This research was supported by the National Natural Science Foundation of China (82201084), China Postdoctoral Science Foundation (2022M722232), Beijing Postdoctoral Research Foundation (2023-ZZ-020), Miaopu Project of Beijing Tiantan Hospital, Capital Medical University (2023MP10) and General Research Fund, Hong Kong Research Grants Council (27111820 and 17116521).

All procedures described below were approved by the Ethical Committee of Beijing Tiantan Hospital, Capital Medical University (NO. KY2023-177-01), and all patients involved in this study provided informed consent.
1. Patient inclusion and exclusion criteria
<ol>
	<li>Inclusion criteria: Classify patients as pSS patients if they fulfill the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria12. Specifically, base the final classification criteria on the weighted sum of five items: anti-SSA/Ro antibody positivity and focal lymphocytic sialadenitis with a focus score of &#8805; 1 foci/4 mm2, each scoring 3; an abnormal Ocular Staining Score of &#8805; 5 (or van Bijsterveld score of &#8805; 4), a Schirmer&#39;s test result of &#8804; 5 mm/5 min and an unstimulated salivary flow rate of &#8804; 0.1 mL/min, each scoring 1. Individuals with signs and/or symptoms suggestive of SS who have a total score of &#8805; 4 for the above items meet the criteria for pSS.</li>
	<li>Exclusion criteria: Exclude patients who cannot cooperate with sample collection and patients who are receiving treatment for oral Candida infection. 
	NOTE: It is essential to note that the methods described below are also suitable for the comprehensive characterization of oral Candida infections in individuals with secondary SS.</li>
	<li>To prevent potential contaminations during the collection, transportation, and culturing of Candida samples, take meticulous precautions. This includes meticulous experimental preparation, use of single-use and sterile materials, proper labeling, secure sealing of sampling tubes, and conducting experimental procedures in a professional biosafety cabinet.</li>
</ol>
2. Sample collection
<ol>
	<li>Saliva collection: Instruct the patients to hold the tube with a funnel and let the saliva flow gradually into the tube along the lower lip. At the end of the collection, ask the patient to spit all the remaining saliva in the mouth into the tube. Collect the saliva for 15 min.</li>
	<li>Mouthwash and swab collection: If the patient has no or extremely low unstimulated saliva flow (less than 0.03 mL/min), swab the oral mucosal area with suspected oral Candida infection at least 10x, then ask the patient to use 5 mL of phosphate-buffered saline (PBS; see Table of Materials) to rinse the mouth for 1 min. Store the mouthwash in a 50 mL sterile tube and put the swab into the mouthwash tube. 
	NOTE: For pSS patients with unstimulated saliva flow of more than 0.03 mL/min, step 2.2 can still be used to collect samples for oral Candida infection detection.</li>
</ol>
3. Sample processing
<ol>
	<li>Add 1 mL of PBS to the collected saliva. Do not add PBS into the mouthwash with PBS. Vibrate the mouthwash tube using a vortex for 1 min.</li>
</ol>
4. Candida culture
<ol>
	<li>To make the Sabourand&#39;s Agar (SDA) medium, dissolve 70 g SDA (see Table of Materials) in 1000 mL of double distilled water.</li>
	<li>Sterile with an autoclave at 121 &#176;C for 15 min, plate 10 mL of this SDA medium in a 10 cm microbiological culture dish (see Table of Materials) and cool down.</li>
	<li>Take 200 &#181;L of sample prepared in step 3 and streak it onto the 10 cm microbiological culture dishes prepared with 10 mL of SDA medium in step 4.2.</li>
	<li>Incubate for 48 h at 37 &#176;C, and the Candida colony will mature. Temporarily store the SDA dish with Candida colonies at 4 &#176;C. The Candida colonies cultured on the SDA dish can be stored for 2-4 weeks.</li>
</ol>
5. Candida strain identification
<ol>
	<li>To make the medium, take out 47.7 g of Candida diagnostic agar (see Table of Materials) powder, put it into 1000 mL of double distilled water, and heat it to 100 &#176;C.</li>
	<li>When the medium is slightly boiling, plate 10 mL in a 10 cm microbiological culture dish and allow to cool.</li>
	<li>Dissolve the Candida colonies in 500 &#181;L of SDA medium (step 4), suspend and dissociate by pipetting.</li>
	<li>Plate 50 &#181;L of the sample with Candida colonies (step 5.3) onto the medium prepared in step 5.2. Incubate for 48 h at 37 &#176;C until the Candida colonies are mature.</li>
	<li>According to the color and the patterns of the Candida colonies, determine the strain(s) of the acquired Candida from pSS patients. Use the following Candida strain identification criteria: the emerald green colony is Candida albicans, the blue-gray colony is Candida tropicalis, the pink colonies with fuzzy edges, and microvilli are Candida krusei, the purplish red small colony is Candida glabrata, the milky white colony contains several strains including Candida parapsilosis.</li>
</ol>
6. Candida biofilm formation assay
<ol>
	<li>To make the Yeast Nitrogen Base (YNB)-50 glucose (G) medium, weigh 1.34 g YNB (see Table of Materials) and 1.98 g D (+)-Glucose (see Table of Materials). Dissolve them in 200 mL of double distilled water.</li>
