This work is supported by the Instituto de Salud Carlos III of the Spanish Government and the European Regional Development Fund (ERDF) through the PI14/02161 and the DTS15/00153 research projects and Xunta de Galicia, Centro singular de investigaci&#243;n de Galicia accreditation 2016-2019 Ref. ED431G/01; and Grupos de Referencia Competitiva, Ref. ED431C 2016-047.

All procedures were conducted under institutionally approved protocols with patient consent.
1. Patient and Checkup Registration
Note: See Figure 1.
<ol>
	<li>Go to http://www.varpa.es/Hydra/&#160;using any modern web browser.</li>
	<li>Use an existing account associated with a doctor to Log In to the Hydra web tool.</li>
	<li>Fill in the patient registration form including patient code, date of birth, gender and ethnicity to register a new patient. Click on the include button to fill in the family background of premature CVDs. Click on the Next button to move forward to introduce the first checkup. 
	Note: These global parameters are included in patient enrollment and the information added from here relates to a specific checkup.</li>
	<li>Add a new checkup. 
	Note: The input data is organized in thematic blocks. Each block includes the option to be hidden or visible. If all the information of a block is unknown, use the hidden option. Keep the option NR/DK (no response/do not know) in the fields that do not match any case. See Figure 2.
	<ol>
		<li>Fill in the checkup date; the current date used by default.</li>
		<li>Fill in the block corresponding to patient habits such as smoking, exercise, diet, etc.</li>
		<li>Fill in the block corresponding to precedents of cardiovascular illness such as cardiopathy, acute aortic dissection, strokes, etc.</li>
		<li>Fill in the block corresponding to concomitant illnesses such as diabetes, obesity, nephropathy, etc.</li>
		<li>Fill in the block corresponding to urological records with the information related to erectile malfunction, prostatic hyperplasia, etc. 
		Note: This block is enabled in the checkup form when the gender of the patient is male.</li>
		<li>Fill in the block corresponding to gynecological records with the information related to hypertension in pregnancy, menopause, the age of menopause, surgical menopause, etc. 
		Note: This block is enabled in the checkup form when the gender of the patient is female.</li>
		<li>Fill in the block corresponding to anti-hypertensive treatment taken before the checkup date including the treatment type, the schedule, and the dose.</li>
		<li>Fill in the block corresponding to treatments that can alter blood pressure such as vasoconstrictors, oral contraceptives, corticosteroids, etc.</li>
		<li>Fill in the block corresponding to any other treatments such as fibrates, statins, insulin, etc. 
		Note: The options to input the timetable, dose or type are only enabled when each specific treatment is selected.</li>
		<li>Click on the Next button to move forward to the second checkup form relating to the physical examination and clinical analysis. 
		Note: See Figure 3.</li>
		<li>Fill in the block corresponding to the physical examination with the information related to height, weight, circumference of the dominant arm, etc. 
		Note: The body mass index and the waist height index are automatically computed from the previous data.</li>
		<li>Fill in the block corresponding to blood pressure recordings such as systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse, including 1 measurement standing and 3 measurements sitting. Check the boxes related to abdominal murmurs, carotid murmur, etc. 
		Note: The mean of the 3 repetitions of sitting blood pressure measurements is automatically computed.</li>
		<li>Fill in the block corresponding to the ABPM recording. Upload the ABPM file and complete the information related to the time during which the patient wore the monitor such as the hours and quality of sleep, the time of going to bed and waking up, etc. 
		Note: The ABPM upload is mandatory for the block related to ABPM information to be included. If there is no ABPM file available, click on the hide button.</li>
		<li>Fill in the block corresponding to biological/analytical recordings with the information related to blood analysis such as glycemia, creatinine, ferritin, microalbuminuria, etc. 
		Note: The standard units for the parameters are indicated on the checkup form, as reference.</li>
		<li>Fill in the block corresponding to the electrocardiogram recording with the information related to the different wave intensities, arrhythmia, ischemic cardiopathy, etc.</li>
		<li>Fill in the block corresponding to the echocardiogram recording with the information related to the interventricular septum, left ventricle diameter in systole, posterior wall of the left ventricle, etc.</li>
		<li>Fill in the block corresponding to other measurements such as pulse wave velocity, carotid stenosis, ankle-arm index, etc.</li>
		<li>Click on the End button to record the checkup associated with the corresponding patient on the platform. 
		Note: The platform moves forward to the checkup page that includes all the introduced data. See Figure 4.</li>
		<li>Click on the Edit button to add new information or update the introduced data throughout the checkup forms. Click on the End button to go back to the checkup page.</li>
