Since echinocandins are recommended as first line therapy for invasive candidiasis, detection of resistance, mainly due to alteration in FKS protein, is of main interest. EUCAST AFST recommends ...testing both MIC of anidulafungin and micafungin, and breakpoints (BPs) have been proposed to detect echinocandin-resistant isolates. We analyzed MIC distribution for all three available echinocandins of 2,787 clinical yeast isolates corresponding to 5 common and 16 rare yeast species, using the standardized EUCAST method for anidulafungin and modified for caspofungin and micafungin (AM3-MIC). In our database, 64 isolates of common pathogenic species were resistant to anidulafungin, according to the EUCAST BP, and/or to caspofungin, using our previously published threshold (AM3-MIC ≥ 0.5 mg/L). Among these 64 isolates, 50 exhibited 21 different FKS mutations. We analyzed the capacity of caspofungin AM3-MIC and anidulafungin MIC determination in detecting isolates with FKS mutation. They were always identified using caspofungin AM3-MIC and the local threshold while some isolates were misclassified using anidulafungin MIC and EUCAST threshold. However, both methods misclassified four wild-type C. glabrata as resistant. Based on a large data set from a single center, the use of AM3-MIC testing for caspofungin looks promising in identifying non-wild-type C. albicans, C. tropicalis and P. kudiravzevii isolates, but additional multicenter comparison is mandatory to conclude on the possible superiority of AM3-MIC testing compared to the EUCAST method.
This 30-mo randomized clinical trial compared the effectiveness of 2 concentrations (12% or 38%) of silver diamine fluoride (SDF) and 2 periodicity of application (once or twice a year) in arresting ...cavitated dentin caries in primary teeth. Children aged 3 to 4 y who had at least 1 active cavitated caries lesion were enrolled and randomly allocated into 4 groups for intervention. Group 1 had 12% SDF applied annually (every 12 mo), group 2 had 12% SDF applied semiannually (every 6 mo), group 3 had 38% SDF applied annually, and group 4 had 38% SDF applied semiannually. Clinical examinations were performed semiannually in kindergarten by a single examiner to investigate whether the SDF-treated caries became arrested. A total of 888 children with 4,220 decayed tooth surfaces received SDF application at baseline, and 799 (90.0%) children with 3,790 surfaces (89.8%) were evaluated at the 30-mo examination. The caries arrest rates were 55.2%, 58.6%, 66.9%, and 75.7% for groups 1, 2, 3, and 4, respectively (P < 0.001). Caries treated with 38% SDF had a higher chance of becoming arrested than those treated with 12% SDF (odds ratio OR, 1.98; 95% confidence interval CI, 1.51–2.60, P < 0.001). The interaction between frequency of SDF application and visible plaque index (VPI) score was significant (P = 0.017). Among those children who received annual SDF application, children with a higher VPI score had a lower chance to have their caries become arrested (OR, 0.59, 95% CI, 0.49–0.72). In conclusion, SDF at a concentration of 38% is more effective than that of 12% in arresting active caries in primary teeth. For children with poor oral hygiene, caries arrest rate of SDF treatment can be increased by increasing the frequency of application from annually to semiannually (ClinicalTrials.gov NCT02385474).
