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> Anatomy > Body Part > Parotid Gland

Parotid Gland

The parotid gland is a major salivary gland located in front of and below the ear.
It is responsible for producing saliva that helps with chewing, swallowing, and digestion.
Diseases and conditions affecting the parotid gland include inflammation, tumors, and infections.
Researchers can explore the latest parotid gland research protocols using PubCompare.ai's AI-powered optimization platform, which provides access to protocols from literature, preprints, and patents.
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Most cited protocols related to «Parotid Gland»

1
SICCA Registry Enrollment Criteria
The participants in the SICCA cohort have been enrolled since 2004 at five collaborating academically-based research groups, located in Argentina, China, Denmark, Japan and the United States, and directed from the University of California, San Francisco (12 (link)) (Table 1). Subsequently, additional research groups joined the SICCA project: in 2007, from the United Kingdom and in 2009, from India and two additional sites in the United States.
To be eligible for the SICCA registry, participants must be at least 21 years of age and have at least one of the following: symptoms of dry eyes or dry mouth; a previous suspicion or diagnosis of SS; elevated serum antinuclear antibodies (ANA), positive rheumatoid factor (RF), or anti-SSA/B; bilateral parotid enlargement in a clinical setting of SS; a recent increase in dental caries; or have diagnoses of rheumatoid arthritis or systemic lupus erythematosus and any of the above. The rationale for these eligibility criteria is that only patients with such characteristics would be evaluated for SS or considered for enrollment in a clinical trial designed to evaluate a potential therapeutic agent for SS. Therefore our classification criteria target individuals with signs and symptoms that may be suggestive of SS, not the general population.
Participants are recruited through local or national SS patient support groups, healthcare providers, public media, and populations served by all nine SICCA research groups. Exclusion criteria include known diagnoses of: hepatitis C, HIV, sarcoidosis, amyloidosis, active tuberculosis, graft versus host disease, autoimmune connective tissue diseases other than rheumatoid arthritis or lupus; past head and neck radiation treatment; current treatment with daily eye drops for glaucoma; corneal surgery in the last 5 years to correct vision; cosmetic eyelid surgery in the last 5 years; or physical or mental condition interfering with successful participation in the study. Contact lens wearers are asked to discontinue wear for 7 days before the SICCA examination. We do not exclude participants taking prescription drugs that may affect salivary or lacrimal secretion, but record their use and all other medications currently taken.
Shiboski S., Shiboski C., Criswell L., Baer A., Challacombe S., Lanfranchi H., Schiødt M., Umehara H., Vivino F., Zhao Y., Dong Y., Greenspan D., Heidenreich A., Helin P., Kirkham B., Kitagawa K., Larkin G., Li M., Lietman T., Lindegaard J., McNamara N., Sack K., Shirlaw P., Sugai S., Vollenweider C., Whitcher J., Wu A., Zhang S., Zhang W., Greenspan J, & Daniels T. (2012). American College of Rheumatology Classification Criteria for Sjögren’s Syndrome: A Data-Driven, Expert Consensus Approach in the SICCA Cohort. Arthritis care & research, 64(4), 475-487.
Publication 2012
Administration, Ophthalmic Amyloidosis Antibodies, Antinuclear Connective Tissue Diseases Contact Lenses Cornea Dental Caries Diagnosis Dry Eye Eligibility Determination Eyelids Glaucoma Graft-vs-Host Disease Head Health Personnel Hepatitis C virus Hypertrophy Lupus Erythematosus, Systemic Lupus Vulgaris Neck Operative Surgical Procedures Parotid Gland Patients Pharmaceutical Preparations Physical Examination Prescription Drugs Radiotherapy Rheumatoid Arthritis Rheumatoid Factor Sarcoidosis secretion Serum Therapeutics Tuberculosis Vision Xerostomia
2
Consensus on Sjögren's Syndrome Criteria
In February 2004, the panel of experts gathered for a face-to-face meeting moderated by a statistician (SCS) and an epidemiologist (CHS). The goal of this meeting was to obtain consensus (at least 80%) on the target population to whom the classification criteria would apply, and the initial list of variables or criteria items that would be collected as part of SICCA. The meeting began with presentation of a comprehensive literature review by one of the senior investigators (TED) of the 11 previous classification and diagnostic criteria for SS that had been published in the past 40 years, none of which had been endorsed by the ACR or EULAR.
