulus; (ii) measurement of the microcirculation; (iii) technologies for assessing dynamic vascular mechanisms; and (iv) machine learning methods. By analyzing these four main research strategies, we aim to convey the key aspects, challenges, and clinical value of measuring novel hemodynamic parameters in critical care.

Modulation of Pulse Propagation and Blood Flow via Cuff Inflation-New Distal Insights.

In standard critical care practice, cuff sphygmomanometry is widely used for intermittent blood pressure (BP) measurements. However, cuff devices offer ample possibility of modulating blood flow and pulse propagation along the artery. We explore underutilized arrangements of sensors involving cuff devices which could be of use in critical care to reveal additional information on compensatory mechanisms. In our previous work, we analyzed the response of the vasculature to occlusion perturbations by means of observations obtained non-invasively. In this study, our aim is to (1) acquire additional insights by means of invasive measurements and (2) based on these insights, further develop cuff-based measurement strategies. Invasive BP experimental data is collected downstream from the cuff in two patients monitored in the OR. It is found that highly dynamic processes occur in the distal arm during cuff inflation. Mean arterial pressure increases in the distal artery by 20 mmHg, leading to a decrease in pulse transit time by 20 ms. Previous characterizations neglected such distal vasculature effects. A model is developed to reproduce the observed behaviors and to provide a possible explanation of the factors that influence the distal arm mechanisms. We apply the new findings to further develop measurement strategies aimed at acquiring information on pulse arrival time vs. BP calibration, artery compliance, peripheral resistance, artery-vein interaction.

Towards continuous non-invasive blood pressure measurements-interpretation of the vasculature response to cuff inflation.

Blood pressure (BP) surrogates, such as pulse transit time (PTT) or pulse arrival time (PAT), have been intensively explored with the goal of achieving cuffless, continuous, and accurate BP inference. In order to estimate BP, a one-point calibration strategy between PAT and BP is typically used. Recent research focuses on advanced calibration procedures exploiting the cuff inflation process to improve calibration robustness by active and controlled modulation of peripheral PAT, as measured via plethysmograph (PPG) and electrocardiogram (ECG) combination. Such methods require a detailed understanding of the mechanisms behind the vasculature's response to cuff inflation; for this, a model has recently been developed to infer the PAT-BP calibration from measured cuff-induced vasculature changes. The model, while promising, is still preliminary and only partially validated; in-depth analysis and further developments are still needed. Therefore, this work aims to improve our understanding of the cuff-vasculature interaction in this model; we seek to define potential opportunities and to highlight which aspects may require further study. We compare model behaviors with clinical data samples based on a set of observable characteristics relevant for BP inference and calibration. It is found that the observed behaviors are qualitatively well represented with the current simulation model and complexity, with limitations regarding the prediction of the onset of the distal arm dynamics and behavior changes at high cuff pressures. Additionally, a sensitivity analysis of the model's parameter space is conducted to show the factors that influence the characteristics of its observable outputs. It was revealed that easily controllable experimental variables, such as lateral cuff length and inflation rate, have a significant impact on cuff-induced vasculature changes. An interesting dependency between systemic BP and cuff-induced distal PTT change is also found, revealing opportunities for improved methods for BP surrogate calibration. However, validation via patient data shows that this relation does not hold for all patients, indicating required model improvements to be validated in follow up studies. These results provide promising directions to improve the calibration process featuring cuff inflation towards accurate and robust non-invasive blood pressure estimation.

On the value of MRI for improved understanding of cuff-based oscillometric measurements.

Blood pressure (BP) is a key parameter in critical care and in cardiovascular disease management. BP is typically measured via cuff-based oscillometry. This method is highly inaccurate in hypo- and hypertensive patients. Improvements are difficult to achieve because oscillometry is not yet fully understood; many assumptions and uncertainties exist in models describing the process by which arterial pulsations become expressed within the cuff signal. As a result, it is also difficult to estimate other parameters via the cuff such as arterial stiffness, cardiac output and pulse wave velocity (PWV)-BP calibration. Many research modalities have been employed to study oscillometry (ultrasound, computer simulations, ex-vivo studies, measurement of PWV, mechanical analysis). However, uncertainties remain; additional investigation modalities are needed. In this study, we explore the extent to which MRI can help investigate oscillometric assumptions. Four healthy volunteers underwent a number of MRI scans of the upper arm during cuff inflation. It is found that MRI provides a novel perspective over oscillometry; the artery, surrounding tissue, veins and the cuff can be simultaneously observed along the entire length of the upper arm. Several existing assumptions are challenged: tissue compression is not isotropic, arterial transmural pressure is not uniform along the length of the cuff and propagation of arterial pulsations through tissue is likely impacted by patient-specific characteristics (vasculature position and tissue composition). Clinical Relevance- The cuff interaction with the vasculature is extremely complex; existing models are oversimplified. MRI is a valuable tool for further development of cuff-based physiological measurements.