	<li>To make the YNB-100G medium, take out 1.34 g YNB and 3.96 g D (+)-Glucose and dissolve them in 200 mL of double distilled water.</li>
	<li>Filter the solutions with a 0.22 &#181;m syringe filter (see Table of Materials). The filtered YNB-50G and YNB-100G medium can be stored at 4 &#176;C for 3 months.</li>
	<li>Pick the 3 (or more) colonies from the same strain on the dishes in step 5 and transfer them into 200 &#181;L of YNB-50G medium (steps 6.1 and 6.3) in a 96-well plate (see Table of Materials). Do this for the strains observed in the dish. Culture overnight at 37 &#176;C with shaking at 200 rpm.</li>
	<li>Aspirate the Candida suspension, add 1 mL of PBS, centrifuge the yeast cells at 1500 x g for 5 min at room temperature, and discard the supernatant. Repeat this step 2x in the same tube.</li>
	<li>Resuspend the cells in 1 mL of YNB-100G medium and prepare different dilutions (1:10, 1:100, and 1:1000) of cells. Take 200 &#181;L of gradient cell suspension and plate it onto the 10 cm SDA medium by the spiral plate method13. The plating is done using a machine that deposits a known volume of sample on a rotating agar plate in an ever-decreasing amount in the form of an Archimedes spiral. Culture for 24-48 h at 37 &#176;C.</li>
	<li>Calculate the concentration of cells in different dilutions according to the number of CFUs in the SDA plate based on a standard method13. Briefly count the well-separated colonies on each plate. Count the colonies in one octant from the outer edge towards the center until at least 25 colonies are observed. Also, count the remainder of that arc where the 25th count occurred. Calculate the concentration of the cells by dividing the colony count by the liquid volume corresponding to the area over which the colony count was obtained13. Adjust the concentration of cells to 1 x 107 cells/mL.</li>
	<li>Put 100 &#181;L of the cell suspension in YNB-100G into a 96-well plate and incubate at 37 &#176;C for 2 h while shaking at 200 rpm.</li>
	<li>Cautiously take out the supernatant, wash 2x with PBS, and get away the floating yeast cells. The Candida biofilm forms at the bottom of the 96-well plate.</li>
</ol>
7. Hyphal formation assay
NOTE: Only Candida that can form hyphae (such as Candida albicans) can be induced for hyphal formation. Go to step 8 for further characterization of Candida that cannot form hyphae (such as Candida glabrata).
<ol>
	<li>Resuspend the yeast cell suspension in step 6.6 and adjust the cell concentration to 1 x 106 cells/mL with YNB-100G medium.</li>
	<li>To prepare the RPMI 1640 complete growth medium, add 50 mL of Fetal Bovine Serum (see Table of Materials) into 450 mL of RPMI 1640 medium (see Table of Materials) and store at 4 &#176;C for further experiment.</li>
	<li>Transfer 2 &#181;L of Candida cell suspension diluted in 200 &#181;L of RPMI 1640 complete growth medium into a 96-well plate and culture overnight at 37 &#176;C to let the hyphae and yeast cells form.</li>
</ol>
8. KOH smear test and CFW staining assay
<ol>
	<li>Take out 1 &#181;L of samples from step 3 or step 6 or step 7 using a precision molded loop (see Table of Materials) and smear an area of 1 cm x 1 cm on the glass slides. Wait for it to dry at room temperature.</li>
	<li>To make 10% KOH solution, weigh 10 g KOH powder (see Table of Materials) and dissolve it in 100 mL of double-distilled water.</li>
	<li>Heat the slide slightly with an alcohol lamp until the specimen dissolves. Stain the slides prepared in step 8.1 with 10% KOH (step 8.2), and cover with a cover slip. Slightly press the cover slip to make the sample transparent.</li>
	<li>Visualize the hyphae and yeast cells under the microscope.</li>
	<li>Stain slides prepared in step 8.1 with a drop of CFW (see Table of Materials), cover with a coverslip, and wait for 1 min.</li>
	<li>Visualize the hyphae using a fluorescence microscope at the magnifications of 100x and 200x. CFW is excited at 355 nm and detected at 300-440 nm. Photograph the images under the exposure time. Repeat 3x to avoid false positive results.</li>
</ol>
9. Antifungal susceptibility test
NOTE: This test is performed according to the manufacturer&#39;s instructions for the Yeast-Like Fungal Susceptibility Kit (Microdilution; see Table of Materials).
<ol>
	<li>Prepare Candida colonies (step 4) less than 4 days old with the 0.85% NaCl ampule (see Table of Materials) and acquire the suspension having the turbidity equivalent to 2 McFarland. Determine the turbidity according to the McFarland Standards Kit (see Table of Materials). Use the prepared Candida suspension instantly.</li>
	<li>Pipette 135 &#181;L of ATB F2 medium in the kit containing 3 x 104 yeast cells/mL into each cupule in the test strip and put the lid on. Put the test strip in a sealed container. Culture for 24 h at 35 &#176;C.</li>
	<li>Observe the growth of the Candida with visual interpretation (refer to the user manual). For the reference value (reference range), refer to the user manual. Check whether the control hole is growing adequately. If the growth of the control hole is insufficient or does not grow, then the results cannot be read and need another 24 h of cultivation.</li>
</ol>

Diagnosis and Strain Identification of pSS-Related Oral Candida

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The authors have no conflicts of interest to declare.

