Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition.

Antimitotic agents are one of the more successful types of anticancer drugs, but they suffer from toxicity and resistance. The application of approved drugs to new indications (i.e., drug repurposing) is a promising strategy for the development of new drugs. It relies on finding pattern similarities: drug effects to other drugs or conditions, similar toxicities, or structural similarity. Here, we recursively searched a database of approved drugs for structural similarity to several antimitotic agents binding to a specific site of tubulin, with the expectation of finding structures that could fit in it. These searches repeatedly retrieved frentizole, an approved nontoxic anti-inflammatory drug, thus indicating that it might behave as an antimitotic drug devoid of the undesired toxic effects. We also show that the usual repurposing approach to searching for targets of frentizole failed in most cases to find such a relationship. We synthesized frentizole and a series of analogs to assay them as antimitotic agents and found antiproliferative activity against HeLa tumor cells, inhibition of microtubule formation within cells, and arrest at the G2/M phases of the cell cycle, phenotypes that agree with binding to tubulin as the mechanism of action. The docking studies suggest binding at the colchicine site in different modes. These results support the repurposing of frentizole for cancer treatment, especially for glioblastoma.

Outcome measurements and quality of randomized controlled clinical trials of tooth-supported fixed dental prostheses: A systematic review and qualitative analysis.

STATEMENT OF PROBLEM: The lack of consensus regarding a standardized set of outcome measurements and noncompliance with current reporting guidelines in clinical trials of tooth-supported fixed dental prostheses (FDPs) hamper interstudy comparability, compromise scientific evidence, and waste research effort and resources in prosthetic dentistry. PURPOSE: The primary objective of this systematic review was to identify all primary and secondary outcome measurements assessed in randomized controlled trials (RCTs) of tooth-supported FDPs. Secondary objectives were to assess their methodological quality by using the Cochrane Collaboration's risk of bias tool (RoB, v2.0) and their reporting quality by means of a standardized 16-item CONSORT assessment tool through published reports. MATERIAL AND METHODS: An electronic search was conducted in MEDLINE, EMBASE, and Cochrane library to identify all RCT-related articles published in the past 10 years. Differences in RoB were tested with the Pearson chi-square test, and those in CONSORT score with the Student t test. RESULTS: A total of 64 RCTs from 79 publications were deemed eligible. The diversity of outcome measures used in the field is apparent. Twenty percent of the included studies had a low RoB, 79% showed some concerns, and 1% had a high RoB. The mean ±standard deviation CONSORT compliance score was 22.56 ±3.17. Trials adhered to the CONSORT statement reported lower RoB than those that did not adhere (P<.001). RCTs with a low RoB reported more comprehensive adherence to CONSORT guidelines than those with some concerns (MD 4 [95% CI 1.52-6.48]; P=.004). CONCLUSIONS: A standardized core outcome reporting set in clinical research on tooth-supported FDPs remains evident. Adherence to the CONSORT statement continues to be low, with some RoB concerns that can be improved.

Combined use of thermo-ultrasound and cinnamon leaf essential oil to inactivate Saccharomyces cerevisiae in culture broth and natural orange juice.

The survival of Sacharomyces cerevisiae in Trypticase Soy Broth and natural orange juice processed by combined use of thermo-ultrasound and cinnamon leaf essential oil has been evaluated and modelled. Minimal inhibitory concentration of cinnamon leaf essential oil against S. cerevisiae was determined using absorbance measurements based on the microtiter plate assay. The resistance of S. cerevisiae cells to the combined action of thermal treatment with ultrasound was analyzed in Trypticase Soy Broth with different concentrations of cinnamon leaf essential oil at 30, 40 and 50 °C. The best conditions of inactivation in TSB to study the inactivation of S. cerevisiae in natural orange juice. Experimental data were fitted by using the "shoulder + log-linear" and "Weibull" models (GInaFiT). The combined use of thermo-ultrasound and cinnamon leaf essential oil enhanced the inactivation of S. cerevisiae in TSB and natural orange juice.

Changes in the teaching of prosthodontics adopted in the last academic course of the degree in dentistry in Spain during the first period of the COVID-19 pandemic.