Modulation of pulse travel and blood flow during cuff inflation- An experimental case study.

The blood pressure (BP) cuff can be used to modulate blood flow and propagation of pressure pulse along the artery. In our previous work, we researched methods to adapt cuff modulation techniques for pulse transit time vs. BP calibration and for measurement of other hemodynamic indices of potential interest to critical care, such as arterial compliance. A model characterized the response of the vasculature located directly under the cuff, but assumed that no significant changes occur in the distal vasculature.This study has been tailored to gain insights into the response of distal BP and pulse transit time to cuff inflation. Invasive BP data collected downstream from the cuff demonstrates that highly dynamic processes occur in the distal arm during cuff inflation. Mean arterial pressure increases in the distal artery by up to 20 mmHg, leading to a decrease in pulse transit time of up to 20 ms. Clinical Relevance: Such significant changes need to be taken into account in order to improve non-invasive BP estimations and to enable inference of other hemodynamic parameters from vasculature response to cuff inflation. A simple model is developed in order to reproduce the observed behaviors. The lumped-parameter model demonstrates opportunities for cuff modulation measurements which can reveal information on parameters such as systemic resistance, distal arterial, venous compliances and artery-vein interaction.

Improved ultrasound transducer positioning by fetal heart location estimation during Doppler based heart rate measurements.

OBJECTIVE: Doppler ultrasound (US) is the most commonly applied method to measure the fetal heart rate (fHR). When the fetal heart is not properly located within the ultrasonic beam, fHR measurements often fail. As a consequence, clinical staff need to reposition the US transducer on the maternal abdomen, which can be a time consuming and tedious task. APPROACH: In this article, a method is presented to aid clinicians with the positioning of the US transducer to produce robust fHR measurements. A maximum likelihood estimation (MLE) algorithm is developed, which provides information on fetal heart location using the power of the Doppler signals received in the individual elements of a standard US transducer for fHR recordings. The performance of the algorithm is evaluated with simulations and in vitro experiments performed on a beating-heart setup. MAIN RESULTS: Both the experiments and the simulations show that the heart location can be accurately determined with an error of less than 7 mm within the measurement volume of the employed US transducer. SIGNIFICANCE: The results show that the developed algorithm can be used to provide accurate feedback on fetal heart location for improved positioning of the US transducer, which may lead to improved measurements of the fHR.

Expression of the coxsackie adenovirus receptor in normal prostate and in primary and metastatic prostate carcinoma: potential relevance to gene therapy.

Adenovirus-based gene therapy may provide an alternative mode of treatment for prostate cancer, especially for late-stage and androgen-independent disease for which there is currently no effective treatment. Efficient adenovirus infection of target cells depends upon the presence of the coxsackie adenovirus cell surface receptor, CAR, which is the primary receptor for group C adenoviruses and is important for the attachment of adenovirus to the cell membrane. To evaluate the potential efficacy of adenoviral therapy for prostate cancer, we evaluated CAR expression in normal prostate tissue and in prostate carcinoma of increasing Gleason grades in paraffin-embedded, archival tissues using a polyclonal antibody raised against human CAR. Immunohistochemical analysis of benign prostate epithelia demonstrated intense luminal and lateral cell membrane staining. There was a statistically significant difference in CAR membrane expression with respect to Gleason score. In addition, metastatic prostate specimens demonstrated strong membrane staining for CAR. Adenovirus therapy may, therefore, provide an alternate modality in the treatment of prostate cancer and may be especially efficacious in the treatment of metastatic disease.

Cuff-pressure induced PAT changes - modelling and experimental verification towards calibration of blood pressure surrogates.

