Sustentacular Cells Research Articles

An Empirical Cross-Sectional Study to Identify the Olfactory and Gustatory Effects of SARS-CoV-2 – A Social Analysis

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a glycan-coated coronavirus with an exposed receptor-binding domain (RBD), capable of binding to the angiotensin-converting enzyme-2 (ACE2) receptors and entering the cell through the cleavage of the spike proteins by the extracellular host enzyme Transmembrane serine protease 2 (TMPRSS2). The severity of the infection is directly associated with loss of taste (ageusia) and loss of smell, varying from hyposmia (reduced perception of smell) to anosmia (complete loss of smell). The mechanisms underlying the independent symptoms remain inconclusive; however, have been linked to sustentacular cell infection, changes in the olfactory bulb and subcortical regions of the brain, defects in the respiratory centres of the central nervous system and cerebral glucose abnormalities. The survey for this cross-sectional study was conducted in 2021 and involved 126 individuals who were exposed to or tested positive for COVID-19, through the Reverse transcription polymerase chain reaction (RT-PCR). 6.3% of covid-negative and 34.9% covid-positive individuals exposed to COVID-19, experienced anosmia and ageusia. This study aims to identify patterns in symptoms presented when an individual is infected with COVID-19; focusing on the correlation between anosmia and ageusia and associated visual impairments or cognitive difficulties. The understanding of varied symptom combinations observed amongst individuals differing in age, sex, comorbidities or vaccination status could aid doctors and healthcare practitioners to provide a prognosis specific to the subset to which the patients belong, depending on their symptom combinations and severity for the same.

Immunohistochemical analysis of extracellular signal-regulated kinase expression in mature and immature bulls' testes and epididymides.

Extracellular signal-regulated kinase (ERK) has been implicated inmammalian testicular and epididymal development. This study aimed toinvestigate ERK expression inthe immature and mature testes and epididymides ofbulls. Weevaluated ERK expression using immunoblot analysis and immunohistochemistry. Immunoblot analysis revealed that immature bull testes and epididymides had higher phosphorylated ERK (pERK) expression than mature bull testes and epididymides. pERK immunoreactivity was higher inimmature epididymides than inimmature testes. pERK was localised mostly inspermatogonia, undifferentiated sustentacular (Sertoli) cells, and interstitial (Leydig) cells inimmature testes, aswell asin some spermatocytes and spermatids inmature testes. Inimmature epididymides, the body and tail had higher pERK expression than the head, whereas pERK was broadly distributed throughout the stereocilia, basal cells, and connective tissues. pERK distribution inthe head ofmature epididymides was similar tothat inimmature epididymides, whereas few connective tissue cells were expressed inthe body and tail ofmature epididymides. Collectively, these results suggest that ERK isexpressed inthe testis and epididymis ofimmature and mature bulls with varying intensities, and therole ofERK inmale reproductive organs may include the specific function ofits development.

Knockout of angiotensin converting enzyme-2 receptor leads to morphological aberrations in rodent olfactory centers and dysfunctions associated with sense of smell.

Neuronal morphological characterization and behavioral phenotyping in mouse models help dissecting neural mechanisms of brain disorders. Olfactory dysfunctions and other cognitive problems were widely reported in asymptomatic carriers and symptomatic patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This led us to generate the knockout mouse model for Angiotensin Converting Enzyme-2 (ACE2) receptor, one of the molecular factors mediating SARS-CoV-2 entry to the central nervous system, using CRISPR-Cas9 based genome editing tools. ACE2 receptors and Transmembrane Serine Protease-2 (TMPRSS2) are widely expressed in the supporting (sustentacular) cells of human and rodent olfactory epithelium, however, not in the olfactory sensory neurons (OSNs). Hence, acute inflammation induced changes due to viral infection in the olfactory epithelium may explain transient changes in olfactory detectabilities. As ACE2 receptors are expressed in different olfactory centers and higher brain areas, we studied the morphological changes in the olfactory epithelium (OE) and olfactory bulb (OB) of ACE2 KO mice in comparison with wild type animals. Our results showed reduced thickness of OSN layer in the OE, and a decrease in cross-sectional area of glomeruli in the OB. Aberrations in the olfactory circuits were revealed by lowered immunoreactivity toward microtubule associated protein 2 (MAP2) in the glomerular layer of ACE2 KO mice. Further, to understand if these morphological alterations lead to compromised sensory and cognitive abilities, we performed an array of behavioral assays probing their olfactory subsystems' performances. ACE2 KO mice exhibited slower learning of odor discriminations at the threshold levels and novel odor identification impairments. Further, ACE2 KO mice failed to memorize the pheromonal locations while trained on a multimodal task implying the aberrations of neural circuits involved in higher cognitive functions. Our results thus provide the morphological basis for the sensory and cognitive disabilities caused by the deletion of ACE2 receptors and offer a potential experimental approach to study the neural circuit mechanisms of cognitive impairments observed in long COVID.