OBJECTIVES: To investigate the impact of the COVID-19 pandemic in the teaching of prosthodontics, on the 5th course of the Bachelor's degree in Dentistry in Spain. METHODS: In June 2021, a two-section survey was submitted to the coordinators of prosthodontics of the 23 Spanish faculties of Dentistry. The first section was focused on the theoretical lessons, seminars, and clinical discussion sessions. The second part relied on the clinical teaching and the implemented preventive measures. RESULTS: The response rate was 100%. By the end of the 2020-21 course, both the theoretical and practical teaching were replaced by online activities, returning to face-to face in 2021-22. While most participants preferred in-person seminars and clinical discussion sessions, concerning the theory, comparable percentages of professors chose either face-to-face or blended learning (BL). The students' satisfaction with BL is high, but they seem more attentive in-person. At the beginning of the pandemic, the most common emergency in prosthodontics was debonding. Overall, a low concern about cross-infection was noticed. The barrier measures were the mainly adopted for prevention. CONCLUSIONS: Although the BL is appreciated in prosthodontics for theoretical lessons, face-to-face teaching appears to be the best option for seminars and clinical case discussions. The students are satisfied with BL. CLINICAL SIGNIFICANCE: In the face of the COVID-19 pandemic, the Spanish faculties of Dentistry responded quickly to continuing offering quality education through an accelerated digitization process that has created a new paradigm. Detailed analyses of these changes may help establish plans to respond systematically to unforeseen emergencies.

'Thermo-mechanical behavior of alternative material combinations for full-arch implant-supported hybrid prostheses with short cantilevers'.

OBJECTIVES: To compare the fracture resistance (FR) of three combinations of materials for full-arch maxillary implant-supported hybrid prostheses (HPs) with short cantilevers (≤ 10 mm). METHODS: Maxillary HPs were fabricated and classified as follows (n = 5 each): Group-1 (CC-A, control): acrylic-resin-veneered Co-Cr frameworks; Group-2 (CF-A): acrylic-resin-veneered carbon-fiber mesostructures; and Group-3 (CF-R): composite-resin-veneered carbon-fiber frames. Specimens were thermal-cycled (5,000 cycles; 5 °C-55 °C; dwell time: 30 s). Vertical loads were applied until failure, first at the 10-mm-long cantilever (LC), and, afterwards, at the anterior region (AR), using a universal testing machine (crosshead speed: 0.05 mm/s). The fracture pattern was assessed by stereomicroscope and SEM. The one-way ANOVA, the Bonferroni, and the independent samples t tests, were run (α= 0.05). RESULTS: At LC, CF-A, and CC-A samples exhibited the highest FR values (p< 0.001), showing no differences to each other. At AR, CC-A specimens recorded the highest FR, followed by CF-A samples (p< 0.001). CF-R HPs displayed the lowest FR at both locations (p< 0.001). The only group with differences between the tested sites was the CC-A, the AR being more resistant (p< 0.001). Most CC-A and CF-A HPs failed cohesively. CF-R prostheses mainly failed adhesively. CONCLUSIONS: Maxillary HPs with short cantilevers (≤ 10 mm) made of Co-Cr or carbon-fiber veneered with acrylic resin demonstrated an adequate mechanical resistance (> 900 N). CLINICAL SIGNIFICANCE: For maxillary HPs with cantilevers up to 10 mm, acrylic-veneered carbon- fiber mesostructures may be recommended, whereas coating carbon-fiber frames with composite resin seems not suitable.

Influence of Splint Support on the Precision of Static Totally Guided Dental Implant Surgery: A Systematic Review and Network Meta-analysis.

