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Functional magnetic resonance imaging (fMRI) suggests that the hypoxic ventilatory response is facilitated by the AMP-activated protein kinase (AMPK), not at the carotid bodies, but within a subnucleus (Bregma -7.5 to -7.1 mm) of the nucleus tractus solitarius that exhibits right-sided bilateral asymmetry. Here, we map this subnucleus using cFos expression as a surrogate for neuronal activation and mice in which the genes encoding the AMPK-α1 (Prkaa1) and AMPK-α2 (Prkaa2) catalytic subunits were deleted in catecholaminergic cells by Cre expression via the tyrosine hydroxylase promoter. Comparative analysis of brainstem sections, relative to controls, revealed that AMPK-α1/α2 deletion inhibited, with right-sided bilateral asymmetry, cFos expression in and thus activation of a neuronal cluster that partially spanned three interconnected anatomical nuclei adjacent to the area postrema: SolDL (Bregma -7.44 mm to -7.48 mm), SolDM (Bregma -7.44 mm to -7.48 mm) and SubP (Bregma -7.48 mm to -7.56 mm). This approximates the volume identified by fMRI. Moreover, these nuclei are known to be in receipt of carotid body afferent inputs, and catecholaminergic neurons of SubP and SolDL innervate aspects of the ventrolateral medulla responsible for respiratory rhythmogenesis. Accordingly, AMPK-α1/α2 deletion attenuated hypoxia-evoked increases in minute ventilation (normalised to metabolism), reductions in expiration time, and increases sigh frequency, but increased apnoea frequency during hypoxia. The metabolic response to hypoxia in AMPK-α1/α2 knockout mice and the brainstem and spinal cord catecholamine levels were equivalent to controls. We conclude that within the brainstem an AMPK-dependent, hypoxia-responsive subnucleus partially spans SubP, SolDM and SolDL, namely SubSol-HIe, and is critical to coordination of active expiration, the hypoxic ventilatory response and defence against apnoea. [ABSTRACT FROM AUTHOR]

Introduction: Carotid body tumors are rare neoplasms with malignant potential. We aim to follow up on our initial experience published in 2015 and compare the occurrence of complications and postoperative outcomes with the use of retrocarotid dissection (RCD) against the standard caudocranial (SCCD) technique. Methods: This was an observational, case–control study in which we analyzed all of the carotid body tumor resections performed from 1986 to 2022. Parametric and nonparametric tests were used accordingly. Statistical analysis was performed on Stata 17. Results: A total of 181 surgical procedures were included, mean age was 56 years (± 13.63), and 168 (93%) were performed in women. The mean medio-lateral diameter was larger in the RCD group (2.85 ± 1.57 cm vs 1.93 ±1.85 cm; p = 0.002) and presurgical embolization was more frequently performed in the SCCD group (27.5% vs 0.7%; p < 0.001). A total of 40 (22.09%) resections were performed using the SCCD technique. In contrast, in 141 (77.91%) procedures the RCD technique was used. The mean surgical time in the RCD group was lower (197.37 ± 70.56 min vs 232 ± 98.34 min; p = 0.01). No statistically significant difference was found between SCCD and RCD in terms of vascular lesions (n = 20 [11.04%], 15% vs 9%, respectively; p = 0.36), transient or permanent nerve injuries (25% vs 33%, respectively; p = 0.31), or mean intraoperative bleeding (SCCD: 689.95 ± 680.05 mL vs RCD: 619.64 ± 837.94 mL; p > 0.05). Conclusions: RCD appears to be a safe and equivalent alternative to the standard caudocranial approach in terms of intraoperative bleeding or vascular lesions, with a sustained, significant decrease in surgical time. [ABSTRACT FROM AUTHOR]

Carotid body tumors (CBTs) are neoplasms that occur at the bifurcation of the carotid artery and are pathologically classified as paragangliomas. In the 4th edition of the WHO classification, paragangliomas are categorized as neoplasms with malignant potential. Clinically, about 5% of CBTs present with malignant features such as metastasis. Currently, it is challenging to distinguish between tumors with benign courses and those that present malignantly. Recent advances in genetic testing have elucidated the genetic characteristics of paragangliomas, including carotid body tumors. Over 20 genes have been identified as being involved in tumor development. Particularly in head and neck paragangliomas, abnormalities in genes related to succinate dehydrogenase are frequently observed. Research is ongoing to understand the mechanisms by which these genes contribute to tumor development. The definitive treatment for CBTs is surgical resection. These tumors are prone to bleeding and often adhere firmly to the carotid artery, making intraoperative bleeding control challenging. The risk of lower cranial nerve paralysis is relatively high, and there is a risk of stroke because of manipulation of the carotid artery. Preoperative evaluation with angiography is essential, and a multi-disciplinary surgical team approach is necessary. In cases where the tumor is difficult to resect or has metastasized, radiation therapy or chemotherapy are employed. Clinical trials involving targeted molecular therapies and radiopharmaceuticals have recently been conducted, with some applied clinically. The development of various new treatments is anticipated, providing hope for therapeutic options in refractory cases. [ABSTRACT FROM AUTHOR]

The patient, a 40-year-old woman, was diagnosed as having a functional right vagal paraganglioma (PGL) 15 years after undergoing resection for a retroperitoneal PGL. 123I-MIBG scintigraphy showed no accumulation, but as the blood noradrenaline and urinary normetanephrine concentrations were elevated, the tumor was judged as being functional, and surgery was scheduled. The patient was started on doxazosin infusion and embolization of the tumor feeding vessel was performed before the surgery. Intraoperative examination showed that the tumor was contiguous with the vagal nerve, necessitating combined resection of the vagal nerve with the tumor. Postoperatively, the catecholamine levels returned to normal range. Histopathologically, the tumor was diagnosed as a moderately differentiated, intermediate-malignant-grade PGL, with a GAPP score of 4 to 6. No non-chromaffin tissue was observed in the tumor background, so that the functional vagal PGL was considered as a sporadic metachronous tumor rather than as a metastasis from the retroperitoneal PGL. More than half of head and neck paragangliomas (HNPGLs) are reported to arise in the carotid body, and about 5% from the vagal nerve. In addition, HNPGLs rarely produce catecholamines. Herein, we consider the relationship with the previously resected retroperitoneal PGL based on a review of the literature. [ABSTRACT FROM AUTHOR]

The Olfr78 gene encodes a G-protein-coupled olfactory receptor that is expressed in several ectopic sites. Olfr78 is one of the most abundant mRNA species in carotid body (CB) glomus cells. These cells are the prototypical oxygen (O2) sensitive arterial chemoreceptors, which, in response to lowered O2 tension (hypoxia), activate the respiratory centers to induce hyperventilation. It has been proposed that Olfr78 is a lactate receptor and that glomus cell activation by the increase in blood lactate mediates the hypoxic ventilatory response (HVR). However, this proposal has been challenged by several groups showing that Olfr78 is not a physiologically relevant lactate receptor and that the O2-based regulation of breathing is not affected in constitutive Olfr78 knockout mice. In another study, constitutive Olfr78 knockout mice were reported to have altered systemic and CB responses to mild hypoxia. To further characterize the functional role of Olfr78 in CB glomus cells, we here generated a conditional Olfr78 knockout mouse strain and then restricted the knockout to glomus cells and other catecholaminergic cells by crossing with a tyrosine hydroxylase-specific Cre driver strain (TH-Olfr78 KO mice). We find that TH-Olfr78 KO mice have a normal HVR. Interestingly, glomus cells of TH-Olfr78 KO mice exhibit molecular and electrophysiological alterations as well as a reduced dopamine content in secretory vesicles and neurosecretory activity. These functional characteristics resemble those of CB neuroblasts in wild-type mice. We suggest that, although Olfr78 is not essential for CB O2 sensing, activation of Olfr78-dependent pathways is required for maturation of glomus cells. Graphical Abstract [ABSTRACT FROM AUTHOR]

