Inhibitors of Trypanosoma brucei trypanothione reductase: comparative molecular field analysis modeling and structural basis for selective inhibition

Background: Sleeping sickness is a major cause of death in Africa. Since no secure treatment is available, the development of novel therapeutic agents is urgent. In this context, the enzyme trypanothione reductase (TR) is a prominent molecular target that has been investigated in drug design for sleeping sickness. Results: In this study, comparative molecular field analysis models were generated for a series of Trypanosoma brucei TR inhibitors. Statistically significant results were obtained and the models were applied to predict the activity of external test sets, with good correlation between predicted and experimental results. We have also investigated the structural requirements for the selective inhibition of the parasite's enzyme over the human glutathione reductase. Conclusion: The quantitative structure-activity relationship models provided valuable information regarding the essential molecular requirements for the inhibitory activity upon the target protein, providing important insights into the design of more potent and selective TR inhibitors.

A simple criterion to predict the glass forming ability of metallic alloys

A new and simple criterion with which to quantitatively predict the glass forming ability (GFA) of metallic alloys is proposed. It was found that the critical cooling rate for glass formation (R-C) correlates well with a proper combination of two factors, the minimum topological instability (lambda(min)) and the Delta h parameter, which depends on the average work function difference (Delta phi) and the average electron density difference (Delta n(ws)(1/3)) among the constituent elements of the alloy. A correlation coefficient (R-2) of 0.76 was found between R-c and the new criterion for 68 alloys in 30 different metallic systems. The new criterion and the Uhlmann's approach were used to estimate the critical amorphous thickness (Z(C)) of alloys in the Cu-Zr system. The new criterion underestimated R-C in the Cu-Zr system, producing predicted Z(C) values larger than those observed experimentally. However, when considering a scale factor, a remarkable similarity was observed between the predicted and the experimental behavior of the GFA in the binary Cu-Zr. When using the same scale factor and performing the calculation for the ternary Zr-Cu-Al, good agreement was found between the predicted and the actual best GFA region, as well as between the expected and the observed critical amorphous thickness. (C) 2012 American Institute of Physics. [doi:10.1063/1.3676196]

Longitudinal reference ranges for fetal ultrasound biometry in twin pregnancies

OBJECTIVE: The purpose of this study was to establish longitudinal reference ranges for fetal ultrasound biometry measurements and growth parameters in twin pregnancies. METHOD: A total of 200 uncomplicated twin pregnancies before 21 weeks of gestation were recruited for this prospective, longitudinal study. Women who abandoned follow-up, pregnancies with unknown outcomes or pregnancies with complications were excluded. Ultrasound scans were performed every three weeks, and biparietal and occipitofrontal diameters, head and abdominal circumferences, and femur diaphysis length measurements were obtained for each fetus at each visit. Estimated fetal weight, biparietal/occipitofrontal diameter, head circumference/abdominal circumference, and femur diaphysis length/abdominal circumference ratios were also calculated. Multilevel regression analysis was performed on normalized data. RESULTS: A total of 807 ultrasound examinations were performed in 125 twin pregnancies between 14 and 38 weeks of gestation (6.5 +/- 1.4 scans/pregnancy). Regression analysis demonstrated significant correlations for all variables with gestational age, namely log of the biparietal diameter (r = 0.98), log of the occipitofrontal diameter (r = 0.98), log of the head circumference (r = 0.99), log of the abdominal circumference (r = 0.98), square root of the femur length (r = 0.99), log of the estimated fetal weight (r = 0.99), biparietal/occipitofrontal ratio (r = -0.11), head/abdomen circumference ratio (r = -0.56), and log of the femur length/abdominal circumference ratio (r = 0.61). Values corresponding to the 10th, 50th, and 90th percentiles for estimated fetal weight at 28, 32, and 36 weeks, respectively, were as follows: 937, 1,096, 1,284 g; 1,462, 1,720, 2,025 g; and 2,020, 2,399, 2,849 g. CONCLUSION: In twin pregnancies, fetal ultrasound biometry measurements and growth parameters show a significant correlation with gestational age.