Purpose: To assess the accuracy of totally guided implant placement with static surgical splints in relation to the different types of supporting tissues (tooth, mucosa, or bone). Materials and Methods: This review was carried out following the PRISMA guidelines. An electronic search was done of the MEDLINE (PubMed), Embase, and Cochrane Library databases, without publication year or language restrictions. Results: The literature search yielded a total of 877 articles; 18 were included in the qualitative synthesis, and 16 of these articles were included in the quantitative analysis. The included studies presented a high risk of bias, except for one randomized clinical trial. The strength of the recommendations is therefore weak. In the angular deviation treatment, statistically significant differences were observed in the accuracy of the implants with tooth vs bone support: Bone support yielded 1.31 degrees greater deviation vs tooth support (SD = 0.43; 95% CI: 0.47, 2.15, P = .002). No significant differences were observed in the linear deviations. Conclusion: Tooth support proved to be significantly more precise than bone support splints. There were no differences referring to horizontal coronal deviation, horizontal apical deviation, or vertical deviation according to the type of splint support used.

Adequacy of the WHOQoL-BREF to Assess the Quality of Life of Victims of Armed Conflicts.

There is a deterioration in the quality of life (QoL) of survivor victims of warlike conflicts. Because there is a need to guarantee the effectiveness of assessment tools for these populations, we studied the adequacy of the World Health Organization Quality of Life Questionnaire (WHOQoL-BREF) to assess the QoL of 1,136 surviving victims of the armed conflict in Colombia. Although this questionnaire has yielded promising results, questions remain about its psychometric suitability for specific populations. We used model modification at the item level, comparisons of models with different factor structures, and dimensionality analysis to address the psychometric problems encountered. Dimensionality analysis using a bifactor model suggests that WHOQoL-BREF total scores might be a more appropriate way of reporting results when model fit adequacy is not reached. Conclusions are offered on the psychometric properties of the WHOQoL-BREF, the evaluation of special populations, and possible strategies to address future questionnaire modifications.

Accuracy of a guided implant system with milled surgical templates.

PURPOSE: This in vitro study analyzed the accuracy of a computer-assisted design (CAD)/computer-assisted manufacturing (CAM) guided implant surgery system by comparing linear, angular, and coronal deviations between the planned and final implant placement. METHODS: By using a fully guided surgery workflow, 32 dental implants were placed in 16 partially edentulous models. After virtual design of the restorations, radiological and CAD files were matched and implant positions were planned by using dedicated implant planning software (Galileo Implant version 1.9.2.). Templates were designed (Cerec Omnicam) and milled (Cerec MC XL) by using chairside workflow. Galileo Implant version 1.9.2. was used to evaluate accuracy. RESULTS: Mean horizontal and angular-coronal total deviation values were 0.2 mm (SD = 0.126) and 1.1º (SD = 0.834) respectively. Multivariate analysis of variance showed significant differences in horizontal and angular-coronal total deviation in the 32 implants (P = 0.0001). Multivariate analysis with one-factor interaction showed no statistical difference in implant position or implant type (P = 0.139) between eight maxilla models and eight jaw models. CONCLUSION: Horizontal and angular-coronal deviations of implants placed with chairside digital workflow were within the recommended safety margin for fully guided surgery.

Fracture resistance of cantilevered full-arch implant-supported hybrid prostheses with carbon fiber frameworks after thermal cycling.

OBJECTIVES: This in vitro study aimed to find the best combination of mesostructure and veneering materials for full-arch implant-supported hybrid prostheses (HPs) in terms of the fracture resistance (FR) of their cantilevers. METHODS: Three groups (n = 5 each) of maxillary HPs were fabricated: Group-1 (CC-A, control): Co-Cr frameworks coated with acrylic resin; Group-2 (CF-A): carbon fiber veneered with acrylic resin; and Group-3 (CF-R): carbon fiber coated with composite resin. All specimens were submitted to 5,000 thermal cycles (5 °C - 55 °C, dwell time: 30 s), and subjected to a single cantilever bending test in a universal testing machine (crosshead speed: 0.5 mm/min) until failure. The fracture pattern was assessed using stereo microscope and SEM. The one-way ANOVA and Bonferroni tests were run (α= 0.05). RESULTS: The FR yielded significant differences among the three groups (p< 0.001). CC-A samples reached the highest FR values (p ≤ 0.001), whereas both CF-A and CF-R HPs exhibited the comparably (p = 0.107) lowest FR. CC-A specimens failed cohesively (100%): mostly without chipping (80%). CF-A mesostructures were always broken at the connections of the distal implants. CF-R prostheses often failed adhesively (80%). CONCLUSIONS: The HPs made of Co-Cr veneered with acrylic demonstrated the best mechanical behavior, being the only group whose 13-mm long cantilevers exceeded the clinically acceptable FR of 900 N. The HPs constructed with carbon fiber frameworks showed, additionally, more unfavorable fracture patterns. CLINICAL SIGNIFICANCE: For HPs with cantilevers up to 13 mm, Co-Cr mesostructures coated with acrylic may represent the optimum combination of materials.