This randomized clinical trial aimed to compare the adverse effects and parental satisfaction following the different regimes of silver diamine fluoride (SDF) treatment among preschool children. A ...total of 888 preschool children who had active dentin caries received different SDF application regimes: group 1, 12% SDF applied annually; group 2, 12% SDF applied semiannually; group 3, 38% SDF applied annually; and group 4, 38% SDF applied semiannually. Information on adverse effects—including tooth or gum pain, gum swelling, gum bleaching, and systemic toxicity—was collected through a parent-reported questionnaire within 1 wk after every SDF or placebo application. Information of parental satisfaction on children’s dental appearance was collected at baseline and 30-mo examination. At the 30 mo, 799 children (90%) remained in the study. No acute systemic illness or major adverse effect was reported. No differences of all minor adverse effects among the 4 groups were found (P > 0.05). Overall, prevalence of tooth and gum pain as perceived by patients and reported by parents was 6.6%, while gum swelling and gum bleaching were 2.8% and 4.7%, respectively. Blackening of carious lesions was common among all groups, with 36.7%, 49.5%, 65.6% and 76.3% in groups 1 to 4, respectively (χ2 test, P < 0.001). The proportion of parents who were satisfied with their children’s dental appearance in groups 1 to 4 was as follows: 67.6%, 61.5%, 70.8%, and 62.3%, respectively (χ2 test, P > 0.05). Based on parental reporting, SDF does not cause acute systemic illness. Tooth or gum pain, gum swelling, and gum bleaching were uncommon and not significantly different among the study groups. Parental satisfaction with children’s dental appearance was similar among all groups. The use of SDF following the study protocol for caries arrest is safe for preschool children. Collecting information on parental satisfaction and adverse effects is beneficial for dental professionals when deciding to adopt SDF treatment for preschool children (ClinicalTrials.gov NCT02385474).
Mitophagy is critical for cell homeostasis. Externalization of the inner mitochondrial membrane phospholipid, cardiolipin (CL), to the surface of the outer mitochondrial membrane (OMM) was identified ...as a mitophageal signal recognized by the microtubule-associated protein 1 light chain 3. However, the CL-translocating machinery remains unknown. Here we demonstrate that a hexameric intermembrane space protein, NDPK-D (or NM23-H4), binds CL and facilitates its redistribution to the OMM. We found that mitophagy induced by a protonophoric uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), caused externalization of CL to the surface of mitochondria in murine lung epithelial MLE-12 cells and human cervical adenocarcinoma HeLa cells. RNAi knockdown of endogenous NDPK-D decreased CCCP-induced CL externalization and mitochondrial degradation. A R90D NDPK-D mutant that does not bind CL was inactive in promoting mitophagy. Similarly, rotenone and 6-hydroxydopamine triggered mitophagy in SH-SY5Y cells was also suppressed by knocking down of NDPK-D. In situ proximity ligation assay (PLA) showed that mitophagy-inducing CL-transfer activity of NDPK-D is closely associated with the dynamin-like GTPase OPA1, implicating fission-fusion dynamics in mitophagy regulation.
Unlike other fluoride-based caries preventive agents, silver diamine fluoride (SDF) can simultaneously prevent and arrest coronal and root dentine caries. The profound clinical success of SDF has ...drawn many clinicians and researchers to study the mechanism of SDF in arresting dentine caries. This critical review discusses how silver and fluoride contribute to caries arrest, in terms of their effects on bacteria as well as on the mineral and organic content of dentine. Silver interacts with bacterial cell membrane and bacterial enzymes, which can inhibit bacterial growth. Silver can also dope into hydroxyapatite and have an antibacterial effect on silver-doped hydroxyapatite. Furthermore, silver is also a strong inhibitor of cathepsins and inhibits dentine collagen degradation. Early studies proposed that silver hardened caries lesions by forming silver phosphate. However, recent studies found that little silver phosphate remained on the arrested dentine lesion. The principal silver precipitate was silver chloride, which could not contribute to the significant hardening of the arrested lesions. On the other hand, fluoride enhances mineral formation by forming fluorohydroxyapatite with reduced solubility. A significant increase in microhardness occurs with an elevated level of calcium and phosphorus but not silver on the surface layer of the arrested dentine caries lesion following SDF treatment. Fluoride also inhibits matrix metalloproteinases activities and therefore inhibits dentine collagen degradation. The combination of silver and fluoride in an alkaline solution has a synergistic effect in arresting dentine caries. The alkaline property of SDF provides an unfavorable environment for collagen enzyme activation. Understanding the mechanisms of SDF in arresting dentine caries helps clinicians to develop appropriate protocols for the use of SDF in clinical care.
