Thinking Out-of-the-Box: A Non-Standard Application of Standard Pulse-Oximetry and Standard Near-Infrared Spectroscopy in a COVID-19 Patient.

PURPOSE: Purpose of this report is to describe the feasibility of lingual pulse oximetry and lingual near-infrared spectroscopy (NIRS) in a COVID-19 patient to assess lingual tissue viability after several days of mechanical ventilation in the prone position. MATERIALS & METHODS: In a COVID-19 ICU-patient, the tongue became grotesquely swollen, hardened and protruding from the oral cavity after 20 h of mechanical ventilation uninterrupted in the prone position. To assess the doubtful viability of the tongue, pulse-oximetric hemoglobin O2-saturation (SpO2; Nellcor, OxiMax MAX-NI, Covidien, MA, USA) and NIRS-based, regional tissue O2-saturation measurements (rSO2; SenSmart, Nonin, MN, USA) were performed at the tongue. RESULTS: At the tongue, regular pulse-oximetric waveforms with a pulse-oximetric hemoglobin O2-saturation (SpO2) of 88% were recorded, i.e. only slightly lower than the SpO2 reading at the extremities at that time (90%). Lingual NIRS-based rSO2 measurements yielded stable tissue rSO2-values of 76-78%, i.e. values expected also in other adequately perfused and oxygenated (muscle-) tissues. CONCLUSION: Despite the alarming, clinical finding of a grotesquely swollen, rubber-hard tongue and clinical concerns on the adequacy of the tongue perfusion and oxygenation, our measurements of both arterial pulsatility (SpO2) and NIRS-based tissue oxygenation (rSO2) suggested adequate perfusion and oxygenation of the tongue, rendering non-vitality of the tongue, e.g. by lingual venous thrombosis, unlikely. To our knowledge, this is the first clinical report of lingual rSO2 measurement.

Increased activity of mesenchymal ALK2-BMP signaling causes posteriorly truncated microglossia and disorganization of lingual tissues.

Proper development of taste organs including the tongue and taste papillae requires interactions with the underlying mesenchyme through multiple molecular signaling pathways. The effects of bone morphogenetic proteins (BMPs) and antagonists are profound, however, the tissue-specific roles of distinct receptors are largely unknown. Here, we report that constitutive activation (ca) of ALK2-BMP signaling in the tongue mesenchyme (marked by Wnt1-Cre) caused microglossia-a dramatically smaller and misshapen tongue with a progressively severe reduction in size along the anteroposterior axis and absence of a pharyngeal region. At E10.5, the tongue primordia (branchial arches 1-4) formed in Wnt1-Cre/caAlk2 mutants while each branchial arch responded to elevated BMP signaling distinctly in gene expression of BMP targets (Id1, Snai1, Snai2, and Runx2), proliferation (Cyclin-D1) and apoptosis (p53). Moreover, elevated ALK2-BMP signaling in the mesenchyme resulted in apparent defects of lingual epithelium, muscles, and nerves. In Wnt1-Cre/caAlk2 mutants, a circumvallate papilla was missing and further development of formed fungiform papillae was arrested in late embryos. Our data collectively demonstrate that ALK2-BMP signaling in the mesenchyme plays essential roles in orchestrating various tissues for proper development of the tongue and its appendages in a region-specific manner.

Prevalence of p53 dysregulations in feline oral squamous cell carcinoma and non-neoplastic oral mucosa.