		<li>Click on the Implemented treatment button to move forward to the form and prescribe any specific treatment.</li>
		<li>Fill in the block corresponding to anti-hypertensive treatment including the dose, the schedule and the type of the prescribed treatment.</li>
		<li>Fill in the block corresponding to treatments that can affect blood pressure such as vasoconstrictors, oral contraceptives, corticosteroids, etc.</li>
		<li>Fill in the block corresponding to other treatments such as fibrates, statins, insulin, etc.</li>
		<li>Click on the Definitive report button to generate the final report. It proceeds to the checkup report including all the introduced data and the prescribed treatment.</li>
	</ol>
	</li>
	<li>Update patient profile and perform checkup management.
	<ol>
		<li>Click on the Find patient link on the main menu bar and insert the patient code, or press the List patients link and select the patient code to proceed to the profile of a registered patient.</li>
		<li>Click on the Update button to revise and update any patient information (except the patient code, which is fixed) in the patient profile.</li>
		<li>Click on the Revise checkup link to access the checkup report (see step 4.2).</li>
		<li>Click on the Smart report link to access a brief checkup overview (see step 4.3).</li>
		<li>Click on the ABPM report link to access an overview of the ABPM results (see step 4.4).</li>
		<li>Click on the Edit link to add new information or modify the information introduced in the checkup. 
		Note: This option is available only before the generation of the definitive report.</li>
		<li>Click on the New checkup button to add a new checkup for the patient. 
		Note: Consecutive checkups are automatically prefilled with the information details that were included in the previous revision. See Figure 5.</li>
	</ol>
	</li>
</ol>
2. Risk Stratification Tables
Note: The risk stratification service provides an automatic computation of the CV risk factor based upon various risk stratification tables that are recommended in the guidelines of the European Society of Hypertension/European Society of Cardiology (ESH/ESC)22. For each of the tables, the CV risk factor is computed and recorded based upon various parameters that are uploaded in the patient profile throughout the steps of the checkup data input. The higher or lower importance of each of the tables in the analysis is provided by the specialist while ensuring that each designed stratification table pays special attention to the specific conditions of the patient.
<ol>
	<li>Click on the Find patient link and insert the patient code or click on the List patients link and select the patient code for a patient with existing registered checkups.</li>
	<li>From the list of checkups, click on the Revise checkup link to access the checkup report and go to the block of risk stratification tables.</li>
	<li>Click on the ESH/ESC table link to access the table page. Check the highlighted cell to get the qualitative level of cardiovascular risk. Check the recommendations and possible antihypertensive treatment related to the resulting risk. Click on the Go back link to access the general checkup report. 
	Note: This decision table uses the SBP and DBP measurements together with several risk factors and diseases (age, abdominal obesity, dyslipidemia, metabolic syndrome, etc.) to provide the CV risk factor as well as recommendations or treatment23.</li>
	<li>Click on the MS table link to access the Metabolic Syndrome (MS) table page. Check the presence of MS on the basis of the Adult Treatment Panel (ATP) III criterion. Check the presence of MS on the basis of the International Diabetes Fund (IDF) 2005 criterion. Click on the Go back link to access the general checkup report. 
	Note: This table uses the information related to abdominal obesity, triglyceridemia, c-HDL, BP and fasting glucose24. ATP III criterion indicates the presence of MS if 3 of the above measures are outside the tolerance levels. According to IDF 2005 criterion, MS is determined by the presence of abdominal obesity together with 2 of the other measures outside the tolerance levels.</li>
	<li>Click on the Score table link to access the Systematic Coronary Risk Evaluation (SCORE) table page. Check the highlighted cell to obtain the 10-year risk of fatal cardiovascular events. Check the color of the highlighted cell in the legend to obtain the qualitative level related to the risk. Click on the Go back link to access the general checkup report. 
	Note: This table uses information related to age, gender, SBP, smoking, and cholesterol25.</li>
	<li>Click on the Framingham table link to access the table page. Check the highlighted cell in the last table to obtain the 10-year risk of suffering a coronary event (angina, heart attack, with or without symptoms, fatal or not). Click on the Go back link to access the general checkup report. 
	Note: This table uses information related to the parameters of age, gender, smoking, diabetes, cholesterol, cholesterol HDL, and BP26. The highlighted cells indicate the contribution of each category to the final risk.</li>
</ol>
3. ABPM Analysis
Note: ABPM is a common test that allows the monitoring of the patient&#8217;s blood pressure throughout their daytime/nocturnal routine9. The device selected for recording ABPM measurements (see the Table of Materials) is among the few BP monitors that are officially validated by international organizations such as the British Hypertension Society (BHS) or the ESH.