There was consensus among the panel that the criteria should apply to the population of patients who may be referred to a specialist because of signs and/or symptoms possibly suggesting SS. Recruitment strategies and eligibility criteria are described below. The rationale for selecting this target population is that a given patient would not be evaluated for SS unless she/he had signs or symptoms suggesting this diagnosis. There was also consensus that if asked to select cases and controls for validation of new classification criteria, panel members would use objective tests (e.g., specific serum measures of autoimmunity, ocular staining reflecting lacrimal hypofunction, and LSG biopsy reflecting FLS) that would likely be part of the new classification criteria, leading to circularity. Therefore, it was agreed that no diagnostic labels would be used for enrollment, and that all participants would undergo the same set of standardized objective tests, and questionnaires capturing various signs and symptoms.
The panel agreed upon examinations and tests used to assess ocular and oral signs and symptoms, tear and salivary function, LSG biopsy results and various serum measures of autoimmunity. The list created was based both on published results and on the clinical experience of panel members. There was discussion among the rheumatologists regarding which extra-glandular manifestations possibly associated with SS should be captured, and a consensus was achieved regarding a list of signs/symptoms that would be measured through a targeted rheumatologic examination, review of systems, careful medical history and serologic laboratory measures. Similarly, the oral medicine specialists agreed on a list of tests measuring salivary function (both stimulated parotid and UWS flow rates), and salivary gland expression of autoimmunity through biopsy of LSG, examining them for the presence of FLS, and measuring FS accordingly as described in detail elsewhere (15 (link)). The ophthalmologists agreed on tests evaluating participants for the presence of keratoconjunctivitis sicca (KCS). There was consensus that, while rose Bengal had been widely used for grading conjunctival and corneal damage in patients with KCS, it is inherently toxic to epithelial cells and very painful for patients. Therefore, fluorescein was selected to grade the cornea and lissamine green the bulbar conjunctiva. Effectiveness for grading KCS is established for both (16 (link)). They agreed on a standardized quantitative grading system that would be easily reproducible and could be used in clinical practice in the future (17 (link)). Ocular staining score (OSS) is the sum of a 0–6 score for fluorescein staining of the cornea and a 0–3 score for lissamine green staining of both nasal and temporal bulbar conjunctivae, yielding a total score ranging from 0 to 12. Alternative established tests for dryness used in prior criteria, such as tear break-up time (TBUT) and unanesthetized Schirmer test, were also included.
The final list of criteria items that was agreed upon by the end of the first meeting included nearly all those previously reported in the relevant literature. It has been described previously (12 (link)) and is available at http://sicca.ucsf.edu.
Shiboski S., Shiboski C., Criswell L., Baer A., Challacombe S., Lanfranchi H., Schiødt M., Umehara H., Vivino F., Zhao Y., Dong Y., Greenspan D., Heidenreich A., Helin P., Kirkham B., Kitagawa K., Larkin G., Li M., Lietman T., Lindegaard J., McNamara N., Sack K., Shirlaw P., Sugai S., Vollenweider C., Whitcher J., Wu A., Zhang S., Zhang W., Greenspan J, & Daniels T. (2012). American College of Rheumatology Classification Criteria for Sjögren’s Syndrome: A Data-Driven, Expert Consensus Approach in the SICCA Cohort. Arthritis care & research, 64(4), 475-487.
Publication 2012
Autoimmunity Biopsy Conjunctiva Conjunctiva, Bulbar Cornea Cornea Injuries Diagnosis Eligibility Determination Epidemiologists Epithelial Cells Eye Face Fast Green FCF Fluorescein Keratoconjunctivitis Sicca Nose Ophthalmologists Pain Parotid Gland Patients Physical Examination Rheumatologist Rose Bengal Salivary Glands Serum Signs and Symptoms Specialists Target Population Tears
3
SICCA Registry: Standardized Protocols
In the SICCA registry, examinations and specimen collections are performed by following standardized operating procedures (SOP) that are identical and consistently applied across all six research sites. Adherence to the SOP is ensured by ongoing specimen examination and quality assurance site visits. Eligibility criteria for enrollment require that a participant be at least 21 years of age and have at least one of the following: a complaint of dry eyes or dry mouth; a previous suspicion or diagnosis of SS; elevated serum ANA, RF, SS-A, or SS-B; bilateral parotid enlargement in the clinical setting of SS; a recent increase in dental caries; or a diagnosis of rheumatoid arthritis or systemic lupus erythematosus and possible secondary SS (1 ). The present analysis is based on a cohort of participants who had been enrolled in the SICCA registry and for whom biopsy results and all other data were available for analysis as of September 20, 2010. Informed consent was in compliance with the Helsinki Declaration and the study was approved by the University of California, San Francisco Committee on Human Research. Additional reviews and approvals were provided by local Institutional Review Boards at each of the institutions listed on the title page.