Evaluation of AQP4 functional variants and its association with fragile X-associated tremor/ataxia syndrome.

Introduction: Fragile X-associated tremor/ataxia syndrome (FXTAS, OMIM# 300623) is a late-onset neurodegenerative disorder with reduced penetrance that appears in adult FMR1 premutation carriers (55-200 CGGs). Clinical symptoms in FXTAS patients usually begin with an action tremor. After that, different findings including ataxia, and more variably, loss of sensation in the distal lower extremities and autonomic dysfunction, may occur, and gradually progress. Cognitive deficits are also observed, and include memory problems and executive function deficits, with a gradual progression to dementia in some individuals. Aquaporin 4 (AQP4) is a commonly distributed water channel in astrocytes of the central nervous system. Changes in AQP4 activity and expression have been implicated in several central nervous system disorders. Previous studies have suggested the associations of AQP4 single nucleotide polymorphisms (SNPs) with brain-water homeostasis, and neurodegeneration disease. To date, this association has not been studied in FXTAS. Methods: To investigate the association of AQP4 SNPs with the risk of presenting FXTAS, a total of seven common AQP4 SNPs were selected and genotyped in 95 FMR1 premutation carriers with FXTAS and in 65 FMR1 premutation carriers without FXTAS. Results: The frequency of AQP4-haplotype was compared between groups, denoting 26 heterozygous individuals and 5 homozygotes as carriers of the minor allele in the FXTAS group and 25 heterozygous and 2 homozygotes in the no-FXTAS group. Statistical analyses showed no significant associations between AQP4 SNPs/haplotypes and development of FXTAS. Discussion: Although AQP4 has been implicated in a wide range of brain disorders, its involvement in FXTAS remains unclear. The identification of novel genetic markers predisposing to FXTAS or modulating disease progression is critical for future research involving predictors and treatments.

Adverse events reported after administration of BNT162b2 and mRNA-1273 COVID-19 vaccines among hospital workers: a cross-sectional survey-based study in a Spanish hospital.

BACKGROUND: The World Health Organization declared COVID-19 a pandemic in March 2020. The first vaccine became available in December, with practically no post-marketing data. METHODS: An analytical cross-sectional survey-based study was conducted in a third-level hospital in Spain between March and April 2021 to describe the difference in adverse events with the BNT162b2 and mRNA-1273 COVID-19 vaccines. The participants were hospital workers who completed a survey voluntarily at least 14 days after the last vaccine. The STROBE checklist was followed. RESULTS: One thousand two hundred and forty-nine respondents completed the survey; 48% (599) received mRNA-1273 and 52% (650) BNT162b2. Fourteen thousand four hundred and two adverse reactions were recorded, 6896 local (3939 with mRNA-1273 and 2957 with BNT162b2 (6.6 vs 4.4 reactions per patient)) and 7506 systemic (4460 with mRNA-1273 and 3046 with BNT162b2 (7.4 vs 4.7 per patient)). Local reactions were more frequent after the first dose, while systemic reactions were higher after the second, for both vaccines and in a higher percentage with mRNA-1273 compared to BNT162b2 (p-value<0.05). CONCLUSIONS: Licensed mRNA vaccines were highly safe when administered under post-marketing conditions among working-age adults. The main adverse events were mild, although they occurred in most patients, especially after the mRNA-1273 vaccine.

Standardization and Chemical Characterization of Intravenous Therapy in Adult Patients: A Step Further in Medication Safety.