Background: The clinical response of patients with severe acute respiratory syndrome (SARS) to a combination of lopinavir/ritonavir and ribavirin was examined after establishing the in vitro ...antiviral susceptibility of the SARS associated coronavirus to a panel of antiviral agents. Methods: The in vitro susceptibility of the prototype of SARS associated coronavirus to a panel of nucleoside analogues and protease inhibitors currently licensed for clinical use was studied. Forty one patients with SARS followed for 3 weeks were treated with a combination of lopinavir/ritonavir and ribavirin. The clinical progress and virological outcomes were monitored and compared with 111 patients treated with ribavirin only who served as historical controls. Results: In vitro antiviral activity against SARS associated coronavirus was demonstrated for lopinavir and ribavirin at concentrations of 4 µg/ml and 50 µg/ml, respectively, only at 48 hours. The adverse clinical outcome (ARDS or death) was significantly lower in the treatment group than in the historical controls (2.4% v 28.8%, p<0.001) at day 21 after the onset of symptoms. The adverse outcome remained significantly lower in the treatment group than in the controls—both those diagnosed early (p<0.001) and those diagnosed later in the course of the epidemic (p = 0.002)—but there was no significant difference in adverse outcome rates between the two time periods (p = 0.548). No time related difference in outcome was observed in the control groups. A reduction in steroid usage and nosocomial infections was seen in patients initially treated with lopinavir/ritonavir, and these patients had a decreasing viral load and rising peripheral lymphocyte count. Multivariate analysis showed that age, hepatitis B carrier status, and lack of treatment with this antiviral combination were independent predictors of an adverse outcome. Lopinavir/ritonavir treatment was associated with a better outcome even when adjusted for baseline lactate dehydrogenase level. Conclusions: The apparent favourable clinical response with lopinavir/ritonavir and ribavirin supports further randomised placebo controlled trials in patients with SARS.
To compare the effectiveness of three applications of silver diammine fluoride (SDF) solution at yearly interval and three applications of SDF solution or sodium fluoride (NaF) varnish at weekly ...interval at baseline in arresting active caries in the primary teeth of preschool children.
Children aged 3–4 years (n = 371) who had at least one active caries lesion (ICDAS codes 3–6) in their primary teeth were randomly allocated into three groups: Group 1 – annual application of 30% SDF solution; Group 2 – three applications of 30% SDF at weekly intervals; and Group 3 – three applications of 5% NaF varnish at weekly intervals. Follow-up examinations were performed every 6 mo nths by the same masked examiner.
After 30 months, 309 (83%) children with 1877 caries lesions remained in the study. For cavitated lesions (ICDAS code 5 or 6), the caries arrest rate of Group 1 (48%) was significantly higher than those of Group 2 (33%) and Group 3 (34%), (p < 0.001). Results of multi-level survival analysis showed that the arrest times of cavitated lesions in both SDF groups (Groups 1 and 2) were significantly shorter than that of the NaF varnish group. For moderate caries lesions without visible dentine (ICDAS code 3 or 4), the caries arrest rates were 45%, 44% and 51% in Groups 1, 2 and 3, respectively (p > 0.05). Presence of plaque on caries lesion, tooth type and tooth surface type had an influence on caries arrest.
Over a 30-month period, annual applications of SDF solution is more effective than three weekly applications of NaF varnish or SDF solution at baseline in arresting active cavitated dentine caries lesions in primary teeth.
As annual application of SDF solution was found to be more effective than 3 weekly applications of NaF varnish or SDF solution at baseline in arresting active cavitated dentine caries lesions, the former application protocol is preferred for young children who are available for regular caries arrest treatment.
Abstract
We have studied the density profile of a dwarf halo in the decaying dark matter (DDM) cosmology, using a new algorithm that resolves halo density profiles down to the innermost 700 pc ...robustly with high efficiency. Following Schwarzschild’s orbit-based method, we have also developed a simplified model to calculate the DDM halo density profiles, which agree remarkably well with those from
N
-body simulations. Both zoom-in simulations and the simplified model reveal that dark matter decay leads to the flattening of the central density and an overall reduction of the density in dwarf halos, and the underlying physics mechanisms are well illustrated by the simplified model. The slowly rising scaled rotation curves of DDM dwarf halos agree with the observations of local dwarf galaxies. Our results suggest that DDM holds great potential for resolving the small-scale problems faced by the cold dark matter model.
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