<ol>
	<li>Put the BP monitor on the patient and check that it is operating properly by taking an initial manual measurement. Instruct the patient on how to obtain the measurements manually before going to sleep and on waking up in order to delimit the day and night recordings.</li>
	<li>After the recording period, remove the BP monitor from the patient and retrieve the ABPM file. Upload the ABMP file to the block of ABPM measurements of an existing or a new checkup related to the patient (step 1.4.13). 
	Note: The monitor remains connected throughout a period of time (usually 24h or 48h) and the measurements are regularly recorded at predefined intervals (typically 15 or 30 minutes).</li>
	<li>Perform ABPM analysis.
	<ol>
		<li>Click on the Find patient link and insert the patient code, or click on the List patients link and select the patient code of a patient with any registered checkup containing ABPM data.</li>
		<li>Click on the Revise checkup link to access the checkup report and go to the block of ABPM analysis.</li>
		<li>Click on the ABPM link to access the ABPM information display.</li>
		<li>Check the rate of valid records in the general information section to ensure that the results extracted from the ABPM file are reliable.</li>
		<li>Check the information regarding the period of time during which the patient wore the monitor such as the number of hours and quality of sleep, the time of going to sleep and waking up, etc.</li>
		<li>Check the ABPM map including the graphical representation of all the recordings, such as the SBP, DBP and pulse as well as the areas under or over the maximum normal levels for each measurement.</li>
		<li>Click on the buttons for 48h, 24h (i) or 24h (ii) to change the visualization mode for the 48 h ABPM files.</li>
		<li>Click on the means button to switch the visualization mode to an even representation of the measurements. 
		Note: This visualization mode computes each point from the average among consecutive measurements in the raw data.</li>
		<li>Check the additional information extracted from the original data such as the means and standard deviations of SBP, DBP, pulse rate and pulse pressure (the difference between SBP and DBP).</li>
		<li>Check the parameters regarding BP evolution that were automatically computed by the tool: nocturnal BP drop, sleep thought, pre-waking morning surge and day/night quotient for SBP and DBP measures.</li>
		<li>Check the summary table that contains the automatically computed areas under or over the maximum clinically defined thresholds for the nocturnal and diurnal measurements of SBP, DBP, and pulse pressure. 
		Note: Furthermore, the ABPM service also calculates the circadian profile from the relation between the daytime and nocturnal BP&#178;&#179;. This profile allows cardiovascular risks to be determined by analyzing the presence of BP deviations. The smart report (step 4.4) and the ABPM report (step 4.5) contain the information related to the circadian profile.</li>
	</ol>
	</li>
</ol>
4. Clinical Reports
Note: The report service provides a set of reports that gather all the relevant information to support the clinical decision-making process, helping physicians in their clinical practice and promoting collaboration among experts.
<ol>
	<li>Click on the Find patient link and insert the patient code, or click on the List patients link and select the code of a patient with any registered checkup.</li>
	<li>Click on the Revise checkup link to access the full checkup report which contains all the data recorded during the checkup registration process grouped into the various categories.</li>
	<li>Click on the ABPM link to access the data extracted from the ABPM analysis. Click on the specific link of each risk stratification table to review all the information regarding the computation of the risk value. Click on the Go back link to return to the patient page. 
	Note: The parameters that are outside their normal levels are shown in red in order to facilitate their identification. In the same way, the Yes/No fields are also marked with green or red icons for an intuitive visualization of the normal and pathological cases, respectively.</li>
	<li>Click on the Smart report link to access a brief overview of the checkup which only contains essential information.
	<ol>
		<li>Check the summary of the risk stratification tables, containing the results that were extracted from each table. Check the ABPM graph included in the final report and click on the ABPM map link for further information. Click on the Go back link to return to the patient page.</li>
	</ol>
	</li>
	<li>Click on the ABPM report link to access an additional smart report, in this case focused on the ABPM information and results. Check the information corresponding to the ABPM recording such as the statistical measurements extracted from the SBP, DBP, and pulse, the areas over and under the normal values, the circadian profile, etc. Click on the Go back link to return to the patient page. 
	Note: The report service provides the option to print the reports or export to standard formats, such as PDF, making it easier to present the report to the patient or use it for discussions with other clinicians.</li>
</ol>