BACKGROUND: Intravenous drug administration is associated with potential complications, such as phlebitis. The physiochemical characteristics of the infusate play a very important role in some of these problems. AIM: The aim of this study was to standardize the dilutions of intravenous drugs most commonly used in hospitalized adult patients and to characterize their pH, osmolarity and cytotoxic nature to better guide the selection of the most appropriate vascular access. METHODS: The project was conducted in three phases: (i) standardization of intravenous therapy, which was conducted using a modified double-round Delphi method; (ii) characterization of the dilutions agreed on in the previous phase by means of determining the osmolarity and pH of each of the agreed concentrations, and recording the vesicant nature based on the information in literature; and (iii) algorithm proposal for selecting the most appropriate vascular access, taking into account the information gathered in the previous phases. RESULTS: In total, 112 drugs were standardized and 307 different admixtures were assessed for pH, osmolarity and vesicant nature. Of these, 123 admixtures (40%), had osmolarity values >600 mOsm/L, pH < 4 or > 9, or were classified as vesicants. In these cases, selection of the most suitable route of infusion and vascular access device is crucial to minimize the risk of phlebitis-type complications. CONCLUSIONS: Increasing safety of intravenous therapy should be a priority in the healthcare settings. Knowing the characteristics of drugs to assess the risk involved in their administration related to their physicochemical nature may be useful to guide decision making regarding the most appropriate vascular access and devices.

Activation of Notch-mediated protective signaling in the myocardium.

The Notch network regulates multiple cellular processes, including cell fate determination, development, differentiation, proliferation, apoptosis, and regeneration. These processes are regulated via Notch-mediated activity that involves hepatocyte growth factor (HGF)/c-Met receptor and phosphatidylinositol 3-kinase/Akt signaling cascades. The impact of HGF on Notch signaling was assessed following myocardial infarction as well as in cultured cardiomyocytes. Notch1 is activated in border zone cardiomyocytes coincident with nuclear c-Met following infarction. Intramyocardial injection of HGF enhances Notch1 and Akt activation in adult mouse myocardium. Corroborating evidence in cultured cardiomyocytes shows treatment with HGF or insulin increases levels of Notch effector Hes1 in immunoblots, whereas overexpression of activated Notch intracellular domain prompts a 3-fold increase in phosphorylated Akt. Infarcted hearts injected with adenoviral vector expressing Notch intracellular domain treatment exhibit improved hemodynamic function in comparison with control mice after 4 weeks, implicating Notch signaling in a cardioprotective role following cardiac injury. These results indicate Notch activation in cardiomyocytes is mediated through c-Met and Akt survival signaling pathways, and Notch1 signaling in turn enhances Akt activity. This mutually supportive crosstalk suggests a positive survival feedback mechanism between Notch and Akt signaling in adult myocardium following injury.

Myocardial induction of nucleostemin in response to postnatal growth and pathological challenge.

Stem cell-specific proteins and regulatory pathways that determine self-renewal and differentiation have become of fundamental importance in understanding regenerative and reparative processes in the myocardium. One such regulatory protein, named nucleostemin, has been studied in the context of stem cells and several cancer cell lines, where expression is associated with proliferation and maintenance of a primitive cellular phenotype. We find nucleostemin is present in young myocardium and is also induced following cardiomyopathic injury. Nucleostemin expression in cardiomyocytes is induced by fibroblast growth factor-2 and accumulates in response to Pim-1 kinase activity. Cardiac stem cells also express nucleostemin that is diminished in response to commitment to a differentiated phenotype. Overexpression of nucleostemin in cultured cardiac stem cells increases proliferation while preserving telomere length, providing a mechanistic basis for potential actions of nucleostemin in promotion of cell survival and proliferation as seen in other cell types.

[Association of FTO gene polymorphisms and morbid obesity in the population of Extremadura (Spain)]. / Asociación de polimorfismos en el gen FTO con la obesidad mórbida en la población extremeña.