Olfactory alterations in long COVID

Olfactory anosmia is the complete loss of the sense of smell, while hyposmia is the partial loss of smell. SARS-CoV-2 is the pathogen responsible for COVID-19. The virus is composed of the membrane, envelope, and spike protein. In the physiology of smell, odoriferous substances bind to proteins secreted by sustentacular cells to be processed by olfactory receptor neurons. Olfactory dysfunction is one of the main manifestations of COVID-19. The duration of persistent symptoms in long COVID is longer in patients who presented severe symptoms compared to those with mild or moderate disease. Therefore, all known risk factors for severe COVID-19, such as obesity or advanced age, fit the risk profile for long COVID.

COVID-19 Induced Enantiopathy to Hyperosmia (P6-10.005)

<h3>Objective:</h3> Pathophysiology behind reduced olfactory ability in hyperosmic individuals. <h3>Background:</h3> COVID-19 infection as an enantiopathy to hyperosmia has not been described. <h3>Design/Methods:</h3> A 63 year-right-handed male presented with hyperosmia of 150% of normal whereby aromas appeared distorted and disgusting. Shortly, he tested positive for COVID-19 which led to a resolution of his hyperosmia. Alcohol Sniff Test scores fluctuated between zero and three (anosmia). Gradually, his smell improved from 80% and 100% of normal. However, post COVID-19 infection, it returned to 130% of normal. <h3>Results:</h3> Neurological abnormalities: Olfactory Testing: Odor Discrimination Memory Test: Total 7/12 (hyposmia). Bilateral Olfactory Threshold Testing to Phenylethyl Alcohol: 3 (hyposmia). Taste Threshold and Suprathreshold Testing: Mild hypogeusia to Sucrose. Ageusia to Hydrochloric acid, urea and propothiocarbamide. Olfactometer Identification Testing: Left nostril: 10 (anosmia), Right nostril: 8 (anosmia). <h3>Conclusions:</h3> The mechanism whereby COVID-19 acts to reduce olfactory ability in normosmic individuals has been postulated as viral involvement of olfactory nerve at olfactory bulb (Lechien, 2020), pathology of sustentacular cells (Zhang, 2021), olfactory receptor site destruction (Xu, 2022) vasculopathy/arteriopathy of cranial nerve or central connections of olfactory nerve (Parry, 2020) or inflammatory response induced destruction of lamina propria and olfactory nerve apoptosis (Lechien, 2020). The same may have incited a reduced olfaction in hyperosmic individuals-such may be under grouped as understanding the pathophysiology of this subject’s hyperosmia. Perceived hyperosmia is often objectively hyposmic: pathology of inhibiting the inhibitory olfactory discharges that result in enhancement of perceived odor (Kalita, 2022). Elimination of hyperosmia reduces functionality of remaining normosmic neurons which then became relatively hyposmic, but were perceived as normal due to lack of the inhibitory factors. Recovery of hyperosmia upon recovery of olfactory function from COVID-19 would be consistent with such a postulation. Of those with preexisting chemosensory dysfunction, query as to impact of COVID-19 on remaining sensory function is warranted. <b>Disclosure:</b> Mrs. Kalita has nothing to disclose. Miss Birwatkar has nothing to disclose. Dr. Hirsch has nothing to disclose.

Zika virus leads to olfactory disorders in mice by targeting olfactory ensheathing cells.