Dasatinib Overrides Imatinib Resistance Mediated by the F359I Residue Mutation in Two Patients with Chronic Myeloid Leukemia

Despite the beneficial effects of imatinib mesylate, some patients may either not respond or respond suboptimally. Here, we report two chronic myelogenous leukemia patients; one had a suboptimal response according to European LeukemiaNet criteria (a major molecular response was not achieved after 18 months of standard-dose imatinib therapy) and the other had failure with a standard dose of imatinib. At the time of the suboptimal response in patient 1 and the failure in patient 2, we were able to detect the F359I mutation in the BCR-ABL tyrosine kinase domain using DNA sequencing in both patients. Therefore, it was decided to change the therapeutic regimen to dasatinib at a dose of 100 mg once daily in both patients. This change resulted in the achievement of complete cytogenetic remission in patient 1 after 4 months and a major molecular response within 2 and 3 months in both patients. Detection of the F359I mutation in our two cases likely explains the suboptimal response to imatinib in case 1 and the failure in case 2. This implies that in such cases dasatinib should be considered to effectively suppress the mutated clones. Copyright (C) 2011 S. Karger AG, Basel

Molecular detection of in-vivo microbial contamination of metallic orthodontic brackets by checkerboard DNA-DNA hybridization

Introduction: Knowing the microbiota that colonizes orthodontic appliances is important for planning strategies and implementing specific preventive measures during treatment. The purpose of this clinical trial was to evaluate in vivo the contamination of metallic orthodontic brackets with 40 DNA probes for different bacterial species by using the checkerboard DNA-DNA hybridization (CDDH) technique. Methods: Eighteen patients, 11 to 29 years of age having fixed orthodontic treatment, were enrolled in the study. Each subject had 2 new metallic brackets bonded to different premolars in a randomized manner. After 30 days, the brackets were removed and processed for analysis by CDDH. Data on bacterial contamination were analyzed descriptively and with the Kruskal-Wallis and Dunn post tests (alpha = 0.05). Forty microbial species (cariogenic microorganisms, bacteria of the purple, yellow, green, orange complexes, "red complex + Treponema socranskii," and the cluster of Actinomyces) were assessed. Results: Most bacterial species were present in all subjects, except for Streptococcus constellatus, Campylobacter rectus, Tannerella forsythia, T socranskii, and Lactobacillus acidophillus (94.4%), Propionibacterium acnes I and Eubacterium nodatum (88.9%), and Treponema denticola (77.8%). Among the cariogenic microorganisms, Streptococcus mutans and Streptococcus sobrinus were found in larger numbers than L acidophillus and Lactobacillus casei (P < 0.001). The periodontal pathogens of the orange complex were detected in larger numbers than those of the "red complex + T socranskii" (P < 0.0001). Among the bacteria not associated with specific pathologies, Veillonella parvula (purple complex) was the most frequently detected strain (P < 0.0001). The numbers of yellow and green complex bacteria and the cluster of Actinomyces were similar (P > 0.05). Conclusions: Metallic brackets in use for 1 month were multi-colonized by several bacterial species, including cariogenic microorganisms and periodontal pathogens, reinforcing the need for meticulous oral hygiene and additional preventive measures to maintain oral health in orthodontic patients. (Am J Orthod Dentofacial Orthop 2012;141:24-9)

Bilateral osteoporotic bone marrow defects of the mandible: a case report

Osteoporotic bone marrow defect of the jaws has been reported as a poorly demarcated radiolucency that affect mainly posterior mandible of middle-aged woman. The incidence of this condition is not exactly established and its pathogenesis remains unknown. An additional unusual case of osteoporotic bone marrow defects occurring bilaterally in the mandibular edentulous regions of a 32-year-old white woman is presented reinforcing its diagnostic criteria and histopathological findings.

A novel strategy for building interoperable MPI environment in heterogeneous high performance systems

Breakthrough advances in microprocessor technology and efficient power management have altered the course of development of processors with the emergence of multi-core processor technology, in order to bring higher level of processing. The utilization of many-core technology has boosted computing power provided by cluster of workstations or SMPs, providing large computational power at an affordable cost using solely commodity components. Different implementations of message-passing libraries and system softwares (including Operating Systems) are installed in such cluster and multi-cluster computing systems. In order to guarantee correct execution of message-passing parallel applications in a computing environment other than that originally the parallel application was developed, review of the application code is needed. In this paper, a hybrid communication interfacing strategy is proposed, to execute a parallel application in a group of computing nodes belonging to different clusters or multi-clusters (computing systems may be running different operating systems and MPI implementations), interconnected with public or private IP addresses, and responding interchangeably to user execution requests. Experimental results demonstrate the feasibility of this proposed strategy and its effectiveness, through the execution of benchmarking parallel applications.