Daniels T.E., Cox D., Shiboski C.H., Schiødt M., Wu A., Lanfranchi H., Umehara H., Zhao Y., Challacombe S., Lam M.Y., DeSouza Y., Schiødt J., Holm H., Bisio P.A., Gandolfo M.S., Sawaki T., Li M., Zhang W., Varghese-Jacob B., Ibsen P., Keszler A., Kurose N., Nojima T., Odell E., Criswell L.A., Jordan R, & Greenspan J.S. (2011). Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjögren’s Syndrome (SS) among 1726 registry participants. Arthritis and rheumatism, 63(7), 2021-2030.
Publication 2011
Biopsy Dental Caries Diagnosis Dry Eye Eligibility Determination Ethics Committees, Research Homo sapiens Hypertrophy Lupus Erythematosus, Systemic Parotid Gland Physical Examination Rheumatoid Arthritis Serum Specimen Collection Xerostomia
4
Radiochemical Synthesis and Characterization of Lu-PSMA
PSMA was obtained from ABX GmbH (Radeberg, Germany). To begin, 1 mg DOTA-PSMA was dissolved in 1 ml 0.05 M HCl. Then, 88.50 ± 9.21 μg DOTA-PSMA per 10 μg Lu was added to 1 ml 0.05 M HCl solution containing 42 mg gentisinic acid and 210 mg sodium ascorbate. This mixture was added to carrier-added 177LuCl3, obtained from IDB Holland, and heated for 30 min at 95 °C. Quality control was performed by spotting 1 μl aliquots on TLC (SilicaGel 60, Merck, Darmstadt, Germany) with 0.1 M citric buffer or ITLC-SG plates (ITLC-SG, Varian, Lake Forest, CA, USA) and with 1 M NH4OAc/MeOH (1:1) as solvent. Analysis was performed using a flat-bed scanner (Rita Star, Raytest-Isotopenmessgeräte GmbH, Straubenhardt, Germany). Radiochemical purity was determined by radio HPLC, which was performed using a gradient system. The gradient elution system utilised mobile phase A (deionised H2O containing 0.1 % TFA) and mobile phase B (100 % acetonitrile) and a flow rate of 1.0 ml/min. Starting with 100 % A/0 % B, the gradient was increased to 100 % B over 30 min and then returned to the initial gradient conditions within 5 min. The retention time of free 177Lu was Rt = 2.5 min, whereas for Lu-PSMA it was 13.3 min.
The labelling yield always exceeded 95 % (98.85 ± 1.29 %); therefore, no purification was performed. The radiochemical purity was higher than 98 %. The specific activity of Lu-PSMA was 89.73 ± 13.61 MBq/μg.
The therapy solution was administered by slow intravenous injection over 1 min followed by 1000 ml of NaCl or Ringer. In order to reduce therapy-induced damage to the salivary glands, the patients received ice packs over the parotid and submandibular glands from 30 min prior to and up to 4 h after administration of the Lu-PSMA. All patients were discharged 48 h after therapy according to the rules of the Federal Office for Radiation Protection in Germany (BfS).
Ahmadzadehfar H., Rahbar K., Kürpig S., Bögemann M., Claesener M., Eppard E., Gärtner F., Rogenhofer S., Schäfers M, & Essler M. (2015). Early side effects and first results of radioligand therapy with 177Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer: a two-centre study. EJNMMI Research, 5, 36.