In the current manuscript, we provide a series of systematic, simple, and feasible methods for detecting oral Candida infections, identifying Candida strains, and testing the antifungal susceptibility of commonly used drugs in patients with pSS. 
In practical settings, not all the methods introduced in this manuscript are necessary. The oral Candida detection method(s) can be chosen based on the specific purpose. KOH smear tests and CFW staining assays, using samples...

Candidiasis is caused by Candida spp., which are opportunistic pathogens. Common strains include Candida albicans, Candida krusei, Candida glabrata, Candida parapsilosis, and Candida dubliniensis1. Opportunistic infections caused by Candida spp. include superficial Candida infections and invasive candidiasis. Invasive candidiasis mainly happens in immunocompromised individuals; for example, in patients with acquired immunodeficiency syndrome (AIDS), invasive candidiasis can significantly threaten the quality of life or even the life span2. Superficial Candida infection, such as mucocutaneous candidiasis, is more common in patients3. 
Oral candidiasis, a superficial Candida infection, is the most common human fungal infection. Candida albicans is a normal commensal of the mouth; the carriage rate of Candida spp. has been reported to range from 20% to 75% in the general population without any symptoms4. Overgrowth of Candida can lead to local discomfort in patients, such as the altered taste of sensation, burning sensation in the mouth, dysphagia due to poor nutrition, delayed recovery, and prolonged hospital stay. Long-term oral candidiasis can lead to severe invasive candidiasis, resulting in significant morbidity and mortality5. Oral candidiasis can also increase the risk of oral cancer5. Impaired salivary gland function is among the risk factors for oral candidiasis6. The initiation of infection is the adhesion of Candida to epithelial cell walls. This is followed by the proliferation and filamentation of Candida and the formation and maturation of biofilm7. Biofilms are extremely difficult to eradicate and are resistant to conventional antifungal treatment, making clinical treatment a challenge for biofilm-associated oral Candida infection7.
Primary Sj&#246;gren's syndrome (pSS) is an autoimmune disease that is characterized by dry mouth, dry eyes, and other systematic symptoms8. Dry mouth is the most frequent symptom of pSS. Saliva has important physiological antifungal functions. On the one hand, it can dilute and scour the mouth and thereafter remove organisms from the mucosa. On the other hand, saliva contains antimicrobial proteins, such as lactoferrin, sialoperoxidase, lysozyme, histidine-rich polypeptides, and specific anti-candidal antibodies, which can interact with the oral mucosa and prevent the overgrowth of Candida6. The reduced saliva flow may predispose pSS patients to oral candidiasis. An observational cross-sectional study conducted in 61 pSS patients found that 13.1% of pSS patients presented oral signs of candidiasis and colony forming unit (CFU)/mL of Candida albicans was found significantly and negatively correlated with levels of unstimulated whole saliva (UWS) and stimulated whole saliva (SWS)9.
The methods introduced in this manuscript can identify oral Candida infection based on characterized morphological attributes (e.g., the hyphae and yeast cells) in direct smear or after culturing10. The strain identification of the Candida using a Candida diagnostic agar is based on the formation of different colored colonies with varied morphology, which result from the cleavage of chromogenic substrates by species-specific enzymes11. In this manuscript, systematic methods for detecting oral Candida infection are introduced, including traditional oral Candida culture and rapid examination by potassium hydroxide (KOH) smear test and calcofluor white (CFW) staining assay10. Additionally, the antifungal susceptibility test, which can guide clinical oral Candida infection treatment, has been introduced. In actual situations, it is not necessary to perform all of the introduced methods in this manuscript; the oral Candida detection method(s) can be selected according to the purpose. The examination of oral Candida infection and the determination of Candida strains in pSS patients not only benefit the disease treatment but also help assess the characterization of oral candidiasis and the species profiles.