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The authors have nothing to disclose.

The early identification and monitoring of various cardiovascular risk factors together with an appropriate treatment are critical for the prevention of cardiovascular diseases and premature deaths. In the daily clinical routine, clinicians have to handle large amounts of diverse information to check all the different variables and parameters that affect the circulatory system. Hence, it is a tedious and time-consuming task that complicates diagnosis and treatment prescription.
The proposed pr...

Cardiovascular diseases (CVDs) are a group of disorders of the circulatory system that constitute the leading cause of disability and premature death throughout the world1,2. According to the World Health Organization (WHO), an estimated 17.7 million people died from CVDs in 2015, representing 31% of all global deaths1,2. There are many risk factors for CVDs, including behavioral factors such as tobacco use, an unhealthy diet, harmful use of alcohol and inadequate physical activity as well as physiological factors, including raised blood pressure (hypertension), high cholesterol or elevated blood glucose, among others2,3. Hypertension represents a major risk factor for premature cardiovascular disease, being responsible for a high level of cardiovascular morbidity and mortality4,5. Furthermore, it is estimated that the incidence of hypertension among adults in developed countries is almost 40%6,7,8. However, it remains widely undetected, undertreated and poorly controlled3,4.
CVD is a major public health problem which imposes a significant economic burden on any given health-care system6. Early identification of the highest cardiovascular risks and appropriate treatment can prevent clinical events and premature deaths4,5. Hence, there are noticeable health and economic gains attached to comprehensively and thoroughly tracking all these factors. The total risk of developing a CVD is determined by the combined effect of cardiovascular risk factors2,4,5, which commonly coexist and act multiplicatively. Therefore, a total-risk approach is advisable for early detection, as well as for clinical decision-making on the intensity of preventive interventions. Thus, morbidity, early mortality and disability could be reduced and the quality of life could be improved in individuals with an elevated total CVD risk2.
The diagnosis of CVDs is determined by the analysis of a wide range of parameters that are gathered by different procedures used by physicians in their clinical practice. The assessment of these parameters allows the computation of a total CV risk factor which is useful for diagnostic and treatment purposes2,4,5. In addition to the stratification of CV risks, ambulatory blood pressure monitoring (ABPM)9 also provides valuable information. The ABPM test allows the tracking of the patient&#39;s blood pressure (BP) during their daily routine, avoiding the influence of the clinical setting (white coat syndrome). Thus, a reliable set of measurements is obtained, allowing the extraction of additional information that supports the clinical decision-making process.
Therefore, the analysis of the cardiovascular system involves a large amount of data, entailing a tedious and time-consuming task that complicates diagnosis and treatment prescription. In this regard, the availability of a patient&#39;s full profile that gathers all the required data together with a set of automated services to extract the necessary information would be a significant improvement to guide clinicians in their decision-making process. Apart from this, the availability of an accessible platform that centralizes all patient information not only enables collaboration among different specialists from different locations but also allows discussion of debatable cases and provides reliable diagnoses.
In recent years, the use of computer-based applications and telemedicine has increased considerably, playing an important role in improving public health and welfare in all sectors of the population. This is due to their ability to extract relevant and useful information for the early diagnosis and treatment of several diseases10. The use of these tools improves the quality of health-care services, thus conveniently and reliably satisfying patient demand as well as reducing costs11. As a reference, the number of global imaging-based procedures has risen considerably, given the increasing availability of medical equipment and more sophisticated capture devices. Therefore, Lundberg et al.12 proposed a telemedicine tool to assess digital image quality and agreement between examiners in the field of the otorhinolaryngology. Ortega et al.13 developed SIRIUS, a computer-aided diagnosis framework for the analysis of retinal images. Novo et al.14 also presented their platform for the analysis of retinal microcirculation in combination with carotid macrocirculation.
With regard to CV assessment, there has been a steady increase in the number of tools available throughout the years. Some of the utilities are designed to predict cardiovascular disease risk &#8212; such as the tool proposed by Paredes et al.15 &#8212; or to calculate risk online by implementing the algorithm proposed by Goff et al.16 according to a guideline on the assessment of cardiovascular risk to calculate the 10-year risk of heart disease. Other systems are designed to be used with mobile phones, such as the proposal of Sufi et al.17 that identifies diseases from body sensors, the device designed by Lin et al.18 for tracking the electrocardiogram in order to detect the presence of abnormal rhythms and send an alarm, the app from Lee et al.19 for monitoring breathing and heart rate values while a person exercising or the application implemented by Kang and Park20 to manage raised blood pressure on the basis of clinical guidelines.
The available utilities are mainly designed to satisfy patient demand in specific scenarios. On the other hand, this article describes a protocol based on Hydra21, a platform focused on the analysis of the cardiovascular system, that is designed entirely to support specialists in their clinical decision-making process. This tool incorporates a set of functionalities and services that physicians require for reliable cardiovascular analysis including risk assessment, early diagnosis, treatment prescription and the monitoring of patients over time. Therefore, there is a tool for the input and management of patient data recorded in different checkups. Then, a risk stratification tool automatically provides a CV risk factor based on different risk stratification tables of reference. In addition to this, the ABPM analysis tool allows the extraction of valuable information from the analysis of blood pressure recordings over a specific period of time. Finally, the most relevant information is summarized in a set of reports that guide clinicians in diagnosis and proper treatment prescription. In this way, the described protocol leads to an improvement in complete cardiovascular analysis supporting a reliable diagnosis and proper treatment. Furthermore, the presented platform allows collaboration among experts, thereby promoting clinical research.

