Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy?

RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/mitogen‐activated protein kinase (Ras/MAPK) pathway components. Cardio‐facio‐cutaneous (CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.3 including MEK2; they present with a distinct phenotype but have overlapping features with CFC syndrome. Phenotypic features of all seven patients include tall forehead, thick nasal tip, underdeveloped cheekbones, long midface, sinuous upper vermilion border, tall chin, angular jaw, and facial asymmetry. Patients also have developmental delay, hypotonia, heart abnormalities, failure to thrive, obstructive sleep apnea, gastroesophageal reflux and integument abnormalities. Analysis of epidermal growth factor‐stimulated fibroblasts revealed that P‐MEK1/2 was ～50% less abundant in cells carrying the MEK2 deletion compared to the control. Significant differences in total MEK2 and Sprouty1 abundance were also observed. Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies. This is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway.     

Gabapentin,a Synthetic Analogue of Gamma Aminobutyric Acid,Reverses Systemic Acute Inflammation and Oxidative Stress in Mice

The aim of this study was to investigate the potential anti-inflammatory and anti-oxidant effects of gabapentin (GBP) in mice. The anti-inflammatory and anti-oxidant effects were evaluated using various mediators that induce paw edema, peritonitis model, myeloperoxidase (MPO) activity, proinflammatory cytokine levels, glutathione (GSH) consumption, and malondialdehyde (MDA) production in mice. Pretreatment of mice with GBP (1 mg/kg) significantly reduced carrageenan or dextran-induced paw edema (P?2. In the carrageenan-induced peritonitis model, GBP significantly decreased total and differential leukocyte counts and reduced the levels of MPO activity in the plantar tissue and IL-1β and TNF-α concentrations in the peritoneal exudate. The same dose of GBP also decreased the MDA concentration and increased the levels of GSH into the peritoneal fluid. In summary, our results demonstrated that GBP exhibited anti-inflammatory activity in mice by reducing the action of inflammatory mediators, neutrophil migration and proinflammatory cytokine levels, and anti-oxidant properties by decreasing the concentration of MDA and increasing the GSH content. These observations raise the possibility that GBP could be used to improve tissue resistance to damage during inflammatory conditions.     

Immunogenicity and In Vitro and In Vivo Protective Effects of Antibodies Targeting a Recombinant Form of the Streptococcus mutans P1 Surface Protein

Streptococcus mutans is a major etiologic agent of dental caries, a prevalent worldwide infectious disease and a serious public health concern. The surface-localized S. mutans P1 adhesin contributes to tooth colonization and caries formation. P1 is a large (185-kDa) and complex multidomain protein considered a promising target antigen for anticaries vaccines. Previous observations showed that a recombinant P1 fragment (P1_39–512), produced in Bacillus subtilis and encompassing a functional domain, induces antibodies that recognize the native protein and interfere with S. mutans adhesion in vitro. In the present study, we further investigated the immunological features of P1_39–512 in combination with the following different adjuvants after parenteral administration to mice: alum, a derivative of the heat-labile toxin (LT), and the phase 1 flagellin of S. Typhimurium LT2 (FliCi). Our results demonstrated that recombinant P1_39–512 preserves relevant conformational epitopes as well as salivary agglutinin (SAG)-binding activity. Coadministration of adjuvants enhanced anti-P1 serum antibody responses and affected both epitope specificity and immunoglobulin subclass switching. Importantly, P1_39–512-specific antibodies raised in mice immunized with adjuvants showed significantly increased inhibition of S. mutans adhesion to SAG, with less of an effect on SAG-mediated bacterial aggregation, an innate defense mechanism. Oral colonization of mice by S. mutans was impaired in the presence of anti-P1_39–512 antibodies, particularly those raised in combination with adjuvants. In conclusion, our results confirm the utility of P1_39–512 as a potential candidate for the development of anticaries vaccines and as a tool for functional studies of S. mutans P1.     

