Oral autoimmune vesicobullous diseases: Classification, clinical presentations, molecular mechanisms, diagnostic algorithms, and management

Mucocutaneous blistering autoimmune diseases are a group of systemic, rare, chronic disorders characterized by humoral-mediated immunologic mechanisms against epithelial, basement membrane, and subepithelial tissues. Morbidity and mortality can be completely different among these diseases, with outcome being dependent on an early and accurate diagnosis, systemic comorbidities, and the patient's response to treatment. Definitive diagnosis is based on clinical and histopathologic findings. Because clinical presentations among these diseases are often similar, different immunofluorescence tests and ELISAs are used to confirm the specific diagnosis. Oral mucosa may often be the first site of clinical manifestation from which the disease spreads to other mucosal surfaces and skin. Thus, often dentists and oral medicine specialists may be the first to encounter patients with such diseases. In this review we discuss the most frequent autoimmune vesicobullous disorders, namely pemphigus vulgaris, mucous membrane pemphigoid, bullous pemphigoid, and linear IgA disease

V’O2 kinetics in response to High-Intensity-Interval Training (HIT) and isoinertial resistance training (IRT) in older, healthy men

High intensity exercise training (HIT) accelerates V’O2 kinetics (VO2k) in older subjects. It is controversial whether IRT may elicit the same adaptation. We explored the effect of HIT and IRT on VO2k and muscle deoxygenation during moderate intensity exercise in older, healthy men. 12 men (68 yy ± 4) were exposed to 8 weeks (3 times a week) of: i) HIT, and, after 4 months, ii) IRT performed with an isoinertial YoYo. Before and after training we measured: i) V’O2 peak (V’O2p); ii) breath-by-breath V’O2 and fractional muscle O2 extraction (∆HHb) of vastus lateralis by quantitative NIRS during step-exercise transitions of moderate intensity. VO2k was modeled by means of a double - exponential function to obtain the time constant (Tau) of its primary component. The normalized ∆HHb to ∆V’O2 ratio (∆HHb/∆V’O2) was calculated as and index of the matching between muscular O2 delivery (VO2m) and uptake (QaO2). V’O2p increased after HIT (29.9 mL min-1 kg-1 ± 4.3 - 32.6 mL min-1 kg-1± 6.0, p<0.05); it was not affected by IRT. Tau decreased after HIT (26.97 s ± 5.54 - 19.63 s ± 4.31, p<0.05); it did not change after IRT. Peak ∆HHb/∆V’O2 was smaller after HIT (1.83 ± 0.63 - 1.23 ± 0.37, p<0.05); it was not affected by IRT. 8 weeks of HIT accelerated V’O2k and improved the matching between QaO2 and VO2m. IRT did not lead to any improvement of ∆HHb/∆V’O2 and left V’O2k unchanged. Results suggest that the acceleration of V’O2k was mainly due to the improved matching of VO2m to QaO2

EFFECT OF HIGH INTENSITY TRAINING AND ISOINERTIAL TRAINING ON MUSCLE FUNCTIONS IN OLDER ADULTS

Introduction Maximal muscle strength is a strong predictor of functional skills and ability to maintain independent living in elderly. Muscle contraction properties has been shown to decline to a greater extent than muscle strength with aging and it has been considered the main responsible of the observed decline in functional status (Izquierdo et al., 1999). Endurance high intensity interval training (HIT), by involving large muscle groups, and eccentric strength exercise (IRT), by producing high mechanical loads, could be used in elderly to improve muscle function and quality of life (Milanovi et al., 2015). Therefore, the aim of this study was to examine the changes in muscle properties in elderly after 8 wk of HIT and IRT. Methods 12 moderately active older adults (age: 69.4±4.3 yy; BMI: 22.9±2.7 kg/m2; V’O2max: 29.5±4.1 mL/kg/min) have completed 8 wk of: i) HIT, 7 two-minute cycling repetitions at 90% of V’O2max, 3 times/wk, and, after 4 months, ii) IRT performed with an isoinertial leg press (YoYo TechnologyAB) comprised 4×7 maximal concentric-eccentric knee extensions, 3 times/wk. Maximum voluntary contraction (MVC) was measured using a cell load in a custom-made setup (90° knee flexion). Electrically evoked muscle single twitch was superimposed onto MVC: neuromuscular activation (NA) was calculated as the ratio between the amplitudes of the superimposed and resting twitches. Muscle volume of the quadriceps (Qvol) was obtained by MRI scans. Results MVC at 90° knee flexion, increase significantly only after IRT (P < 0.01). Both training modalities affected significantly NA (P < 0.05): +12.4% after HIT and +14.2 after IRT. Similarly, Qvol increase by 5.1% (P < 0.05) after HIT intervention and by 4.9% (P < 0.05) after IRT. Discussion Our results confirm the feasibility and effectiveness of HIT and IRT to improve muscle qualities: 8 wk of specific training are able to modify muscle mass, MVC and neuromuscular activation in elderly subjects. This stresses the importance of using effective approaches such as exercise treatment with high loads and high intensities in the prevention of disuse in elderly individuals who are concurrently exposed to the deleterious effects of aging on muscle contractile function and mass (Behrens et al., 2016). We can therefore speculate that the two proposed training modalities may be helpful in improving functional status and prevent frailty in elderly subjects. References Izquierdo M, Aguado X, Gonzalez R, Lopez JL, Hakkinen K. (1999). Eur J Appl Physiol Occup Physiol, 79, 260-7. Milanovi Z, Sporiš G, Weston M. (2015). Sports Med, 45(10), 1469-81. Behrens M, Brown N, Bollinger R, Bubeck D, Mau-Moeller A, Weippert M, Zschorlich V, Bruhn S, Alt W. (2016). Appl Physiol Nutr Metab, 41(1), 110-3