<table>
	<tbody>
		<tr>
			<td>Computer with color screen</td>
			<td>N/A</td>
			<td>N/A</td>
			<td></td>
		</tr>
		<tr>
			<td>Internet connection</td>
			<td>N/A</td>
			<td>N/A</td>
			<td></td>
		</tr>
		<tr>
			<td>Modern web broser</td>
			<td>N/A</td>
			<td>N/A</td>
			<td>Google Chrome, Internet Explorer, Safari, Fierfox, etc.</td>
		</tr>
		<tr>
			<td>Blood pressure monitor</td>
			<td>Spacelabs</td>
			<td>N/A</td>
			<td>Spacelabs 90217</td>
		</tr>
	</tbody>
</table>

hydra, a computer-based platform for aiding clinicians in cardiovascular analysis and diagnosis

Cardiovascular diseases (CVDs) are the leading cause of death throughout the world. The total risk of developing CVD is determined by the combined effect of different cardiovascular risk factors (e.g., diabetes, raised blood pressure, unhealthy diet, tobacco use, stress, etc.) that commonly coexist and act multiplicatively. Most CVDs can be prevented by an early identification of the highest risk factors and an appropriate treatment. The stratification of cardiovascular risk factors involves a wide range of parameters and tests that specialists use in their clinical practice. In addition to cardiovascular (CV) risk stratification, ambulatory blood pressure monitoring (ABPM) also provides relevant information for diagnostic and treatment purposes. This work presents a list of protocols based on the Hydra platform, a web-based system for clinical decision support which incorporates a set of functionalities and services that are required for complete cardiovascular analysis, risk assessment, early diagnosis, treatment and monitoring of patients over time. The program includes tools for inputting and managing comprehensive patient data, organized into different checkups to track the evolution over time. It also has a risk stratification tool to compute a CV risk factor based upon several risk stratification tables of reference. Additionally, the program includes a tool that incorporates ABPM analysis and allows the extraction of valuable information by monitoring blood pressure over a specific period of time. Finally, the reporting service summarizes the most relevant information in a set of reports that aid clinicians in their clinical decision-making process.

The patient registration described in step 1 is carried out by filling in the form presented in Figure 1. Once the user registers a new patient, the application moves forward to introduce the first checkup, which allows the input of comprehensive patient data. Figure 2 shows a screenshot of the first form of the checkup information. Once the Next button is clicked, the application moves forward to the second chec...

Watch this Scientific Journal Video about Hydra, a Computer-Based Platform for Aiding Clinicians in Cardiovascular Analysis and Diagnosis at JoVE.com

Hydra, a Computer-Based Platform for Aiding Clinicians in Cardiovascular Analysis and Diagnosis

This article presents a protocol based on Hydra &#8212; a web-based system for clinical decision support that integrates a full and detailed set of functionalities and services required by physicians for complete cardiovascular analysis, risk assessment, early diagnosis, treatment, and monitoring over time.

Cardiovascular diseases (CVDs) are the leading cause of death throughout the world. The total risk of developing CVD is determined by the combined effect ...

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Research

JoVE Journal

Medicine

7.5K Views.  University of A Coruña. This article presents a protocol based on Hydra — a web-based system for clinical decision support that integrates a full and detailed set of functionalities and services required by physicians for complete cardiovascular analysis, risk assessment, early diagnosis, treatment, and monitoring over time.

Video: Hydra, a Computer-Based Platform for Aiding Clinicians in Cardiovascular Analysis and Diagnosis

Transabdominal Ultrasound for Pregnancy Diagnosis in Reeves' Muntjac Deer

Reeves' muntjac deer (Muntiacus reevesi) are a small cervid species native to southeast Asia, and are currently being investigated as a potential model of prion disease transmission and pathogenesis. Vertical transmission is an area of interest among researchers studying infectious diseases, including prion disease, and these investigations require efficient methods for evaluating the effects of maternal infection on reproductive performance. Ultrasonographic examination is a well-established tool for diagnosing pregnancy and assessing fetal health in many animal species1-7, including several species of farmed cervids8-19, however this technique has not been described in Reeves' muntjac deer. Here we describe the application of transabdominal ultrasound to detect pregnancy in muntjac does and to evaluate fetal growth and development throughout the gestational period. Using this procedure, pregnant animals were identified as early as 35 days following doe-buck pairing and this was an effective means to safely monitor the pregnancy at regular intervals. Future goals of this work will include establishing normal fetal measurement references for estimation of gestational age, determining sensitivity and specificity of the technique for diagnosing pregnancy at various stages of gestation, and identifying variations in fetal growth and development under different experimental conditions.

Transabdominal ultrasound is described as an effective, noninvasive means for assessing reproductive status in Reeves' muntjac deer. These methods can be used to achieve early pregnancy diagnosis and to evaluate fetal viability. Future applications of this technique include estimation of gestational age and effects of maternal disease on fetal development.

Reeves' muntjac deer (Muntiacus reevesi) are a small cervid species native to southeast Asia, and are currently being investigated as a potential model of ...

