Correlation of Thin-Film Bond Compliance and Bond Fracture Resistance

The integrity of the interfacial bond between a coating and its substrate is of primary importance for any application. A technique for the quantitative nondestructive measurement of the bond fracture energy is essential for evaluating bond integrity. Scanning acoustic microscopy (SAM) provides a method for making localized measurements of film dis-bonds and film bond compliance based on the changes in the surface acoustic wave velocity in the layered medium. The results of these measurements for chrome/gold and gold films on glass substrates are summarized. The compliance of the bond and its fracture energy can be correlated in some film systems. An experiment to determine if this correlation exists for chrome/gold and gold films on sapphire substrates is described. Results of such an experiment would provide an empirical correlation between surface acoustic wave velocity measurements and the fracture energy of the film. The results of an experiment to measure the fracture energy of the interfacial bond between a gold film and the sapphire substrate are described.</p

Hypomineralized Second Primary Molars as Predictor of Molar Incisor Hypomineralization

Molar incisor hypomineralization (MIH) is a developmental defect of dental enamel that shares features with hypomineralized second primary molars (HSPM). Prior to permanent tooth eruption, second primary molars could have predictive value for permanent molar and incisor hypomineralization. To assess this possible relationship, a cross-sectional study was conducted in a sample of 414 children aged 8 and 9 years from the INMA cohort in Valencia (Spain). A calibrated examiner (linear-weighted Kappa 0.83) performed the intraoral examinations at the University of Valencia between November 2013 and 2014, applying the diagnostic criteria for MIH and HSPM adopted by the European Academy of Paediatric Dentistry. 100 children (24.2%) presented MIH and 60 (14.5%) presented HSPM. Cooccurrence of the two defects was observed in 11.1% of the children examined. The positive predictive value was 76.7% (63.9-86.6) and the negative predictive value 84.7% (80.6-88.3). The positive likelihood ratio (S/1-E) was 10.3 (5.9-17.9) and the negative likelihood ratio (1-S/E) 0.57 (0.47-0.68). The odds ratio was 18.2 (9.39-35.48). It was concluded that while the presence of HSPM can be considered a predictor of MIH, indicating the need for monitoring and control, the absence of this defect in primary dentition does not rule out the appearance of MIH

SMN1 dosage analysis in spinal muscular atrophy from India

BACKGROUND: Spinal muscular atrophy (SMA) represents the second most common fatal autosomal recessive disorder after cystic fibrosis. Due to the high carrier frequency, the burden of this genetic disorder is very heavy in developing countries like India. As there is no cure or effective treatment, genetic counseling becomes very important in disease management. SMN1 dosage analysis results can be utilized for identifying carriers before offering prenatal diagnosis in the context of genetic counseling. METHODS: In the present study we analyzed the carrier status of parents and sibs of proven SMA patients. In addition, SMN1 copy number was determined in suspected SMA patients and parents of children with a clinical diagnosis of SMA. RESULTS: wenty nine DNA samples were analyzed by quantitative PCR to determine the number of SMN1 gene copies present, and 17 of these were found to have one SMN1 gene copy. The parents of confirmed SMA patients were found to be obligate carriers of the disease. Dosage analysis was useful in ruling out clinical suspicion of SMA in four patients. In a family with history of a deceased floppy infant and two abortions, both parents were found to be carriers of SMA and prenatal diagnosis could be offered in future pregnancies. CONCLUSION: SMN1 copy number analysis is an important parameter for identification of couples at risk for having a child affected with SMA and reduces unwarranted prenatal diagnosis for SMA. The dosage analysis is also useful for the counseling of clinically suspected SMA with a negative diagnostic SMA test