The carotid body paraganglioma is a rare benign neoplasm arising from the chemoreceptor cells of the carotid bulb. The carotid body has the largest collection of paraganglia in the head and neck with 60–70% of head and neck paraganglioma. Paraganglia are clusters of cells originating from the neural crest with histological and cytochemical characteristics of neuroendocrine cells. It is mostly asymptomatic in early presentation but become symptomatic and difficult to manage when the tumor is large. We present a case of a 26-year-old male who presented with a painless, pulsatile, progressively increasing left lateral neck swelling of 5 years duration with Shamblin IIIa. The diagnosis of the tumor was confirmed based on clinical features, histology, and radiological findings. We had difficult surgical dissection of the tumor with neurovascular damage. [ABSTRACT FROM AUTHOR]

Background: Carotid body paraganglioma (CBP) is a rare, highly vascularized, and slow-growing neuroendocrine tumor. Surgical resection is the definitive treatment for CBP, however, it remains challenging due to the tumor's proximity to critical blood vessels and cervical cranial nerves. This study aimed to document the characteristics of CBP and examine the clinical outcomes of patients following surgical extirpation of CBP. Methods: This is a single-center retrospective review analyzed patients who underwent CBP extirpation. We examined the patient demographics, preoperative clinical features, tumor characteristics, levels of catecholamines and their metabolites in the serum and urine. Surgeries were performed by one vascular surgeon with follow-ups at 1,3,6 months and yearly thereafter. Logistic regression analysis was conducted to identify risk factors associated with the occurrence of either permanent or temporary cervival cranial nerve palsy (CNP). Results: From September 2020 to February 2023, this study examined 21 cases of CBP removal surgeries that were carried out in 19 patients. The mean age of the patients was 38.9 ± 10.9 years and the percentage of males was 57.1% (n = 12). The most common preoperative clinical feature was painless neck mass (n = 12; 57.1%). Complete resection was achieved in 20 cases; excluding one case with pathologically proven sclerosing paraganglioma. Vascular procedures were performed in four cases (ECA resection, n = 2; primary repair of ICA tear without carotid shunting, n = 1; and ICA patch angioplasty with carotid shunting, n = 1). Temporary cranial neurologic complications, specifically aspiration and hoarseness occurred in four (19.0%), and three (14.3%) cases, respectively. Hoarseness associated with permanent CNP persisted for more than 6 months in two cases (9.5%). No recurrence or mortality was observed during the follow-up period. Conclusions: Surgical resection is the primay treatment approach for CBP; however, it poses risks of vascular or cervical CNP. The intraoperative estimated blood loss was the only identified risk factor for CNP. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck paragangliomas (HNPGLs) are rare and have high rates of genetic mutations. SDHx mutations currently account for the vast majority of mutations identified in HNPGLs, and SDHB and SDHD are the two most common types. Surgery remains the definitive treatment, while radiation therapy is being increasingly used as an adjuvant or primary treatment for surgically challenging or inoperable cases. Our study provided clinical and outcome data on a large cohort of patients with HNPGLs and the results can help provide guidance on improving the care and outcomes of patients with HNPGL. Head and neck paragangliomas (HNPGLs) are rare and have high rates of genetic mutations. We conducted a retrospective review of 187 patients with 296 PGLs diagnosed between 1974 and 2023. The mean age of diagnosis was 48.8 years (range 10 to 82) with 69.0% female and 26.5% patients with multiple PGLs. Among 119 patients undergoing genetic testing, 70 (58.8%) patients had mutations, with SDHB (30) and SDHD (26) being the most common. The rates of metastasis and recurrence were higher among patients with SDHB mutations or SDHD mutations associated with multiple PGLs. Metabolic evaluation showed elevated plasma dopamine levels were the most common derangements in HNPGL. MRI and CT were the most common anatomic imaging modalities and DOTATATE was the most common functional scan used in this cohort. Most patients (81.5%) received surgery as the primary definitive treatment, while 22.5% patients received radiation treatment, mostly as an adjuvant therapy or for surgically challenging or inoperable cases. Systemic treatment was rarely used in our cohort. Our single-center experience highlights the need for referral for genetic testing and metabolic evaluation and for a team-based approach to improve the clinical outcomes of patients with HNPGLs. [ABSTRACT FROM AUTHOR]

Carotid body tumor (CBT) is a rare neck tumor located at the adventitia of the common carotid artery bifurcation. The prominent pathological features of CBT are high vascularization and abnormal proliferation. However, single‐cell transcriptome analysis of the microenvironment composition and molecular complexity in CBT has yet to be performed. In this study, we performed single‐cell RNA sequencing (scRNA‐seq) analysis on human CBT to define the cells that contribute to hypervascularization and chronic hyperplasia. Unbiased clustering analysis of transcriptional profiles identified 16 distinct cell populations including endothelial cells (ECs), smooth muscle cells (SMCs), neuron cells, macrophage cells, neutrophil cells, and T cells. Within the ECs population, we defined subsets with angiogenic capacity plus clear signs of later endothelial progenitor cells (EPCs) to normal ECs. Two populations of macrophages were detectable in CBT, macrophage1 showed enrichment in hypoxia‐inducible factor‐1 (HIF‐1) and as well as an early EPCs cell‐like population expressing CD14 and vascular endothelial growth factor. In addition to HIF‐1‐related transcriptional protein expression, macrophages1 also display a neovasculogenesis‐promoting phenotype. SMCs included three populations showing platelet‐derived growth factor receptor beta and vimentin expression, indicative of a cancer‐associated fibroblast phenotype. Finally, we identified three types of neuronal cells, including chief cells and sustentacular cells, and elucidated their distinct roles in the pathogenesis of CBT and abnormal proliferation of tumors. Overall, our study provided the first comprehensive characterization of the transcriptional landscape of CBT at scRNA‐seq profiles, providing novel insights into the mechanisms underlying its formation. [ABSTRACT FROM AUTHOR]

An adequate supply of O2 is essential for the maintenance of cellular activity. Systemic or local hypoxia can be experienced during decreased O2 availability or associated with diseases, or a combination of both. Exposure to hypoxia triggers adjustments in multiple physiological systems in the body to generate appropriate homeostatic responses. However, with significant reductions in the arterial partial pressure of O2, hypoxia can be life‐threatening and cause maladaptive changes or cell damage and death. To mitigate the impact of limited O2 availability on cellular activity, O2 chemoreceptors rapidly detect and respond to reductions in the arterial partial pressure of O2, triggering orchestrated responses of increased ventilation and cardiac output, blood flow redistribution and metabolic adjustments. In mammals, the peripheral chemoreceptors of the carotid body are considered to be the main hypoxic sensors and the primary source of excitatory feedback driving respiratory, cardiovascular and autonomic responses. However, current evidence indicates that the CNS contains specialized brainstem and spinal cord regions that can also sense hypoxia and stimulate brain networks independently of the carotid body inputs. In this manuscript, we review the discoveries about the functioning of the O2 chemoreceptors and their contribution to the monitoring of O2 levels in the blood and brain parenchyma and mounting cardiorespiratory responses to maintain O2 homeostasis. We also discuss the implications of the chemoreflex‐related mechanisms in paediatric and adult pathologies. What is the topic of this review?Hypoxia is a life‐threatening condition. Specialized sensory mechanisms in the periphery and CNS respond to reduced O2 levels, triggering ventilatory and haemodynamic responses to enhance O2 uptake and delivery to the tissues.What advances does it highlight?Although anatomically distinct, both peripheral and central mechanisms should be considered when examining the homeostatic responses to hypoxia. Herein, we review past and current research on O2 monitoring in the periphery and CNS, discussing how their sensing mechanisms, pathways and interactions modify respiratory and sympathetic activities. [ABSTRACT FROM AUTHOR]

The global impact of severe acute respiratory syndrome COVID-19 has extended beyond physical health, significantly affecting mental well-being worldwide. Amid the pandemic's initial wave, COVID-19 patients exhibited symptoms of post-traumatic stress disorder and notably depressive symptoms. Alongside manifestations like delirium, confusion, agitation, and altered consciousness, prevalent mental health issues during the pandemic encompassed depression, anxiety, and insomnia. Individuals recovering from COVID-19 may face enduring psychiatric challenges post-hospital discharge, potentially linked to dopamine. Dopaminergic receptors might heighten the susceptibility of certain viruses to bind with the central nervous system, instigating viral encephalitis in the virus's early infection stages. Dopamine could also disrupt the human basal carotid body's respiratory response to hypoxia. Additionally, the virus could manipulate the immune system by elevating dopamine levels, facilitating viral entry. These findings emphasize the significance of considering dopamine's role in the diagnosis, treatment, and care of COVID-19 patients and those with diagnosed psychosis. Tailored interventions are crucial for individuals exhibiting distinctive features. Another intriguing aspect worthy of investigation is whether dopamine confers protection against COVID-19. This review article aims to elucidate the intricate relationship between the impactful COVID-19 pandemic and dopamine, shedding light on its potential implications and avenues for further exploration. [ABSTRACT FROM AUTHOR]