Carotid Artery Infusions for Pharmacokinetic and Pharmacodynamic Analysis of Taxanes in Mice

When proposing the use of a drug, drug combination, or drug delivery into a novel system, one must assess the pharmacokinetics of the drug in the study model. As the use of mouse models are often a vital step in preclinical drug discovery and drug development1-8, it is necessary to design a system to introduce drugs into mice in a uniform, reproducible manner. Ideally, the system should permit the collection of blood samples at regular intervals over a set time course. The ability to measure drug concentrations by mass-spectrometry, has allowed investigators to follow the changes in plasma drug levels over time in individual mice1, 9, 10. In this study, paclitaxel was introduced into transgenic mice as a continuous arterial infusion over three hours, while blood samples were simultaneously taken by retro-orbital bleeds at set time points. Carotid artery infusions are a potential alternative to jugular vein infusions, when factors such as mammary tumors or other obstructions make jugular infusions impractical. Using this technique, paclitaxel concentrations in plasma and tissue achieved similar levels as compared to jugular infusion. In this tutorial, we will demonstrate how to successfully catheterize the carotid artery by preparing an optimized catheter for the individual mouse model, then show how to insert and secure the catheter into the mouse carotid artery, thread the end of the catheter out through the back of the mouse&#8217;s neck, and hook the mouse to a pump to deliver a controlled rate of drug influx. Multiple low volume retro-orbital bleeds allow for analysis of plasma drug concentrations over time.

This method was developed with the goal of delivering a steady drug solution via the carotid artery, to assess the pharmacokinetics of novel drugs in mouse models.

When proposing the use of a drug, drug combination, or drug delivery into a novel system, one must assess the pharmacokinetics of the drug in the study ...

A Flow Cytometry-based Assay for Measuring Mitochondrial Membrane Potential in Cardiac Myocytes After Hypoxia/Reoxygenation

Timely and efficient reperfusion of the occluded coronary artery is the best strategy for decreasing myocardial infarct size in patients with a ST-segment elevated myocardial infarction. However, reperfusion per se can result in further cardiomyocyte death, a phenomenon known as reperfusion injury. The opening of the mitochondrial permeability transition pore (mPTP), with the decrease of the mitochondrial membrane potential (MMP), or mitochondrial depolarization, is universally recognized as the final step of reperfusion injury and is responsible for mitochondrial and cardiomyocyte death. JC-1 is a lipophilic cationic dye that accumulates in mitochondria depending on the value of MMP. The higher the MMP is, the more JC-1 accumulates in the mitochondria. The increasing amounts of JC-1 in mitochondria can be reflected by a fluorescence emission shift from green (~530 nm) to red (~590 nm). Therefore, the reduction of the red/green fluorescence intensity ratio can indicate the depolarization of mitochondria. Here, we take advantage of JC-1 to measure MMP, or the opening of mPTP in human cardiac myocytes after hypoxia/reoxygenation, detected by flow cytometry.

Here, we present a protocol that uses JC-1 dye to assess the mitochondrial membrane potential of cells after being exposed to hypoxia/reoxygenation with or without a protective agent.

Timely and efficient reperfusion of the occluded coronary artery is the best strategy for decreasing myocardial infarct size in patients with a ST-segment ...

High-Throughput Analysis of Optical Mapping Data Using ElectroMap

Optical mapping is an established technique for high spatio-temporal resolution study of cardiac electrophysiology in multi-cellular preparations. Here we present, in a step-by-step guide, the use of ElectroMap for analysis, quantification, and mapping of high-resolution voltage and calcium datasets acquired by optical mapping. ElectroMap analysis options cover a wide variety of key electrophysiological parameters, and the graphical user interface allows straightforward modification of pre-processing and parameter definitions, making ElectroMap applicable to a wide range of experimental models. We show how built-in pacing frequency detection and signal segmentation allows high-throughput analysis of entire experimental recordings, acute responses, and single beat-to-beat variability. Additionally, ElectroMap incorporates automated multi-beat averaging to improve signal quality of noisy datasets, and here we demonstrate how this feature can help elucidate electrophysiological changes that might otherwise go undetected when using single beat analysis. Custom modules are included within the software for detailed investigation of conduction, single file analysis, and alternans, as demonstrated here. This software platform can be used to enable and accelerate the processing, analysis, and mapping of complex cardiac electrophysiology.

This protocol describes the setup and use of ElectroMap, a MATLAB-based open-source software platform for analysis of cardiac optical mapping data. ElectroMap provides a versatile high-throughput tool for analysis of optical mapping voltage and calcium datasets across a wide range of cardiac experimental models.

Optical mapping is an established technique for high spatio-temporal resolution study of cardiac electrophysiology in multi-cellular preparations. Here we ...