<table><tbody><tr><td>0.22 &amp;micro;m Syringe Filter</td><td>MERCK</td><td>SLGV004SL</td><td></td></tr><tr><td>1.5 mL Centrifuge Tube</td><td>axygen</td><td>MCT-150-C-S</td><td></td></tr><tr><td>10 cm Microbiological Culture Dishes</td><td>Jet Bio-Filtration Co. Ltd</td><td>TCD000100</td><td></td></tr><tr><td>15 mL Centrifuge Tube</td><td>Jet Bio-Filtration Co., Ltd</td><td>CFT011150</td><td></td></tr><tr><td>50 mL Centrifuge Tube</td><td>Corning</td><td>430290</td><td></td></tr><tr><td>96-well Microplates</td><td>Corning</td><td>3599</td><td></td></tr><tr><td>API 0.85% NaCl ampule</td><td>BIOMERIEUX</td><td>20070</td><td></td></tr><tr><td>Calcofluor White Stain</td><td>Sigma-Aldrich</td><td>18909-100ML-F</td><td></td></tr><tr><td>CHROMagar Candida</td><td>CHROMagar</td><td>P002860</td><td>&lt;em&gt;Candida &lt;/em&gt;diagnostic agar</td></tr><tr><td>D(+)-Glucose Monohydrate</td><td>Sinopharm Chemical Reagent Co.,Ltd</td><td>10010518</td><td></td></tr><tr><td>Fetal Bovine Serum&amp;nbsp;</td><td>Gibco</td><td>26170035</td><td></td></tr><tr><td>McFarland Standards Kit</td><td>BIOMERIEUX</td><td>70900</td><td></td></tr><tr><td>Nunc precision molded loops&amp;nbsp;</td><td>ThermoFisher Scientific</td><td>254399</td><td></td></tr><tr><td>Phosphate Buffered Saline</td><td>Gibco</td><td>C10010500BT</td><td></td></tr><tr><td>Potassium Hydroxide</td><td>Aladdin</td><td>P112284-500g</td><td></td></tr><tr><td>PowerSoil DNA Isolation Kit&amp;nbsp;</td><td>MO BIO</td><td>12888-50</td><td></td></tr><tr><td>RPMI 1640 Medium</td><td>Gibco</td><td>11875119</td><td></td></tr><tr><td>Sabourand&#039;s Agar Medium</td><td>Solarbio</td><td>S9710</td><td></td></tr><tr><td>Yeast Nitrogen Base Without Amino acids</td><td>Solarbio</td><td>Y8040</td><td></td></tr><tr><td>Yeast-like Fungal Susceptibility Kit (Microdilution)</td><td>BIOMERIEUX</td><td>14204</td><td></td></tr></tbody></table>

examination of oral candida infection in primary sj&#246;gren&#39;s syndrome patients

Primary Sj&#246;gren's syndrome (pSS) is an autoimmune disease characterized by symptoms such as dry mouth, dry eyes, and other systematic symptoms. Due to the hyposalivation experienced by pSS patients, oral dysbacteriosis often occurs. A common complication of pSS is the oral Candida infection. In this article, the authors describe systematic methods that can effectively diagnose oral Candida infection and identify the Candida strains using saliva, oral mucosal swabs, or mouthwash from pSS patients. The Sabouraud's Dextrose Agar (SDA), hyphal formation assay, potassium hydroxide (KOH) smear test, and calcofluor white (CFW) staining assay are used for the diagnosis of oral Candida infection. A Candida diagnostic agar is used for the identification of Candida strains. Finally, antifungal susceptibility testing is used to determine appropriate antifungal drug treatment. This standardized method can enhance the diagnosis, treatment, and future research of pSS-related oral Candida infections. Early diagnosis, using this method, can also prevent any complications arising due to delay in receiving appropriate treatment.

In this study, 12 patients with pSS were selected as representative patients and screened for oral Candida infection (Table 1). Among these patients, some patients exhibited typical oral lesions of Candida infection, including angular cheilitis (characterized by cracks at the corners of the mouth, desquamation, and hyperemia, Figure 1A), bright red edema on the gingival mucosa, yellowish-white stringy pseudo-membrane (Figure 1B...

Watch this Scientific Journal Video about Author Spotlight: Oral Candida Diagnosis to Advance Clinical Treatment Regimen for pSS Patients at JoVE.com

Author Spotlight: Oral Candida Diagnosis to Advance Clinical Treatment Regimen for pSS Patients

Here, we present a protocol for the examination of oral Candida infection in patients with primary Sj&#246;gren's syndrome, which can be used for timely treatment and, thereafter, avoiding related complications.

Examination of Oral Candida Infection in Primary Sj&#246;gren&#39;s Syndrome Patients

Primary Sj&#246;gren's syndrome (pSS) is an autoimmune disease characterized by symptoms such as dry mouth, dry eyes, and other systematic symptoms. Due ...

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843 Views.  Capital Medical University. In dit onderzoek presenteren we een protocol voor het onderzoek naar orale candida-infectie bij patiënten met het primaire Sjögren-syndroom, dat kan worden gebruikt voor tijdige behandeling om infectiegerelateerde complicaties te voorkomen. We bieden een reeks systematische, eenvoudige en haalbare methoden voor het detecteren van orale candida-infecties, het identificeren van candida-stammen en het testen van de antischimmelgevoeligheid van veelgebruikte geneesmiddelen bij patiënten met he...