Squamous cell carcinoma is the most common malignant oral tumor in cats. The late presentation is one of the factors contributing to the detrimental prognosis of this disease. The immunohistochemical expression of the p53 tumor suppressor protein has been reported in 24% to 65% of feline oral squamous cell carcinomas, but no study has systematically evaluated in this tumor the presence of p53 encoding gene (TP53) mutations. The aim of this retrospective study was to determine whether p53 immunohistochemistry accurately reflects the mutational status of the TP53 gene in feline oral squamous cell carcinoma. Additionally, the prevalence of p53 dysregulation in feline oral squamous cell carcinoma was compared with that of feline non-neoplastic oral mucosa, in order to investigate the relevance of these dysregulations in cancer development. The association between p53 dysregulations and exposure to environmental tobacco smoke and tumor characteristics was further assessed. Twenty-six incisional biopsies of oral squamous cell carcinomas and 10 cases each of lingual eosinophilic granuloma, chronic gingivostomatitis and normal oral mucosa were included in the study. Eighteen squamous cell carcinomas (69%) expressed p53 and 18 had mutations in exons 5-8 of TP53. The agreement between immunohistochemistry and mutation analysis was 77%. None of non-neoplastic oral mucosa samples had a positive immunohistochemical staining, while one case each of eosinophilic granuloma and chronic gingivostomatitis harbored TP53 mutations. Unlike previously hypothesized, p53 dysregulations were not associated with exposure to environmental tobacco smoke. These results suggest an important role of p53 in feline oral tumorigenesis. Additionally, the immunohistochemical detection of p53 expression appears to reflect the presence of TP53 mutations in the majority of cases. It remains to be determined if the screening for p53 dysregulations, alone or in association with other markers, can eventually contribute to the early detection of this devastating disease.

Association Between Macroscopic Tongue Ischemia and Enterocyte Injury and Poor Outcome in Patients With Septic Shock: A Preliminary Observational Study.

A correlation between sublingual and intestinal mucosa microcirculation, and ischemic necrosis of the tongue as a sign of poor prognosis has been reported. However, an association between tongue ischemia and intestinal health and subsequent outcome has never been studied. This preliminary prospective observational study evaluated the association between macroscopic tongue ischemia and enterocyte injury and poor outcome in patients with septic shock. In this study, 57 adults with septic shock on mechanical ventilators were enrolled. Macroscopic tongue ischemia upon intensive care unit (ICU) admission was assessed by two independent intensivists. We used intestinal fatty-acid binding protein (I-FABP) as a biomarker of enterocyte injury and evaluated the association with tongue ischemia. Demographic variables, risk factor data, and 28-day mortality information were also collected. Compared with patients with normal tongues (n = 45), those with ischemic tongues (n = 12) had a significantly higher Acute Physiology and Chronic Health Evaluation II score (29.0 [25.0-34.0] vs. 36.5 [30.5-44.5], P = 0.017), lactate level (2.8 [2.0-5.0] vs. 9.3 [4.5-10.6], P = 0.002), and I-FABP level (1.9 [0.8-4.0] vs. 54.4 [19.5-159.3], P < 0.001) and the all-cause 28-day mortality was significantly higher (7% vs. 83%, P < 0.001). In conclusion, macroscopic tongue ischemia at ICU admission was associated with enterocyte injury and poor outcome in patients with septic shock. Although there is a disadvantage in that assessment of the tongue was subjective, tongue ischemia could be used to gauge the severity of intestinal injury and to estimate poor outcome in the clinical setting.

Development of a systems-based in situ multiplex biomarker screening approach for the assessment of immunopathology and neural tissue plasticity in male rats after traumatic brain injury.

Traumatic brain injuries (TBIs) pose a massive burden of disease and continue to be a leading cause of morbidity and mortality throughout the world. A major obstacle in developing effective treatments is the lack of comprehensive understanding of the underlying mechanisms that mediate tissue damage and recovery after TBI. As such, our work aims to highlight the development of a novel experimental platform capable of fully characterizing the underlying pathobiology that unfolds after TBI. This platform encompasses an empirically optimized multiplex immunohistochemistry staining and imaging system customized to screen for a myriad of biomarkers required to comprehensively evaluate the extent of neuroinflammation, neural tissue damage, and repair in response to TBI. Herein, we demonstrate that our multiplex biomarker screening platform is capable of evaluating changes in both the topographical location and functional states of resident and infiltrating cell types that play a role in neuropathology after controlled cortical impact injury to the brain in male Sprague-Dawley rats. Our results demonstrate that our multiplex biomarker screening platform lays the groundwork for the comprehensive characterization of changes that occur within the brain after TBI. Such work may ultimately lead to the understanding of the governing pathobiology of TBI, thereby fostering the development of novel therapeutic interventions tailored to produce optimal tissue protection, repair, and/or regeneration with minimal side effects, and may ultimately find utility in a wide variety of other neurological injuries, diseases, and disorders that share components of TBI pathobiology.