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Publication 2015
acetonitrile Acids Aftercare Buffers Citric Acid Forests High-Performance Liquid Chromatographies Lutetium-177 Parotid Gland Patients Radiation Protection Radiopharmaceuticals Retention (Psychology) Salivary Glands Sodium Ascorbate Sodium Chloride Solvents Submandibular Gland tetraxetan Therapeutics Training Programs
5
Preventing Xerostomia in HNSCC Radiotherapy
We undertook a phase 3 randomised controlled trial at six UK radiotherapy centres (recruitment between Jan 21, 2003, and Dec 7, 2007). Eligible patients had histologically confirmed HNSCC that arose from the oropharynx or hypopharynx and were to be treated by radiotherapy either primarily or postoperatively without concomitant chemotherapy. These patients were at high risk of radiation-induced xerostomia—ie, if they were treated with conventional radiotherapy the estimated mean dose to both parotid glands would be greater than 24 Gy. Patients had WHO performance status 0 or 1 and any stage of disease except M1. Patients were required to attend regular follow-up, undergo salivary flow measurements, and complete self-assessed QoL questionnaires.
Exclusion criteria included previous head or neck radiotherapy; previous malignancy except non-melanoma skin cancer; pre-existing salivary gland disease; tumour involvement of the parotid glands; or previous or concurrent illness that would compromise completion of treatment or follow-up. Prophylactic amifostine or pilocarpine was not permitted. Patients who had received neoadjuvant chemotherapy were eligible.
All patients provided written informed consent. PARSPORT (CRUK/03/005) was approved by the national South-West Multicentre Research Ethics Committee (MREC 03/6/79) and the local ethics committees of all participating centres. Our trial was sponsored by the Royal Marsden NHS Foundation Trust and undertaken in accordance with the principles of Good Clinical Practice.
Nutting C.M., Morden J.P., Harrington K.J., Urbano T.G., Bhide S.A., Clark C., Miles E.A., Miah A.B., Newbold K., Tanay M., Adab F., Jefferies S.J., Scrase C., Yap B.K., A'Hern R.P., Sydenham M.A., Emson M, & Hall E. (2011). Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. The Lancet. Oncology, 12(2), 127-136.
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Publication 2011
Amifostine Condoms Ethics Committees, Research Familial Atypical Mole-Malignant Melanoma Syndrome Head Hypopharynx Neck Neoadjuvant Chemotherapy Oropharynxs Parotid Gland Parotid Neoplasms Patients Pharmacotherapy Pilocarpine Radiotherapy Regional Ethics Committees Salivary Glands Squamous Cell Carcinoma of the Head and Neck Xerostomia

Most recents protocols related to «Parotid Gland»

1
Comprehensive Evaluation of Ocular and Systemic Toxicity

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Publication 2023
Animals Autopsy Biceps Femoris Brain Electrocardiography Ethanol Eye Fixatives Formalin Heart Jejunum Kidney Liver Lung Macaca Mandible Mesentery Microscopy Muscle Tissue Mydriatics Nodes, Lymph Ocular Toxicity Ophthalmologists Ophthalmoscopes Optic Nerve Ovary Pancreas Parotid Gland Physical Examination proparacaine Radionuclide Imaging Slit Lamp Spleen Testis Tissues Urinalysis
2
Retrospective Study of Primary Sjögren's Syndrome
Based on computerised and paper medical files, we retrospectively collected sex, age at beginning of symptoms and age at diagnosis of pSS. We gathered Sjögren’s-related symptoms such as sicca, parotid gland enlargement and extraglandular manifestations of pSS including occurrence of lymphoma at any time before or after diagnosis. Biological and immunological features included anti-nuclear antibodies (ANA), anti-SSA/Ro, anti- SSB/La, anti-DNA, anti-Sm and anti-RNP, gammaglobulins and β2-microglobulinaemia titres, complement levels and presence of cryoglobulinaemia. We gathered histological data of accessory salivary glands biopsies. We assessed EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) at each consult with available information and retained each category’s maximum ESSDAI score during the follow-up. We then calculated a cumulative ESSDAI (cumESSDAI) score per patient as the sum of each category’s maximum score during the follow-up. Using the same method, we calculated a cumulative ClinESSDAI (cumClinESSDAI) score, a variant which excludes the biological domain.11 (link) We additionally calculated a median EULAR Sjögren’s Syndrome Patient Reported Index score per patient when possible. Lastly, we gathered any pSS-related treatments prescribed at diagnosis and onward.