Use of a gold microelectrode for discrimination of gunshot residues

Gunshot residues (GSR) can be used in forensic evaluations to obtain information about the type of gun and ammunition used in a crime. In this work, we present our efforts to develop a promising new method to discriminate the type of gun [four different guns were used: two handguns (0.38 revolver and 0.380 pistol) and two long-barrelled guns (12-calibre pump-action shotgun and 0.38 repeating rifle)] and ammunition (five different types: normal, semi-jacketed, full-jacketed, green, and 3T) used by a suspect. The proposed approach is based on information obtained from cyclic voltammograms recorded in solutions containing GSR collected from the hands of the shooters, using a gold microelectrode; the information was further analysed by non-supervised pattern-recognition methods [(Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA)]. In all cases (gun and ammunition discrimination), good separation among different samples in the score plots and dendrograms was achieved. (C) 2012 Elsevier B.V. All rights reserved.

Fracture resistance of endodontically treated teeth restored with different intraradicular posts with different lengths

Aim: This study compared the resistance to fracture of endodontically treated teeth restored with different intraradicular posts with different lengths and full coverage metallic crowns. Methods: Sixty extracted human canine teeth were randomly divided into 6 groups. Groups CP5, CP75 and CP10 were restored using custom cast post and core (CP) and groups PF5, PF75 and PF10 were restored with provisional pre-fabricated tin post (PF) and composite resin core at 5 mm, 7.5 mm and 10 mm of intraradicular length, respectively. The specimens were submitted to dynamic cyclic loading and those that resisted to this load were submitted to load compression using a universal testing machine. Compressive load was applied at a 45-degree angle to the long axis of the tooth until failure. Results: Kruskal-Wallis one-way analysis of variance by ranks showed statistically significant differences among the groups (p<0.0001). However, when the means were compared using the Tukey’s test, significant differences were noted between groups CP5 and CP10 and between groups CP10 and PF5. All groups presented root fractures and post displacements during mechanical cycling. All teeth in groups CP5 and PF5 failed the dynamic cycling test. Conclusions: This study showed that increasing intraradicular post length also increases resistance to fracture of endodontically treated teeth. On the other hand, most endodontically treated teeth restored with pre-fabricated tin posts (provisional posts) failed in the dynamic cycling test

Bilateral osteoporotic bone marrow defects of the mandible: a case report

Osteoporotic bone marrow defect of the jaws has been reported as a poorly demarcated radiolucency that affect mainly posterior mandible of middle-aged woman. The incidence of this condition is not exactly established and its pathogenesis remains unknown. An additional unusual case of osteoporotic bone marrow defects occurring bilaterally in the mandibular edentulous regions of a 32-year-old white woman is presented reinforcing its diagnostic criteria and histopathological findings.

Avaliação da reprodutibilidade das medidas da camada de fibras nervosas retiniana e da cabeça do nervo óptico pela tomografia de coerência óptica

OBJETIVO: Determinar a reprodutibilidade da espessura da camada de fibras nervosas da retina peripapilar e dos parâmetros da cabeça do nervo óptico em olhos normais, utilizando a tomografia de coerência óptica de domínio espectral (SD-OCT). MÉTODOS: Trinta e quatro olhos de 34 indivíduos saudáveis foram incluídos no estudo. O protocolo do cubo do disco óptico 200x200 do OCT Cirrus foi utilizado para gerar 3 imagens de cada olho para avaliar a reprodutibilidade. O coeficiente de correlação intraclasse (ICC) foi calculado para as medidas da espessura da camada de fibras nervosas da retina e da cabeça do nervo óptico. RESULTADOS: A correlação foi excelente para todas as medidas da espessura da camada de fibras nervosas da retina (ICC entre 0,87 e 0,98). O mesmo ocorreu com os parâmetros da cabeça do nervo óptico que, com exceção da razão E/D vertical (ICC 0,56), apresentou ICC entre 0,83 e 0,99. CONCLUSÃO: As medidas de espessura da camada de fibras nervosas da retina peripapilar e os parâmetros da cabeça no nervo óptico demonstraram uma excelente reprodutibilidade com o OCT Cirrus, indicando que este aparelho poderá ser uma ferramenta útil no estudo do glaucoma. Este estudo apresenta algumas limitações, como o pequeno número de casos avaliados, sendo necessários maiores estudos para corroborar nossos achados.

