Tachykinins and the potential causal factors for post-COVID-19 condition.

The most prevalent symptoms of post-COVID-19 condition are pulmonary dysfunction, fatigue and muscle weakness, anxiety, anosmia, dysgeusia, headaches, difficulty in concentrating, sexual dysfunction, and digestive disturbances. Hence, neurological dysfunction and autonomic impairments predominate in post-COVID-19 condition. Tachykinins including the most studied substance P are neuropeptides expressed throughout the nervous and immune systems, and contribute to many physiopathological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems and participate in inflammation, nociception, and cell proliferation. Substance P is a key molecule in neuroimmune crosstalk; immune cells near the peripheral nerve endings can send signals to the brain with cytokines, which highlights the important role of tachykinins in neuroimmune communication. We reviewed the evidence that relates the symptoms of post-COVID-19 condition to the functions of tachykinins and propose a putative pathogenic mechanism. The antagonism of tachykinins receptors can be a potential treatment target.

Oral hygiene, mouthwash usage and cardiovascular mortality during 18.8 years of follow-up.

Aim(s) We tested the following hypotheses: would better oral hygiene self-care (OHS) influence cardiovascular (CVD) mortality? Will using mouthwash in addition to OHS affect CVD mortality? How does mouthwash usage impact the oral microbes?Design and methods Among 354 dentate subjects from the Kuopio Oral Health and Heart study, the association of OHS with CVD mortality was assessed using Cox regression analyses, adjusting for age, sex, smoking, dyslipidemia, diabetes, hypertension and education. Additionally, whether using mouthwash would affect this relationship was evaluated.Results In the multivariable-adjusted models, OHS was associated with a 51% reduction in the risk of CVD mortality (hazard ratio [HR] 0.49 [0.28-0.85]; p = 0.01). Even those who had coronary artery disease at baseline showed a marginally significant benefit (0.50 [0.24-1.06]; p = 0.07). However, mouthwash usage did not change OHS effects (HR = 0.49 [0.27-0.87]; p = 0.01), indicating no additional benefits nor detriments. All tested microbes trended to decrease with mouthwash usage in the short term, but none were statistically significant.Conclusion Good OHS significantly lowered the risk of CVD mortality relative to poor OHS. Mouthwash usage did not show any long-term harm or benefit on CVD mortality beyond the benefits rendered by brushing and flossing.

Periodontitis and edentulism as risk indicators for mortality: Results from a prospective cohort study with 20 years of follow-up.

AIM: To investigate the association between periodontitis and edentulism with cardiovascular disease (CVD) and all-cause mortality. METHODS: Baseline data of 506 subjects including 256 angiographically verified coronary artery disease patients and 250 matched participants in cardiovascular health from the Kuopio Oral Health and Heart study were collected from 1995-1996. Mortality data were accrued until May 31, 2015, and related to baseline periodontal health and edentulism, assessed as exposure and collected by means of clinical and radiographic examination by a single examiner. Cox proportional hazards regression models were fit using covariates such as age, gender, smoking, BMI, and education. The final sample size for the periodontitis models ranged from 358 to 376, while the edentate models included 413 to 503 subjects for CVD and all-cause mortality, respectively with no missing values in the predictor, confounders, and outcome. RESULTS: The strongest association was found between edentulism and CVD and all-cause mortality (HR: 1.9 CVD , HR: 1.6all-cause ; p < .01). CONCLUSIONS: Edentulism considered as a poor oral health marker was associated strongly with CVD mortality while periodontitis was not.

The therapeutic relevance of the Kallikrein-Kinin axis in SARS-cov-2-induced vascular pathology.