This study provides a single-center experience involving intracapsular dissection for Shamblin II carotid body tumors (CBTs) and compares the outcomes with the classic technique of subadventitial resection. Based on the preliminary results, it seems that the enucleation technique facilitates the dissection of carotid body tumors, offering protection to cranial nerves and the internal/external/common carotid artery by utilizing the capsule as a barrier. The classic subadventitial resection approach and the enucleation technique have comparable postoperative complications. However, it is crucial to continue following the patients who underwent these resection techniques to determine the long-term outcomes. Moreover, the enucleation technique significantly reduces surgery duration and intraoperative blood loss. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnoea (OSA) and components of metabolic syndrome (MetS) are inextricably connected. Considering the increasing burden of MetS and OSA, in the present review, we aimed to collate and summarise the potential pathophysiological mechanisms linking these pathologies. In short, obesity appears to promote OSA development via multiple pathways, some of which are not directly related to mass but rather to metabolic complications of obesity. Simultaneously, OSA promotes weight gain through central mechanisms. On the other hand, diabetes mellitus contributes to OSA pathophysiology mainly through effects on peripheral nerves and carotid body desensitization, while intermittent hypoxia and sleep fragmentation are the principal culprits in OSA-mediated diabetes. Apart from a bidirectional pathophysiological relationship, obesity and diabetes mellitus together additively increase cardiovascular risk in OSA patients. Additionally, the emergence of new drugs targeting obesity and unequivocal results of the available studies underscore the need for further exploration of the mechanisms linking MetS and OSA, all with the aim of improving outcomes in these patients. [ABSTRACT FROM AUTHOR]

The carotid body (CB), located bilaterally at the carotid artery bifurcations, is the primary sensory organ for monitoring arterial blood O2 levels. Carotid bodies are immature at birth, exhibiting low sensitivity to hypoxia, and become more sensitive with maturation during the first few weeks of neonatal life. To understand the molecular basis for the postnatal developmental hypoxic responses of CB, we isolated CBs from 5-day and 21-day-old Sprague–Dawley rats and performed RNA sequencing, which allows comprehensive analysis of gene expression. Differentially expressed genes (DEGs) were generated using Edge R, while functional enrichment analysis was performed using gene-set enrichment analysis (GSEA). Analysis of RNA-Seq data showed 2604 DEGs of the total 12,696 genes shared between neonates and adults. Of the 2604 DEGs, 924 genes were upregulated, and 1680 genes were downregulated. Further analysis showed that genes related to oxidative phosphorylation (Ox/phos) and hypoxia-signaling pathways were significantly upregulated in neonatal CBs compared to adult CBs, suggesting a possible link to differential developmental hypoxic responses seen in CB. Genes related to cytokine signaling (INFγ and TNFα) and transcription factors (CREB and NFΚB) mediated pathways were enriched in adult CBs, suggesting that expression of these pathways may be linked to developmental regulation. The RNA-Seq results were verified by analyzing mRNA changes in selected genes by qRT-PCR. Our results of enrichment analysis of biological pathways offer valuable insight into CB hypoxic sensing responses related to the development process. [ABSTRACT FROM AUTHOR]

Anurans of the genus Brachycephalus are among the smallest vertebrates in the world, due to an extreme process of miniaturization. As an example of this process, Brachycephalus species show loss of fingers, loss of the eardrum and middle ear, bone fusions, and the presence of paravertebral plates and parotic plaque. However, no studies addressing the consequences of miniaturization on internal organs, such as the lungs and heart, are currently available. Thus, this study aimed to investigate if overall small body size has affected the cardiorespiratory system. We investigated, via dissections, individuals of four Brachycephaloidea species: Brachycephalus rotenbergae, B. pitanga, Eleutherodactylus johnstonei, and Ischnocnema parva. We observed that B. rotenbergae and B. pitanga present a reduction of the atrial septum and absence of the carotid body. On the other hand, despite being a member of the sister genus to Brachycephalus (both genera belong to the Brachycephalidae), individuals of Ischnocnema present a heart with a complete septum and carotid body; this is also observed in E. johnstonei (Eleutherodactylidae). We observed that B. rotenbergae and B. pitanga have thin skin with a one to two cell thick germ layer, and their lungs likely exhibit lower blood supply when compared to individuals of the E. johnstonei and I. parva species. Based on the observed structures, we suggest that in species of Brachycephalus, respiration is performed mainly through the skin, and their lungs may have a reduced respiratory function. [ABSTRACT FROM AUTHOR]

This article, published in the Journal of Neurological Surgery, describes a surgical procedure for the removal of a large carotid body paraganglioma that had invaded the internal carotid artery. The surgeons encountered an injury to the artery during the tumor dissection, and therefore had to trap and resect the artery. They successfully reconstructed the artery using a heparin-coated vascular graft with an end-to-end "parachute" anastomosis. The procedure was confirmed using ICG angiography. The authors of the article are Joseph M. Wardell, Trong D. Hyunh, Andrea L. Castillo, Amanda N. Bosland, Richard Chan Woo Park, Cindy Sturt, and James K. Liu. [Extracted from the article]

This article, published in the Journal of Neurological Surgery, discusses the use of direct puncture embolization (DTE) in the resection of hypervascular head and neck tumors. DTE involves injecting the Onyx Liquid Embolic System directly into the tumor, reducing blood loss and complications during surgery. The study reviewed seven patients who underwent DTE prior to tumor resection, with successful embolization and minimal complications. The authors conclude that DTE is a safe and effective technique for resecting hypervascular skull base tumors, offering advantages such as lower risk of artery injury and stroke. [Extracted from the article]

Simple Summary: Carotid body tumors (CBTs) are rare tumors and only appear in 1–2 individuals per 100,000. The etiology of CBTs remains unclear; however, SDH mutations and familial inheritance have been reported to be related to CBTs. SDH complexes play crucial roles in aerobic respiration, and SDH mutations in CBTs have been reported to be associated with hypoxia. Hypoxic signaling pathways, specifically hypoxic markers, have attracted more research attention in tumor exploration. However, the existing literature on these signaling and markers lacks a systematic review. Also, therapeutic approaches in CBTs based on hypoxic signaling are rarely used in clinics. In this review, we highlighted the role of hypoxic signaling pathways and markers and their potential implications in the initiation and progression of CBTs. Our findings underscore the involvement of the SDH family, the HIF family, VEGFs, and inflammatory cytokines in tumorigenesis and treatment based on them. Moreover, this review offers valuable insights for future research directions on understanding the relationship between hypoxia and CBTs. Carotid body tumors (CBTs) are rare tumors with a 1–2 incidence per 100,000 individuals. CBTs may initially present without apparent symptoms, and symptoms begin to arise since tumors grow bigger to compress surrounding tissue, such as recurrent laryngeal nerve and esophagus. Also, the etiology of CBTs remains unclear since it is more likely to occur in those who live in high-altitude areas or suffer from chronic hypoxic diseases such as COPD. SDH mutations and familial inheritance have been reported to be related to CBTs. SDH complexes play crucial roles in aerobic respiration, and SDH mutations in CBTs have been reported to be associated with hypoxia. Hypoxic signaling pathways, specifically hypoxic markers, have attracted more research attention in tumor exploration. However, the existing literature on these signaling and markers lacks a systematic review. Also, therapeutic approaches in CBTs based on hypoxic signaling are rarely used in clinics. In this review, we concluded the role of hypoxic signaling and markers and their potential implications in the initiation and progression of CBTs. Our findings underscore the involvement of the SDH family, the HIF family, VEGFs, and inflammatory cytokines (ICs) in tumorigenesis and treatment. Of particular interest is the role played by SDHx, which has recently been linked to oxygen sensing through mutations leading to hereditary CBTs. Among the SDH family, SDHB and SDHD exhibit remarkable characteristics associated with metastasis and multiple tumors. Besides SDH mutations in CBTs, the HIF family also plays crucial roles in CBTs via hypoxic signaling pathways. The HIF family regulates angiogenesis during mammalian development and tumor growth by gene expression in CBTs. HIF1α could induce the transcription of pyruvate dehydrogenase kinase 1 (PDK1) to inhibit pyruvate dehydrogenase kinase (PDH) by inhibiting the TCA cycle. Then, carotid body cells begin to hyperplasia and hypertrophy. At the same time, EPAS1 mutation, an activating mutation, could decrease the degradation of HIF2α and result in Pacak–Zhuang syndrome, which could result in paraganglioma. HIFs can also activate VEGF expression, and VEGFs act on Flk-1 to control the hyperplasia of type I cells and promote neovascularization. ICs also play a pivotal signaling role within the CB, as their expression is induced under hypoxic conditions to stimulate CB hyperplasia, ultimately leading to CBTs detecting hypoxic areas in tumors, and improving the hypoxic condition could enhance photon radiotherapy efficacy. Moreover, this review offers valuable insights for future research directions on understanding the relationship between hypoxic signaling pathways and CBTs. [ABSTRACT FROM AUTHOR]