Long-term outcomes five years after selective dorsal rhizotomy

<p>Abstract</p> <p>Background</p> <p>Selective dorsal rhizotomy (SDR) is a well accepted neurosurgical procedure performed for the relief of spasticity interfering with motor function in children with spastic cerebral palsy (CP). The goal is to improve function, but long-term outcome studies are rare. The aims of this study were to evaluate long-term functional outcomes, safety and side effects during five postoperative years in all children with diplegia undergoing SDR combined with physiotherapy.</p> <p>Methods</p> <p>This study group consisted of 35 children, consecutively operated, with spastic diplegia, of which 26 were Gross Motor Function Classification System (GMFCS) levels III–V. Mean age was 4.5 years (range 2.5–6.6). They were all assessed by the same multidisciplinary team at pre- and at 6, 12, 18 months, 3 and 5 years postoperatively. Clinical and demographic data, complications and number of rootlets cut were prospectively registered. Deep tendon reflexes and muscle tone were examined, the latter graded with the modified Ashworth scale. Passive range of motion (PROM) was measured with a goniometer. Motor function was classified according to the GMFCS and measured with the Gross Motor Function Measure (GMFM-88) and derived into GMFM-66. Parent's opinions about the children's performance of skills and activities and the amount of caregiver assistance were measured with Pediatric Evaluation Disability Inventory (PEDI).</p> <p>Results</p> <p>The mean proportion of rootlets cut in S2-L2 was 40%. Muscle tone was immediately reduced in adductors, hamstrings and dorsiflexors (p < 0.001) with no recurrence of spasticity over the 5 years. For GMFCS-subgroups I–II, III and IV–V significant improvements during the five years were seen in PROM for hip abduction, popliteal angle and ankle dorsiflexion (p = 0.001), capacity of gross motor function (GMFM) (p = 0.001), performance of functional skills and independence in self-care and mobility (PEDI) (p = 0.001).</p> <p>Conclusion</p> <p>SDR is a safe and effective method for reducing spasticity permanently without major negative side effects. In combination with physiotherapy, in a group of carefully selected and systematically followed young children with spastic diplegia, it provides lasting functional benefits over a period of at least five years postoperatively.</p

A Yersinia Effector with Enhanced Inhibitory Activity on the NF-κB Pathway Activates the NLRP3/ASC/Caspase-1 Inflammasome in Macrophages

A type III secretion system (T3SS) in pathogenic Yersinia species functions to translocate Yop effectors, which modulate cytokine production and regulate cell death in macrophages. Distinct pathways of T3SS-dependent cell death and caspase-1 activation occur in Yersinia-infected macrophages. One pathway of cell death and caspase-1 activation in macrophages requires the effector YopJ. YopJ is an acetyltransferase that inactivates MAPK kinases and IKKβ to cause TLR4-dependent apoptosis in naïve macrophages. A YopJ isoform in Y. pestis KIM (YopJKIM) has two amino acid substitutions, F177L and K206E, not present in YopJ proteins of Y. pseudotuberculosis and Y. pestis CO92. As compared to other YopJ isoforms, YopJKIM causes increased apoptosis, caspase-1 activation, and secretion of IL-1β in Yersinia-infected macrophages. The molecular basis for increased apoptosis and activation of caspase-1 by YopJKIM in Yersinia-infected macrophages was studied. Site directed mutagenesis showed that the F177L and K206E substitutions in YopJKIM were important for enhanced apoptosis, caspase-1 activation, and IL-1β secretion. As compared to YopJCO92, YopJKIM displayed an enhanced capacity to inhibit phosphorylation of IκB-α in macrophages and to bind IKKβ in vitro. YopJKIM also showed a moderately increased ability to inhibit phosphorylation of MAPKs. Increased caspase-1 cleavage and IL-1β secretion occurred in IKKβ-deficient macrophages infected with Y. pestis expressing YopJCO92, confirming that the NF-κB pathway can negatively regulate inflammasome activation. K+ efflux, NLRP3 and ASC were important for secretion of IL-1β in response to Y. pestis KIM infection as shown using macrophages lacking inflammasome components or by the addition of exogenous KCl. These data show that caspase-1 is activated in naïve macrophages in response to infection with a pathogen that inhibits IKKβ and MAPK kinases and induces TLR4-dependent apoptosis. This pro-inflammatory form of apoptosis may represent an early innate immune response to highly virulent pathogens such as Y. pestis KIM that have evolved an enhanced ability to inhibit host signaling pathways