Congenital lingual cyst: Expression of MUC protein and report of a new case.

Lingual congenital cysts are uncommon lesions that alter the functions of speech, swallowing and breathing when they have considerable dimension. They usually appear from birth and increase in size gradually in childhood and adolescence. While there are a considerable number of case reports, the nomenclature and origin of this lesion are controversial. Congenital lingual cysts are composed of an epithelial lining that can show heterogeneous histological features, such as globed, ciliated, squamous and parietal cells, while the wall presents mature connective tissue and eventually smooth muscle. In the present manuscript, we report a case of a congenital lingual cyst in a 13-year-old boy, as well as the immunoexpression of MUC family proteins (MUC-1 and MUC-5AC), hoping to provide data that will help to clarify the possible etiology of this lesion.

Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation.

Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like changes in social behaviour. These data are the first to show neurodegeneration in mice expressing mutant CHMP2B and indicate that our mouse model is able to recapitulate neurodegenerative changes observed in FTD. Neuroinflammation has been increasingly implicated in neurodegeneration, including FTD. Therefore, we investigated neuroinflammation in our CHMP2B mutant mice. We observed very early microglial proliferation that develops into a clear pro-inflammatory phenotype at late stages. Importantly, we also observed a similar inflammatory profile in CHMP2B patient frontal cortex. Aberrant microglial function has also been implicated in FTD caused by GRN, MAPT and C9orf72 mutations. The presence of early microglial changes in our CHMP2B mutant mice indicates neuroinflammation may be a contributing factor to the neurodegeneration observed in FTD.

Dynamic changes in cell-surface expression of mannose in the oral epithelium during the development of graft-versus-host disease of the oral mucosa in rats.

BACKGROUND: The role of cell-surface glycoconjugates in oral mucosal graft-versus-host disease (GVHD) is still unclear, even though molecular changes in the oral epithelium are essential for the pathogenesis of these lesions. In this study, we investigated changes in the binding of mannose (Man)-specific Lens culinaris lectin (LCA) in the oral mucosa of rats with GVHD. METHODS: Lewis rat spleen cells were injected into (Lewis x Brown Norway) F1 rats to induce systemic GVHD, including oral mucosal lesions. Tongue and spleen samples were evaluated using lectin histochemistry, immunohistochemistry, Western blotting, transwell migration assays and Stamper-Woodruff binding assays. RESULTS: Binding of Man-specific LCA expanded to the epithelial layers of the tongue in GVHD-rats. An expansion of LCA binding was related to the increased expression of mannosyltransferase in the oral mucosa. CD8+ cells, effector cells of oral mucosal GVHD, expressed mannose-binding protein (MBP) and migrated to the medium containing Man in the transwell migration assay. Adherence of CD8+ cells to the oral epithelium could be inhibited by pretreating CD8+ cells with MBP antibody and/or by pretreating sections with Man-specific LCA. CONCLUSIONS: Increased expression of Man on keratinocytes leads to the migration and/or adhesion of CD8+ cells in the surface epithelium, which is mediated in part by the MBP/Man-binding pathway during the development of oral mucosal GVHD.

Localized tongue amyloidosis: a single institutional case series.

OBJECTIVE: Review Mayo Clinic experience of localized tongue amyloidosis. STUDY DESIGN: Case series with retrospective chart review. SETTING: Academic medical center. SUBJECTS AND METHODS: Cases of localized tongue amyloidosis were identified from the dysproteinemia database at the Mayo Clinic in Rochester, Minnesota. Electronic records were reviewed with focus on presenting symptoms, laboratory results (ie, serum or urine immunoelectrophoresis, bone marrow biopsy, and fat aspirate analysis), treatment modality, and status of disease at follow-up. RESULTS: Six cases of localized tongue amyloidosis presented to the Mayo Clinic between 1969 and 2011. Mean patient age was 69 years (range, 43-90). Patients presented with asymptomatic tongue mass(es). Biopsy of the tongue mass in all patients showed amyloid on Congo red stains. Work-up for systemic amyloidosis, including bone marrow biopsy, fat aspiration, and serum and urine protein immunoelectrophoresis, was negative for all 6 patients, nor was there other organ involvement. Two patients underwent resection of the lesions, and the remaining patients elected for observation. Recurrence requiring repeat excision occurred in 1 of the patients that underwent resection. Repeat evaluation for systemic involvement was performed in 3 patients 1 to 3 years after the initial diagnosis. None of these patients went on to develop systemic involvement. CONCLUSIONS: Localized tongue amyloidosis remains a rare diagnosis and requires exclusion of systemic involvement. Localized lesions may be observed or resected; however, recurrence may occur with resection. Patients with localized tongue amyloidosis do not appear to be at increased risk of developing systemic involvement.