Background: Peripheral blood oxygen monitoring via chemoreceptors in the carotid body (CB) is an integral function of the autonomic cardiorespiratory regulation. The presence of the purinergic P2Y12 receptor (P2Y12R) has been implicated in CB; however, the exact role of the receptor in O2 sensing and signal transduction is unknown. Methods: The presence of P2Y12R was established by immunoblotting, RT qPCR and immunohistochemistry. Primary glomus cells were used to assess P2Y12R function during hypoxia and hypercapnia, where monoamines were measured by HPLC; calcium signal was recorded utilizing OGB-1 and N-STORM Super-Resolution System. Ingravescent hypoxia model was tested in anaesthetized mice of mixed gender and cardiorespiratory parameters were recorded in control and receptor-deficient or drug-treated experimental animals. Results: Initially, the expression of P2Y12R in adult murine CB was confirmed. Hypoxia induced a P2Y12R-dependent release of monoamine transmitters from isolated CB cells. Receptor activation with the endogenous ligand ADP promoted release of neurotransmitters under normoxic conditions, while blockade disrupted the amplitude and duration of the intracellular calcium concentration. In anaesthetised mice, blockade of P2Y12R expressed in the CB abrogated the initiation of compensatory cardiorespiratory changes in hypoxic environment, while centrally inhibited receptors (i.e. microglial receptors) or receptor-deficiency induced by platelet depletion had limited influence on the physiological adjustment to hypoxia. Conclusions: Peripheral P2Y12R inhibition interfere with the complex mechanisms of acute oxygen sensing by influencing the calcium signalling and the release of neurotransmitter molecules to evoke compensatory response to hypoxia. Prospectively, the irreversible blockade of glomic receptors by anti-platelet drugs targeting P2Y12Rs, propose a potential, formerly unrecognized side-effect to anti-platelet medications in patients with pulmonary morbidities. [ABSTRACT FROM AUTHOR]

Paragangliomas are rare neuroendocrine tumors that are usually benign in nature. They may be either familial or sporadic in their occurrence. Numerous neuroendocrine tumors are collectively included under the umbrella of paragangliomas. Among them, carotid body tumors and glomus jugulare tumors are extremely rare. Thus, we present a rare case of 29-year-old male who was admitted with hearing difficulties and tinnitus in the left ear, with swelling on the left side of the neck. Based on clinical and radiological findings, a diagnosis of left-sided glomus jugulare with carotid body tumor was made. The patient underwent a twostage surgery with an interval of approximately 2 months. Histopathology revealed a paraganglioma. Herein, we present the clinical features, imaging findings, management, and a brief review of literature on the classification, evaluation, and management of carotid body and glomus jugulare tumors. Paraganglioma is a slow-growing tumor. The synchronous occurrence of carotid body and glomus jugulare tumors is infrequent. Microsurgical resection remains the primary treatment modality. Therefore, our patient underwent two-stage surgery. The rarity of occurrence and the proximity and adherence to vital neurovascular structures have resulted in the treatment of paragangliomas remaining a challenge. [ABSTRACT FROM AUTHOR]

In the carotid body of laboratory rodents, adenosine 5′-triphosphate (ATP)-mediated transmission is regarded as critical for transmission from chemoreceptor type I cells to P2X3 purinoceptor-expressing sensory nerve endings. The present study investigated the distribution of P2X3-immunoreactive sensory nerve endings in the carotid body of the adult male Japanese monkey (Macaca fuscata) using multilabeling immunofluorescence. Immunoreactivity for P2X3 was detected in nerve endings associated with chemoreceptor type I cells immunoreactive for synaptophysin. Spherical or flattened terminal parts of P2X3-immunoreactive nerve endings were in close apposition to the perinuclear cytoplasm of synaptophysin-immunoreactive type I cells. Immunoreactivity for ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2), which hydrolyzes extracellular ATP, was localized in the cell body and cytoplasmic processes of S100B-immunoreactive cells. NTPDase2-immunoreactive cells surrounded P2X3-immunoreactive terminal parts and synaptophysin-immunoreactive type I cells, but did not intrude into attachment surfaces between terminal parts and type I cells. These results suggest ATP-mediated transmission between type I cells and sensory nerve endings in the carotid body of the Japanese monkey, as well as those of rodents. [ABSTRACT FROM AUTHOR]

Current models of respiratory CO2 chemosensitivity are centred around the function of a specific population of neurons residing in the medullary retrotrapezoid nucleus (RTN). However, there is significant evidence suggesting that chemosensitive neurons exist in other brainstem areas, including the rhythm‐generating region of the medulla oblongata – the preBötzinger complex (preBötC). There is also evidence that astrocytes, non‐neuronal brain cells, contribute to central CO2 chemosensitivity. In this study, we reevaluated the relative contributions of the RTN neurons, the preBötC astrocytes, and the carotid body chemoreceptors in mediating the respiratory responses to CO2 in experimental animals (adult laboratory rats). To block astroglial signalling via exocytotic release of transmitters, preBötC astrocytes were targeted to express the tetanus toxin light chain (TeLC). Bilateral expression of TeLC in preBötC astrocytes was associated with ∼20% and ∼30% reduction of the respiratory response to CO2 in conscious and anaesthetized animals, respectively. Carotid body denervation reduced the CO2 respiratory response by ∼25%. Bilateral inhibition of RTN neurons transduced to express Gi‐coupled designer receptors exclusively activated by designer drug (DREADDGi) by application of clozapine‐N‐oxide reduced the CO2 response by ∼20% and ∼40% in conscious and anaesthetized rats, respectively. Combined blockade of astroglial signalling in the preBötC, inhibition of RTN neurons and carotid body denervation reduced the CO2‐induced respiratory response by ∼70%. These data further support the hypothesis that the CO2‐sensitive drive to breathe requires inputs from the peripheral chemoreceptors and several central chemoreceptor sites. At the preBötC level, astrocytes modulate the activity of the respiratory network in response to CO2, either by relaying chemosensory information (i.e. they act as CO2 sensors) or by enhancing the preBötC network excitability to chemosensory inputs. Key points: This study reevaluated the roles played by the carotid bodies, neurons of the retrotrapezoid nucleus (RTN) and astrocytes of the preBötC in mediating the CO2‐sensitive drive to breathe.The data obtained show that disruption of preBötC astroglial signalling, blockade of inputs from the peripheral chemoreceptors or inhibition of RTN neurons similarly reduce the respiratory response to hypercapnia.These data provide further support for the hypothesis that the CO2‐sensitive drive to breathe is mediated by the inputs from the peripheral chemoreceptors and several central chemoreceptor sites. [ABSTRACT FROM AUTHOR]

