The natural history of COVID-19 in vaccinated inflammatory bowel disease patients.

AIM: Assess the characteristics of break through COVID-19 in Inflammatory Bowel Disease (IBD) patients, despite complete vaccination. METHODS: Patients who reported a COVID-19 at least 3 weeks after complete vaccination were asked to answer an on-line anonymous questionnaire which included patient and disease characteristics, vaccination history, and the evolution of COVID-19. RESULTS: Among 3240 IBD patients who reported complete vaccination between 1st May 2021 and 30thJune 2022, 402 (12.4%) were infected by SARS Cov-2 [223 male, 216 Crohn's disease (CD), 186 Ulcerative Colitis (UC), mean (SD) age 42.3 (14.9) years, mean (SD) IBD duration 10.1 (9.7) years]. Three hundred and sixty-nine patients (91.8%) were infected once and 33 (8.2%) twice. The mean (SD) time between last vaccination and infection was 4.1 (1.6) months. Overall, 351 (87.3%) patients reported mild constitutional and/or respiratory symptoms, 34 (8.4%) were asymptomatic and only 17 patients (4.2%) required hospitalization. Of hospitalized patients, 2 UC patients died of COVID-19 pneumonia. The remaining hospitalized patients did not need high flow oxygen supply or ICU admission. CONCLUSIONS: A minority of completely vaccinated IBD patients developed COVID-19 which evolved with mild symptoms and a favorable outcome. These results reinforce the importance of vaccination especially in vulnerable populations.

Host Modulation and Treatment of Periodontal Disease.

Periodontitis is the sixth-most prevalent disease in the world and the first cause for tooth loss in adults. With focus shifted to the inflammatory/immune response in the pathogenesis of periodontitis, there is a critical need to evaluate host modulatory agents. Synthetic and biological disease-modifying antirheumatic drugs are a cornerstone for the treatment of inflammatory diseases. Recent prospective cohort studies showed that synthetic disease-modifying antirheumatic drugs improved periodontal clinical parameters following nonsurgical periodontal treatment in patients with rheumatoid arthritis. Treatment with recombinant humanized monoclonal antibodies against CD20 (rituximab) and IL-6 receptor (tocilizumab), the latter also in clinical trials for the treatment of COVID-19 pneumonia, resulted in decreased periodontal inflammation and improved periodontal status. Studies on the effect of TNF-α inhibitors in patients with periodontitis yielded inconsistent results. Recent data suggest that probiotics provide anti-inflammatory clinical benefit, as do nutritional supplements, such as n-3 fatty acids, when combined with periodontal therapy. Probiotics reduce the production of proinflammatory cytokines/chemokines by suppressing NF-κB pathways and promote the accumulation of T regulatory cells. Statins, like aspirin, have been shown to exhibit anti-inflammatory and bone-preserving actions by upregulating production of Specialized Proresolving Mediators (SPMs). Currently, there is insufficient scientific support for the topical delivery of statins or bisphosphonates as adjuncts to periodontal therapy. Here, we present a critical review of the most recent host modulatory agents applied in humans and the key immune pathways that they target. Emerging evidence from novel drug candidates, including SPMs and complement inhibitors as previously studied in animal models and currently in human clinical trials, suggests future availability of adjunctive therapeutic strategies for the management of periodontitis.

IL-1 Superfamily Members and Periodontal Diseases.

Periodontitis is a complex, multifactorial chronic disease involving continuous interactions among bacteria, host immune/inflammatory responses, and modifying genetic and environmental factors. More than any other cytokine family, the interleukin (IL)-1 family includes key signaling molecules that trigger and perpetuate periodontal inflammation. Over the years, the IL-1 family expanded to include 11 members of cytokines, some with agonist activity (IL-1α, IL-1ß, IL-18, IL-33, IL-36α, IL-36ß, and IL-36γ), receptor antagonists (IL-1Ra, IL-36Ra), and 2 anti-inflammatory cytokines (IL-37, IL-38). The IL-1 receptor antagonist (IL-1Ra) has emerged as a pivotal player in the defense against periodontitis. IL-33 primarily induces the production of Th2-associated cytokines but acts as an "alarmin" via stimulation of mast cells. The IL-36 subclass of cytokines may be important in regulating mucosal inflammation and homeostasis. IL-37 suppresses innate and acquired immune responses. IL-38 is the most recent member of the IL-1 superfamily and has anti-inflammatory properties similar to those of IL-37 but through different receptors. However, limited evidence exists regarding the role of IL-37 and IL-38 in periodontitis. Despite the development of IL-1 blocking agents, therapeutic blockade of select IL-1 family members for periodontitis has only been partially investigated in preclinical and clinical research, while the development of IL-37 and IL-38 as novel anti-inflammatory drugs has not been considered adequately. Here, we review the key properties of the IL-1 family members and provide insights into targeting or promoting select cytokines as new therapeutic agents.