Depletion of Langerhans cells in the tongue from patients with advanced-stage acquired immune deficiency syndrome: relation to opportunistic infections.

AIMS: To quantify and compare the expression of Langerhans cells (LCs) in the tongue mucosa of AIDS patients with different opportunistic infections, and from acquired immune deficiency syndrome (AIDS) and non-AIDS patients with normal tongues, using autopsy material. METHODS AND RESULTS: Human leucocyte antigen D-related (HLA-DR), CD1a and CD83 antibodies were used to identify and quantify LCs by immunohistochemistry in tongue tissue of 40 AIDS patients (10 with lingual candidiasis, 10 with lingual herpes, 10 with oral hairy leukoplakia and 10 with no lesions) and 23 tongues from human immunodeficiency virus (HIV)-negative control patients. Quantification was performed by means of conventional morphometry in four different regions (anterior, middle, posterior and lateral) of the tongue. The results were expressed as positive cells per area of epithelium. The AIDS patients presented a lower density of CD1a(+) cells (P < 0.001), HLA-DR (P < 0.003) and CD83 (P < 0.001) in all regions of the tongue compared to the non-AIDS control group. However, no differences in any of the markers were found when AIDS patients with different opportunistic infections were compared with AIDS patients without tongue infection. CONCLUSIONS: Advanced stage AIDS patients showed a depletion of LCs in the tongue mucosa. HIV infection induces cytopathic changes in LCs, contributing to their depletion regardless of the presence of oral infections.

Endothelial cells of oral pyogenic granulomas express eNOS and CD105/endoglin: an immunohistochemical study.

BACKGROUND: The pyogenic granuloma (PG) is a common localized hyperplastic lesion of the oral cavity. The purpose of the present study was to investigate the immunohistochemical expression of endothelial nitric oxide synthases (eNOS) and CD105/endoglin in oral PGs, to evaluate their involvement in the angiogenetic pathways of the lesion. MATERIALS AND METHODS: Ninety-three PGs were included in the study. Sixteen tumors were further sub-classified as pregnancy tumors (PT) and seventeen as pyogenic granulomas with fibrosis (PGFM). Immunohistochemical expression of eNOS and CD105/endoglin was quantified by computerized image analysis with a semi-automated system. Percentage of staining and number of objects (positive vessels) were recorded for each case. RESULTS: Intense eNOS expression was seen in 92 of 93 lesions. A statistically significant association was found between eNOS percentage of staining/eNOS positive vascular spaces (objects) and age of the patients (9% increase per decade of life). Approximately 40% less eNOS positive objects were recorded in PGFM compared with PGs. Intense membranous CD105/endoglin expression was seen in all cases. The percentage of CD105/endoglin staining was statistically increased in PGs compared with PT. Approximately 40% less CD105/endoglin objects were found in PGFM compared with PGs; 56% more CD105/endoglin objects were found in tongue lesions, compared with gingival lesions. There was no statistically significant correlation considering percentage of staining and number of objects between CD105/endoglin and eNOS. CONCLUSIONS: It is suggested that eNOS and CD105/endoglin are involved in the angiogenetic pathways of PG.

Amyloid deposition in the tongue: clinical and histopathological profile.