SPEEDING OF V’O2 KINETICS IN RESPONSE TO HIGH-INTENSITY-INTERVAL TRAINING IN OLDER, HEALTHY MEN

Introduction Experimental evidence suggests that High Intensity Interval Training (HIT, high intensity - low volume exercise) may be effective in accelerating the dynamic response pulmonary O2 uptake (V’O2) in older subjects through an improvement of the matching between local O2 delivery and uptake (Williams et al., 2013). This study explores the effect of HIT on V’O2 kinetics and muscle deoxygenating during step transitions of moderate intensity, cycling exercise in older, healthy men. Methods 12 moderately active older adults (68-yy ± 4) were exposed to 8 weeks of HIT training with 7 two-minute repetitions at 40 and 90% of V ̇O2max, 3 times a week. Before and after training we measured: i) V’O2 peak (V’O2p), gas exchange threshold (GET) and respiratory compensation point (RCP) during an incremental test up to exhaustion; ii) breath-by-breath V’O2 and change of fractional muscle O2 extraction (ΔHHb) of vastus lateralis by quantitative NIRS during three step-exercise transitions performed at a workload corresponding to 90% of GET. V’O2 kinetics was modeled, after synchronization and overlapping of the three series, by means of a double - exponential function so that we estimated the time constant (Tau) of the primary component of VO2 kinetics. Finally, the normalized ΔHHb to ΔV’O2 ratio was obtained as index of the matching between muscular O2 delivery and uptake (De Roia et al., 2012; Murias et al., 2011). Results V’O2max increased by 9% (29.9 mL min-1 kg-1 ±4.3 - 32.6 mL min-1 kg-1± 6.0, p<0.01, ES 0.51) after 8 weeks of HIT. RCP (respiratory compensation point, per cent of V’O2max) significantly improved by 10% (76.4 % ± 8.3 - 82.9 % ± 4.9, p<0.05, ES 0.97); Tau decreased by about 26% (26.97 s ± 5.54 - 19.63 s ± 4.31, p<0.001, ES 1.48), suggesting a substantial acceleration of V’O2 kinetics; peak value of ΔHHb to ΔV’O2 ratio was smaller after HIT (∼ 29%) (1.83 ± 0.63 - 1.23 ± 0.37, p<0.01, ES 1.17). Discussion This study shows that 8 weeks of HIT were sufficient to induce a significant acceleration of V’O2 kinetics during moderate intensity exercise and to improve the matching between muscular O2 delivery and uptake in older, healthy men. These results suggest that the acceleration of the dynamic response of aerobic metabolism was due to an improved matching of O2 utilization to microvascular delivery. References Williams AM, Paterson DH, Kowalchuk JM. (2013) J Appl Physiol 114, 1550–1562. De Roia G, Pogliaghi S, Adami A, Papadopoulou C, Capelli C. (2012) Am J Physiol Regul Integr Comp Physiol. 302, R1158- R1166. Murias JM, Spencer MD, DeLorey DS, Gurd BJ, Kowalchuk JM, Paterson DH. (2011) J Appl Physiol 111, 1410–1415