Arterial Blood Pressure (ABP) is one of the most often measured vital parameters in daily clinical practice. State-of-the-Art non-invasive ABP measurement technologies have obvious limitations and are still mainly based on uncomfortable techniques by complete or partial occlusions of arteries. Additionally, embodiments are bulky, difficult to apply for the layman, or provide only intermittent measurements. We have been investigating the pulse arrival time (PAT) and pulse transit time (PTT) methodology for unobtrusive blood pressure (BP) measurements. However, BP surrogates like PAT or PTT require a calibration step, which is currently an unresolved problem. In this paper we report on our investigations using cuff-pressure induced PAT changes in order to provide insights in the BP-PAT sensitivities for subjects at rest.

Comparison of pulse wave velocity derived from accelerometer and reflective photo-plethysmography signals placed at the carotid and femoral artery.

Carotid - femoral pulse wave velocity is an established measure to assess cardiovascular risk and an interesting surrogate parameter towards non-invasive continuous blood pressure inference. Due to progress in sensing technologies for wearable wrist worn sensors, there are low cost sensor combinations of photo-plethysmography and high fidelity accelerometers available offering access to pulse information from larger arteries complemented by blood volume changes in the superficial tissue. In this work we compare pulse wave velocities derived from accelerometer and reflective photo-plethysmography signals placed at the carotid and femoral artery. We discuss the different underlying physiological processes for the two sensing principles and present experimental results obtained in a study with healthy subjects.

Ultrasound transducer positioning aid for fetal heart rate monitoring.

Fetal heart rate (fHR) monitoring is usually performed by Doppler ultrasound (US) techniques. For reliable fHR measurements it is required that the fetal heart is located within the US beam. In clinical practice, clinicians palpate the maternal abdomen to identify the fetal presentation and then the US transducer is fixated on the maternal abdomen where the best fHR signal can be obtained. Finding the optimal transducer position is done by listening to the strength of the Doppler audio output and relying on a signal quality indicator of the cardiotocographic (CTG) measurement system. Due to displacement of the US transducer or displacement of the fetal heart out of the US beam, the fHR signal may be lost. Therefore, it is often necessary that the obstetrician repeats the tedious procedure of US transducer positioning to avoid long periods of fHR signal loss. An intuitive US transducer positioning aid would be highly desirable to increase the work flow for the clinical staff. In this paper, the possibility to determine the fetal heart location with respect to the transducer by exploiting the received signal power in the transducer elements is shown. A commercially available US transducer used for fHR monitoring is connected to an US open platform, which allows individual driving of the elements and raw US data acquisition. Based on the power of the received Doppler signals in the transducer elements, the fetal heart location can be estimated. A beating fetal heart setup was designed and realized for validation. The experimental results show the feasibility of estimating the fetal heart location with the proposed method. This can be used to support clinicians in finding the optimal transducer position for fHR monitoring more easily.

Integration of high-resolution array comparative genomic hybridization analysis of chromosome 16q with expression array data refines common regions of loss at 16q23-qter and identifies underlying candidate tumor suppressor genes in prostate cancer.

We have constructed a high-resolution genomic microarray of human chromosome 16q, and used it for comparative genomic hybridization analysis of 16 prostate tumors. We demarcated 10 regions of genomic loss between 16q23.1 and 16qter that occurred in five or more samples. Mining expression array data from four independent studies allowed us to identify 11 genes that were frequently underexpressed in prostate cancer and that co-localized with a region of genomic loss. Quantitative expression analyses of these genes in matched tumor and benign tissue from 13 patients showed that six of these 11 (WWOX, WFDC1, MAF, FOXF1, MVD and the predicted novel transcript Q9H0B8 (NM_031476)) had significant and consistent downregulation in the tumors relative to normal prostate tissue expression making them candidate tumor suppressor genes.

Chemokines involved in tumor promotion and dissemination in patients with renal cell cancer.

BACKGROUND: Chemokines play a critical role in tumor initiation, progression, and metastasis and have been associated with poor prognosis in diverse malignancies. The prognostic impact of chemokines for renal cell cancer (RCC) remains to be defined. METHODS: Patients diagnosed with RCC and operated between 07/07 and 05/11 were differentially assessed for expression profiles of a series of chemokines and their receptors by RT-qPCR and Western Blot analysis (tumor and adjacent normal tissue, n=37) and by Luminex for corresponding serum expression levels. Results were statistically correlated with clinicopathologic parameters. RESULTS: Gene expression of CCL2, CCR7, CXCL12, CXCR3, CXCR5 and CX3CL1 chemokines was significantly down-regulated in tumor compared to normal tissue. The gene profile for CCR6 was positively correlated with tumor size and stage. A positive linear correlation was found between CXCL12 and tumor stage as well as between CX3CR1 and C-reactive protein. In contrast to clear cell RCCs those of a chromophobe type showed a significantly down-regulated gene expression for CCR6, CCL20, and CXCL12. The CXCR7 serum level was significantly increased in patients with tumor-related mortality during postoperative follow-up. CONCLUSIONS: Chemokines may serve as novel diagnostic and prognostic biomarkers for RCC. Studies on larger collectives are required for further assessment of potential clinical application.