AIMS: Oral amyloidosis is a rare and debilitating disease that, whether primary or secondary, may severely impact the quality of a patient's life. The study investigated the characteristics of amyloid deposition in the tongue from the clinical and histopathological profiles. MATERIALS AND METHODS: Biopsy specimens were received from five patients: 2 female, 3 male. All biopsies were taken from the tongue, and all had amyloid deposition in the subepithelial connective tissue, conclusive for a diagnosis of amyloidosis. All patients showed macroglossia and difficulty in eating and impairment of speech. RESULTS: In three cases there was no evidence of systemic involvement or associated disease; these were characterized as localized amyloidosis of the tongue. The other two cases revealed multisystemic involvement. Histologically, the disease was diagnosed through specific staining with Congo red, which examined under polarized light revealed the amyloid deposits as apple-green birefringence. CONCLUSION: The findings show the tongue to be the site most frequently affected in forms of localised amyloidosis, and that a tongue biopsy possess a highly diagnostic value for amyloidosis. There is still no consensus regarding the management of lingual amyloidosis, although numerous therapies have been proposed, including surgical excision and pharmacological treatment. However lesions often persist or recur. The prognosis is uncertain, owing to the rarity of the condition, requiring regular follow-up and monitoring.

Immunolocalization of heat shock proteins 27 and 47 during repair of induced oral ulcers.

Heat shock proteins (Hsps) 27 and 47 are involved in the control of apoptosis, cell migration, and collagen synthesis. There is some understanding of the immunolocalization of these proteins during the repair process in skin and gastrointestinal mucosa, but their expressions in normal and injured oral mucosa are unknown. The aim of this study was to analyze the immunolocalization and intensity of these proteins in oral ulcers induced in rats and to compare these expression levels with those reported in skin and gastric mucosa. Ulcers were induced on the ventral surface of the tongues of rats. The rats were then euthanized at 0, 24, 48, 72, and 120 h. Hsp27 expression remained low in the first hours of repair, but was higher at 72 h, mainly in the migrating epithelium. Expression of Hsp47 was high at 48 h, mainly in fibroblasts, cells of the vascular wall, and basal keratinocytes of migrating epithelium. In the control group, expressions of these proteins were low, which indicates that these Hsps are constitutive proteins in oral mucosa. Expression levels were similar to those reported in the healing of skin lesions and gastric ulcer, suggesting a common mechanism of Hsp activation in the repair of these tissues.

Flat-type verruciform xanthoma of the tongue and its differential diagnosis.

We present herein a case of oral verruciform xanthoma (VX) in order to discuss this relatively rare entity in light of current information. A 38-year-old woman, non-smoker, presented with a lesion at the left ventral surface of the tongue. The lesion is characterized by a mild epithelial proliferation and sub-epithelial accumulation of foam cells, which were positive for CD68, and negative for CD1a and S-100 protein. Human papillomavirus (HPV) DNA typing for low, intermediate, and high-risk groups was also performed and no etiological link between HPV and this lesion was found. The past medical history of the patient was unremarkable and further investigations did not reveal any biochemical abnormalities or systemic disease. Verruciform xanthoma is an uncommon benign lesion of undetermined etiology. It is a superficial normolipemic xanthoma, probably reflecting a multifactorial reactive and dystrophic process unrelated to HPV. It is noteworthy that in a small and superficial biopsy, xanthoma cells may be scanty and can be missed, especially if the pathologist is unfamiliar with the existence of this uncommon lesion. Its clinical and pathological recognition and correct diagnosis is critical because VX can occur in conjunction with other systemic and cutaneous inflammatory diseases; therefore, it necessitates further clinical assessment.

Salivary dehydroepiandrosterone (DHEA) levels in patients with the complaint of burning mouth: a case-control study.

OBJECTIVE: This study was conducted to evaluate salivary dehydroepiandrosterone (DHEA) levels, salivary flow rate (SFR), depression, and hopelessness in patients with the complaint of burning mouth (BM). STUDY DESIGN: Thirty female patients with BM and 30 age-matched control women without any complaint of burning mouth were enrolled. After anamnesis and oral examination, the salivary flow rate was determined. Depression and hopelessness were evaluated by the application of inventories. Two saliva samples were collected for DHEA analysis. RESULTS: Dysgeusia (P = .045) and xerostomia (P = .003) were significantly higher in the BM group. The BM patients showed significantly lower salivary flow rate, both under stimulation (P = .001) and at rest (P < .001). Significant differences between the groups were not found in the depression (P = .416) or hopelessness (P = .597) scores. The BM group revealed significantly lower salivary DHEA levels in the morning samples (P = .003). CONCLUSION: Patients with BM exhibit decreased morning salivary DHEA as well as dysgeusia and hyposalivation more frequently than control subjects. Additional investigations are needed to clarify this association.