A Cryoinjury Model to Study Myocardial Infarction in the Mouse

The use of animal models is essential for developing new therapeutic strategies for acute coronary syndrome and its complications. In this article, we demonstrate a murine cryoinjury infarct model that generates precise infarct sizes with high reproducibility and replicability. In brief, after intubation and sternotomy of the animal, the heart is lifted from the thorax. The probe of a handheld liquid nitrogen delivery system is applied onto the myocardial wall to induce cryoinjury. Impaired ventricular function and electrical conduction can be monitored with echocardiography or optical mapping. Transmural myocardial remodeling of the infarcted area is characterized by collagen deposition and loss of cardiomyocytes. Compared to other models (e.g., LAD-ligation), this model utilizes a handheld liquid nitrogen delivery system to generate more uniform infarct sizes.

This article demonstrates a model to study cardiac remodeling after myocardial cryoinjury in mice.

The use of animal models is essential for developing new therapeutic strategies for acute coronary syndrome and its complications. In this article, we ...

Integrating Augmented Reality Tools in Breast Cancer Related Lymphedema Prognostication and Diagnosis

Breast cancer related lymphedema (BCRL) is a detrimental condition characterized by fluid accumulation in the upper limb in breast cancer patients subjected to axillary surgery and/or radiations. Its etiology is multifactorial and include also tumor-specific pathological features, such as lymphovascular invasion (LVI) and extranodal extension (ENE). To date, no widely employed guidelines for the early diagnosis of BCRL are available. Here, we illustrate a protocol for a digitally assisted BCRL assessment using a 3D laser scanner (3DLS) and a tablet computer. It has been specifically optimized in a discovery cohort of high-risk breast cancer patients. This study provides a proof-of-principle that augmented reality tools, such as 3DLS, can be incorporated into the clinical workup of BCRL to allow for a precise, reproducible, reliable, and cheap diagnosis.

Breast cancer related lymphedema is frequent in breast cancer survivors, but there are not widely employed guidelines for its diagnosis and quantification. Here, we introduce a reliable and cost-effective protocol to define, quantify, and compare upper limb volume in breast cancer patients.

Breast cancer related lymphedema (BCRL) is a detrimental condition characterized by fluid accumulation in the upper limb in breast cancer patients ...

On-Site Sampling and Extraction of Brain Tumors for Metabolomics and Lipidomics Analysis

Despite the variety of tools available for cancer diagnosis and classification, methods that enable fast and simple characterization of tumors are still in need. In recent years, mass spectrometry has become a method of choice for untargeted profiling of discriminatory compound as potential biomarkers of a disease. Biofluids are generally considered as preferable matrices given their accessibility and easier sample processing while direct tissue profiling provides more selective information about a given cancer. Preparation of tissues for the analysis via traditional methods is much more complex and time-consuming, and, therefore, not suitable for fast on-site analysis. The current work presents a protocol combining sample preparation and extraction of small molecules on-site, immediately after tumor resection. The sampling device, which is of the size of an acupuncture needle, can be inserted directly into the tissue and then transported to the nearby laboratory for instrumental analysis. The results of metabolomics and lipidomics analyses demonstrate the capability of the approach for the establishment of phenotypes of tumors related to the histological origin of the tumor, malignancy, and genetic mutations, as well as for the selection of discriminating compounds or potential biomarkers. The non-destructive nature of the technique permits subsequent performance of routinely used tests e.g., histological tests, on the same samples used for SPME analysis, thus enabling attainment of more comprehensive information to support personalized diagnostics.

The manuscript presents on-site sampling of human brain tumors with solid phase microextraction followed by their biochemical profiling towards the discovery of biomarkers.

Despite the variety of tools available for cancer diagnosis and classification, methods that enable fast and simple characterization of tumors are still ...

Development and Evaluation of 3D-Printed Cardiovascular Phantoms for Interventional Planning and Training