The carotid body is a major peripheral chemoreceptor that senses changes in arterial blood oxygen, carbon dioxide, and pH, which is important for the regulation of breathing and cardiovascular function. The mechanisms by which the carotid body senses O2 and CO2 are well known; conversely, the mechanisms by which it senses pH variations are almost unknown. Here, we used immunohistochemistry to investigate how the human carotid body contributes to the detection of acidosis, analyzing whether it expresses acid-sensing ion channels (ASICs) and determining whether these channels are in the chemosensory glomic cells or in the afferent nerves. In ASIC1, ASIC2, and ASIC3, and to a much lesser extent ASIC4, immunoreactivity was detected in subpopulations of type I glomus cells, as well as in the nerves of the carotid body. In addition, immunoreactivity was found for all ASIC subunits in the neurons of the petrosal and superior cervical sympathetic ganglia, where afferent and efferent neurons are located, respectively, innervating the carotid body. This study reports for the first time the occurrence of ASIC proteins in the human carotid body, demonstrating that they are present in glomus chemosensory cells (ASIC1 < ASIC2 > ASIC3 > ASIC4) and nerves, presumably in both the afferent and efferent neurons supplying the organ. These results suggest that the detection of acidosis by the carotid body can be mediated via the ASIC ion channels present in the type I glomus cells or directly via sensory nerve fibers. [ABSTRACT FROM AUTHOR]

Carotid body pathophysiology is associated with many cardiovascular–respiratory–metabolic diseases. This pathophysiology reflects both hyper‐sensitivity and hyper‐tonicity. From both animal models and human patients, evidence indicates that amelioration of this pathophysiological signalling improves disease states such as a lowering of blood pressure in hypertension, a reduction of breathing disturbances with improved cardiac function in heart failure (HF) and a re‐balancing of autonomic activity with lowered sympathetic discharge. Given this, we have reviewed the mechanisms of carotid body hyper‐sensitivity and hyper‐tonicity across disease models asking whether there is uniqueness related to specific disease states. Our analysis indicates some commonalities and some potential differences, although not all mechanisms have been fully explored across all disease models. One potential commonality is that of hypoperfusion of the carotid body across hypertension and HF, where the excessive sympathetic drive may reduce blood flow in both models and, in addition, lowered cardiac output in HF may potentiate the hypoperfusion state of the carotid body. Other mechanisms are explored that focus on neurotransmitter and signalling pathways intrinsic to the carotid body (e.g. ATP, carbon monoxide) as well as extrinsic molecules carried in the blood (e.g. leptin); there are also transcription factors found in the carotid body endothelium that modulate its activity (Krüppel‐like factor 2). The evidence to date fully supports that a better understanding of the mechanisms of carotid body pathophysiology is a fruitful strategy for informing potential new treatment strategies for many cardiovascular, respiratory and metabolic diseases, and this is highly relevant clinically. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnoea (OSA), characterized by chronic intermittent hypoxia (CIH), is considered to be an independent risk for hypertension. The pathological cardiorespiratory consequences of OSA have been attributed to systemic oxidative stress, inflammation and sympathetic overflow induced by CIH, but an emerging body of evidence indicates that a nitro‐oxidative and pro‐inflammatory milieu within the carotid body (CB) is involved in the potentiation of CB chemosensory responses to hypoxia, which contribute to enhance the sympathetic activity. Accordingly, autonomic and cardiovascular alterations induced by CIH are critically dependent on an abnormally heightened CB chemosensory input to the nucleus of tractus solitarius (NTS), where second‐order neurons project onto the rostral ventrolateral medulla (RVLM), activating pre‐sympathetic neurons that control pre‐ganglionic sympathetic neurons. CIH produces oxidative stress and neuroinflammation in the NTS and RVLM, which may contribute to the long‐term irreversibility of the CIH‐induced alterations. This brief review is mainly focused on the contribution of nitro‐oxidative stress and pro‐inflammatory molecules on the hyperactivation of the hypoxic chemoreflex pathway including the CB and the brainstem centres, and whether the persistence of autonomic and cardiorespiratory alterations may depend on the glial‐related neuroinflammation induced by the enhanced CB chemosensory afferent input. [ABSTRACT FROM AUTHOR]

The carotid body, which is located bilaterally on the medial side of the carotid bifurcation, is the largest group of paraganglia in the head and neck. Chemoreceptor cells in the carotid bulb give rise to uncommon tumours known as Carotid Body Tumours (CBTs). The authors describe a case of a CBT in a 40-year-old woman who had a painful, pulsatile, lateral neck enlargement on the right side that had been developing over time. Due to the numerous difficulties and problems brought on by their high vascularity and close proximity to cranial nerves in the neck near the carotid bifurcation, they pose a surgical challenge. Based on the patient's medical history, the results of clinical and radiological examinations, and the successful surgical removal of the tumour, the diagnosis was suspected. The results of histological analysis supported the diagnosis of a CBT. [ABSTRACT FROM AUTHOR]

Uncontrolled hypertension drives the global burden of increased cardiovascular disease (CVD) morbidity and mortality. Although high blood pressure (BP) is treatable and preventable, only half of the patients with hypertension undergoing treatment have their BP controlled. The failure of polypharmacy to attain adequate BP control may be due to a lack of physiological response, however, medication non-adherence and clinician inertia to increase treatment intensity are critical factors associated with poor hypertension management. The long-time medication titration, lifelong drug therapy, and often multi-drug treatment strategy are frustrating when the BP goal is not achieved, leading to increased CVD risk and a substantial burden on the healthcare system. Growing evidence indicates that neurohumoral activation is critical in initiating and maintaining elevated BP and its adverse consequences. Over the past decades, device-based therapies targeting the mechanisms underlying hypertension pathophysiology have been extensively studied. Among these, robust clinical experience for hypertension management exists for renal denervation (RDN) and baroreflex activation therapy (BAT), carotid body denervation (CBD), central arteriovenous anastomosis, and to a lesser extent, deep brain stimulation. Future studies are warranted to define the role of device-based approaches as an alternative or adjunctive treatment option to treat hypertension. Systemic hypertension is a growing contributor to global disease burden and premature cause of death worldwide. The percentage of patients achieving target BP levels remains largely inadequate. Hypertension is characterised by activation of the sympathetic nervous system, with the magnitude depending on age and the disease severity. Device-based interventions have been extensively studied to directly target the relevant sympathetic neural pathophysiological mechanisms involved in BP control. Modulation of the chronic sympathetic outflow with CBD or BAT shows promise for the treatment of poorly controlled hypertension in addition to antihypertensive medicines. The BP response to device-based therapies appears variable and cannot be predicted before the procedure. Until more robust evidence related to patient selection, procedural and technical aspects is available, chemoreflex and baroreflex neuromodulation therapy should be restricted to randomised sham-controlled trials performed in experienced centres. [ABSTRACT FROM AUTHOR]

Objective: Carotid resection for head and neck cancer is rare, and serious complications may arise since such cancer is frequently detected in advanced stages. The objective is to describe nine cases of carotid artery resection and reconstruction due to tumor invasion. Methods: The clinical records of nine patients who underwent carotid resection and reconstruction at our hospital were retrospectively reviewed. Carotid body tumors were evaluated with the aid of a vascular team in case carotid resection was necessary at the time of surgery. CT angiography to determine the status of the circle of Willis was performed in all patients who might undergo carotid resection and reconstruction in case of failure to restore cerebral blood flow and thus reduce possible sequelae due to ligation. Results: Of nine patients, 6 had carotid body tumors, 1 had a thyroid tumor of conglomerate lymph nodes, 1 had a larynx tumor of conglomerate lymph nodes, and 1 had a myofibroblastic tumor. There were no intraoperative cerebrovascular accidents. One patient (11.1%) had a cerebrovascular accident secondary to carotid hematoma in the intermediate postoperative period that required vascular graft removal. One patient (11.1%) died seven days after surgery following an ischemic cerebrovascular accident. Eight patients remain asymptomatic, and 1 patient with recurrence and metastasis. Conclusions: Carotid resection remains a controversial issue in the treatment of advanced head and neck cancer. However, carotid resection and reconstruction are required for disease control, and complications such as thrombosis or vascular accidents may arise. Fortunately, this is a rare condition. We recommend carotid reconstruction for all patients in whom resection is required for tumor control. Ligation should be a last resort, as seen in the management of one of our patients. [ABSTRACT FROM AUTHOR]

