Differential Regulation of host cellular gene expression by HIV-1 Viral protein R (Vpr): Implications for host cell function

The HIV/AIDS epidemic is one of the most important public health problems facing this generation. The failure of recent vaccine trials and growing resistance to anti-retroviral drugs underscores the need for novel therapeutic strategies. Design of such therapies will depend on a detailed understanding of the mechanism of action of the HIV-1 gene products. To further that goal, we have undertaken a detailed investigation of the HIV-1 viral protein R (Vpr). We employed cDNA microarray and antibody array analyses using isogenic virus with or without Vpr to determine the effect on host cellular gene expression. Vpr induced differential regulation of 109 cellular genes representing diverse families of signaling molecules. Two gene products, NHE1 and TNF alpha, were further studied for their potential roles in Vpr-mediated apoptosis. NHE1 expression was decreased by 50% at both the protein and mRNA levels in the presence of Vpr. Vpr-mediated NHE1 downregulation correlated with a dose dependent decrease in intracellular pH as well as a decrease in the active form of the pro-survival kinase Akt. The loss of these anti-apoptotic functions of NHE1 is proposed to contribute to the apoptotic role of Vpr. The pro-inflammatory cytokine TNF alpha may also play a part in Vpr-mediated apoptosis. Macrophages infected with vpr-expressing virus secreted 1.1-8.5 fold more soluble TNF alpha in response to LPS stimulation than their counterparts infected with isogenic virus lacking Vpr expression. Fold upregulation of TNF alpha directly correlated with induction of apoptosis in uninfected lymphocytes, implicating TNF alpha regulation by Vpr in bystander cell death. Two polymorphisms in the TNF alpha promoter, positions -238 and -963, were found at a higher prevalence in donors showing the lowest and highest effect of Vpr on the TNF alpha response. These results suggest that host genetic determinants may affect bystander cell death and thus the course of HIV pathogenesis. Together, the results of this study present a molecular basis for changes induced in the host cell by HIV-1 Vpr and elucidate two potential pathways for the design of anti-retroviral therapeutics targeting HIV-1 Vpr

Lower risk for cardiovascular mortality for patients with root filled teeth in a Finnish population

AimTo investigate the relationship of radiographic evidence of root filled teeth to cardiovascular outcomes.MethodologyBaseline data for 506 subjects including 256 angiographically verified heart disease patients and 250 matched cardiologically healthy controls participating in the Kuopio Oral Health and Heart study were collected in 1995â 1996. Cardiovascular disease (CVD) mortalities were accrued until 31 May 2015 and appended to the baseline data. Mortality status data were obtained from the Finnish National Death Register where all mortality cases and the causes of death are compiled for all Finnish citizens. Of the 506 participants, 473 subjects who had no missing values in the predictor, outcome or confounding factors were included in the analyses to assess the relationship of radiographic evidence of root filled teeth with prevalent coronary artery disease (CAD) cross sectionally and also with CVD mortality longitudinally. Multivariable logistic regression was used for the crossâ sectional part and proportional hazard regression analyses for the longitudinal part of the study were used adjusting for age, sex, smoking, edentulism, diabetes, hypertension, total/HDL cholesterol ratio and income. Additionally, whether this association was independent of periodontitis, and a systemic marker of inflammation, serum Câ reactive protein (CRP) was examined.ResultsHaving â ¥1 root filled teeth was associated with 84% lower odds of prevalent CAD with Odds Ratio (OR) = 0.16, 95% confidence interval (CI) 0.09â 0.28, P < 0.0001. The OR for edentulism was 1.32 (CI: 0.73â 2.38), P = 0.36, suggesting a nonsignificant increase in risk. Prospectively, having at least one root filled teeth was associated with a 49% lower risk of CVD mortality (hazard ratio [HR] = 0.51, CI = 0.27â 0.97, P = 0.04) whilst edentulism was associated with nonsignificantly increased risk for CVD mortality: HR = 1.25 (CI: 0.65â 2.42), P = 0.36. Adjustment for periodontitis or serum CRP levels changed the OR or HR slightly but the associations remained significant.ConclusionsHaving â ¥1 root filled teeth was associated with significantly lower odds for prevalent CAD cross sectionally and lower risk of cardiovascular mortality prospectively. These reduced associations with CVD were independent of periodontitis or serum CRP levels.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139934/1/iej12772_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139934/2/iej12772.pd