The potential of label-free nonlinear optical molecular microscopy to non-invasively characterize the viability of engineered human tissue constructs

Nonlinear optical molecular imaging and quantitative analytic methods were developed to non-invasively assess the viability of tissue-engineered constructs manufactured from primary human cells. Label-free optical measures of local tissue structure and biochemistry characterized morphologic and functional differences between controls and stressed constructs. Rigorous statistical analysis accounted for variability between human patients. Fluorescence intensity-based spatial assessment and metabolic sensing differentiated controls from thermally-stressed and from metabolically-stressed constructs. Fluorescence lifetime-based sensing differentiated controls from thermally-stressed constructs. Unlike traditional histological (found to be generally reliable, but destructive) and biochemical (non-invasive, but found to be unreliable) tissue analyses, label-free optical assessments had the advantages of being both non-invasive and reliable. Thus, such optical measures could serve as reliable manufacturing release criteria for cell-based tissue-engineered constructs prior to human implantation, thereby addressing a critical regulatory need in regenerative medicine.     

Urodynamic effects of the combination of tamsulosin and daily tadalafil in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: a randomized, placebo-controlled clinical trial

Objectives

To evaluate the effect of association of tamsulosin/tadalafil taken daily compared with tamsulosin/placebo in the lower urinary tract with urodynamic study (UDS).

Methods

All patients underwent baseline UDS before randomization to tamsulosin 0.4 mg/tadalafil 5 mg (Group 1; n = 20) or tamsulosin 0.4 mg/placebo (Group 2; n = 20) once daily for 30 days. End-of-study UDS were performed on completion of the treatment period. The primary end point was to demonstrate changes in urodynamic variables in the voiding phase, detrusor pressure at maximum flow (PdetQmax), and maximum flow rate (Qmax), from baseline to week four.

Results

The primary outcome measure of this clinical trial, PdetQmax, showed a significant reduction in tamsulosin/tadalafil group (13 ± 17.0) compared to tamsulosin/placebo (?1.2 ± 14.35) group (P = 0.03). Qmax increased in both groups, tamsulosin/tadalafil (1.0 ± 2.4) and tamsulosin/placebo (1.4 ± 2.4), but the difference was not significant between treatment groups (P = 0.65). Total IPSS, storage, and voiding sub-score improved significantly in tamsulosin/tadalafil compared with tamsulosin/placebo group.

Conclusions

The association of tamsulosin/tadalafil reduces detrusor pressure at maximum flow without changing the maximum flow rate during micturition and significantly improves lower urinary tract symptoms compared with the isolated use of tamsulosin.     

Association Between Attributed Cause of End-Stage Renal Disease and Risk of Death in Brazilian Patients Receiving Renal Replacement Therapy

Background. Studies conducted in several countries have indicated that the survival of patients undergoing renal replacement therapy (RRT) depends on the attributed cause of end-stage renal disease (ESRD). Objectives. This study was conducted to evaluate the association between attributed cause of ESRD and mortality risk in RRT patients in Brazil. Methods. We analyzed 88,881 patients from the Brazilian Ministry of Health Registry who were undergoing RRT between April 1997 and July 2000. Cox proportional hazards models were used to estimate the relative risk (RR) of death in patients with ESRD secondary to diabetes mellitus (DM), polycystic kidney disease (PKD), and primary glomerulopathies (GN) compared with a reference group comprised of patients with ESRD caused by hypertensive nephropathy. Patient's age, gender, and length of time (years) in RRT before inclusion in the registry (vintage) were included in the adjusted Cox model. Results. Compared with the reference group, the mortality risk was 27% lower in patients with PKD (RR = 0.73, 95% CI: 0.65–0.83, p< 0.0001); 29% lower in patients with GN (RR = 0.71, 95% CI: 0.68–0.74, p< 0.0001); and 100% greater in DM patients (RR = 2.00, 95% CI: 1.92–2.10, p< 0.0001). These relative risks remained statistically significant after adjustment for age, gender, and length of time in RRT before inclusion in the registry. Conclusions. Our data indicate that compared with the patients with hypertensive nephrosclerosis as attributed cause of ESRD, patients undergoing RRT in Brazil with idiopathic glomerulopathy and polycystic kidney disease have a lower risk of mortality, and patients with diabetes mellitus have a greater risk of mortality.     