Both L- and D-isomers of S-nitrosocysteine (CSNO) can bind to the intracellular domain of voltage-gated potassium channels in vitro. CSNO binding inhibits these channels in the carotid body, leading to increased minute ventilation in vivo. However, only the l -isomer is active in vivo because it requires the l -amino acid transporter (LAT) for transmembrane transport. In rodents and dogs, the esterified D-CSNO precursor— d -cystine dimethyl ester (ATLX-0199)—overcomes opioid- and benzodiazepine-induced respiratory depression while maintaining analgesia. Although ATLX-0199 can enter cells independently of LAT because it is an ester, its stability in plasma is limited by the presence of esterases. Here, we hypothesized that the drug could be sequestered in erythrocytes to avoid de-esterification in circulation. We developed a liquid chromatography-mass spectrometry method for detecting ATLX-0199 and characterized a new metabolite, S-nitroso- d -cysteine monomethyl ester (DNOCE), which is also a D-CSNO precursor. We found that both ATLX-0199 and DNOCE readily enter erythrocytes and neurons and remain stable over 20 min; thus ATLX-0199 can enter cells where the ester is stable, but the thiol is reduced. Depending on hemoglobin conformation, the reduced ester can be S-nitrosylated and enter carotid body neurons, where it then increases minute ventilation. These data may help explain the paradox that ATLX-0199, a dimethyl ester, can avoid de-esterification in plasma and exert its effects at the level of the carotid body. • S-nitroso- d -cysteine monomethyl ester is a novel compound that is readily synthesized. • ATLX-0199 and its breakdown products diffuse into erythrocytes and neurons, and are stable over the course of 20 min. • Diffusion into erythrocytes suggest a potential mechanism ATLX-0199 avoids degradation by esterases in the plasma. [ABSTRACT FROM AUTHOR]

Carotid body tumors are rare benign tumors that arise in the carotid space of neck typically presenting as soft to firm, painless swelling in the neck. While specific imaging characteristics have been previously described for carotid body tumors, we report a new imaging sign in three cases of carotid body tumors on computed tomography angiography. [ABSTRACT FROM AUTHOR]

Carotid body tumour (CBT) is the most common paraganglioma of the head and neck and may compromise neurovascular structures such as carotid vessels, and cranial nerves. Intracranial extension from the mass is possible if left untreated. The main treatment for CBT is surgical resection albeit extremely challenging due to tumour hypervascularity and its relationship to the carotid artery. A bilateral CBT, however, is a rare occurrence. Herein, we present a case of a man who presented to us with bilateral painless and palpable neck mass. He underwent staged bilateral CBT excision and it was complicated with left hypoglossal nerve palsy, which recovered over time. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is a common breathing disorder that affects a significant portion of the adult population. In addition to causing excessive daytime sleepiness and neurocognitive effects, OSA is an independent risk factor for cardiovascular disease; however, the underlying mechanisms are not completely understood. Using exposure to intermittent hypoxia (IH) to mimic OSA, we have recently reported that mice exposed to IH exhibit endothelial cell (EC) activation, which is an early process preceding the development of cardiovascular disease. Although widely used, IH models have several limitations such as the severity of hypoxia, which does not occur in most patients with OSA. Recent studies reported that mice with deletion of hemeoxygenase 2 (Hmox2-/-), which plays a key role in oxygen sensing in the carotid body, exhibit spontaneous apneas during sleep and elevated levels of catecholamines. Here, using RNA-sequencing we investigated the transcriptomic changes in aortic ECs and heart tissue to understand the changes that occur in Hmox2-/- mice. In addition, we evaluated cardiac structure, function, and electrical properties by using echocardiogram and electrocardiogram in these mice. We found that Hmox2-/- mice exhibited aortic EC activation. Transcriptomic analysis in aortic ECs showed differentially expressed genes enriched in blood coagulation, cell adhesion, cellular respiration and cardiac muscle development and contraction. Similarly, transcriptomic analysis in heart tissue showed a differentially expressed gene set enriched in mitochondrial translation, oxidative phosphorylation and cardiac muscle development. Analysis of transcriptomic data from aortic ECs and heart tissue showed loss of Hmox2 gene might have common cellular network footprints on aortic endothelial cells and heart tissue. Echocardiographic evaluation showed that Hmox2-/- mice develop progressive dilated cardiomyopathy and conduction abnormalities compared to Hmox2+/+ mice. In conclusion, we found that Hmox2-/- mice, which spontaneously develop apneas exhibit EC activation and transcriptomic and functional changes consistent with heart failure. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects and outcomes of multidisciplinary surgical approaches in the management of carotid body tumors (CBT). Methods: A single‐center retrospective study at the University of California—Los Angeles Medical Center was conducted on patients who presented with CBTs and underwent surgical resections from 1998 to 2020. Statistical analysis was performed using IBM SPSS v27 and Excel. Results: A total of 75 patients with 79 CBT resections were included. Operating surgical subspecialties included: 41.8% vascular surgery, 24.1% otolaryngology head and neck surgeons (OHNS), and 31.6% combined OHNS and vascular. 68.4% of tumors underwent preoperative embolization. EBL was directly correlated with tumor size. CBT size was similar for OHNS (30 mm) and vascular (31 mm) but was significantly larger for combined OHNS and vascular cases (38 mm). EBL was higher in combined cases (301 mL) compared to OHNS (124 mL) or vascular (203 mL) alone. Incidence of postoperative cranial nerve deficits was 7.8%, with combined OHNS and vascular cases having an incidence of 4.0% when compared to OHNS (5.3%) versus vascular surgery alone (12.1%). Conclusion: CBTs can be managed effectively by single surgical specialties with similar outcomes between vascular surgery and OHNS. In larger, higher grade tumors, however, a combined vascular and OHNS approach had lower incidence of postoperative cranial nerve injuries when compared to single specialty resections, despite a larger EBL. Thus, a multidisciplinary surgical approach suggests favorable outcomes with fewer incidence of cranial nerve deficits for larger, more complex CBT resections. Level of Evidence: 2b—Individual retrospective cohort study. [ABSTRACT FROM AUTHOR]

Objective: To compare the differences in the short-term recovery from neurological symptoms (SRN) (≤ 6 months) and clinical characteristics of patients with different Shamblin classifications carotid body tumor (CBT) resection and to analyze the risk factors affecting SRN after surgery. Methods: Patients who underwent CBT resection between June 2018 and September 2022 were recruited. Perioperative factors and indicators of the nature of the tumor were recorded. The risk factors affecting SRN after CBT resection were analyzed using logistic regression analysis. Results: Eighty-five patients (43.86 ± 12.7 years, 46 females) were included, 40 (47.06%) of whom exhibited SRN. Univariate logistic regression showed that preoperative symptoms, surgical side, bilateral posterior communicating artery (PcoA) opening, some indicators of tumor size, operative/anesthesia time, and Shamblin III classification were correlated with postoperative neurological prognosis (all p < 0.05). After adjusting for confounders, preoperative symptoms (OR, 5.072; 95% CI 1.027–25.052; p = 0.046), surgical side (OR, 0.025; 95% CI 0.003–0234; p = 0.001), bilateral PcoA opening (OR, 22.671; 95% CI 2.549–201.666; p = 0.005), distance from the tip of the C2 dens to the superior aspect (dens-CBT) (OR, 0.918; 95% CI 0.858–0.982; p = 0.013) and Shamblin III classification (OR, 28.488; 95% CI 1.986–408.580; p = 0.014) were correlated with postoperative neurological symptom recovery. Conclusion: Preoperative symptoms, surgical side (right), bilateral PcoA opening, a short dens-CBT and Shamblin III classification are risk factors affecting SRN after CBT resection. Early resection is recommended for small-volume CBTs without neurovascular compression or invasion to obtain SRN. [ABSTRACT FROM AUTHOR]

Background: To investigate the impact of preoperative embolization (p-TAE) on CBT surgical resection and explore the optimal tumor volume for p-TAE of CBT resection. Methods: This retrospective study reviewed 139 surgically excised CBTs. According to Shamblin classification, tumor volumes, and whether to carry out the p-TAE, the patients were classified into different groups. The demographic, clinical features, and the intraoperative and post-operative information about the patients were retrieved and analyzed from the patient records. Results: A total of 139 CBTs was excised in 130 patients. According to the results of subgroup analysis, there were no significant differences in surgical time, blood loss, adverse events (AEs), and the revascularization when compared with non-embolization group (NEG) for type I, II, III, respectively (all p > 0.05) except for the surgical time in type I (p < 0.05). Then the X-tile program was employed and determine the cutoff point (tumor volume = 6670 mm3) for tumor volumes and blood loss. The average tumor volume was (29,782.37 vs. 31,345.10 mm3, p = 0.65) for embolization group (EG) and NEG. The mean surgical time (208.86 vs. 264.67 min, p > 0.05) and intraoperative blood loss (252.78 vs. 430.00 mL, p < 0.05) were less, and the incidence of revascularization required (35.56 vs. 52.38%, p > 0.05) and total complications (27.78 vs. 57.14%, p < 0.05) were lower in EG when compared with NEG (tumor volume ≥ 6670 mm3). However, the results were not statistically significant when the tumor size was less than 6670 mm3. No surgery-related mortality was observed during the follow-up. Conclusions: Preoperative selective embolization of CBT is an effective and safe adjunct for surgical resection, especially for Shamblin class II and III tumors (≥ 6670 mm3). [ABSTRACT FROM AUTHOR]