Na(v)1.7 sodium channel expression in human lingual nerve neuromas.

OBJECTIVE: Peripheral branches of the trigeminal nerve are often damaged during the removal of lower third molar teeth, and a small proportion of patients who sustain an injury develop persistent chronic pain. The cause of the pain is not clear and there are no satisfactory methods of treatment. The aim of the present study was to examine the expression of the sodium channel subtype Na(v)1.7 in damaged human lingual nerves, and to identify any association between Na(v)1.7 expression and reported symptoms of dysaesthesia. METHODS: Eleven neuromas-in-continuity (NICs) and 11 nerve-end neuromas (NENs) were studied, and were all obtained at the time of surgical repair of the damaged lingual nerve. Specimens were categorised as being obtained from patients with symptoms or without symptoms, according to the degree of pain, tingling or discomfort that had been experienced. The tissue was prepared and processed for indirect immunofluorescence, and image analysis was used to quantify the percentage area of PGP 9.5-labelled tissue that also contained Na(v)1.7. RESULTS: The results demonstrated that sodium channel Na(v)1.7 was expressed in human lingual nerve neuromas. There was no direct relationship between the level of expression of Na(v)1.7 and the patients' symptoms of dysaesthesia. However, in NICs there was found to be an inverse correlation between Na(v)1.7 and macrophage expression, and in symptomatic NICs a direct correlation was found between Na(v)1.7 expression and axonal apposition. CONCLUSIONS: These data suggest that Na(v)1.7 expression alone does not play a primary role in initiating the painful symptoms of dysaesthesia. The development of neuropathic pain may involve complex interactions including changes in ultrastructure and ion channel density.

Lingual subgemmal neurogenous plaques with pseudoepitheliomatous hyperplasia: incidental pseudomalignant condition.

Pseudoepitheliomatous hyperplasia is a reactive proliferation of benign squamous epithelium that can mimic squamous cell carcinoma. Herein is a report on this type of reaction on two subgemmal neurogenous plaques in a lingual circumvallate papilla. To the authors' knowledge this is the first report on this combination of lesions. A 66-year-old man died with disseminated squamous cell carcinoma of the lung. At autopsy the tongue was found to have an incidental pseudoepitheliomatous hyperplasia on two subgemmal neurogenous plaques with ganglion cells. Subgemmal neurogenous plaque should be included in the differential diagnosis of causes of lingual pseudoepitheliomatous hyperplasia. Awareness of the morphological spectrum of subgemmal neurogenous plaques can avoid the overdiagnosis of these lesions as neural tumors or squamous cell carcinoma.

Clinical pathological feature of early tongue amyloidosis.

OBJECTIVE: To investigate the clinical pathological feature and diagnostic criteria of tongue amyloidosis (AL). METHODS: During 1992 to 2005, 25 patients pathologically diagnosed as tongue AL in our hospital were reviewed retrospectively, and all of them had no enlarged tongue. Haematoxylin and eosin (HE) and immunohistochemical staining were used to detect the amyloid deposition on the tongue. RESULTS: Totally 84% (21/25) patients had symptoms of xerostomia and taste-blindness, 44% (11/25) patients complained of activity limitation of tongue. Macroscopic observation showed mucosa pallescence, punctuate hemorrhage, red grain particles, and ulcers on the tongue. HE staining indicated amyloid depositions in basement membrane, muscle cell, vessel wall, and nerve fiber. Immunohistochemical study demonstrated kappa light-chain deposition in 64% (16/25) cases, and lambda light-chain deposition in 36% (9/25) cases. They presented in vessel wall, nerve fiber, and muscle cells. CONCLUSION: The biopsy is an important means for the diagnosis of early tongue AL, and the wide variety of amyloid light chain is helpful to differential diagnosis.