Video: Auteur in de schijnwerpers: Orale Candida-diagnose om het klinische behandelingsregime voor pSS-patiënten te bevorderen

Multi-photon Imaging of Tumor Cell Invasion in an Orthotopic Mouse Model of Oral Squamous Cell Carcinoma

Loco-regional invasion of head and neck cancer is linked to metastatic risk and presents a difficult challenge in designing and implementing patient management strategies. Orthotopic mouse models of oral cancer have been developed to facilitate the study of factors that impact invasion and serve as model system for evaluating anti-tumor therapeutics. In these systems, visualization of disseminated tumor cells within oral cavity tissues has typically been conducted by either conventional histology or with in vivo bioluminescent methods. A primary drawback of these techniques is the inherent inability to accurately visualize and quantify early tumor cell invasion arising from the primary site in three dimensions. Here we describe a protocol that combines an established model for squamous cell carcinoma of the tongue (SCOT) with two-photon imaging to allow multi-vectorial visualization of lingual tumor spread. The OSC-19 head and neck tumor cell line was stably engineered to express the F-actin binding peptide LifeAct fused to the mCherry fluorescent protein (LifeAct-mCherry). Fox1nu/nu mice injected with these cells reliably form tumors that allow the tongue to be visualized by ex-vivo application of two-photon microscopy. This technique allows for the orthotopic visualization of the tumor mass and locally invading cells in excised tongues without disruption of the regional tumor microenvironment. In addition, this system allows for the quantification of tumor cell invasion by calculating distances that invaded cells move from the primary tumor site. Overall this procedure provides an enhanced model system for analyzing factors that contribute to SCOT invasion and therapeutic treatments tailored to prevent local invasion and distant metastatic spread. This method also has the potential to be ultimately combined with other imaging modalities in an in vivo setting.

A comprehensive overview of the techniques involved in generating a mouse model of oral cancer and quantitative monitoring of tumor invasion within the tongue through multi-photon microscopy of labeled cells is presented. This system can serve as a useful platform for the molecular assessment and drug efficacy of anti-invasive compounds.

Loco-regional invasion of head and neck cancer is linked to metastatic risk and presents a difficult challenge in designing and implementing patient ...

A Research Method For Detecting Transient Myocardial Ischemia In Patients With Suspected Acute Coronary Syndrome Using Continuous ST-segment Analysis

Each year, an estimated 785,000 Americans will have a new coronary attack, or acute coronary syndrome (ACS). The pathophysiology of ACS involves rupture of an atherosclerotic plaque; hence, treatment is aimed at plaque stabilization in order to prevent cellular death. However, there is considerable debate among clinicians, about which treatment pathway is best: early invasive using percutaneous coronary intervention (PCI/stent) when indicated or a conservative approach (i.e., medication only with PCI/stent if recurrent symptoms occur).
There are three types of ACS: ST elevation myocardial infarction (STEMI), non-ST elevation MI (NSTEMI), and unstable angina (UA). Among the three types, NSTEMI/UA is nearly four times as common as STEMI. Treatment decisions for NSTEMI/UA are based largely on symptoms and resting or exercise electrocardiograms (ECG). However, because of the dynamic and unpredictable nature of the atherosclerotic plaque, these methods often under detect myocardial ischemia because symptoms are unreliable, and/or continuous ECG monitoring was not utilized.
Continuous 12-lead ECG monitoring, which is both inexpensive and non-invasive, can identify transient episodes of myocardial ischemia, a precursor to MI, even when asymptomatic. However, continuous 12-lead ECG monitoring is not usual hospital practice; rather, only two leads are typically monitored. Information obtained with 12-lead ECG monitoring might provide useful information for deciding the best ACS treatment.
Purpose. Therefore, using 12-lead ECG monitoring, the COMPARE Study (electroCardiographic evaluatiOn of ischeMia comParing invAsive to phaRmacological trEatment) was designed to assess the frequency and clinical consequences of transient myocardial ischemia, in patients with NSTEMI/UA treated with either early invasive PCI/stent or those managed conservatively (medications or PCI/stent following recurrent symptoms). The purpose of this manuscript is to describe the methodology used in the COMPARE Study.
Method. Permission to proceed with this study was obtained from the Institutional Review Board of the hospital and the university. Research nurses identify hospitalized patients from the emergency department and telemetry unit with suspected ACS. Once consented, a 12-lead ECG Holter monitor is applied, and remains in place during the patient's entire hospital stay. Patients are also maintained on the routine bedside ECG monitoring system per hospital protocol. Off-line ECG analysis is done using sophisticated software and careful human oversight.

Continuous 12-lead electrocardiographic (ECG) monitoring can identify transient myocardial ischemia, even when asymptomatic, among patients with suspected acute coronary syndrome (ACS). In this article we describe our method for initiating patient monitoring using a Holter device, downloading the ECG data for off-line analysis, and how to utilize the ECG software to identify transient ischemia.

Each year, an estimated 785,000 Americans will have a new coronary attack, or acute coronary syndrome (ACS). The pathophysiology of ACS involves rupture ...