Why and when to refer patients for vestibular evoked myogenic potentials: A critical review.

Cervical and ocular vestibular evoked myogenic potentials (cVEMPs and oVEMPs respectively) are now used by an increasing number of laboratories to evaluate otolith inner ear function and their pathways through the central nervous system. However, the literature is incomplete or unclear as to what information both c- and oVEMPs can add beyond what a good clinical examination can provide, and what other paramedical tests can provide also, and the present review aims to clarify what is known so far. The following review will describe what is known with regards to both c- and oVEMPs and their use. MEDLINE (accessed by PubMed, years 1994-2018) was searched with the following string: ("vestibular evoked myogenic potentials" [all fields]). Only articles published in English were evaluated. Both c- and oVEMPs are useful not only for confirming the presence of superior semicircular canal dehiscence (SSCD), but also for confirming the presence of acoustic neuromas when MRI is not available, bilateral vestibulopathies, inferior vestibular neuritis and vestibular dysfunction in inherited neuropathies. Further work is required, especially with respect to oVEMPs. The usefulness of both c- and oVEMPs goes beyond the confirmation of SSCDs, and is useful in many clinical cases.

Current and Emerging Treatments for Postsurgical Cleft Lip Scarring: Effectiveness and Mechanisms.

Cleft lip with or without cleft palate is the most common congenital malformation of the head and the third-most common birth defect. Surgical repair of the lip is the only treatment and is usually performed during the first year of life. Hypertrophic scar (HTS) formation is a frequent postoperative complication that impairs soft tissue form, function, or movement. Multiple lip revision operations are often required throughout childhood, attempting to optimize aesthetics and function. The mechanisms guiding HTS formation are multifactorial and complex. HTS is the result of dysregulated wound healing, where excessive collagen and extracellular matrix proteins are deposited within the wound area, resulting in persistent inflammation and resultant fibrosis. Many studies support the contribution of dysregulated, exaggerated inflammation in scar formation. Fibrosis and scarring result from chronic inflammation that interrupts tissue remodeling in normal wound healing. Failure of active resolution of inflammation pathways has been implicated. The management of HTS has been challenging for clinicians, since current therapies are minimally effective. Emerging evidence that specialized proresolving mediators of inflammation accelerate wound healing by preventing chronic inflammation and allowing natural uninterrupted tissue remodeling suggests new therapeutic opportunities in the prevention and management of HTS.

Neuroradiological, neurophysiological and molecular findings in infantile Krabbe disease: two case reports.

Krabbe disease is an autosomal recessive neurodegenerative disorder due to a defect of the lysosomal enzyme ß-galactocerebrosidase (ß-GALC). Depending on the age of onset, the disease is classified into infantile and later-onset forms. We report neuroradiological, neurophysiological and molecular findings in two Greek patients with the infantile form of Krabbe disease. The index patients presented at the age of 3.5 and 6 months, respectively, due to developmental delay. Magnetic resonance imaging (MRI) of the first patient's brain demonstrated signs of leukodystrophy, while nerve conduction velocities (NCVs) were significantly decreased. The second patient's MRI at the age of 4 months was initially normal, but at 18 months demonstrated leukodystrophic alterations as well, whereas NCVs were also significantly delayed. In both patients, a severe decrease in ß-GALC, activity supported the diagnosis of Krabbe disease, while the final diagnosis was confirmed by molecular genetic testing. Two homozygous mutations of the GALC gene, the c.411_413delTAA [p.K139del] mutation in the first patient, and the c.749T>C [p.I250T] mutation in the second patient, were identified. At their last follow-up visit at the age of 4 and 6 years, respectively, both patients were bedridden and quadri-plegic, suffering from frequent respiratory tract infections and fed through a gastrostomy. Both mutations found in homozygosity in these two unrelated patients of Greek ancestry, could pinpoint a common origin. Genotyping of patients with Krabbe disease is important, in order to contribute to the creation of a European mutation database and to further study possible genotype-phenotype correlations of the disease.