Theoretical models to predict the mechanical behavior of thick composite tubes

This paper shows theoretical models (analytical formulations) to predict the mechanical behavior of thick composite tubes and how some parameters can influence this behavior. Thus, firstly, it was developed the analytical formulations for a pressurized tube made of composite material with a single thick ply and only one lamination angle. For this case, the stress distribution and the displacement fields are investigated as function of different lamination angles and reinforcement volume fractions. The results obtained by the theoretical model are physic consistent and coherent with the literature information. After that, the previous formulations are extended in order to predict the mechanical behavior of a thick laminated tube. Both analytical formulations are implemented as a computational tool via Matlab code. The results obtained by the computational tool are compared to the finite element analyses, and the stress distribution is considered coherent. Moreover, the engineering computational tool is used to perform failure analysis, using different types of failure criteria, which identifies the damaged ply and the mode of failure.

The effect of beta-blockade on myocardial remodelling in Chagas' cardiomyopathy

OBJECTIVE: Chagas' disease has spread throughout Latin America because of the high rate of migration among these countries. Approximately 30% of Chagas' patients will develop cardiomyopathy, and 10% of these will develop severe cardiac damage leading to heart failure. Beta-blockade improves symptoms and survival in heart failure patients; however, its efficacy has not been well established in Chagas' disease. We evaluated the role of carvedilol in cardiac remodeling and mortality in a Chagas' cardiomyopathy animal model. METHODS: We studied Trypanosoma cruzi infection in 55 Syrian hamsters that were divided into three groups: control (15), infected (20), and infected + carvedilol (20). Animals underwent echocardiography, electrocardiography, and morphometry for collagen evaluation in ventricles stained with picrosirius red. RESULTS: The left ventricular diastolic diameter did not change between groups, although it was slightly larger in infected groups, as was left ventricular systolic diameter. Fractional shortening also did not change between groups, although it was slightly lower in infected groups. Collagen accumulation in the interstitial myocardial space was significantly higher in infected groups and was not attenuated by carvedilol. The same response was observed in the perivascular space. The survival curve showed significantly better survival in the control group compared with the infected groups; but no benefit of carvedilol was observed during the study. However, in the acute phase (up to 100 days of infection), carvedilol did reduce mortality. CONCLUSION: Carvedilol did not attenuate cardiac remodeling or mortality in this model of Chagas' cardiomyopathy. The treatment did improve survival in the acute phase of the disease.

Microbial Translocation Is Associated with Extensive Immune Activation in Dengue Virus Infected Patients with Severe Disease

Background: Severe dengue virus (DENV) disease is associated with extensive immune activation, characterized by a cytokine storm. Previously, elevated lipopolysaccharide (LPS) levels in dengue were found to correlate with clinical disease severity. In the present cross-sectional study we identified markers of microbial translocation and immune activation, which are associated with severe manifestations of DENV infection. Methods: Serum samples from DENV-infected patients were collected during the outbreak in 2010 in the State of Sa˜o Paulo, Brazil. Levels of LPS, lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14) and IgM and IgG endotoxin core antibodies were determined by ELISA. Thirty cytokines were quantified using a multiplex luminex system. Patients were classified according to the 2009 WHO classification and the occurrence of plasma leakage/shock and hemorrhage. Moreover, a (non-supervised) cluster analysis based on the expression of the quantified cytokines was applied to identify groups of patients with similar cytokine profiles. Markers of microbial translocation were linked to groups with similar clinical disease severity and clusters with similar cytokine profiles. Results: Cluster analysis indicated that LPS levels were significantly increased in patients with a profound pro-inflammatory cytokine profile. LBP and sCD14 showed significantly increased levels in patients with severe disease in the clinical classification and in patients with severe inflammation in the cluster analysis. With both the clinical classification and the cluster analysis, levels of IL-6, IL-8, sIL-2R, MCP-1, RANTES, HGF, G-CSF and EGF were associated with severe disease. Conclusions: The present study provides evidence that both microbial translocation and extensive immune activation occur during severe DENV infection and may play an important role in the pathogenesis.