In coronavirus disease 2019 (COVID‐19), higher morbidity and mortality are associated with age, male gender, and comorbidities, such as chronic lung diseases, cardiovascular pathologies, hypertension, kidney diseases, diabetes mellitus, and obesity. All of the above conditions are characterized by increased sympathetic discharge, which may exert significant detrimental effects on COVID‐19 patients, through actions on the lungs, heart, blood vessels, kidneys, metabolism, and/or immune system. Furthermore, COVID‐19 may also increase sympathetic discharge, through changes in blood gases (chronic intermittent hypoxia, hyperpnea), angiotensin‐converting enzyme (ACE)1/ACE2 imbalance, immune/inflammatory factors, or emotional distress. Nevertheless, the potential role of the sympathetic nervous system has not yet been considered in the pathophysiology of COVID‐19. In our opinion, sympathetic overactivation could represent a so‐far undervalued mechanism for a vicious circle between COVID‐19 and comorbidities.
The Subthalamic Nucleus (STh) is an oval-shaped diencephalic structure located ventrally to the thalamus, playing a fundamental role in the circuitry of the basal ganglia. In addition to being involved in the pathophysiology of several neurodegenerative disorders, such as Huntington's and Parkinson's disease, the STh is one of the target nuclei for deep brain stimulation. However, most of the anatomical evidence available derives from non-human primate studies. In this review, we will present the topographical and morphological organization of the nucleus and its connections to structurally and functionally related regions of the basal ganglia circuitry. We will also highlight the importance of additional research in humans focused on validating STh connectivity, cytoarchitectural organization, and its functional subdivision.
The carotid body (CB) plays a contributory role in the pathogenesis of various respiratory, cardiovascular, renal and metabolic diseases, through reflex changes in ventilation and sympathetic output. On the basis of available data about peripheral arterial chemoreception and Severe Acute Respiratory Syndrome - Coronavirus 2 (SARS-CoV2), a potential involvement in the Coronavirus Disease 2019 (COVID-19) may be hypothesized through different mechanisms. The CB could be a site of SARS-CoV2 invasion, due to local expression of its receptor (Angiotensin-Converting Enzyme (ACE) 2), and an alternative route of nervous system invasion, through retrograde transport along the carotid sinus nerve. The CB function could be affected by COVID-19-induced inflammatory/immune reactions and/or ACE1/ACE2 imbalance, both at local or systemic level. Increased peripheral arterial chemosensitivity and reflex sympatho-activation may contribute to the increased morbidity/mortality in COVID-19 patients with respiratory, cardiovascular, renal or metabolic comorbidities.
Neurological manifestations are common in COVID-19, the disease caused by SARS-CoV-2. Despite reports of SARS-CoV-2 detection in the brain and cerebrospinal fluid of COVID-19 patients, it is still unclear whether the virus can infect the central nervous system, and which neuropathological alterations can be ascribed to viral tropism, rather than immune-mediated mechanisms. Here, we assess neuropathological alterations in 24 COVID-19 patients and 18 matched controls who died due to pneumonia/respiratory failure. Aside from a wide spectrum of neuropathological alterations, SARS-CoV-2-immunoreactive neurons were detected in the dorsal medulla and in the substantia nigra of five COVID-19 subjects. Viral RNA was also detected by real-time RT-PCR. Quantification of reactive microglia revealed an anatomically segregated pattern of inflammation within affected brainstem regions, and was higher when compared to controls. While the results of this study support the neuroinvasive potential of SARS-CoV-2 and characterize the role of brainstem inflammation in COVID-19, its potential implications for neurodegeneration, especially in Parkinson’s disease, require further investigations.
Various authors have hypothesized carotid body (CB) involvement in Coronavirus Disease 2019 (COVID-19), through direct invasion or indirect effects by systemic stimuli (‘cytokine storm’, angiotensin-converting enzyme [ACE]1/ACE2 imbalance). However, empirical evidence is limited or partial. Here, we present an integrated histopathological and virological analysis of CBs sampled at autopsy from four subjects (2 males and 2 females; age: >70 years old) who died of COVID-19. Histopathological, immunohistochemical and molecular investigation techniques were employed to characterize Severe Acute Respiratory Syndrome – Coronavirus 2 (SARS-CoV2) viral invasion and inflammatory reaction. SARS-CoV2 RNA was detected in the CBs of three cases through Real-Time Reverse Transcription Polymerase Chain Reaction (RT-PCR). In these cases, positive immunostaining for Nucleocapsid and Spike protein were also demonstrated, mainly at the level of large roundish cells consistent with type I cells, confirming direct CB invasion. In these cases, T lymphocytes showed focal aggregations in the CBs, suggestive of local inflammatory reaction. Blood congestion and microthrombosis were also found in one of the positive cases. Intriguingly, microthrombosis, blood congestion and microhaemorrages were also bilaterally detected in the CBs of the negative case, supporting the possibility of COVID-19 effects on the CB even in the absence of its direct invasion. SARS-CoV-2 direct invasion of the CB is confirmed through both immunohistochemistry and RT-PCR, with likely involvement of different cell types. We also reported histopathological findings which could be ascribed to local and/or systemic actions of SARS-CoV-2 and which could potentially affect chemoreception.