SOCS-3 Regulates Alveolar Bone Loss in Experimental Periodontitis.

The host immune response plays a key role in bacteria-induced alveolar bone resorption. Endogenous control of the magnitude and duration of inflammatory signaling is considered an important determinant of the extent of periodontal pathology. Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytokine signaling pathways and may play a role in restraining periodontal inflammation. We hypothesized that SOCS-3 regulates alveolar bone loss in experimental periodontitis. Periodontal bone loss was induced in 16-wk-old myeloid-specific SOCS-3-knockout and wild-type (WT) C57Bl6-B.129 mice by oral inoculation 9 times with 10(9) colony-forming units of Porphyromonas gingivalis A7436 through an oral gavage model for periodontitis. Sham controls for both types of mice received vehicle without bacteria. The mice were euthanized 6 wk after the last oral inoculation. Increased bone loss was demonstrated in P. gingivalis-infected SOCS-3-knockout mice as compared with P. gingivalis-infected WT mice by direct morphologic measurements, micro-computed tomography analyses, and quantitative histology. Loss of SOCS-3 function resulted in an increased number of alveolar bone osteoclasts and increased RANKL expression after P. gingivalis infection. SOCS-3 deficiency in myeloid cells also promotes a higher P. gingivalis lipopolysaccharide-induced inflammatory response with higher secretion of IL-1ß, IL-6, and KC (IL-8) by peritoneal macrophages as compared with WT controls. Our data implicate SOCS-3 as a critical negative regulator of alveolar bone loss in periodontitis.

Periodontal disease and risk of all cancers among male never smokers: an updated analysis of the Health Professionals Follow-up Study.

BACKGROUND: Periodontal disease has a direct impact on the immune response and has been linked to several chronic diseases, including atherosclerosis and stroke. Few studies have examined the association between periodontal disease and cancer. PATIENTS AND METHODS: A total of 19 933 men reported being never smokers (of cigarette, pipes or cigars) in the Health Professionals' Follow-up Study. Periodontal disease status and teeth number were self-reported at baseline and during follow-up. All cancers were ascertained during 26 years of follow-up. Cox's proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) adjusting for risk factors. RESULTS: A 13% increase in total cancer was observed among men reporting periodontitis at baseline, and a 45% increase in risk was observed among men with advanced periodontitis (periodontitis with <17 remaining teeth). Periodontitis was not associated with prostate cancer, colorectal cancer or melanoma, the three most common cancers in this cohort of never smokers, but a 33% increase in risk was observed for smoking-related cancers (lung, bladder, oropharnygeal, esophageal, kidney, stomach and liver cancers; HR = 1.33, 95% CI 1.07-1.65). Men with advanced periodontitis had an HR of 2.57 (95% CI 1.56-4.21; P = 0.0002) for smoking-related cancers, compared with men who did not have periodontitis and had 17 teeth or more. Advanced periodontitis was associated with elevated risks of esophageal and head and neck cancers (HR = 6.29, 95% CI 2.13-18.6; based on five cases with advanced periodontitis) and bladder cancer (HR = 5.06, 95% CI 2.32-11.0; based on nine cases with advanced periodontitis). CONCLUSIONS: Advanced periodontitis was associated with a 2.5-fold increase in smoking-related cancers among never smokers. Periodontitis may impact cancer risk through system immune dysregulation. Further studies need to examine the immune impact of advanced periodontitis on cancer, especially for cancers known to be caused by smoking.

Pharmacoresistant partial-onset epilepsy misdiagnosed as panic disorder: a case report.