Zika virus (ZIKV) is an emerging arbovirus of the genus flavivirus that is associated with congenital Zika syndrome (CZS) in newborns. A wide range of clinical symptoms including intellectual disability, speech delay, coordination or movement problems, and hearing and vision loss, have been well documented in children with CZS. However, whether ZIKV can invade the olfactory system and lead to post-viral olfactory dysfunction (PVOD) remains unknown. We investigated the susceptibility and biological responses of the olfactory system to ZIKV infection using mouse models and human olfactory organoids derived from patient olfactory mucosa. We demonstrate that neonatal mice infected with ZIKV suffer from transient olfactory dysfunction when they reach to puberty. Moreover, ZIKV mainly targets olfactory ensheathing cells (OECs) and exhibits broad cellular tropism colocalizing with small populations of mature/immature olfactory sensory neurons (mOSNs/iOSNs), sustentacular cells and horizontal basal cells in the olfactory mucosa (OM) of immunodeficient AG6 mice. ZIKV infection induces strong antiviral immune responses in both the olfactory mucosa and olfactory bulb tissues, resulting in the upregulation of proinflammatory cytokines/chemokines and genes related to the antiviral response. Histopathology and transcriptomic analysis showed typical tissue damage in the olfactory system. Finally, by using an air-liquid culture system, we showed that ZIKV mainly targets sustentacular cells and OECs and support robust ZIKV replication. Our results demonstrate that olfactory system represents as significant target for ZIKV infection, and that PVOD may be neglected in CZS patients. Stated in the acknowledgment.

Pericytes may facilitate SARS-CoV-2 entry into the nervous system

Objective: Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified, the neurotropic properties of the causative virus, severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2), remain unknown. We sought to identify the susceptible cell types and potential routes of SARS-CoV-2 entry into the central nervous system, olfactory system, and respiratory system. Methods: We collected single-cell RNA data from normal brain and nasal epithelium specimens, along with bronchial, tracheal, and lung specimens in public datasets. The susceptible cell types that express SARS-CoV-2 entry genes were identified using single-cell RNA sequencing and the expression of the key genes at protein levels was verified by immunohistochemistry. We compared the coexpression patterns of the entry receptor angiotensin-converting enzyme 2 (ACE2) and the spike protein priming enzyme transmembrane serine protease (TMPRSS)/cathepsin L among the specimens. Results: The SARS-CoV-2 entry receptor ACE2 and the spike protein priming enzyme TMPRSS/cathepsin L were coexpressed by pericytes in brain tissue; this coexpression was confirmed by immunohistochemistry. In the nasal epithelium, ciliated cells and sustentacular cells exhibited strong coexpression of ACE2 and TMPRSS. Neurons and glia in the brain and nasal epithelium did not exhibit coexpression of ACE2 and TMPRSS. However, coexpression was present in ciliated cells, vascular smooth muscle cells, and fibroblasts in tracheal tissue; ciliated cells and goblet cells in bronchial tissue; and alveolar epithelium type 1 cells, AT2 cells, and ciliated cells in lung tissue. Conclusion: Neurological symptoms in patients with coronavirus disease 2019 could be associated with SARS-CoV-2 invasion across the blood–brain barrier via pericytes. Additionally, SARS-CoV-2–induced olfactory disorders could be the result of localized cell damage in the nasal epithelium.

Human Nasal Epithelium Damage as the Probable Mechanism Involved in the Development of Post-COVID-19 Parosmia.

Since the beginning of the COVID-19 pandemic, understanding the physiopathological mechanisms of its manifestations has been crucial to understand the disease and its implications. As the disease evolved, post-infection complications have arisen such as olfactory dysfunctions including parosmia in which odourants are perceived in a distorted or an unpleasant way. In this article, we attempt to clarify these mechanisms and the role of human nasal epithelium in the development of post-COVID-19 parosmia. The mechanisms by which SARS-CoV-2 generates olfactory dysfunction have not been elucidated, and multiple theories have been proposed pointing to the sustentacular cells of the olfactory epithelium as the main probable target of the virus. Establishing the main physiopathological mechanism of post-COVID-19 parosmia will set a path for further investigations and determine treatment and preventive options for patients who have been reported to be extensively affected in multiple aspects of their lives such as eating habits and mental health.

Development of an olfactory epithelial organoid culture system based on small molecule screening