Advocate cultivation of academic ethics : Why is it necessary? [version 2; peer review: 2 approved]

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. © 2020 Janket SJ et al.Peer reviewe

Number of teeth, C‐reactive protein, fibrinogen and cardiovascular mortality: a 15‐year follow‐up study in a Finnish cohort

Aim To test whether the number of teeth, an inverse proxy for composite oral infection scores is associated with better survival. Materials and Methods The Kuopio Oral Health and Heart study initiated a case–control study in 1995–1996 consisting of 256 consecutive coronary artery disease patients and 250 age and gender‐matched controls. We appended the mortality data and formulated a longitudinal study. By May 31st, 2011, 124 mortalities had occurred and 80 of which were of cardiovascular origin. Using Cox proportional hazards models, we assessed the association of the teeth group (Teethgrp) – consisting of 10 teeth – with cardiovascular and all‐cause mortality after 15.8 years of median follow‐up. Results In multivariate models, with the edentulous state as reference, one level increase in Teethgrp was associated with significantly increased survival from cardiovascular disease (CVD) mortality with a Hazard Ratio (HR) 0.73, p ‐value = 0.02 but not with all‐cause mortality (HR = 0.87, p  = 0.13). The findings were not mediated by C‐reactive protein (CRP) levels ≥3 mg/L or by median fibrinogen levels, but were mediated by CRP levels >5 mg/L. Conclusion Each increment of 10 teeth from the edentulous state was associated with a 27% improved CVD survival, independent of low‐grade systemic inflammation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102655/1/jcpe12192.pd

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

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

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: 1.6(all-cause); p < .01). Conclusions Edentulism considered as a poor oral health marker was associated strongly with CVD mortality while periodontitis was not.Peer reviewe

Tutorial in oral antithrombotic therapy: Biology and dental implications

Objectives: Recent developments of new direct oral anticoagulants that target specific clotting factors necessitate understanding of coagulation biology. The objective of this tutorial is to offer dental professionals a review of coagulation mechanisms and the pharmacodynamics of the conventional and new oral anticoagulants. Also, we summarized the dental implications of the conventional and new anticoagulants. Method : We searched Medline using search terms "antithrombotic", "antihemostasis" or "anticoagulation" and combined them with the search results of "dental", "oral surgery" or "periodontal". We restricted the results to "human" and "English". Results: The early coagulation cascade, the new cell-based coagulation model, the pharmacokinetics and pharmacodynamics of conventional antithrombotics, and new oral anticoagulants were reviewed. The new direct factor Xa inhibitors and the direct thrombin inhibitor (s), called direct oral anticoagulants (DOAs) have rapid onset of action, fast elimination on cessation, and fewer drug-drug or drug-food interactions than warfarin. However, the lack of antidotes raises concerns that some dental procedures may trigger serious hemorrhagic events. Additionally, careful perioperative withdrawal and resumption protocols for the DOAs are reviewed, because DOAs' blood levels are dependent on renal function. Also, various reversal strategies in the event of excessive bleedings are summarized. Perioperative management of dental patients taking new DOAs and conventional oral anticoagulants are also discussed. However, the perioperative strategies for DOAs are yet to be validated in randomized trials

Clinical efficacy of tocilizumab in patients with active rheumatoid arthritis in real clinical practice

The previous clinical studies have demonstrated tocilizumab monotherapy to be highly effective in rheumatoid arthritis (RA). The objectives of the present article are to report the efficacy and safety of tocilizumab in patients with active RA in real clinical practice. In total, 61 patients with RA were treated with tocilizumab. Any comorbidities they had, especially infections, were treated thoroughly before they were given the drug. We provided guidance on infection control and prevention. Mean age of the patients was 60.9 ± 12.4 years, and their mean disease duration 10.9 ± 9.2 years. The patients remained on steroids, methotrexate, and tacrolimus as before, but were taken off any other drugs they had been using prior to the treatment. Mean of the 28-joint disease activity score using erythrocyte sedimentation rate was 4.75 ± 1.15 initially and fell to 2.21 ± 0.97 after two doses (n = 50). After four doses, the remission rate was 83.8% (31/37). All patients responded well to the therapy and there was no decrease in the efficacy of tocilizumab during the treatment. Even in the real clinical setting, treatment with tocilizumab can rapidly induce remission in RA in a high proportion of patients and is generally safe and well tolerated. Tocilizumab would seem to be promising as a first-line choice for the treatment of RA