The clinical differentiation between simple partial epileptic seizures of temporal lobe origin and panic attacks is often difficult on clinical grounds alone, because both conditions are characterized by common symptomatology which includes the feeling of fear, autonomic system dysfunction, disorientation and alternation of the level of consciousness when these conditions evolve clinically. The symptoms stem from common pathophysiologic and anatomic substrates of these two conditions, localized in the limbic system, especially the amygdala. We present the case of a young woman who had a febrile seizure in childhood and subsequent episodes of fear accompanied by tremor and possible alteration of consciousness followed by headache. These spells were diagnosed as panic attacks during her teenage years and she was given Clobazam in order to suppress them. The patient responded well for several years without attacks but her symptoms reappeared following discontinuation of her medication in order to conceive. At that time a detailed history was taken from her spouse and further clinical evaluation raised the suspicion of seizures especially due to the fact that her spells were characterized by alteration of consciousness; she was therefore referred for additional investigations which included admission to a monitoring unit for epilepsy. Long-term video-EEG recording revealed the presence of simple partial seizures with secondary generalization confirming the clinical impression. She was subsequently treated with antiepileptic medications; however the patient's condition worsened to the point where she became pharmacoresistant having failed several antiepileptic drug trials in monotherapy or combination. An MRI scan of the brain revealed the presence of right-sided mesial temporal sclerosis, a known consequence of febrile seizures. Her seizures were nocturnal tonic-clonic and gradually worsened to the point of occurring during most nights. She was therefore referred for a presurgical evaluation which confirmed that the epileptic focus was associated with the area of mesial temporal sclerosis. The epileptic focus was successfully removed from the right anterior temporal lobe and since then she remained free of seizures whereas, in addition, the presumed symptoms of panic attacks also resolved. This case indicates the occasional difficulty in diagnosing simple partial seizures and how it may be confused with psychiatric conditions. Therefore, the treating physician, especially the psychiatrist, should remain vigilant when treating cases of panic attacks, especially when they present with either atypical symptomatology, such as the case described, or when they do not respond to appropriately chosen treatment; such cases may warrant referral for further investigation.

Gingival crevicular fluid levels of interferon-γ, but not interleukin-4 or -33 or thymic stromal lymphopoietin, are increased in inflamed sites in patients with periodontal disease.

OBJECTIVE: To investigate the hypothesis that levels of interferon (IFN)-γ and interleukin (IL)-4, as well as the newer cytokines IL-33 and thymic stromal lymphopoietin (TSLP), in gingival crevicular fluid (GCF) samples differ from sites of patients at various clinical stages of periodontal disease and controls. BACKGROUND: Periodontal diseases result from the complex interplay between pathogenic bacteria and the host's immune responses. Several inflammatory mediators, such as IFN-γ and IL-4, have been detected in GCF samples in patients with periodontitis, but the results are mostly contradicting due to the lack of uniformity and collection of sites and methods of analysis. MATERIAL AND METHODS: GCF samples were collected from sites with different clinical characteristics (healthy, gingivitis and periodontitis sites) from periodontally healthy ( n = 14), plaque-induced gingivitis (n = 17) and chronic periodontitis (n = 11) subjects. The GCF samples were analyzed for the frequency of detection and levels of IFN-γ, IL-4, IL-33 and TSLP using a multiplex bead immunoassay. RESULTS: Inflamed sites in both patients with plaque-induced gingivitis and chronic periodontitis showed statistically significantly higher volume of GCF compared to non-inflamed sites in all patients. IFN-γ could be detected in about 50-70% of the samples analyzed and at significantly higher levels in sites with periodontitis compared to healthy sites in patients with chronic periodontitis (p = 0.035). We also show a statistically significant decrease of IFN-? in healthy sites of patients with chronic periodontitis as compared to gingivitis sites in patients with plaque-induced gingivitis (p = 0.047). Only some of the GCF samples showed detectable levels for IL-4 and TSLP, while IL-33 was below the detection level in all samples collected. CONCLUSIONS: These results suggest that IFN-γ levels in GCF depend on the clinical stage of the site and not on the disease stage of the patient, but need to be expanded to a greater number of subjects and additional analysis of corresponding gingival tissue biopsies for cytokine gene expression.

Stress hormones regulate periodontal inflammation.

Periodontal disease involves inflammation of the gingival tissues, caused by microbial pathogens. Recent papers suggest that emotional stress worsens periodontal disease. Here we review the literature and propose that corticotropin-releasing hormone (CRH) secreted under stress stimulates gingival mast cells together with other neuropeptides and cytokines to secrete pro-inflammatory molecules that contribute to periodontal pathology. Stress reduction and/or mast cell inhibition may provide additional therapeutic approaches.