Catheter-based interventions are standard treatment options for cardiovascular pathologies. Therefore, patient-specific models could help training physicians&#39; wire-skills as well as improving planning of interventional procedures. The aim of this study was to develop a manufacturing process of patient-specific 3D-printed models for cardiovascular interventions.
To create a 3D-printed elastic phantom, different 3D-printing materials were compared to porcine biological tissues (i.e., aortic tissue) in terms of mechanical characteristics. A fitting material was selected based on comparative tensile tests and specific material thicknesses were defined. Anonymized contrast-enhanced CT-datasets were collected retrospectively. Patient-specific volumetric models were extracted from these datasets and subsequently 3D-printed. A pulsatile flow loop was constructed to simulate the intraluminal blood flow during interventions. Models&#39; suitability for clinical imaging was assessed by x-ray imaging, CT, 4D-MRI and (Doppler) ultrasonography. Contrast medium was used to enhance visibility in x-ray-based imaging. Different catheterization techniques were applied to evaluate the 3D-printed phantoms in physicians&#39; training as well as for pre-interventional therapy planning.
Printed models showed a high printing resolution (~30 &#181;m) and mechanical properties of the chosen material were comparable to physiological biomechanics. Physical and digital models showed high anatomical accuracy when compared to the underlying radiological dataset. Printed models were suitable for ultrasonic imaging as well as standard x-rays. Doppler ultrasonography and 4D-MRI displayed flow patterns and landmark characteristics (i.e., turbulence, wall shear stress) matching native data. In a catheter-based laboratory setting, patient-specific phantoms were easy to catheterize. Therapy planning and training of interventional procedures on challenging anatomies (e.g., congenital heart disease (CHD)) was possible.
Flexible patient-specific cardiovascular phantoms were 3D-printed, and the application of common clinical imaging techniques was possible. This new process is ideal as a training tool for catheter-based (electrophysiological) interventions and can be used in patient-specific therapy planning.

Here we present development of a mock circulation setup for multimodal therapy evaluation, pre-interventional planning, and physician-training on cardiovascular anatomies. With the application of patient-specific tomographic scans, this setup is ideal for therapeutic approaches, training, and education in individualized medicine.

Catheter-based interventions are standard treatment options for cardiovascular pathologies. Therefore, patient-specific models could help training ...

Measurement of Myocardial Lactate Production for Diagnosis of Coronary Microvascular Spasm

In about a quarter of patients with angina and non-obstructive coronary arteries, no epicardial spasm is noted on coronary arteriography during an angina attack. Since the pressure-rate product is almost identical at rest and the onset of attack in those patients, the decrease in coronary blood flow rather than increased myocardial oxygen consumption is likely to explain myocardial ischemia, indicating a substantial involvement with coronary microvascular spasm (MVS). Myocardial lactate production, which could be defined as a negative myocardial lactate extraction ratio (ratio of the coronary arterial-venous difference in lactate concentration to arterial concentration), is considered indicative of objective evidence to support the emerging myocardial ischemia. Thus, monitoring of the myocardial lactate production and the emergence of chest pain and ischemic electrocardiographic changes during acetylcholine (ACh) provocation testing is of significant value for detecting the entity of MVS. Practically, 1 min after incremental doses of ACh (20, 50, and 100 &#956;g) are administered into the left coronary artery (LCA), paired samples of 1 mL of blood are collected from the LCA ostium and coronary sinus for measurement of lactate concentration by a calibrated automatic lactate analyzer. Then, the development of MVS could be confirmed by negative myocardial lactate extraction ratio despite the absence of angiographically demonstrable epicardial coronary spasm or before its occurrence throughout ACh provocation testing. In conclusion, assessment of myocardial lactate production is essential and valuable for the diagnosis of MVS.

Myocardial lactate production (coronary arterial-venous difference in serum lactate level) during coronary spasm provocation testing is considered as a highly sensitive marker that reflects acetylcholine-induced myocardial ischemia due to microvascular spasm. This article presents the procedures to assess myocardial lactate production for the diagnosis of coronary microvascular spasm.

In about a quarter of patients with angina and non-obstructive coronary arteries, no epicardial spasm is noted on coronary arteriography during an angina ...

Basophil Activation Test for Allergy Diagnosis

The basophil activation test (BAT) is a complementary in vitro diagnostic test that can be used in addition to clinical history, skin test (ST), and specific IgE (sIgE) determination in the evaluation of IgE-mediated allergic reactions to food, insect venom, drugs, as well as some forms of chronic urticaria. However, the role of this technique in the diagnostic algorithms is highly variable and not well determined.
BAT is based on the determination of basophil response to allergen/drug cross-linking IgE activation through the measurement of activation markers (such as CD63, CD203c) by flow cytometry. This test can be a useful and complementary tool to avoid controlled challenge tests&#160;to confirm allergy diagnosis, especially in subjects experiencing severe life-threatening reactions. In general, the performance of BAT should be considered if i) the allergen/drug produces false positive results in ST; ii) there is no allergen/drug source to use for ST or sIgE determination; iii) there is discordance between patient history and ST or sIgE determination; iv) symptoms suggest that ST may result in systemic response; v) before considering a CCT to confirm the culprit allergen/drug. The main limitations of the test are related to non-optimal sensitivity, especially in drug allergy, the need to perform the test no longer than 24 h after sample extraction, and the lack of standardization between laboratories in terms of procedures, concentrations, and cell markers.

The basophil activation test is a complementary in vitro diagnostic test for the evaluation of IgE-mediated allergic reactions based on the detection of basophil activation in the presence of a specific stimulus through the measure of activation markers by flow cytometry.

The basophil activation test (BAT) is a complementary in vitro diagnostic test that can be used in addition to clinical history, skin test (ST), and ...