The Infrapatellar Fat Pad (IFP) is a fibro-adipose tissue of the knee recently reconsidered as part of a single anatomo-functional unit (AFU) together with the synovial membrane (SM). Several evidence support the role of this unit in the mechanisms that trigger and perpetuate the onset and progression of osteoarthritis (OA) disease. Additionally, the contribution of IFP-SM AFU in OA-associated pain has also been supposed, but this assumption still needs to be fully elucidated. Within this context, the recent discovery of the mechanoceptive Piezo ion channels (i.e., Piezo1 and Piezo2) in mammals and consciousness on their role in mediating both mechanoceptive and inflammatory stimuli could shed some light on knee OA pain, as well as on the process leading from acute to chronic nociceptive responses. For this purpose, the IFP-SM AFUs of both healthy donors (non-OA IFP-SM AFUs, n = 10) and OA patients (OA IFP-SM AFUs, n = 10) were processed by histology and immunohistochemistry. After the attribution of a histopathological score to IFP-SM AFUs to confirm intrinsic differences between the two groups, the specimens were investigated for the expression and localization/distribution pattern of the mechanosensors Piezo1 and Piezo2. In addition, the presence of monocytes/macrophages (CD68), peripheral nerve endings (PGP9.5) and neoangiogenesis signs (YAP1) was evaluated for a broad tissue characterization. The study results lead to a better description of the IFP-SM AFU microscopic features in both healthy and pathological conditions, highlighting peculiar differences in the study cohort. Specifically, immunopositivity towards Piezo1/2, CD68 and YAP1 markers was detected at vessels level in the OA- IFP-SM AFUs compartments, differently from the non-OA-group. A correlation with pain was also inferred, paving the way for the identification of new and effective molecules in OA management.
In coronavirus disease 2019 (COVID-19), ulcerative lesions have been episodically reported in various segments of the gastrointestinal (GI) tract, including the oral cavity, oropharynx, esophagus, stomach and bowel. In this report, we describe an autopsy case of a COVID-19 patient who showed two undiagnosed ulcers at the level of the anterior and posterior walls of the hypopharynx. Molecular testing of viruses involved in pharyngeal ulcers demonstrated the presence of severe acute respiratory syndrome – coronavirus type 2 (SARS-CoV-2) RNA, together with herpes simplex virus 1 DNA. Histopathologic analysis demonstrated full-thickness lympho-monocytic infiltration (mainly composed of CD68-positive cells), with hemorrhagic foci and necrosis of both the mucosal layer and deep skeletal muscle fibers. Fibrin and platelet microthrombi were also found. Cytological signs of HSV-1 induced damage were not found. Cells expressing SARS-CoV-2 spike subunit 1 were immunohistochemically identified in the inflammatory infiltrations. Immunohistochemistry for HSV1 showed general negativity for inflammatory infiltration, although in the presence of some positive cells. Thus, histopathological, immunohistochemical and molecular findings supported a direct role by SARS-CoV-2 in producing local ulcerative damage, although a possible contributory role by HSV-1 reactivation cannot be excluded. From a clinical perspective, this autopsy report of two undiagnosed lesions put the question if ulcers along the GI tract could be more common (but frequently neglected) in COVID-19 patients.
High‐quality digital three‐dimensional (3D) reconstructions of microscopic findings have been used in anatomical and histopathologic research, but their use in forensic pathology may also be of interest. This paper presents an application of these methods to better characterize the pathway of a stab wound of the anterior surface of the heart in a case of suicide. A portion of the heart wall including the stab wound was serially sectioned for microscopic analysis along the full extent of the wound. Histologic sections were digitally acquired, and a 3D reconstruction was created with ImageJ software for 3D computer graphics. This showed a full‐thickness wound path extending to the endocardial surface of the left ventricle, curvilinear in appearance. After correction for shrinkage, 3D reconstruction allowed estimation of the dimensions of the myocardial injury and comparison of the appearance of the wound with the suspected knife used. The curvilinear appearance was considered to reflect injury during myocardial contraction. Complete microscopic sectioning and 3D reconstruction may allow virtual sectioning through various orientations and also provide useful forensic information for selected injuries.
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