A coexisting anatomical variation of median and ulnar nerves in a cadaver palm.

During a routine dissection we observed an anatomical variation of the median nerve and an atypical anastomosis in the palm region of a male cadaver. There were four distinct recurrent motor branches of the left median nerve, and the palmar cutaneous branch of the ulnar nerve communicated directly with the third common palmar digital nerve. The presence of such an anatomical variant in the hand should keep surgeons alert in the management of hand pathology especially in carpal tunnel syndrome, which is a routine operation for many medical centres.

Fleshy palmaris longus muscle - a cadaveric finding and its clinical significance: a case report.

INTRODUCTION: Palmaris longus variations may include complete agenesis, variation in the location and form of the fleshy portion, aberrancy in attachment, duplication or triplication, accessory tendinous slips, replacing elements of similar form or position. Description of case: An anomalous palmaris longus muscle was found in the right upper extremity of a 63 year-old male cadaver. The muscle was totally fleshy without a long insertion tendon. Its origin was normal, the belly was rather broad and long, fusiform at the upper half and unipennate at the lower half of the forearm, and it was toggled into a short and thick tendon. At its insertion the tendon was split forming a second thinner tendon. The thick tendon was inserted into the flexor retinaculum and the thinner one into the palmar aponeurosis. The muscle compressed the median nerve although no related symptoms were reported on the cadaver's medical history. DISCUSSION: This variation is of clinical importance because it may cause carpal tunnel syndrome or difficulties in image interpretation by radiologists. In addition the palmaris longus muscle is an anatomical landmark for operations at the forearm and wrist and its tendon can be used as a graft.

A correlative study of quantitative EMG and biopsy findings in 31 patients with myopathies.

A direct correlation of QEMG with muscle biopsy findings might help delineate the sensitivity of QEMG in identifying muscle pathology as well as provide information on electrophysiological-histological correlations. In a study of 31 patients with a variety of myopathies we found that the sensitivity of QEMG was between 24 to 69% depending of the specific method of signal analysis. The positive predictive value of abnormal QEMG was more than 90% while its negative predictive value was only about 20%. Amplitude outlier analysis was superior especially in minimally weak muscles (MRC > 4) and was particularly sensitive at detecting increased variability in fiber size and more subtle myopathic changes.

A bicarotid trunk in association with an aberrant right subclavian artery. Report of two cases, clinical impact, and review of the literature.

A combination of an aberrant right subclavian artery (ARSA) and a bicarotid trunk (BCT) appears in up to 2.5% of the population. The aim of this study is to report the higher total and male incidence of this variation in the literature and to summarise its clinical impact, providing useful knowledge to anatomists, radiologists, cardiologists, and vascular and thoracic surgeons in order to avoid diagnostic pitfalls and therapeutic complications. A total of 72 (43 female and 29 male) Greek Caucasian formalin-embalmed cadavers were studied. The international literature was reviewed along with the dissection archives of the Department of Anatomy from 1986 to 2009. Two male cadavers were found to have an ARSA combined with a BCT (incidence: total 2.78%, males 6.9%, females 0%). Both aortic arches consisted of three branches: (1) the BCT, (2) the left subclavian artery, and (3) the ARSA. The common carotids followed a normal route to the neck; the ARSA passed between the trachea and the oesophagus in the first case and behind the oesophagus in the second case, and was accompanied by a non-recurrent laryngeal nerve. In the second cadaver the ARSA formed a sharp angle (kinking/buckling) on its route to the right arm. The ARSA is associated with several congenital cardiovascular anomalies and some chromosomal and other syndromes. It is occasionaly responsible for causing dysphagia, dyspnoea, or acute ischaemia to the right upper limb, and it may present as a superior mediastinal mass in cases of aneurysm formation.

Management of obstructive sleep apnea in Europe.