Carotid body tumors (CBTs) are uncommon benign head and neck neoplasms. Surgical resection is the treatment of choice for CBTs. However, the anatomical structures adjacent to the tumor tissue may encounter serious injuries during the surgery. Shamblin grading system is a surgical intra-operative scoring system to determine the risks associated with the surgery. Therefore, we aimed to evaluate the correlation of pre-surgical imaging parameters with Shamblin grades and intra-operative complications. In this cross sectional study, we enrolled 36 patients with CBTs. Preoperative cervical CT angiography was acquired in each participant and following parameters were reported in each case: Tumor volume, tumor distance to the base of the skull (TDBS), tumor contact with the internal carotid artery (ICA), and external carotid artery (ECA) and tumor density. Finally, we assessed the relation of pre-surgical imaging parameters with Shamblin grades, and intra-operative complications. Only tumor volume was significantly correlated with Shamblin grades (P < 0.05). The tumor contact with ECA was marginally correlated with Shamblin grades (P = 0.103); however, other imaging parameters were not significantly correlating with Shamblin grades. There was a statistically significant correlation between ICA contact and tumor volume with ECA injury. In addition, the tumor density significantly correlated with cranial nerves injury. The results of STATA analysis were indicative for 69.44% accordance between radiologic typing and Shamblin grading system. We found that tumor volume correlates significantly with Shamblin grading system, and there is significant correlation between tumor ICA contact, and tumor density and intra-operative complications. [ABSTRACT FROM AUTHOR]

To study the causes of the Pseudo- Lyre sign which is radiologically demonstrated in tumours other than the carotid body tumour. The study is based on an unusual case of neurofibroma of the cervical sympathetic chain presenting as a pulsatile mass in the carotid triangle in a 34 years female. Radiological investigation pointed to a diagnosis of a carotid body tumour because of typical splaying of the internal and external arteries causing the Lyre sign. At surgery, the tumour which was arising from the cervical sympathetic chain (CSC) was excised with minimum blood loss and histopathology confirmed it to be neurofibroma. This, we presume is the first ever report of a neurofibroma of the cervical sympathetic chain causing Lyre sign which we have referred to as Pseudo-Lyre sign. The various investigations which help in diagnosing the cause of Pseudo-Lyre sign have been discussed. All tumours causing Lyre sign on radio-imaging are not carotid body tumours. Other masses mostly neurogenic can demonstrate this sign and an attempt should be made preoperatively to confirm the diagnosis. [ABSTRACT FROM AUTHOR]

Currently, there is no consensus on estimating the malignant potential of Carotid Body Tumor (CBT) and the only way to predict a metastatic CBT is through DOTANOC Positron Emission Tomography (PET) scan. There is a well-established correlation between CBT and superoxide anions inside tumor cells. The purpose of this pilot study was to measure superoxide anions inside CBT cells and find if these can be used as marker to predict malignant potential of CBT. The results were also co-related with findings of DOTANOC PET scan retrospectively. The CBT tissue from 10 patients was stained using a fluorogenic dye and superoxide anions were measured by analysis of fluorescent image. The patients were divided into two groups – First group with four patients having potentially malignant CBT based upon clinico-surgical characteristics and second group with the rest of the six patients. It was seen that the superoxide anions were highest in the first group which included patients with metastatic carotid body tumor, patients with multiple paragangliomas and patient with positive family history (p = 0.011). The same patients also had metastasis and multiple tumors detected on DOTANOC PET scan. It was concluded that measuring superoxide anions in excised tumor tissue can be used to estimate malignant potential of CBT and can identify patients who truly require DOTANOC PET scan; without affecting the treatment, as it is an expensive investigation involving ionizing radiation and may not be available in all centres. [ABSTRACT FROM AUTHOR]

Respiratory chemoreceptor activity encoding arterial PCO2 and PO2 is a critical determinant of ventilation. Currently, the relative importance of several putative chemoreceptor mechanisms for maintaining eupneic breathing and respiratory homeostasis is debated. Transcriptomic and anatomic evidence suggests that bombesin-related peptide Neuromedin-B (Nmb) expression identifies chemoreceptor neurons in the retrotrapezoid nucleus (RTN) that mediate the hypercapnic ventilatory response, but functional support is missing. In this study, we generated a transgenic Nmb-Cre mouse and used Cre-dependent cell ablation and optogenetics to test the hypothesis that RTNNmb neurons are necessary for the CO2-dependent drive to breathe in adult male and female mice. Selective ablation of ;95% of RTNNmb neurons causes compensated respiratory acidosis because of alveolar hypoventilation, as well as profound breathing instability and respiratory-related sleep disruption. Following RTNNmb lesion, mice were hypoxemic at rest and were prone to severe apneas during hyperoxia, suggesting that oxygen-sensitive mechanisms, presumably the peripheral chemoreceptors, compensate for the loss of RTNNmb neurons. Interestingly, ventilation following RTNNmb-lesion was unresponsive to hypercapnia, but behavioral responses to CO2 (freezing and avoidance) and the hypoxia ventilatory response were preserved. Neuroanatomical mapping shows that RTNNmb neurons are highly collateralized and innervate the respiratory-related centers in the pons and medulla with a strong ipsilateral preference. Together, this evidence suggests that RTNNmb neurons are dedicated to the respiratory effects of arterial PCO2/pH and maintain respiratory homeostasis in intact conditions and suggest that malfunction of these neurons could underlie the etiology of certain forms of sleep-disordered breathing in humans. [ABSTRACT FROM AUTHOR]

The article focuses on the role of hydrogen sulfide (H2S) in activating olfactory receptor 78 (Olfr78) and its involvement in the carotid body's response to hypoxia. It mentions the study shows that H2S induces persulfidation of Olfr78, leading to impaired carotid body activation, glomus cell responses, and breathing responses to H2S and hypoxia in mutant mice.

Introduction: nephrotic syndrome is due to diverse etiologies; only a relatively small number of diseases are responsible for the majority of patients seen. Patient information: a 14-year-old African female patient is presented with previous health history until detecting a left cervical enlargement, with slow growth of two years of evolution. Generalized edema was noted until the diagnosis of nephrotic syndrome was confirmed, which was associated with a carotid body tumor (paraganglioma) and acute renal dysfunction. The patient required hemodialysis treatment according to needs without functional recovery and permanent substitution therapies. Conclusions: It is remarkable the infrequency of this tumor process and its association with a renal lesion that evolved to chronicity in a pediatric patient. [ABSTRACT FROM AUTHOR]

Background: The gold standard for patients with carotid body tumors (CBT) is surgical resection; nevertheless, some patients are unfit for surgery or, for other reasons, could not be operated on. Active surveillance has been known to be a reasonable strategy for these cases. This study aimed to evaluate tumor growth in unoperated patients with CBTs. Methods: A retrospective review of all unoperated patients with CBT from a single academic hospital diagnosed between 2014 and 2021 was performed. Results of nonparametric testing were presented using the median and ranges for Mann-Whitney-U or Kruskal-Wallis. Significance was defined as a 2-tailed P <.05. Results: The cohort included a total of 31 patients, with a median age of 60 years (range: 37-80 years), of which 27 (87.1%) were females. The patients live at a median altitude of 2800 meters (range: 2756-2980 meters) above sea level. Twenty (64.5%) patients had Shamblin I tumors, eight (25.8%) patients had Shamblin II tumors, and three (9.7%) patients had Shamblin III tumors. Median CBT volume at diagnosis was 14.1 cm3 (range:.9 - 213.3 cm3). Median volume at diagnosis of symptomatic tumors was substantially larger than asymptomatic tumors, 49.2 cm3 vs 7.9 cm3, respectively (P =.03). Median growth of the tumors during a median 15-month follow-up (range: 3-43 months) was 3.3 cm3 (range: 0-199.9 cm3). Overall, 77% (n = 24) of the CBTs grew at least 1 cm3. Conclusion: Most patients in the present study had tumor growth by at least 1 cm3, with a median tumor growth of 3.3 cm.3 In the present study tumor growth was shown to be greater than other low altitude CBT active surveillance studies; therefore, surgical resection should be recommended in patients with CBT living at high altitudes. [ABSTRACT FROM AUTHOR]