Regulator of G-Protein Signaling 14 (RGS14) Is a Selective H-Ras Effector

Background: Regulator of G-protein signaling (RGS) proteins have been well-described as accelerators of Ga-mediated GTP hydrolysis (‘‘GTPase-accelerating proteins’’ or GAPs). However, RGS proteins with complex domain architectures are now known to regulate much more than Ga GTPase activity. RGS14 contains tandem Ras-binding domains that have been reported to bind to Rap- but not Ras GTPases in vitro, leading to the suggestion that RGS14 is a Rap-specific effector. However, more recent data from mammals and Drosophila imply that, in vivo, RGS14 may instead be an effector of Ras.Methodology/Principal Findings: Full-length and truncated forms of purified RGS14 protein were found to bind indiscriminately in vitro to both Rap- and Ras-family GTPases, consistent with prior literature reports. In stark contrast, however, we found that in a cellular context RGS14 selectively binds to activated H-Ras and not to Rap isoforms. Co- transfection / co-immunoprecipitation experiments demonstrated the ability of full-length RGS14 to assemble a multiprotein complex with components of the ERK MAPK pathway in a manner dependent on activated H-Ras. Small interfering RNA-mediated knockdown of RGS14 inhibited both nerve growth factor- and basic fibrobast growth factor- mediated neuronal differentiation of PC12 cells, a process which is known to be dependent on Ras-ERK signaling.Conclusions/Significance: In cells, RGS14 facilitates the formation of a selective Ras?GTP-Raf-MEK-ERK multiprotein complex to promote sustained ERK activation and regulate H-Ras-dependent neuritogenesis. This cellular function for RGS14 is similar but distinct from that recently described for its closely-related paralogue, RGS12, which shares the tandem Ras- binding domain architecture with RGS14

Gallbladder Cancer Predisposition: A Multigenic Approach to DNA-Repair, Apoptotic and Inflammatory Pathway Genes

Gallbladder cancer (GBC) is a multifactorial disease with complex interplay between multiple genetic variants. We performed Classification and Regression Tree Analysis (CART) and Grade of Membership (GoM) analysis to identify combinations of alleles among the DNA repair, inflammatory and apoptotic pathway genetic variants in modifying the risk for GBC. We analyzed 16 polymorphisms in 8 genes involved in DNA repair, apoptotic and inflammatory pathways to find out combinations of genetic variants contributing to GBC risk. The genes included in the study were XRCC1, OGG1, ERCC2, MSH2, CASP8, TLR2, TLR4 and PTGS2. Single locus analysis by logistic regression showed association of MSH2 IVS1+9G>C (rs2303426), ERCC2 Asp312Asn (rs1799793), OGG1 Ser326Cys (rs1052133), OGG1 IVS4-15C>G (rs2072668), CASP8 -652 6N ins/del (rs3834129), PTGS2 -1195G>A (rs689466), PTGS2 -765G>C (rs20417), TLR4 Ex4+936C>T (rs4986791) and TLR2 –196 to –174del polymorphisms with GBC risk. The CART analysis revealed OGG1 Ser326Cys, and OGG1 IVS4-15C>G polymorphisms as the best polymorphic signature for discriminating between cases and controls. In the GoM analysis, the data was categorized into six sets representing risk for GBC with respect to the investigated polymorphisms. Sets I, II and III described low intrinsic risk (controls) characterized by multiple protective alleles while sets IV, V and VI represented high intrinsic risk groups (GBC cases) characterized by the presence of multiple risk alleles. The CART and GoM analyses also showed the importance of PTGS2 -1195G>A polymorphism in susceptibility to GBC risk. In conclusion, the present multigenic approach can be used to define individual risk profiles for gallbladder cancer in North Indian population