Beydon M., Seror R., Le Guern V., Chretien P., Mariette X, & Nocturne G. (2023). Impact of patient ancestry on heterogeneity of Sjögren’s disease. RMD Open, 9(1), e002955.
Publication 2023
Antibodies, Anti-DNA Antibodies, Antinuclear Biopharmaceuticals Biopsy Cryoglobulinemia Diagnosis Hypertrophy Lymphoma Parotid Gland Patients Salivary Glands Sjogren's Syndrome
3
PSMA-PET/CT Imaging Protocol for Prostate Cancer
Imaging is performed at the Department of Nuclear Medicine of the University Hospital Bonn in all patients. [68 Ga]Ga-DKFZ-PSMA-11 (HBED-CC) is prepared on-site in compliance with good laboratory practice guidelines. [68 Ga]Ga-DKFZ-PSMA-11 will be administered based on patient weight (2 MBq/kg). After an adequate incubation time (optimal range: 50–100 min), PSMA-PET examination and non-contrast-enhanced low-dose CT are performed. Two highly experienced nuclear medicine physicians at the study site rate PSMA-PET/CTs for each patient and lesion using the PROMISE miTNM V1.0 evaluation system published by Eiber et al. [22 (link)]. According to PROMISE miTNM V1.0, intraprostatic lesions are visually graded in terms of PSMA expression by miPSMA expression scores 0 (“none,” uptake below blood pool), 1 (“low,” uptake equal to or higher than blood pool, but less than liver), 2 (“intermediate,” uptake equal to or higher than liver, but less than parotid gland), and 3 (“high,” uptake equal to or higher than parotid gland). Intraprostatic lesions with an miPSMA expression score ≥ 2 (uptake equal to or higher than the liver) are rated as positive for PCA [22 (link)]. Lesions rated with an miPSMA expression score of 1 are defined as equivocal findings. Intraprostatic extension and location of targetable lesions (miPSMA ≥ 1) are reported in detail by annotation (Fig. 1). For effective and clear interdisciplinary communication, PSMA-PET/CT findings will be additionally reported using a study-specific map derived from the PIRADS V2.1 prostate sector map [21 (link)]. In addition, the maximum standardized uptake value (SUVmax) per suspicious lesion is collected, and suspicious lymph nodes and bone metastasis as well as capsular infiltration and extraprostatic extension are determined. The reporting nuclear medicine radiologists will be blinded to the corresponding MRI report to avoid bias.
Krausewitz P., Bundschuh R.A., Gaertner F.C., Essler M., Attenberger U., Luetkens J., Kristiansen G., Muders M., Ohlmann C.H., Hauser S., Ellinger J, & Ritter M. (2023). DEPROMP Trial: the additive value of PSMA-PET/CT-guided biopsy for prostate cancer management in biopsy naïve men—study protocol for a randomized trial. Trials, 24, 167.
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Publication 2023
BLOOD Bones Capsule gallium GA-68 gozetotide Liver N,N'-bis(2-hydroxy-5-(ethylene-beta-carboxy)benzyl)ethylenediamine N,N'-diacetic acid Neoplasm Metastasis Nodes, Lymph Parotid Gland Patients Physicians Prostate Radiologist Radionuclide Imaging Scan, CT PET
4
Mitigating Center-Specific Factors in Model Deployment
As our models are of most interest when deployed across centers, it is important to address the potential for center specific factors in the data during the fitting process. To address these, we have deployed the ComBat Algorithm [[22] (link), [23] (link), [24] (link), [25] , [26] (link)] to correct for potential center effects. As shown in Supplementary Fig. 1, there are batch effects present between our training and test data, including with the important parameter of mean dose to the parotid gland. At the same time, to ensure model generalizability across centers, care must be taken such that the test set is as independent as possible to the training set (ideally from a difference center). Therefore, batch effect correction was necessary.