Using the Self-etch Adhesives in Anterior Restoration

With the arrival of self-etch adhesives systems, there has been a rise in interest among clinicians, making it imperative for health professionals to have knowledge of the properties, characteristics, the association as well as the dental structures of these materials, in order to select them and use them correctly. The self-etch adhesive systems show good values of bond strength, microleakage and performance, and have therefore become an option in direct adhesive restorations. In the regard, this case study aims to describe the technique involving the use of selfetch adhesives system for direct restoration of anterior teeth. Keywords: Esthetics, Self-etch adhesives, Restoration. How to cite this article: Tonetto MR, Kabbach W, de Campos EA, de Oliveira Junior OB, de Toledo Porto Neto S, Saad JRC, de Andrade MF. Using the Self-etch Adhesives in Anterior Restoration. J Contemp Dent Pract 2012;13(3):421-424. Source of support: Nil Conflict of interest: None declared.     

Effect of light source and solvent on the sorption and solubility of two dual-cured cements photocured through ceramic

The purpose of this study was to verify the polymerization efficiency of two curing units through a ceramic barrier. Forty specimens apiece of two resin luting cements (AllCem and RelyX U100) were made in a stainless steel mold. The experimental group was photocured through a ceramic barrier, while the control group was photocured without a barrier. The specimens were stored in deionized water or 75% ethanol for 28 days and submitted to tests of sorption and solubility (ISO 4049:2000). Values obtained were subjected to ANOVA and Tukey multiple comparison tests (P < 0.05). RelyX U100 suffered more sorption and solubility than AllCem. The light sources did not influence sorption and solubility values, except for the specimens of RelyX U100 that were photocured with an LED unit through ceramic and stored in ethanol; these specimens demonstrated higher values than those photocured using a halogen lamp.     

The influence of "C-factor" and light activation technique on polymerization contraction forces of resin composite

Objectives

This study evaluated the influence of the cavity configuration factor ("C-Factor") and light activation technique on polymerization contraction forces of a Bis-GMA-based composite resin (Charisma, Heraeus Kulzer).

Material and Methods

Three different pairs of steel moving bases were connected to a universal testing machine (emic DL 500): groups A and B - 2x2 mm (CF=0.33), groups C and D - 3x2 mm (CF=0.66), groups e and F - 6x2 mm (CF=1.5). After adjustment of the height between the pair of bases so that the resin had a volume of 12 mm³ in all groups, the material was inserted and polymerized by two different methods: pulse delay (100 mW/cm² for 5 s, 40 s interval, 600 mW/cm² for 20 s) and continuous pulse (600 mW/cm² for 20 s). Each configuration was light cured with both techniques. Tensions generated during polymerization were recorded by 120 s. The values were expressed in curves (Force(N) x Time(s)) and averages compared by statistical analysis (ANOVA and Tukey''s test, p<0.05).

Results:

For the 2x2 and 3x2 bases, with a reduced C-Factor, significant differences were found between the light curing methods. For 6x2 base, with high C-Factor, the light curing method did not influence the contraction forces of the composite resin.

Conclusions

Pulse delay technique can determine less stress on tooth/restoration interface of adhesive restorations only when a reduced C-Factor is present.     

Cigarette smoke inhalation influences bone healing of post-extraction tooth socket: a histometric study in rats

The aim of this study was to evaluate, histometrically, the bone healing of the molar extraction socket just after cigarette smoke inhalation (CSI). Forty male Wistar rats were randomly assigned to a test group (animals exposed to CSI, starting 3 days before teeth extraction and maintained until sacrifice; n=20) and a control group (animals never exposed to CSI; n=20). Second mandibular molars were bilaterally extracted and the animals (n=5/group/period) were sacrificed at 3, 7, 10 and 14 days after surgery. Digital images were analyzed according to the following histometric parameters: osteoid tissue (OT), remaining area (RA), mineralized tissue (MT) and non-mineralized tissue (NMT) in the molar socket. Intergroup analysis showed no significant differences at day 3 (p>0.05) for all parameters. On the 7(th) day, CSI affected negatively (p<0.05) bone formation with respect to NMT and RA (MT: 36%, NMT: 53%, RA: 12%; and MT: 39%, NMT: 29%, RA: 32%, for the control and test groups, respectively). In contrast, no statistically significant differences (p>0.05) were found at days 10 and 14. It may be concluded that CSI may affect socket healing from the early events involved in the healing process, which may be critical for the amount and quality of new-bone formation in smokers.