OBJECTIVE: To select individuals whose morbid obesity can be attributed mainly to their individual genetic profile. After excluding patients with potential monogenic syndromes or diseases associated with obesity, we evaluated the association of the single nucleotide polymorphisms (SNPs) rs1861868 and rs9939609 of the fat-mass and obesity-associated FTO gene with an inherited predisposition to morbid obesity. PATIENTS AND METHODS: We evaluated 270 patients with morbid obesity and onset before the age of 14 years and selected 194 due to their phenotypes and family history; 289 control individuals were included. The rs1861868 and rs9939609 variants, located in the FTO gene, were genotyped. Genotype and haplotype frequencies were compared between cases and controls. RESULTS: The A allele of rs9939609 was associated with severe obesity starting in childhood among the Spanish population. The rs1861868 G/rs9939609 A haplotype of the FTO gene was also significantly associated with severe obesity in our population, with an odds ratio of 3.03 (95% confidence interval, 1.74-5.27). CONCLUSION: Analysis of the genetic basis of obesity requires rigorous selection of cases. In this study, the association of the rs9939609 SNP with obesity widely described in distinct populations was confirmed among overweight Spanish children. Genotyping rs1861868 allowed us to identify the first risk haplotype in the FTO gene, which is located in the adjacent haplotype block containing rs9939609. In-depth study of the variability of the FTO gene is essential to define its deleterious capacity.

Neuropathological Characterization of a Dravet Syndrome Knock-In Mouse Model Useful for Investigating Cannabinoid Treatments.

Dravet syndrome (DS) is an epileptic syndrome caused by mutations in the Scn1a gene encoding the α1 subunit of the sodium channel Nav1.1, which is associated with febrile seizures that progress to severe tonic-clonic seizures and associated comorbidities. Treatment with cannabidiol has been approved to reduce seizures in DS, but it may also be active against these comorbidities. The aim of this study was to validate a new mouse model of DS having lower mortality than previous models, which may serve to further evaluate therapies for the long-term comorbidities. This new model consists of heterozygous conditional knock-in mice carrying a missense mutation (A1783V) in Scn1a gene expressed exclusively in neurons of the CNS (Syn-Cre/Scn1aWT/A1783V). These mice have been used here to determine the extent and persistence of the behavioral deterioration in different postnatal days (PND), as well as to investigate the alterations that the disease produces in the endocannabinoid system and the contribution of inflammatory events and impaired neurogenesis in the pathology. Syn-Cre/Scn1aWT/A1783V mice showed a strong reduction in hindlimb grasp reflex at PND10, whereas at PND25, they presented spontaneous convulsions and a greater susceptibility to pentylenetetrazole-induced seizures, marked hyperactivity, deficient spatial working memory, lower levels of anxiety, and altered social interaction behavior. These differences disappeared at PND40 and PND60, except the changes in social interaction and anxiety. The analysis of CNS structures associated with these behavioral alterations revealed an elevated glial reactivity in the prefrontal cortex and the dentate gyrus. This was associated in the dentate gyrus with a greater cell proliferation detected with Ki67 immunostaining, whereas double-labeling analyses identified that proliferating cells were GFAP-positive suggesting failed neurogenesis but astrocyte proliferation. The analysis of the endocannabinoid system of Syn-Cre/Scn1aWT/A1783V mice confirmed reductions in CB1 receptors and MAGL and FAAH enzymes, mainly in the cerebellum but also in other areas, whereas CB2 receptors became upregulated in the hippocampus. In conclusion, Syn-Cre/Scn1aWT/A1783V mice showed seizuring susceptibility and several comorbidities (hyperactivity, memory impairment, less anxiety, and altered social behavior), which exhibited a pattern of age expression similar to DS patients. Syn-Cre/Scn1aWT/A1783V mice also exhibited greater glial reactivity and a reactive response in the neurogenic niche, and regional changes in the status of the endocannabinoid signaling, events that could contribute in behavioral impairment.