Limiting Behaviour of the Mean Residual Life

In survival or reliability studies, the mean residual life or life expectancy is an important characteristic of the model. Here, we study the limiting behaviour of the mean residual life, and derive an asymptotic expansion which can be used to obtain a good approximation for large values of the time variable. The asymptotic expansion is valid for a quite general class of failure rate distributions--perhaps the largest class that can be expected given that the terms depend only on the failure rate and its derivatives.Comment: 19 page

When orofacial pain needs a heart repair

Objectives: The association of chronic orofacial pain (COFP) and congenital heart disease has never previously been reported. We report the first case of COFP secondary to a right-to-left shunt (RLS) due to asymptomatic patent foramen ovale (PFO) in a patient with prothrombotic states. Materials and methods: A 48-year-old female patient presented with a 10-month history of left-sided facial pain who was initially diagnosed with persistent idiopathic facial pain (PIFP) on account of its similar characteristics. Magnetic resonance imaging (MRI) of the brain revealed gliosis and carotid siphon tortuosity; in addition, hyperhomocysteinaemia due to the homozygosis mutation for 5,10 MethyleneTetraHydroFolate Reductase was identified. Transcranial doppler ultrasonography was requested from a neurology consultant which revealed a high degree of RLS. Subsequently, a cardiological evaluation was performed; the specialist requested a transesophageal echocardiography that detected an interatrial septum aneurysm with PFO. Results: Based on the analysis of the patient's high degree of RLS, prothrombotic state and gliosis in relation to age, the cardiological consultant chose to perform a percutaneous closure of the PFO to avoid the risk of a cryptogenic stroke. After PFO closure, a complete remission of the pain was obtained. Conclusions: The disappearance of the pain supports the possible association between RLS and COFP. PFO with RLS has been suggested as a risk factor for cryptogenic stroke, especially in association with other thromboembolic risk factors. Therefore, the early detection, in this case, could be considered a possible lifesaver. Communication between different care providers is essential when the patient presents symptoms of facial pain which are of an atypical nature

Autoimmune mucocutaneous blistering diseases after SARS-Cov-2 vaccination: A Case report of Pemphigus Vulgaris and a literature review

Background: Cases of severe autoimmune blistering diseases (AIBDs) have recently been reported in association with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Aims: To describe a report of oropharyngeal Pemphigus Vulgaris (OPV) triggered by the mRNABNT162b2 vaccine (Comirnaty®/ Pfizer/ BioNTech) and to analyze the clinical and immunological characteristics of the AIBDs cases reported following the SARS-CoV-2 vaccination. Methods: The clinical and immunological features of our case of OPV were documented. A review of the literature was conducted and only cases of AIBDs arising after the SARS-CoV-2 vaccination were included. Case report: A 60-year old female patients developed oropharyngeal and nasal bullous lesions seven days after the administration of a second dose of the mRNABNT162b2 vaccine (Comirnaty®/ Pfizer/BioNtech). According to the histology and direct immunofluorescence findings showing the presence of supra-basal blister and intercellular staining of IgG antibodies and the presence of a high level of anti-Dsg-3 antibodies (80 U/ml; normal < 7 U/ml) in the serum of the patients, a diagnosis of oropharyngeal Pemphigus Vulgaris was made. Review: A total of 35 AIBDs cases triggered by the SARS-CoV-2 vaccination were found (including our report). 26 (74.3%) were diagnosed as Bullous Pemphigoid, 2 (5.7%) as Linear IgA Bullous Dermatosis, 6 (17.1%) as Pemphigus Vulgaris and 1 (2.9%) as Pemphigus Foliaceus. The mean age of the sample was 72.8 years and there was a predominance of males over females (F:M=1:1.7). In 22 (62.9%) cases, the disease developed after Pfizer vaccine administration, 6 (17.1%) after Moderna, 3 (8.6%) after AstraZeneca, 3 (8.6%) after CoronaVac (one was not specified). All patients were treated with topical and/or systemic corticosteroids, with or without the addition of immunosuppressive drugs, with a good clinical response in every case. Conclusion: Clinicians should be aware of the potential, though rare, occurrence of AIBDs as a possible adverse event after the SARS-CoV-2 vaccination. However, notwithstanding, they should encourage their patients to obtain the vaccination in order to assist the public health systems to overcome the COVID-19 pandemic