OBJECTIVES: In Europe, the services provided for the investigation and management of obstructive sleep apnoea (OSA) varies from country to country. The aim of this questionnaire-based study was to investigate the current status of diagnostic pathways and therapeutic approaches applied in the treatment of OSA in Europe, qualification requirements of physicians involved in diagnosis and treatment of OSA, and reimbursement of these services. METHODS: Two questionnaires were sent to 39 physicians in 22 countries in Europe. In order to standardize the responses, the questionnaire was accompanied by an example. RESULTS: Sleep centers from 21 countries (38 physicians) participated. A broad consistency among countries with respect to the following was found: pathways included referral to sleep physicians/sleep laboratories, necessity for objective diagnosis (primarily by polysomnography), use of polygraphic methods, analysis of polysomnography (PSG), indications for positive airway pressure (PAP) therapy, application of standard continuous PAP (CPAP) therapy (100% with an CPAP/APAP ratio of 2.24:1), and the need (90.5%) and management of follow-up. Differences were apparent in reimbursement of the diagnostic procedures and follow-up, in the procedures for PAP titration from home APAP titration with portable sleep apnea monitoring (38.1%) up to hospital monitoring with PSG and APAP (85.7%), and in the qualification requirements of sleep physicians. CONCLUSIONS: Management of OSA in different European countries is similar except for reimbursement rules, qualification of sleep specialists and procedures for titration of the CPAP treatment. A European network (such as the one accomplished by the European Cooperation in Science and Technology [COST] B26 Action) could be helpful for implementing these findings into health-service research in order to standardize management in a cost effective perspective.

Brainstem lesions may be important in the development of epilepsy in multiple sclerosis patients: an evoked potential study.

OBJECTIVE: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, with epileptic seizures sometimes observed in the same patients. In this study, we used evoked responses to study the pathogenesis of epilepsy in MS. METHODS: Patients with a diagnosis of definite MS and who had EPs performed (visual (VEP), brainstem auditory (BAEP) and short latency somatosensory (upper (USSEP) and lower (LSSEP))) were retrospectively included in this study. They were divided into three groups; Group I: Patients with no epilepsy and who were not taking anti-epileptic drugs (AED); Group II: Patients with epilepsy and taking AEDs; and Group III: Patients with no epilepsy who were taking AEDs for symptoms related to neuropathic pain. RESULTS: Three hundred and fifty-five patients were included in this study; Group I: 229 patients (64.5%), Group II: 20 patients (5.6%) and Group III: 106 patients (29.9%). The proportion of patients with abnormal BAEP and USSEP was higher in Group II. CONCLUSIONS: A positive association exists between the presence of epilepsy in MS patients and BAEP and USSEP abnormalities. Analysis of Group III ruled out AED use as a factor. SIGNIFICANCE: Brainstem lesions may be the cause of epileptogenicity in MS.

A rare case of bilateral supernumerary heads of sternocleidomastoid muscle and its clinical impact.

The sternocleidomastoid muscle (SCM) functions as a landmark for physicians such as anatomists, orthopaedic surgeons, neurosurgeons, and anaesthesiologists, who intervene in the minor supraclavicular fossa located at the base of the neck. The variability of SCM anatomy may cause complications while trying to access the vital elements that are located in the minor supraclavicular fossa. This study aims to present a case of supernumerary heads of the sternocleidomastoid muscle and to discuss its clinical significance. The cervical region of an elderly male cadaver was dissected and the findings were recorded and photographed. On both sides, the SCM muscle had an additional sternal head, and simultaneously there were three additional clavicular heads, four in total. These additional heads, the sternal and the clavicular, reduced the interval between them causing significant stenosis of the minor supraclavicular fossa. Sternocleidomastoid muscle variations with regard to the number of its heads are very rare in the literature, but this variation may cause severe complications. The minor supraclavicular fossa is important for anaesthesiologists because of the anterior central venous catheterization approach. Physicians should be aware of this anatomical variation in order to prevent complications.

Axial transformation of the profunda femoris vein: formation, relations and course in a cadaveric specimen.

When the superficial femoral vein is obstructed by thrombosis, the profunda femoris vein provides an important collateral pathway, transforming into the axial vein of the lower limb. When operating on a transformed axial vein, a surgeon should be aware of the formation, the relations and the course of the vein. A precise description of these anatomical features is not feasible on the basis of ultrasound, venographic or surgical study but only from anatomical studies. We present a case of axial transformation of the profunda femoris vein found in a cadaver, focusing on the anatomical features of the transformed axial vein.