Th17 Inflammation Model of Oropharyngeal Candidiasis in Immunodeficient Mice

Oropharyngeal Candidiasis (OPC) disease is caused not only due to the lack of host immune resistance, but also the absence of appropriate regulation of infection-induced immunopathology. Although Th17 cells are implicated in antifungal defense, their role in immunopathology is unclear. This study presents a method for establishing oral Th17 immunopathology associated with oral candidal infection in immunodeficient mice. The method is based on reconstituting lymphopenic mice with in vitro cultured Th17 cells, followed by oral infection with Candida albicans (C. albicans). Results show that unrestrained Th17 cells result in inflammation and pathology, and is associated with several measurable read-outs including weight loss, pro-inflammatory cytokine production, tongue histopathology and mortality, showing that this model may be valuable in studying OPC immunopathology. Adoptive transfer of regulatory cells (Tregs) controls and reduces the inflammatory response, showing that this model can be used to test new strategies to counteract oral inflammation. This model may also be applicable in studying oral Th17 immunopathology in general in the context of other oral diseases.

Although Candida infection models are available to study host immune resistance, a model to study T cell mediated immunopathology in the context of Candida infection is absent. Here we describe a method to establish Th17 immunopathology associated with oral Candida infection in immunodeficient mice.

Oropharyngeal Candidiasis (OPC) disease is caused not only due to the lack of host immune resistance, but also the absence of appropriate regulation of ...

Exosomal miRNA Analysis in Non-small Cell Lung Cancer (NSCLC) Patients' Plasma Through qPCR: A Feasible Liquid Biopsy Tool

The discovery of alterations in the EGFR and ALK genes, amongst others, in NSCLC has driven the development of targeted-drug therapy using selective tyrosine kinase inhibitors (TKIs). To optimize the use of these TKIs, the discovery of new biomarkers for early detection and disease progression is mandatory. These plasma-isolated exosomes can be used as a non-invasive and repeatable way for the detection and follow-up of these biomarkers. One ml of plasma from 12 NSCLC patients, with different mutations and treatments (and 6 healthy donors as controls), were used as exosome sources. After RNAse treatment, in order to degrade circulating miRNAs, the exosomes were isolated with a commercial kit and resuspended in specific buffers for further analysis. The exosomes were characterized by western blotting for ALIX and TSG101 and by transmission electron microscopy (TEM) analysis, the standard techniques to obtain biochemical and dimensional data of these nanovesicles. Total RNA extraction was performed with a high yield commercial kit. Due to the limited miRNA-content in exosomes, we decided to perform retro-transcription PCR using an individual assay for each selected miRNA. A panel of miRNAs (30b, 30c, 103, 122, 195, 203, 221, 222), all correlated with NSCLC disease, were analyzed taking advantage of the remarkable sensitivity and specificity of Real-Time PCR analysis; mir-1228-3p was used as endogenous control and data were processed according to the formula 2-&#916;&#916;ct 13. Control values were used as baseline and results are shown in logarithmic scale.

Exosomal miRNA Analysis in Non-small Cell Lung Cancer NSCLC Patients' Plasma Through qPCR: A Feasible Liquid Biopsy Tool

This protocol describes the feasibility to perform miRNA profiling in exosomes, released in plasma of NSCLC patients, through a commercial exosome isolation kit with Proteinase K and RNAse treatments, in order to avoid circulating miRNAs contamination and evaluate their biomarker features in NSCLC.

The discovery of alterations in the EGFR and ALK genes, amongst others, in NSCLC has driven the development of targeted-drug therapy using selective ...

Two Techniques to Create Hypoparathyroid Mice: Parathyroidectomy Using GFP Glands and Diphtheria-Toxin-Mediated Parathyroid Ablation

Hypoparathyroidism (HP) is a disorder characterized by low levels of PTH which lead to hypocalcemia, hyperphosphatemia, and low bone turnover. The most common cause of the disease is accidental removal of the parathyroid glands during thyroid surgery. Novel therapies for HP are needed, but testing them requires reliable animal models of acquired HP. 
Here, we demonstrate the generation of two mouse models of acquired HP. In the GFP-PTX model, mice with green fluorescent protein (GFP) expressed specifically in the parathyroids (PTHcre-mTmG) were created by crossing PTHcre+ mice with Rosa-mTmGfl/fl mice. Green fluorescing parathyroid glands are easily identified under a fluorescence dissecting microscope and parathyroidectomy is performed in less than 20 min. After fluorescence-guided surgery, mice are profoundly hypocalcemic. Contrary to the traditional thyro-parathyroidectomy, this precise surgical approach leaves thyroid glands and thyroid function intact. The second model, which does not require surgery, is based on a diphtheria-toxin approach. PTHcre-iDTR mice, which express the diphtheria toxin (DT) receptor specifically in the parathyroids, were generated by crossing the inducible DTR mouse with the PTHcre mouse. Parathyroid cells are thus rendered sensitive to diphtheria toxin (DT) and can be selectively destroyed by systemically injecting mice with DT. The resulting hypocalcemic phenotype is stable.