Olfactory epithelium, which detects and transmits odor signals, is critical for the function of olfactory system. Olfactory epithelium is able to recover spontaneously after injury under normal circumstances, but this ability is dampened in certain diseases or senility, which causes olfactory dysfunction. The olfactory epithelium consists of basal cells, sustentacular cells and olfactory sensory neurons. In order to develop an olfactory epithelial organoid containing multiple olfactory cell types in vitro, we used three-dimensional culture model and small molecules screening. This organoid system consists of horizontal basal-like cells, globose basal-like cells, sustentacular-like cells and olfactory sensory neurons-like cells. Through statistical analysis of clone diameter, immunofluorescence staining and qPCR detection of the expression level of related marker genes. We identified a series of growth factors and small molecule compounds that affected the proliferation, composition and gene expression of the organoids. CHIR-99021, an activator of Wnt signaling pathway, increased the colony formation and proliferation rate of olfactory epithelial organoids and the expression level of marker genes of olfactory sensory neurons-like cells. In addition, each factor in the culture system increased the proportion of c-Kit-positive globose basal-like cell colonies in organoids. Moreover, EGF and vitamin C were both beneficial to the expression of horizontal basal-like cell marker genes in organoids. The established olfactory epithelial organoid system mimicked the process of olfactory epithelial stem cells differentiating into various olfactory epithelial cell types, thus providing a research model for studying olfactory epithelial tissue regeneration, the pathological mechanism of olfactory dysfunction and drug screening for olfactory dysfunction treatment.

The Luminescence Hypothesis of Olfaction.

A new hypothesis for the mechanism of olfaction is presented. It begins with an odorant molecule binding to an olfactory receptor. This is followed by the quantum biology event of inelastic electron tunneling as has been suggested with both the vibration and swipe card theories. It is novel in that it is not concerned with the possible effects of the tunneled electrons as has been discussed with the previous theories. Instead, the high energy state of the odorant molecule in the receptor following inelastic electron tunneling is considered. The hypothesis is that, as the high energy state decays, there is fluorescence luminescence with radiative emission of multiple photons. These photons pass through the supporting sustentacular cells and activate a set of olfactory neurons in near-simultaneous timing, which provides the temporal basis for the brain to interpret the required complex combinatorial coding as an odor. The Luminescence Hypothesis of Olfaction is the first to present the necessity of or mechanism for a 1:3 correspondence of odorant molecule to olfactory nerve activations. The mechanism provides for a consistent and reproducible time-based activation of sets of olfactory nerves correlated to an odor. The hypothesis has a biological precedent: an energy feasibility assessment is included, explaining the anosmia seen with COVID-19, and can be confirmed with existing laboratory techniques.

SARS-CoV-2 infection of sustentacular cells disrupts olfactory signaling pathways.

Loss of olfactory function has been commonly reported in SARS-CoV-2 infections. Recovery from anosmia is not well understood. Previous studies showed that sustentacular cells, and occasionally olfactory sensory neurons (OSNs) in the olfactory epithelium (OE), are infected in SARS-CoV-2-infected patients and experimental animals. Here, we show that SARS-CoV-2 infection of sustentacular cells induces inflammation characterized by infiltration of myeloid cells to the olfactory epithelium and variably increased expression of proinflammatory cytokines. We observed widespread damage to, and loss of cilia on, OSNs, accompanied by downregulation of olfactory receptors and signal transduction molecules involved in olfaction. A consequence of OSN dysfunction was a reduction in the number of neurons in the olfactory bulb expressing tyrosine hydroxylase, consistent with reduced synaptic input. Resolution of the infection, inflammation, and olfactory dysfunction occurred over 3-4 weeks following infection in most but not all animals. We also observed similar patterns of OE infection and anosmia/hyposmia in mice infected with other human coronaviruses such as SARS-CoV and MERS-CoV. Together, these results define the downstream effects of sustentacular cell infection and provide insight into olfactory dysfunction in COVID-19-associated anosmia.

Cauda Equina Neuroendocrine Tumors: Distinct Epithelial Neuroendocrine Neoplasms of Spinal Origin.