EFFECT OF HIGH INTENSITY TRAINING AND ISOINERTIAL TRAINING ON INTERMUSCULAR ADIPOSE TISSUE IN OLDER ADULTS

Introduction Recent findings suggest that, in elderly, Intermuscular Adipose Tissue (IMAT) may be associated with inactivity and that exercise training may be able to mitigate the content of IMAT (Murphy et al., 2012; Santanasto et al., 2011). The purpose was to determine how IMAT can be influenced by exercise and if a greater reduction in IMAT occurs with concurrent aerobic High Intensity Training (HIT) and Isoinertial Resistance Training (IRT). Methods 12 moderately active older adults (age: 69.4±4.3 yy; weight: 78.5±10.5 kg; height: 171.2±5.3 cm; BMI: 22.9±2.7 kg/m2; V'O2max: 29.5±4.1 mL/kg/min) were exposed to 8 weeks of: i) HIT training with 7 two-minute cycling repetitions at 90% of V'O2max, 3 times/week and, after 4 months, ii) IRT performed with an isoinertial leg press (YoYo Technology AB) comprised 4×7 maximal concentric-eccentric knee extensions, 3 times/week. MRI of the mid-thigh was examined to determine changes in muscle composition (Cross Sectional Area (CSA) and IMAT) after exercise intervention using SliceOmatic image analysis software (Rossi et al., 2010). IMAT was defined as adipose tissue area visible between quadriceps muscle groups. Results Quadriceps CSA increased significantly after HIT and after IRT by 6% (P<0.05) and 7% (P<0.05) respectively. IMAT decreased after HIT and IRT by 31% (P<0.05) and 41% (P<0.05) respectively. Net thigh lean mass increased significantly after both training by 10% (P<0.05). Discussion Our data, in contrast with Jacobs (2014) and Goodpaster (2008) but in agreement with other previous studies (Murphy et al., 2012; Santanasto et al., 2011), show that IMAT decrease after a 8 weeks exercise intervention in older adults both after HIT and IRT. Preliminary data show that exercise training performed at high intensity in older adults may contrast skeletal muscle fat infiltration. Our study is non-randomized, not-counterbalanced and limited by small sample size: additional studies are needed to determine the most effective exercise (type, intensity, modalities) able to decrease IMAT and how this decrease may positively affect health in elderly

Aseptic Meningitis in Oral Medicine: Exploring the Key Elements for a Challenging Diagnosis: A Review of the Literature and Two Case Reports

Aseptic meningitis (AM) is a potentially severe and life-threatening disease characterized by meningeal inflammation, usually with mononuclear pleocytosis. It represents a challenging and controversial issue in medicine for multiple etiologies, classification, and difficult diagnosis in the face of nonspecific sets of signs and symptoms. In the area of interest of oral medicine, in specific clusters of patients, even if rare, the occurrence of aseptic meningitis can pose a diagnostic and management dilemma in the following potential etiologies: (i) systemic diseases with oral and meningeal involvement, which include Behçet’s disease and Sjögren syndrome; (ii) drug-induced aseptic meningitis; (iii) aseptic viral meningitis, mostly related to herpes simplex virus infection and hand, foot, and mouth disease, caused by enteroviruses. In this review, clinical manifestations, diagnostic methodologies, incidence, treatment, and prognosis for each of these clinical entities are provided. Furthermore, two illustrative case reports are described: a patient suffering from recurrent oral ulcers, in which a sudden onset of AM allows us to diagnose Neuro Behçet’s disease, and a patient affected by pemphigus vulgaris, manifesting a drug-induced AM. Exploring this complex clinical entity scenario, it is clear that an oral medicine specialist has a place on any multidisciplinary team in making such a challenging diagnosis

Smartphone-based chemiluminescent origami µpad for the rapid assessment of glucose blood levels

Microfluidic paper analytical devices (µPADs) represent one of the most appealing trends in the development of simple and inexpensive analytical systems for diagnostic applications at the point of care (POC). Herein, we describe a smartphone-based origami µPAD for the quantitative determination of glucose in blood samples based on the glucose oxidase-catalyzed oxidation of glucose leading to hydrogen peroxide, which is then detected by means of the luminol/hexacyanoferrate(III) chemiluminescent (CL) system. By exploiting the foldable µPAD format, a two-step analytical procedure has been implemented. First, the diluted blood sample was added, and hydrogen peroxide was accumulated, then the biosensor was folded, and a transport buffer was added to bring hydrogen peroxide in contact with CL reagents, thus promoting the CL reaction. To enable POC applicability, the reagents required for the assay were preloaded in the µPAD so that no chemicals handling was required, and a 3D-printed portable device was developed for measuring the CL emission using the smartphone’s CMOS camera. The µPAD was stable for 30-day storage at room temperature and the assay, displaying a limit of detection of 10 µmol L−1, proved able to identify both hypoglycemic and hyperglycemic blood samples in less than 20 min