While coronavirus disease 2019 (COVID-19) begins as a respiratory infection, it progresses as a systemic disease involving multiorgan microthromboses that underly the pathology. SARS-CoV-2 enters host cells via attachment to the angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is widely expressed in a multitude of tissues, including the lung (alveolar cells), heart, intestine, kidney, testis, gallbladder, vasculature (endothelial cells), and immune cells. Interference in ACE2 signaling could drive the aforementioned systemic pathologies, such as endothelial dysfunction, microthromboses, and systemic inflammation, that are typically seen in patients with severe COVID-19. ACE2 is a component of the renin-angiotensin system (RAS) and is intimately associated with the plasma kallikrein-kinin system (KKS). As many papers are published on the role of ACE and ACE2 in COVID-19, we will review the role of bradykinin, and more broadly the KSS, in SARS-CoV-2-induced vascular dysfunction. Furthermore, we will discuss the possible therapeutic interventions that are approved and in development for the following targets: coagulation factor XII (FXII), tissue kallikrein (KLK1), plasma kallikrein (KLKB1), bradykinin (BK), plasminogen activator inhibitor (PAI-1), bradykinin B1 receptor (BKB1R), bradykinin B2 receptor (BKB2R), ACE, furin, and the NLRP3 inflammasome. Understanding these targets may prove of value in the treatment of COVID-19 as well as in other virus-induced coagulopathies in the future.

Babesia microti-induced fulminant sepsis in an immunocompromised host: A case report and the case-specific literature review.

Babesia microti is an obligate intra-erythrocytic parasite transmitted by infected ticks. B. microti is a eukaryote much larger than prokaryotic microbes and more similar to human hosts in their biochemistry and metabolism. Moreover, Babesia spp. possess various immune evasion mechanisms leading to persistent and sometimes life-threatening diseases in immunocompromised hosts. Chronic lymphocytic leukemia (CLL) is the most prevalent adult B-cell malignancy, and a small percentage of CLL transforms into aggressive lymphomas. CLL also causes immune dysfunction due to the over-expansion of immature and ineffective B-cells. When our patient with indolent CLL presented with anemia, pancytopenia, and splenomegaly, all his healthcare providers presumptively assumed a malignant transformation of CLL. However, these are also the signs and symptoms of babesiosis. Herein, we report a case where B. microti infection was presumed as a malignant transformation of CLL and narrowly avoided a devastating outcome. Although the patient developed fulminant sepsis, he finally received the correct diagnosis and treatment. Unfortunately, the disease recrudesced twice. Each time, it became more difficult to control the infection. We describe the clinical course of the case and discuss the case-specific literature review. This report highlights the importance of differential diagnoses ruling out infections which include babesiosis, prior to initiating the treatment of B-cell malignancy.

Mouthwash Effects on LGG-Integrated Experimental Oral Biofilms.

In order to investigate the effects of mouthwashes on oral biofilms with probiotics, we compared in biofilms the susceptibility to mouthwashes of probiotic Lactobacillus rhamnosus GG (LGG) and oral pathogens Streptococcus mutans, Streptococcus sanguinis, and Candida albicans. We also evaluated these pathogens' susceptibility to the mouthwashes and their recovery after mouthwash-rinsing in biofilms with/without LGG. First, 1-day-/3-day-old LGG-integrated multi-species biofilms were exposed for 1 min to mouthwashes containing chlorhexidine, essential oils, or amine fluoride/stannous fluoride. Cells were plate-counted and relative survival rates (RSRs) of LGG and pathogens calculated. Second, 1-day-/3-day-old multispecies biofilms with and without LGG were exposed for 1 min to mouthwashes; cells were plate-counted and the pathogens' RSRs were calculated. Third, 1-day-old biofilms were treated for 1 min with mouthwashes. Cells were plate-counted immediately and after 2-day cultivation. Recovery rates of pathogens were calculated and compared between biofilms with/without LGG. Live/Dead® staining served for structural analyses. Our results showed that RSRs of LGG were insignificantly smaller than those of pathogens in both 1-day and 3-day biofilms. No significant differences appeared in pathogens' RSRs and recovery rates after treatment between biofilms with/without LGG. To conclude, biofilm LGG was susceptible to the mouthwashes; but biofilm LGG altered neither the mouthwash effects on oral pathogens nor affected their recovery.

Gut microbiotas and immune checkpoint inhibitor therapy response: a causal or coincidental relationship?