The tumor formerly known as "cauda equina paraganglioma" was recently renamed as cauda equina neuroendocrine tumor (CENET) based on distinct biological and genetic properties. Nevertheless, it remains insufficiently understood. For this study, we retrieved CENETs (some previously reported), from the pathology files of 3 institutions; we examined their immunohistochemical profile, including common neuroendocrine tumor-associated hormones and transcription factors. We identified 24 CENETs from 7 female and 17 male adult patients, with a median age of 47 years. Six included neurofilament-positive ganglion cells. All tumors tested were positive for INSM1, synaptophysin, chromogranin A, SSTR2, and CD56 as well as at least 1 keratin (AE1/AE3, CAM5.2); CK7 and CK20 were negative. Glial fibrillary acidic protein was negative, except for peripheral nontumoral elements. S100 protein was variable but mainly expressed in scattered sustentacular cells. All but 1 tumor tested were positive for HOXB13; several stained for SATB2, and all tumors were consistently negative for GATA3. All tumors tested were negative for transcription factors found in various other epithelial neuroendocrine neoplasms including TTF1, CDX2, PIT1, TPIT, SF1, and PAX8; staining for T-brachyury was negative. Four of 5 CENETs tested had at least focal tyrosine hydroxylase reactivity. Serotonin expression was detected in all 21 tumors tested; it was diffusely positive in 5 and had variable positivity in the remainder. A few tumors had scattered cells expressing gastrin, calcitonin, pancreatic polypeptide, and peptide YY, while glucagon, adrenocorticotropic hormone, and monoclonal carcinoembryonic antigen were negative. PSAP expression was found focally in 4 of 5 tumors examined. SDHB was consistently intact; ATRX was intact in 14 tumors and showed only focal loss in 3. The median Ki-67 labeling index was 4.5% (range: 1% to 15%). We conclude that CENET represents a distinct neuroendocrine neoplasm; the subset with ganglion cells qualifies for designation as composite gangliocytoma/neuroma-neuroendocrine tumor (CoGNET) as defined in the 2022 WHO classification of neuroendocrine neoplasms. In addition to INSM1, chromogranin, synaptophysin, and keratins, the most characteristic finding is nuclear HOXB13 expression; a subset also express SATB2. Serotonin is the most common hormone expressed. The cytogenesis and pathogenesis of these lesions remains unclear.

Persistent post-COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium.

SARS-CoV-2 causes profound changes in the sense of smell, including total smell loss. Although these alterations are often transient, many patients with COVID-19 exhibit olfactory dysfunction that lasts months to years. Although animal and human autopsy studies have suggested mechanisms driving acute anosmia, it remains unclear how SARS-CoV-2 causes persistent smell loss in a subset of patients. To address this question, we analyzed olfactory epithelial samples collected from 24 biopsies, including from nine patients with objectively quantified long-term smell loss after COVID-19. This biopsy-based approach revealed a diffuse infiltrate of T cells expressing interferon-γ and a shift in myeloid cell population composition, including enrichment of CD207+ dendritic cells and depletion of anti-inflammatory M2 macrophages. Despite the absence of detectable SARS-CoV-2 RNA or protein, gene expression in the barrier supporting cells of the olfactory epithelium, termed sustentacular cells, appeared to reflect a response to ongoing inflammatory signaling, which was accompanied by a reduction in the number of olfactory sensory neurons relative to olfactory epithelial sustentacular cells. These findings indicate that T cell-mediated inflammation persists in the olfactory epithelium long after SARS-CoV-2 has been eliminated from the tissue, suggesting a mechanism for long-term post-COVID-19 smell loss.

Glial regulators of ions and solutes required for specific chemosensory functions in Caenorhabditis elegans.

Glia and accessory cells regulate the microenvironment around neurons and primary sensory cells. However, the impact of specific glial regulators of ions and solutes on functionally diverse primary cells is poorly understood. Here, we systemically investigate the requirement of ion channels and transporters enriched in Caenorhabditis elegans Amsh glia for the function of chemosensory neurons. Although Amsh glia ablated worms show reduced function of ASH, AWC, AWA, and ASE neurons, we show that the loss of glial enriched ion channels and transporters impacts these neurons differently, with nociceptor ASH being the most affected. Furthermore, our analysis underscores the importance of K+, Cl-, and nucleoside homeostasis in the Amphid sensory organ and uncovers the contribution of glial genes implicated in neurological disorders. Our findings build a unique fingerprint of each glial enriched ion channel and transporter and may provide insights into the function of supporting cells of mammalian sensory organs.

Neutrophils play a major role in the destruction of the olfactory epithelium during SARS-CoV-2 infection in hamsters.