Gradient direction (blue arrow) and magnitude (colour map) as D50 and n are varied. Depending on choice of initial guess, the gradients will lead in opposite directions. This behavior is the likely cause of GD failing in several instances to fit the LKB model. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Center specific effects can be treated similarly to batch effects in microarray expression because the ComBat algorithm’s transformation correcting for batch effect is mathematically similar regardless of the source of variation. Therefore, ComBat is well suited to correct for these effects as has been done in other studies [[22] (link), [25] , [26] (link)].
Samant P., Ruysscher D.D., Hoebers F., Canters R., Hall E., Nutting C., Maughan T, & Van den Heuvel F. (2023). Machine learning for normal tissue complication probability prediction: Predictive power with versatility and easy implementation. Clinical and Translational Radiation Oncology, 39, 100595.
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Publication 2023
Microarray Analysis Parotid Gland
5
Carcass Inspection for Zoonotic Diseases
Thorough PMI of carcasses/meats (head, pluck, organs and muscles) was conducted as described by Biffa et al. [37 (link)] and Woldemariyam et al [38 (link)] to determine the presence of lesions of common zoonotic or economically important livestock diseases such as bovine tuberculosis, contagious bovine pleuro-pneumonia, porcine cysticercosis, contagious caprine pleuro-pneumonia and fascioliasis. A minimum sample size of 385 for each of the animal/carcass types was computed for the purposes of PMI study, using the Raosoft® sample size calculator freely available online at http://www.raosoft.com/samplesize.htm. The sample size computation assumed 50% prevalence (since there is no report on the prevalence of the lesions in the Southeast Nigeria, to the best of our knowledge), 5% error margin and 95% confidence level. Carcasses inspected were randomly selected. Systematic sampling was used to select one in every five carcass (for each species: cattle, pigs or goats). However, the first carcass for each FPA type to be inspected was selected by simple random sampling (toss of coin, the display of head meant yes–to be sampled). Each selected carcass was then subjected to PMI. The PMI protocol involved visual inspection, palpation and incision of organs/tissues (massetter muscle, tongue, lungs, tracheal, liver, heart, intercostal muscle, spleen and the kidneys). Also, the retropharyngeal, tracheobronchial, mediastinal, mandibular, parotid and prescapular lymph nodes were palpated, longitudinally incised and inspected. Diseased carcasses/organs/meats were weighed and wholly or partially condemned, depending on the severity of the lesion. Whole carcass condemnation involves total condemnation while partial condemnation means passing the carcass as fit for human consumption only after the observed lesions were trimmed-off, or the carcasses were subjected to further treatment. Economic losses associated with the condemned meats were estimated based on the weight of the condemned meant and the prevailing average market prices of beef, pork, and chevon (2500 Naira/ 6 USD) in the study area. The monetary values were calculated in Nigerian Naira and converted to US dollar based on the official exchange rate of 416 Naira per US dollar.
Njoga E.O., Ilo S.U., Nwobi O.C., Onwumere-Idolor O.S., Ajibo F.E., Okoli C.E., Jaja I.F, & Oguttu J.W. (2023). Pre-slaughter, slaughter and post-slaughter practices of slaughterhouse workers in Southeast, Nigeria: Animal welfare, meat quality, food safety and public health implications. PLOS ONE, 18(3), e0282418.
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Publication 2023
Animals Beef Cattle Cattle Diseases Cysticercosis Fascioliasis Goat Head Heart Homo sapiens Intercostal Muscle Kidney Liver Livestock Lung Mandible Meat Mediastinum Muscle Tissue Nodes, Lymph Palpation Parotid Gland Pigs Pneumonia Pork Spleen Sus scrofa Tissues Tongue Trachea Tuberculosis Tuberculosis, Bovine

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More about "Parotid Gland"

The parotid gland is a crucial component of the salivary gland system, responsible for producing saliva that aids in chewing, swallowing, and digestion.
This major salivary gland is located in front of and below the ear, and its importance extends beyond its primary functions.
Researchers exploring the parotid gland may encounter a variety of diseases and conditions affecting this structure, including inflammation, tumors, and infections.
These medical challenges require a thorough understanding of the gland's anatomy and physiology, as well as the latest advancements in research protocols and techniques.
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By harnessing the power of AI-driven optimization and accessing a wealth of research protocols, scientists can delve deeper into the intricacies of the parotid gland, uncover new insights, and drive advancements in the field of salivary gland biology and related medical applications.