Zirconia-ceramic versus metal-ceramic posterior multiunit tooth-supported fixed dental prostheses: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The authors aimed to compare the survival and complication rates of zirconia-ceramic (ZC) versus metal-ceramic (MC) restorative material in multiunit tooth-supported posterior fixed dental prostheses (FDP). TYPES OF STUDIES REVIEWED: The authors conducted a systematic search of randomized controlled trials (RCTs), with no time or language restrictions, up to May 2019 using the MEDLINE (PubMed), Scopus, Web of Science, and Cochrane Central Register of Controlled Trials databases, followed by a manual search. RESULTS: The authors included 7 RCTs in the review and 5 RCTs in the meta-analysis. All studies had a low risk of bias. The authors included 330 participants (177 ZC and 173 MC tooth-supported FDP) in the meta-analysis, which revealed a medium-term survival rate of 95.4% (95% confidence interval [CI], 90.5% to 99.1%) for ZC FDP compared with 96.9% (95% CI, 94.3% to 99.4%) for MC FDP, with no significant differences (P = .364). The biological or technical complications did not show statistically significant differences, except in the global ceramic veneering chipping analysis (P = .023; risk difference [RD], 22.3%; 95% CI, 3.0% to 41.6%) and their subanalysis: minor chipping or chipping that can be solved with polishing (P = .044; RD, 19.5%; 95% CI, 0.5% to 38.4%), and major chipping or chipping that needs repair in the laboratory (P = .023; RD, 6.0%; 95% CI, 0.8% to 11.3%). CONCLUSIONS AND PRACTICAL IMPLICATIONS: Posterior multiunit ZC restorations are considered a predictable treatment in the medium term, although they are slightly more susceptible to chipping of the veneering ceramic than MC restorations.

Ion mobility spectrometry and mass spectrometry coupled to gas chromatography for analysis of microbial contaminated cosmetic creams.

The most commonly used technique for monitoring microbial contamination in cosmetic products is plate counting. In this contribution, headspace - gas chromatography (HS-GC) coupled to mass spectrometry (MS) or ion mobility spectrometry (IMS) is proposed as a technique to evaluate rapidly and accurately the state of microbial colonies in cosmetic creams using the volatile organic compounds produced by microorganisms (MVOC). The work focuses on monitoring two of the microorganisms that most frequently occur in such creams, Candida albicans and Staphylococcus aureus. In addition, two different types of ingredient with antimicrobial properties (a chemical preservative and a natural preservative) were added to study the behaviour of these microorganisms under different conditions. The facial creams were elaborated and inoculated with the two above microorganisms, and then sampled weekly for 4 weeks, analysing the evolution of the MVOCs by HS-GC-MS and HS-GC-IMS. In addition, microbial contamination was determined by the classical plate counting method. The pH, colour, viscosity and water activity parameters were also measured. The use of chemometric tools is essential because of the large amount of data generated, and different models based on discriminant analysis with an orthogonal projection on latent structures (OPLS-DA) were constructed. The optimal models obtained by both analytical techniques allowed differentiation between contaminated and non-contaminated creams, with a validation success rate of 94.4%. In addition, MVOC monitoring also allowed assessment of the microbial concentration.

Cardioprotective stimuli mediate phosphoinositide 3-kinase and phosphoinositide dependent kinase 1 nuclear accumulation in cardiomyocytes.

The phosphoinositide 3-kinase (PI3K)/phosphoinositide dependent kinase 1 (PDK1) signaling pathway exerts cardioprotective effects in the myocardium through activation of key proteins including Akt. Activated Akt accumulates in nuclei of cardiomyocytes suggesting that biologically relevant targets are located in that subcellular compartment. Nuclear Akt activity could be potentiated in both intensity and duration by the presence of a nuclear-associated PI3K/PDK1 signaling cascade as has been described in other non-myocyte cell types. PI3K/PDK1 distribution was determined in vitro and in vivo by immunostaining and nuclear extraction of cultured rat neonatal cardiomyocytes or transgenic mouse hearts. Results show that PI3K and PDK1 are present at a basal level in cardiomyocytes nuclei and that cardioprotective stimulation with atrial natriuretic peptide (ANP) increases their nuclear localization. In comparison, overexpression of nuclear-targeted Akt does not mediate increased translocation of either PI3K or PDK1 indicating that accumulation of Akt does not drive PI3K or PDK1 into the nuclear compartment. Furthermore, PI3K and phospho-Akt(473) show parallel temporal accumulation in the nucleus following (MI) infarction challenge. These findings demonstrate the presence of a dynamically regulated nuclear-associated signaling cascade involving PI3K and PDK that presumably influences nuclear Akt activation.