The loss of smell (anosmia) related to SARS-CoV-2 infection is one of the most common symptoms of COVID-19. Olfaction starts in the olfactory epithelium mainly composed of olfactory sensory neurons surrounded by supporting cells called sustentacular cells. It is now clear that the loss of smell is related to the massive infection by SARS-CoV-2 of the sustentacular cells in the olfactory epithelium leading to its desquamation. However, the molecular mechanism behind the destabilization of the olfactory epithelium is less clear. Using golden Syrian hamsters infected with an early circulating SARS-CoV-2 strain harboring the D614G mutation in the spike protein; we show here that rather than being related to a first wave of apoptosis as proposed in previous studies, the innate immune cells play a major role in the destruction of the olfactory epithelium. We observed that while apoptosis remains at a low level in the damaged area of the infected epithelium, the latter is invaded by Iba1+ cells, neutrophils and macrophages. By depleting the neutrophil population or blocking the activity of neutrophil elastase-like proteinases, we could reduce the damage induced by the SARS-CoV-2 infection. Surprisingly, the impairment of neutrophil activity led to a decrease in SARS-CoV-2 infection levels in the olfactory epithelium. Our results indicate a counterproductive role of neutrophils leading to the release of infected cells in the lumen of the nasal cavity and thereby enhanced spreading of the virus in the early phase of the SARS-CoV-2 infection.

THE GROSS AND MICROSCOPIC ANATOMY OF THE CAROTID BODY OF AN ENDOGENOUS DUCK

The carotid body in an endogenous duck was closely related to the ventral surface of the common carotid bifurcation zone caudal to the parathyroid glands. The carotid body was characterized by its compact and fusiform shape. Taking into account all carotid bodies, the mean length was 1.058 +0.95 micrometers. The blood supply of the carotid body in duck was not detected easily but caudal and cranial thyroid arteries gave many branches to it. Histologically, the carotid body of an endogenous duck was consisted of two types of cells; chief cells which occurred in groups and were invested by sustentacular cells. These cells were embedded within a connective tissue fibers to form glomic tissue. A collection of ganglionic cells were observed in the vicinity of the carotid body

A rare case of Composite Gangliocytoma/Neuroma and Neuroendocrine Tumor (CoGNET) of the Duodenum - A case report

Abstract Introduction/Objective The unique morphologic and clinical features of neuroendocrine tumors have attracted the attention of physicians, most especially pathologists for more than a century. Neuroendocrine tumor of the duodenum is a rare entity and only accounts for ~ 2% of gastrointestinal neuroendocrine tumors. Though it was initially classified as duodenal gangliocytic paraganglioma due to the presence of sustentacular cells and its association with ganglion cells, it has now been reclassified in 2022 WHO classification as “composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET) due to its clinical features and immunophenotypic characteristics. Hence, we report a rare case of CoGNET in the duodenum. Methods/Case Report We present a 72-year-old female with a past medical history of hypothyroidism, hyperlipidemia, hypertension, deep vein thrombosis, and pulmonary embolism presenting with a 1-day history of abdominal pain and vomiting. Esophagogastroduodenoscopy (EGD) was performed, and it was concerning for a duodenal mass and the specimen was biopsied. Results (if a Case Study enter NA) The biopsy consisted of multiple tan-red hemorrhagic soft tissue, which on microscopic examination showed a triphasic histological pattern which includes neuroendocrine cells, spindle-shaped Schwannian/ sustentacular cells, and neuronal ganglion cells. Immunohistochemical stains performed showed the tumor cells are strongly positive for synaptophysin, and chromogranin; moderately positive with AE1/AE3, and patchy positive with S100. Desmin, CD117, DOG-1, CD34, and GATA were all negative in the tumor cells; the Ki-67 proliferative index was 1%. These morphological and immunophenotypic features are consistent with CoGNET. Conclusion CoGNET is a rare entity in the gastrointestinal tract especially in the duodenum and given its recent reclassification in 2022 WHO classification; pathologists, surgeons, and physicians need to be aware of such rare entities to improve patient care.

Incidental Succinate Dehydrogenase (SDH) Deficient Renal Cell Carcinoma and Paraganglioma in a 24-Year-Old