Thyroid nodule is the most common presentation of thyroid carcinoma. Considering the indolent course of the disease, indeed, the papillary thyroid cancer (PTC) microcarcinoma puts much debate regarding large-scale cohorts on patient follow-up over several decades to detect differences in aggressiveness and outcome. Lymph node metastases might be the salient manifestation of the disease. The nodal metastases usually appear in the central and to a lesser degree in the lateral neck mostly as a solid nodule and rarely in form of a cystic mass. In this study, we describe a case of lymph node metastasis from thyroid papillary carcinoma that clinically and radiologically mimicked a carotid body tumor and despite all pre-surgical evaluations; papillary thyroid carcinoma was detected in the final histopathology report. We intend to describe the initial clinical evaluation, radiological survey and pathology report. [ABSTRACT FROM AUTHOR]

The brain requires over one-fifth of the total body oxygen demand for normal functioning. At high altitude (HA), the lower atmospheric oxygen pressure inevitably challenges the brain, affecting voluntary spatial attention, cognitive processing, and attention speed after short-term, long-term, or lifespan exposure. Molecular responses to HA are controlled mainly by hypoxia-inducible factors. This review aims to summarize the cellular, metabolic, and functional alterations in the brain at HA with a focus on the role of hypoxia-inducible factors in controlling the hypoxic ventilatory response, neuronal survival, metabolism, neurogenesis, synaptogenesis, and plasticity. [ABSTRACT FROM AUTHOR]

Carotid body tumors are slow growing neck masses that arise from the neural crest cells at the carotid bifurcation. Majority are asymptomatic and are diagnosed incidentally. Surgical excision is accepted as the treatment of choice to reduce complications. In the present series, we report 10 cases of carotid body tumors and our institutional experience. All patients underwent radiological evaluation with an ultrasonography with Doppler, contrast enhanced computed tomography and MR angiography. 6 cases were operated by a transcervical excision. The tumor was excised in tototranscervically. One of the cases required saphenous vein graft intraoperatively due to vascular injury and also had postoperative vocal cord palsy. The rest had an uneventful recovery. Carotid body tumors although rare and seemingly indolent can cause substantial symptoms if left untreated. A prompt multi modality approach is needed for both diagnosis and treatment to avoid major complications. [ABSTRACT FROM AUTHOR]

The classic peripheral chemoreflex response is a critical homeostatic mechanism. In healthy individuals, appropriate chemoreflex responses are triggered by acute activation of the carotid body - the principal chemosensory organ in mammals. However, the aberrant chronic activation of the carotid body can drive the elevated sympathetic activity underlying cardio-respiratory diseases such as hypertension, diabetes and heart failure. Carotid body resection induces intolerable side effects and so understanding how to modulate carotid body output without removing it, and whilst maintaining the physiological chemoreflex response, represents the next logical next step in the development of effective clinical interventions. By definition, excessive carotid body output must result from altered intra-carotid body inter-cellular communication. Alongside the canonical synaptic transmission from glomus cells to petrosal afferents, many other modes of information exchange in the carotid body have been identified, for example bidirectional signalling between type I and type II cells via ATP-induced ATP release, as well as electrical communication via gap junctions. Thus, herein we review the carotid body as an integrated circuit, discussing a variety of different inter-cellular signalling mechanisms and highlighting those that are potentially relevant to its pathological hyperactivity in disease with the aim of identifying novel therapeutic targets. [ABSTRACT FROM AUTHOR]

New Findings: What is the topic of this review?Regarding the global metabolic syndrome crisis, this review focuses on common mechanisms for high blood sugar and high blood pressure. Connections are made between the homeostatic regulation of blood pressure and blood sugar and their dysregulation to reveal signalling mechanisms converging on the carotid body.What advances does it highlight?The carotid body plays a major part in the generation of excessive sympathetic activity in diabetes and also underpins diabetic hypertension. As treatment of diabetic hypertension is notoriously difficult, we propose that novel receptors within the carotid body may provide a novel treatment strategy. The maintenance of glucose homeostasis is obligatory for health and survival. It relies on peripheral glucose sensing and signalling between the brain and peripheral organs via hormonal and neural responses that restore euglycaemia. Failure of these mechanisms causes hyperglycaemia or diabetes. Current anti‐diabetic medications control blood glucose but many patients remain with hyperglycemic condition. Diabetes is often associated with hypertension; the latter is more difficult to control in hyperglycaemic conditions. We ask whether a better understanding of the regulatory mechanisms of glucose control could improve treatment of both diabetes and hypertension when they co‐exist. With the involvement of the carotid body (CB) in glucose sensing, metabolic regulation and control of sympathetic nerve activity, we consider the CB as a potential treatment target for both diabetes and hypertension. We provide an update on the role of the CB in glucose sensing and glucose homeostasis. Physiologically, hypoglycaemia stimulates the release of hormones such as glucagon and adrenaline, which mobilize or synthesize glucose; however, these counter‐regulatory responses were markedly attenuated after denervation of the CBs in animals. Also, CB denervation prevents and reverses insulin resistance and glucose intolerance. We discuss the CB as a metabolic regulator (not just a sensor of blood gases) and consider recent evidence of novel 'metabolic' receptors within the CB and putative signalling peptides that may control glucose homeostasis via modulation of the sympathetic nervous system. The evidence presented may inform future clinical strategies in the treatment of patients with both diabetes and hypertension, which may include the CB. [ABSTRACT FROM AUTHOR]

The development and survival of dopaminergic neurons are influenced by the fibroblast growth factor (FGF) pathway. Anosmin-1 (A1) is an extracellular matrix protein that acts as a major regulator of this signaling pathway, controlling FGF diffusion, and receptor interaction and shuttling. In particular, previous work showed that A1 overexpression results in more dopaminergic neurons in the olfactory bulb. Prompted by those intriguing results, in this study, we investigated the effects of A1 overexpression on different populations of catecholaminergic neurons in the central (CNS) and the peripheral nervous systems (PNS). We found that A1 overexpression increases the number of dopaminergic substantia nigra pars compacta (SNpc) neurons and alters the striosome/matrix organization of the striatum. Interestingly, these numerical and morphological changes in the nigrostriatal pathway of A1-mice did not confer an altered susceptibility to experimental MPTP-parkinsonism with respect to wild-type controls. Moreover, the study of the effects of A1 overexpression was extended to different dopaminergic tissues associated with the PNS, detecting a significant reduction in the number of dopaminergic chemosensitive carotid body glomus cells in A1-mice. Overall, our work shows that A1 regulates the development and survival of dopaminergic neurons in different nuclei of the mammalian nervous system. [ABSTRACT FROM AUTHOR]

Objectives: To assess outcomes of carotid body tumors (CBTs) managed with active surveillance. Methods: Retrospective chart review of CBTs managed with active surveillance from 2001 to 2019. Results: A total of 115 cases were identified during chart review. Sixty-five of these patients were managed with active surveillance, and 11 patients had bilateral tumors for a total of 76 tumors. Follow-up records with symptomatic outcomes were available for 51 patients, and 47 tumors had follow-up imaging. Thirty-one (66%) actively surveilled CBTs remained stable or decreased in size while 16 (34%) increased in size. Patients undergoing active surveillance developed symptoms in 12 cases, 6 of these patients underwent surgical intervention. Nine CBTs managed with active surveillance (18%) were ultimately resected. The majority of patients who did not undergo surgical intervention never developed symptoms (36/42, 86%). Conclusions: Active surveillance may be a reasonable approach for a subset of CBTs. [ABSTRACT FROM AUTHOR]