High-grade prostatic intraepithelial neoplasia in patients with prostate cancer: MR and MR spectroscopic imaging features--initial experience.

PURPOSE: To retrospectively determine the magnetic resonance (MR) and MR spectroscopic imaging features of high-grade prostatic intraepithelial neoplasia (HGPIN) in patients with prostate cancer. MATERIALS AND METHODS: Approval of the committee on human research was obtained, with a waiver of consent for this HIPAA-compliant study. Endorectal MR imaging and MR spectroscopic imaging were performed in 48 men (mean age, 59 years; range, 47-75 years) prior to radical prostatectomy for prostate cancer. T2-weighted signal intensity and metabolic ratios of peripheral zone HGPIN foci of 6 mm or greater in diameter were recorded by two readers with knowledge of step-section histopathologic findings using areas of confirmed normal and cancerous peripheral zone tissue for comparison. A random effects statistical model was used to compare metabolic ratios from normal, HGPIN, and cancer voxels. RESULTS: A total of 123 peripheral zone HGPIN foci with a mean diameter of 3 mm (range, 1-28 mm) were identified in 37 (77%) patients, but only 20 foci in 14 patients had a diameter of 6 mm or greater. Six foci were excluded, yielding 14 large HGPIN lesions from 11 patients in the final statistical analysis. The larger HGPIN foci were not associated with any focal reduction in T2-weighted signal intensity but demonstrated metabolic findings intermediate between normal and cancerous tissue; the mean ratios of choline (Cho) to creatine (Cr) for normal, HGPIN, and cancer were 0.92, 1.75, and 1.99, respectively, (P < .01), and the corresponding ratios of Cho plus Cr to citrate were 0.34, 0.50, and 0.78 (P < .01). CONCLUSION: HGPIN is metabolically intermediate between normal peripheral zone tissue and prostate cancer at MR spectroscopic imaging but does not manifest any MR imaging abnormality and is rarely of sufficient size to cause substantial error in evaluation of peripheral zone tumor extent in patients with prostate cancer.

Prostate cancer: endorectal MR imaging and MR spectroscopic imaging--distinction of true-positive results from chance-detected lesions.

PURPOSE: To retrospectively investigate size criteria for the identification of chance-detected lesions at endorectal magnetic resonance (MR) imaging and MR spectroscopic imaging of prostate cancer. MATERIALS AND METHODS: Approval of the committee on human research and written informed consent were obtained. This study was HIPAA compliant. Endorectal MR imaging and MR spectroscopic imaging were performed with a 1.5-T MR imager in 48 men with a mean age of 59 years (age range, 47-75 years) prior to radical prostatectomy. Two independent readers recorded the size and location of all suspected peripheral zone tumor nodules on MR images alone and on images obtained with combined MR imaging and MR spectroscopic imaging. Nodules detected at MR imaging were classified as matched lesions if tumor was present in the same location at step-section histopathologic review. For all matched lesions, kappa values were calculated to examine agreement between measured and actual tumor size. Lesions that were overmeasured at MR imaging with a kappa value of less than 0.2 were considered chance-detected lesions. RESULTS: At MR imaging, two of 27 and four of 35 matched lesions for readers 1 and 2, respectively, were chance-detected lesions. The corresponding numbers of lesions at combined MR imaging and MR spectroscopic imaging were one of 21 and one of 31, respectively. In all but two cases, the measured diameter of chance-detected lesions was more than twice that of the diameter at histopathologic analysis. By using this diameter threshold to distinguish true-positive results, the mean diameter of detected tumors at histopathologic analysis was 15 mm compared with 4 mm for both undetected and chance-detected tumors (P < .05). CONCLUSION: To ensure uniformity in the comparison of scientific studies, peripheral zone tumors detected at MR imaging and MR spectroscopic imaging of the prostate that are in the same location as tumors detected at histopathologic review should be considered chance-detected lesions if the MR transverse diameter is more than twice the histopathologic transverse diameter.