Abstract Introduction/Objective Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is rare neoplasm (&amp;lt;0.2% of all RCCs) caused by SDH-subunit gene mutation, usually SDHB. Patients carrying such mutations are also predisposed to other SDH-deficient neoplasms such as paraganglioma, gastrointestinal stromal tumor, and pituitary adenoma. Here, we report a case of incidental SDH-deficient RCC and paraganglioma. Methods/Case Report A 24-year-old male without past medical or family history presented to ED for perianal abscess. Imaging showed 8-cm heterogeneous left renal mass (figure-A) and 3.3-cm mass below aortic bifurcation, highly concerning for RCC with metastasis. Biopsy of kidney mass showed nested and trabecular epithelial neoplasm with weakly eosinophilic and occasionally vacuolated cytoplasm (figure-B). Nuclei were round with smooth contour and inconspicuous nucleoli. Tumor was immunopositive for PAX8, e-cadherin, P504S, and CD10, while negative for CK7, CD117, and Melan-A. SDHB immunostain was negative in tumor with intact staining in intervening endothelium. Findings were consistent with SDH-deficient RCC. Biopsy of pelvic mass showed low-grade neoplasm that was immunopositive for synaptophysin, chromogranin, and GATA3, with S100-positive sustentacular cells, consistent with paraganglioma. Patient underwent radical nephrectomy which revealed 7.5-cm, well-circumscribed, tan-red, predominantly solid mass with few cysts. Histologically, tumor had thin fibrous capsule and morphologically similar to biopsy. Tumor was limited to kidney without necrosis, sarcomatoid/rhabdoid differentiation, or vascular invasion. Results (if a Case Study enter NA) NA. Conclusion SDH-deficient RCC is rare low-grade entity with risk of metastasis and development of other neoplasms, which requires continued follow-up and potential genetic testing for patient and family members. Therefore, including SDH-deficient RCC in differential diagnosis of eosinophilic renal neoplasms is essential.

Management of Anosmia in COVID-19: A Comprehensive Review.

With the evolving understanding of COVID-19, a thorough analysis of the effects of this unique coronavirus on the affected people's olfactory abilities could highlight the disease's specific course of treatment. Researchers have discovered that the neurological side effects of SARS-CoV-2 infection include acute anosmia and ageusia. This work aims to review the relevant mechanisms, provide information on COVID-19-related anosmia, and suggest a novel approach to treating long-term anosmia brought on by coronavirus disease. For that, we did a thoroughliterature assessment of the subject from various online resources, including PubMed, Scopus, and Google Scholar. We evaluated the publications that described anosmia in COVID-19 and its management. In patients with SARS-CoV-2 infections, the angiotensin-converting enzyme two receptor plays a crucial role in the anosmia process. Olfactory systems are directly harmed by new coronaviruses when they connect with sustentacular cells' ACE-2 (Angiotensin converting enzyme-2) receptors. Other suggested processes include the virus's infiltration of the olfactory nerve and the ensuing local inflammation. Therefore, neuroprotective, anti-inflammatory, or depolarizing medications may be helpful for COVID-19 individuals who have lost their sense of smell. According to the available data, we found outolfactory training, topical or oral corticosteroids, caffeine, insulin, or minocycline may effectively treat COVID-19 odor loss. A novel method of treating long-term COVID-19 with persistent anosmia can be suggested based on recent investigations. The path to effective anosmia management is still somewhat hazy, but there is hope that we can find the right treatment plan with the right clinical trials and additional research. People who lost their sense of smell during COVID-19 can be reassured that recovery is typically possible.

Long-term in vitro 2D-culture of SDHB and SDHD-related human paragangliomas and pheochromocytomas.

The neuroendocrine tumours paraganglioma and pheochromocytoma (PPGLs) are commonly associated with succinate dehydrogenase (SDH) gene variants, but no human SDH-related PPGL-derived cell line has been developed to date. The aim of this study was to systematically explore practical issues related to the classical 2D-culture of SDH-related human paragangliomas and pheochromocytomas, with the ultimate goal of identifying a viable tumour-derived cell line. PPGL tumour tissue/cells (chromaffin cells) were cultured in a variety of media formulations and supplements. Tumour explants and dissociated primary tumour cells were cultured and stained with a range of antibodies to identify markers suitable for use in human PPGL culture. We cultured 62 PPGLs, including tumours with confirmed SDHB, SDHC and SDHD variants, as well as several metastatic tumours. Testing a wide range of basic cell culture media and supplements, we noted a marked decline in chromaffin cell numbers over a 4-8 week period but the persistence of small numbers of synaptophysin/tyrosine hydroxylase-positive chromaffin cells for up to 99 weeks. In cell culture, immunohistochemical staining for chromogranin A and neuron-specific enolase was generally negative in chromaffin cells, while staining for synaptophysin and tyrosine hydroxylase was generally positive. GFAP showed the most consistent staining of type II sustentacular cells. Of the media tested, low serum or serum-free media best sustained relative chromaffin cell numbers, while lactate enhanced the survival of synaptophysin-positive cells. Synaptophysin-positive PPGL tumour cells persist in culture for long periods but show little evidence of proliferation. Synaptophysin was the most consistent cell marker for chromaffin cells and GFAP the best marker for sustentacular cells in human PPGL cultures.