As the largest immune organ, human gut microbiome could influence the efficacy of immune checkpoint inhibitor therapy (ICI). However, identifying contributory microbes from over 35,000 species is virtually impossible and the identified microbes are not consistent among studies. The reason for the disparity may be that the microbes found in feces are markers of other factors that link immune response and microbiotas. Notably, gut microbiome is influenced by stool consistency, diet and other lifestyle factors. Therefore, the ICI and microbiotas relationship must be adjusted for potential confounders and analyzed longitudinally. Moreover, a recent study where 11 low-abundance commensal bacteria induced interferon-γ-producing CD8 T cells, challenges the validity of the abundance-oriented microbiotas investigations. This study also confirmed the hierarchy in immunogenic roles among microbiotas. Fecal transplantation trials in germ-free mice provided "the proof of principle" that germ-free mice reproduce the donor's microbiome and corresponding ICI efficacy. However, species-specific biological differences prevent direct extrapolation between the results in murine and human models. Fecal transplantation or supplementation with microbes found in ICI responders requires caution due to potential adverse events.

Oral and Systemic Effects of Xylitol Consumption.

Recent results of randomized trials testing the efficacy of xylitol in caries prevention have been conflicting. This narrative review reveals the sources of discrepancy. The following databases were searched for the terms "xylitol" or "artificial sweeteners" restricted to the English language: PubMed, Web of Science, Evidenced-Based Medicine, Scopus, and the Cochrane database. In a separate search, the terms "dental caries" or "cariogenicity" or "glucosyltransferase" or "low glycemic" or "low insulinemic" or "dysbiosis" or "gut microbiome" were used and then combined. In section I, findings regarding the role of xylitol in dental caries prevention, the appropriateness of research methods, and the causes for potential biases are summarized. In section II, the systemic effects of xylitol on gut microbiota as well as low-glycemic/insulinogenic systemic effects are evaluated and summarized. The substitution of a carbonyl group with an alcohol radical in xylitol hinders its absorption and slowly releases sugar into the bloodstream. This quality of xylitol is beneficial for diabetic patients to maintain a constant glucose level. Although this quality of xylitol has been proven in in vitro and animal studies, it has yet to be proven in humans. Paradoxically, recent animal studies reported hyperglycemia and intestinal dysbiosis with artificial sweetener consumption. Upon careful inspection of evidence, it was revealed that these reports may be due to misinterpretation of original references or flaws in study methodology. Any systemic benefits of xylitol intake must be weighed in consideration with the well-established adverse gastrointestinal consequences. The contribution of xylitol to gut dysbiosis that may affect systemic immunity warrants further research.

Advocate cultivation of academic ethics: why is it necessary?

We teach and practice ethical behavior with all clinical and research activities. Notably, we are well educated to treat the subjects participating in research studies with high ethical standards. However, the ethics of interacting with colleagues, or with junior faculty members, are neither well defined nor taught. Dealing with junior faculty has parallels to dealing with vulnerable research subjects such as children, mentally or physically challenged groups, prison inmates or army recruits. Like any other vulnerable population, lower-ranking faculty members are often at the mercy of department chairs or other higher-ranked faculty members. Herein we present some potentially unethical or unfair examples related to academic research. Our goal is to educate the academic community of conceptual paths and to prevent similar untoward occurrences from happening in the future. Unethical behaviors related to sexual misconduct have already been described elsewhere and are not included in this manuscript.

What is passing through toll gate 4: lipids or infection?

In this issue of the journal, Zhou and colleagues reported that hyperlipidemia might play a role in the expression of pro-inflammatory cytokines such as TNF-α and IL-1ß which are associated with type 2 diabetes (T2D) and periodontitis. Not only hyperlipidemia but many obesity-related conditions such as hyperglycemia, insulin resistance, and metabolic syndrome are perceived as "threats" or as a "danger" by the innate immune system and express these cytokines. T2D is one of these conditions that elicit metabolic inflammation (meta-inflammation) and the hallmark of meta-inflammation is low grade inflammation. In addition, T2D and periodontitis are strongly correlated to each other and to innate immunity. This creates a confounding relationship. The dental research community is now required to acknowledge the concept that infection is not the only trigger for innate immune activation. The review by Zhou et al. may be the first step in the right direction to establish the orthogonal contribution of oral infection independent of meta-inflammation.