Mice with acquired hypoparathyroidism would be useful for studying novel drug therapies for hypoparathyroidism. Two procedures to create such mice are demonstrated. The GFP-PTX mouse is generated by surgical parathyroidectomy guided by green fluorescing parathyroid glands. A second, non-surgical approach is based on parathyroid-specific expression of the diphtheria toxin receptor.

Hypoparathyroidism (HP) is a disorder characterized by low levels of PTH which lead to hypocalcemia, hyperphosphatemia, and low bone turnover. The most ...

Echocardiographic and Histological Examination of Cardiac Morphology in the Mouse

An increasing number of genetically modified mouse models has become available in recent years. Moreover, the number of pharmacological studies performed in mice is high. Phenotypic characterization of these mouse models also requires the examination of cardiac function and morphology. Echocardiography and magnetic resonance imaging (MRI) are commonly used approaches to characterize cardiac function and morphology in mice. Echocardiographic and MRI equipment specialized for use in small rodents is&#160;expensive and requires a dedicated space. This protocol describes cardiac measurements in mice using a clinical echocardiographic system with a 15 MHz human vascular probe. Measurements are performed on anesthetized adult mice. At least three image sequences are recorded and analyzed for each animal in M-mode in the parasternal short-axis view. Afterwards, cardiac histological examination is performed, and cardiomyocyte diameters are determined on hematoxylin-eosin- or wheat germ agglutinin (WGA)-stained paraffin sections. Vessel density is determined morphometrically after Pecam-1 immunostaining. The protocol has been applied successfully to pharmacological studies and different genetic animal models under baseline conditions, as well as after experimental myocardial infarction by the permanent ligation of the left anterior descending coronary artery (LAD). In our experience, echocardiographic investigation is limited to anesthetized animals and is feasible in adult mice weighing at least 25 g.

Echocardiographic examination is frequently used in mice. Expensive high-resolution ultrasound devices have been developed for this purpose. This protocol describes an affordable echocardiographic procedure combined with histological morphometric analyses to determine cardiac morphology.

An increasing number of genetically modified mouse models has become available in recent years. Moreover, the number of pharmacological studies performed ...

Oral Biofilm Sampling for Microbiome Analysis in Healthy Children

Oral biofilm and its molecular analysis provide a basis for investigating various dental research and clinical questions. Knowledge of biofilm composition leads to a better understanding of cariogenic and periopathogenic mechanisms. Microbial changes taking place in the oral cavity during childhood are of interest for several reasons. The evolution of the child oral microbiota and shifts in its composition need to be analyzed further to understand and possibly prevent the onset of disease. At the same time, advanced knowledge of the natural composition of oral biofilm is needed. Early stages of caries-free permanent dentition with healthy gums provide a widely unaffected subgingival habitat that can serve as an in situ baseline for studying features of oral health and disease. Analysis of children's oral biofilm during different stages in life is thus an important theme in the field. Modern molecular analysis methods can provide comprehensive information about the bacterial diversity of such biofilms. To enable microbiota data comparison, it is important to standardize each step in the procedure for molecular data generation. This procedure spans from clinical sampling, Next Generation Sequencing (NGS), bioinformatic data processing, to taxonomic interpretation. One of the most critical factors here is biofilm sampling. Sampling in children is even more challenging in particular due to limited space in subgingival areas. We thus focus on the use of paper points for subgingival sampling. This article provides a detailed protocol for oral biofilm sampling of the subgingival sulcus, the mucosa, and saliva in children.

Changes in the oral microbiome throughout childhood are of growing interest. Comparison of different microbiome studies reveals a lack of standardized sampling protocols. Limited space makes sampling the sound subgingival sulcus of children challenging. Paper point sampling is presented here in detail as the method of choice for this area.

Oral biofilm and its molecular analysis provide a basis for investigating various dental research and clinical questions. Knowledge of biofilm composition ...

Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance

Candida glabrata can rapidly acquire mutations that result in drug resistance, especially to azoles and echinocandins. Identification of genetic mutations is essential, as resistance detected in vitro can often be correlated with clinical failure. We examined the feasibility of using whole genome sequencing (WGS) for genome-wide analysis of antifungal drug resistance in C. glabrata. The aim was torecognize enablers and barriers in the implementation WGS and measure its effectiveness. This paper outlines the key quality control checkpoints and essential components of WGS methodology to investigate genetic markers associated with reduced susceptibility to antifungal agents. It also estimates the accuracy of data analysis and turn-around-time of testing.
Phenotypic susceptibility of 12 clinical, and one ATCC strain of C. glabrata was determined through antifungal susceptibility testing. These included three isolate pairs, from three patients, that developed rise in drug minimum inhibitory concentrations. In two pairs, the second isolate of each pair developed resistance to echinocandins. The second isolate of the third pair developed resistance to 5-flucytosine. The remaining comprised of susceptible and azole resistant isolates. Single nucleotide polymorphisms (SNPs) in genes linked to echinocandin, azole and 5-flucytosine resistance were confirmed in resistant isolates through WGS using the next generation sequencing.&#160;Non-synonymous SNPs in antifungal resistance genes such as FKS1, FKS2, CgPDR1, CgCDR1 and FCY2 were identified. Overall, an average of 98% of the WGS reads of C. glabrata isolates mapped to the reference genome with about 75-fold read depth coverage. The turnaround time and cost were comparable to Sanger sequencing.
In conclusion, WGS of C. glabrata was feasible in revealing clinically significant gene mutations involved in resistance to different antifungal drug classes without the need for multiple PCR/DNA sequencing reactions. This represents a positive step towards establishing WGS capability in the clinical laboratory for simultaneous detection of antifungal resistance conferring substitutions.

Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance

This study implemented whole genome sequencing for analysis of mutations in genes conferring antifungal drug resistance in Candida glabrata. C. glabrata isolates resistant to echinocandins, azoles and 5-flucytosine, were sequenced to illustrate the methodology. Susceptibility profiles of the isolates correlated with presence or absence of specific mutation patterns in genes.

Candida glabrata can rapidly acquire mutations that result in drug resistance, especially to azoles and echinocandins. Identification of genetic mutations ...

Transthoracic Echocardiographic Examination in the Rabbit Model

Large animal models such as the rabbit are valuable for translational preclinical research. Rabbits have a similar cardiac electrophysiology compared to that of humans and that of other large animal models such as dogs and pigs. However, the rabbit model has the additional advantage of lower maintenance costs compared to other large animal models. The longitudinal evaluation of cardiac function using echocardiography, when appropriately implemented, is a useful methodology for preclinical assessment of novel therapies for heart failure with reduced ejection fraction (e.g. cardiac regeneration). The correct use of this non-invasive tool requires the implementation of a standardized examination protocol following international guidelines. Here we describe, step by step, a detailed protocol supervised by veterinary cardiologists for performing echocardiography in the rabbit model, and demonstrate how to correctly obtain the different echocardiographic views and imaging planes, as well as the different imaging modes available in a clinical echocardiography system routinely used in human and veterinary patients.

Here we describe, step by step, a detailed protocol for performing echocardiography in the rabbit model. We show how to correctly obtain the different echocardiographic views and imaging planes, as well as the different imaging modes available in a clinical echocardiography system routinely used in human and veterinary patients.

Large animal models such as the rabbit are valuable for translational preclinical research. Rabbits have a similar cardiac electrophysiology compared to ...

Technique for Salivary Gland Ultrasound Examination of Sjogren's Syndrome

Ultrasonographic Evaluation of Salivary Glands for Sjogren's Syndrome: Diagnostic and Monitoring Insights

Sjogren's syndrome (SS) is a chronic autoimmune condition commonly affecting the exocrine glands, causing oral or ocular dryness and extraglandular manifestations including arthralgia, cytopenia, and lymphoma. The presence of autoantibodies against SSA/Ro, labial salivary gland biopsy, ocular staining, Schirmer's test, or salivary flow assessment are included in the current classification criteria of SS. However, the availability and invasiveness of these procedures limit their widespread use in clinical settings. Salivary gland ultrasonography (SGUS) is a non-invasive imaging modality for the evaluation of the salivary gland parenchyma and is increasingly utilized to aid diagnosis and monitoring in SS. 
This article presents the protocol of SGUS for image acquisition at the parotid and submandibular glands. The objective is to present a standardized, reproducible, and practical approach to diagnostic SGUS for SS in daily clinical settings. Major salivary glands are scanned in a stepwise approach, beginning at the angle of the mandible for the superficial lobe of the parotid gland, followed by the deep lobe below the ramus of the mandible. Submandibular areas are then scanned for the submandibular glands. The steps in obtaining salivary gland images at each anatomical site are explained in the accompanying video. The echogenicity and echotexture at the thyroid gland are taken as a reference. The homogeneity, the presence and distribution of hypoechoic areas within the glands, and the border of the salivary glands are examined. The sizes and features of intra-/peri-glandular lymph nodes are recorded. The most distinctive sonographic feature in SS is glandular heterogeneity with the presence of hypoechoic/hyperechoic areas within the glands. 
In summary, while SGUS cannot diagnose SS on its own, it can supplement the current classification criteria of SS and guide the clinical decision for salivary gland biopsy to support the diagnosis of SS in patients with sicca syndrome or suspicious systemic features, combined with autoantibody testing.

Author Spotlight: A Focus on Standardized Salivary Gland Ultrasound Protocol in Connective Tissue Disease Research

Salivary gland ultrasonography is a promising tool for the diagnosis and evaluation of disease activity and complications in Sjogren's syndrome (SS). The scanning technique for salivary gland ultrasound examination relevant to SS is described in the article.

Sjogren's syndrome (SS) is a chronic autoimmune condition commonly affecting the exocrine glands, causing oral or ocular dryness and extraglandular ...

Examination of Oral Candida Infection in Primary Sjögren's Syndrome Patients

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