Quantitative analysis of prostate metabolites using 1H HR-MAS spectroscopy.

A method was developed to quantify prostate metabolite concentrations using (1)H high-resolution magic angle spinning (HR-MAS) spectroscopy. T(1) and T(2) relaxation times (in milliseconds) were determined for the major prostate metabolites and an internal TSP standard, and used to optimize the acquisition and repetition times (TRs) at 11.7 T. At 1 degrees C, polyamines (PAs; T(1mean) = 100 +/- 13, T(2mean) = 30.8 +/- 7.4) and citrate (Cit; T(1mean) = 237 +/- 39, T(2mean) = 68.1 +/- 8.2) demonstrated the shortest relaxation times, while taurine (Tau; T(1mean) = 636 +/- 78, T(2mean) = 331 +/- 71) and choline (Cho; T(1mean) = 608 +/- 60, T(2mean) = 393 +/- 81) demonstrated the longest relaxation times. Millimolal metabolite concentrations were calculated for 60 postsurgical tissues using metabolite and TSP peak areas, and the mass of tissue and TSP. Phosphocholine plus glycerophosphocholine (PC+GPC), total choline (tCho), lactate (Lac), and alanine (Ala) concentrations were higher in prostate cancer ([PC+GPC](mean) = 9.34 +/- 6.43, [tCho](mean) = 13.8 +/- 7.4, [Lac](mean) = 69.8 +/- 27.1, [Ala](mean) = 12.6 +/- 6.8) than in healthy glandular ([PC+GPC](mean) = 3.55 +/- 1.53, P < 0.01; [tCho](mean) = 7.06 +/- 2.36, P < 0.01; [Lac](mean) = 46.5 +/- 17.4, P < 0.01; [Ala](mean) = 8.63 +/- 4.91, P = 0.051) and healthy stromal tissues ([PC+GPC](mean) = 4.34 +/- 2.46, P < 0.01; [tCho](mean) = 7.04 +/- 3.10, P < 0.01; [Lac](mean) = 45.1 +/- 18.6, P < 0.01; [Ala](mean) = 6.80 +/- 2.95, P < 0.01), while Cit and PA concentrations were significantly higher in healthy glandular tissues ([Cit](mean) = 43.1 +/- 21.2, [PAs](mean) = 18.5 +/- 15.6) than in healthy stromal ([Cit](mean) = 16.1 +/- 5.6, P < 0.01; [PAs](mean) = 3.15 +/- 1.81, P < 0.01) and prostate cancer tissues ([Cit](mean) = 19.6 +/- 12.7, P < 0.01; [PAs](mean) = 5.28 +/- 5.44, P < 0.01). Serial spectra acquired over 12 hr indicated that the degradation of Cho-containing metabolites was minimized by acquiring HR-MAS data at 1 degree C compared to 20 degrees C.

Proton HR-MAS spectroscopy and quantitative pathologic analysis of MRI/3D-MRSI-targeted postsurgical prostate tissues.

Proton high-resolution magic angle spinning ((1)H HR-MAS) NMR spectroscopy and quantitative histopathology were performed on the same 54 MRI/3D-MRSI-targeted postsurgical prostate tissue samples. Presurgical MRI/3D-MRSI targeted healthy and malignant prostate tissues with an accuracy of 81%. Even in the presence of substantial tissue heterogeneity, distinct (1)H HR-MAS spectral patterns were observed for different benign tissue types and prostate cancer. Specifically, healthy glandular tissue was discriminated from prostate cancer based on significantly higher levels of citrate (P = 0.04) and polyamines (P = 0.01), and lower (P = 0.02) levels of the choline-containing compounds choline, phosphocholine (PC), and glycerophosphocholine (GPC). Predominantly stromal tissue lacked both citrate and polyamines, but demonstrated significantly (P = 0.01) lower levels of choline compounds than cancer. In addition, taurine, myo-inositol, and scyllo-inositol were all higher in prostate cancer vs. healthy glandular and stromal tissues. Among cancer samples, larger increases in choline, and decreases in citrate and polyamines (P = 0.05) were observed with more aggressive cancers, and a MIB-1 labeling index correlated (r = 0.62, P = 0.01) with elevated choline. The elucidation of spectral patterns associated with mixtures of different prostate tissue types and cancer grades, and the inclusion of new metabolic markers for prostate cancer may significantly improve the clinical interpretation of in vivo prostate MRSI data.