Estudo da infestação por Haematobia irritans e por larvas de Dermatobia hominis em bovinos de corte.

As miíases provocadas por larvas de conhecidas como berne e o parasitismo pela mosca-dos-chifres, causam graves prejuízos aos pecuaristas no Brasil. Como têm sido observadas diferenças nas infestações entre animais de diferentes grupos genéticos, o presente estudo teve por objetivo verificar se existe diferença na suscetibilidade/resistência às infestações por bernes e mosca-dos-chifres, em bovinos de dois grupos genéticos diferentes. Foram utilizados bovinos machos e fêmeas, nascidos de outubro a dezembro de 2008 puros , da raça Nelore (n=28) e animais com maior grau de sangue , filhos de vacas ½ Canchim + ½ Nelore inseminadas com Angus (TC, n=17). Estes animais foram mantidos sem qualquer tratamento químico para controle de parasitas, em piquetes rotacionados de capim tanzânia ( ), na fazenda experimental da Embrapa Pecuária Sudeste e receberam suplementação somente no inverno. Mensalmente foram feitas avaliações por meio de inspeções visuais e táteis para contagem dos nódulos de bernes presentes em todo o corpo dos animais. As contagens das moscas-dos-chifres foram feitas simultaneamente às contagens de bernes, por meio da análise em computador de fotografias da região lombar de cada animal. Até o momento foram realizadas 10 contagens, totalizando 450 observações (de agosto de 2009 a maio de 2010). Todos os dados obtidos foram transformados em log (n+1) e analisados por meio do procedimento MIXED do SAS (2002/2003), de acordo com um modelo que incluiu os efeitos de grupo genético (GG), sexo (SX), contagem (CO) e interações, além do resíduo. Os resultados obtidos até o momento mostraram que os animais ?Nelore intensivo? (NI) apresentaram menores infestações pelos ectoparasitas estudados, que os animais ?Tricross? (TC). As maiores diferenças entre os grupos genéticos foram observadas para as infestações por bernes, sendo que as médias erro padrão foram de 0,10 0,04 e 0,58 0,05, para os animais NI e TC, respectivamente. As maiores infestações por bernes ocorreram durante os meses mais quentes e úmidos (dezembro/janeiro ). Para a mosca-dos-chifres as médias erro padrão foram de 1,01 0,05 para os animais NI e 1,41 0,064 para os animais TC e os machos apresentaram infestações superiores àquelas observadas para as fêmeas

Validation of three predictive models for suboptimal cytoreductive surgery in advanced ovarian cancer

The standard treatment for advanced ovarian cancer (AOC) is cytoreduction surgery and adjuvant chemotherapy. Tumor volume after surgery is a major prognostic factor for these patients. The ability to perform complete cytoreduction depends on the extent of disease and the skills of the surgical team. Several predictive models have been proposed to evaluate the possibility of performing complete cytoreductive surgery (CCS). External validation of the prognostic value of three predictive models (Fagotti index and the R3 and R4 models) for predicting suboptimal cytoreductive surgery (SCS) in AOC was performed in this study. The scores of the 3 models were evaluated in one hundred and three consecutive patients diagnosed with AOC treated in a tertiary hospital were evaluated. Clinicopathological features were collected prospectively and analyzed retrospectively. The performance of the three models was evaluated, and calibration and discrimination were analyzed. The calibration of the Fagotti, R3 and R4 models showed odds ratios of obtaining SCSs of 1.5, 2.4 and 2.4, respectively, indicating good calibration. The discrimination of the Fagotti, R3 and R4 models showed an area under the ROC curve of 83%, 70% and 81%, respectively. The negative predictive values of the three models were higher than the positive predictive values for SCS. The three models were able to predict suboptimal cytoreductive surgery for advanced ovarian cancer, but they were more reliable for predicting CCS. The R4 model discriminated better because it includes the laparotomic evaluation of the peritoneal carcinomatosis index

Biochemical comparison of two Hypostomus populations (Siluriformes, Loricariidae) from the Atlântico Stream of the upper Paraná River basin, Brazil

Two syntopic morphotypes of the genus Hypostomus - H. nigromaculatus and H. cf. nigromaculatus (Atlântico Stream, Paraná State) - were compared through the allozyme electrophoresis technique. Twelve enzymatic systems (AAT, ADH, EST, GCDH, G3PDH, GPI, IDH, LDH, MDH, ME, PGM and SOD) were analyzed, attributing the score of 20 loci, with a total of 30 alleles. Six loci were diagnostic (Aat-2, Gcdh-1, Gpi-A, Idh-1, Ldh-A and Mdh-A), indicating the presence of interjacent reproductive isolation. The occurrence of few polymorphic loci acknowledge two morphotypes, with heterozygosity values He = 0.0291 for H. nigromaculatus and He = 0.0346 for H. cf. nigromaculatus. FIS statistics demonstrated fixation of the alleles in the two morphotypes. Genetic identity (I) and distance (D) of Nei (1978) values were I = 0.6515 and D = 0.4285. The data indicate that these two morphotypes from the Atlântico Stream belong to different species

N-Acetylglutamate Synthase Deficiency Due to a Recurrent Sequence Variant in the N-acetylglutamate Synthase Enhancer Region

N-acetylglutamate synthase deficiency (NAGSD, MIM #237310) is an autosomal recessive disorder of the urea cycle that results from absent or decreased production of N-acetylglutamate (NAG) due to either decreased NAGS gene expression or defective NAGS enzyme. NAG is essential for the activity of carbamylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of the urea cycle. NAGSD is the only urea cycle disorder that can be treated with a single drug, N-carbamylglutamate (NCG), which can activate CPS1 and completely restore ureagenesis in patients with NAGSD. We describe a novel sequence variant NM_153006.2:c.-3026C > T in the NAGS enhancer that was found in three patients from two families with NAGSD; two patients had hyperammonemia that resolved upon treatment with NCG, while the third patient increased dietary protein intake after initiation of NCG therapy. Two patients were homozygous for the variant while the third patient had the c.-3026C > T variant and a partial uniparental disomy that encompassed the NAGS gene on chromosome 17. The c.-3026C > T sequence variant affects a base pair that is highly conserved in vertebrates; the variant is predicted to be deleterious by several bioinformatics tools. Functional assays in cultured HepG2 cells demonstrated that the c.-3026C > T substitution could result in reduced expression of the NAGS gene. These findings underscore the importance of analyzing NAGS gene regulatory regions when looking for molecular causes of NAGSD

Retinoic Acid-Dependent Signaling Pathways and Lineage Events in the Developing Mouse Spinal Cord

Studies in avian models have demonstrated an involvement of retinoid signaling in early neural tube patterning. The roles of this signaling pathway at later stages of spinal cord development are only partly characterized. Here we use Raldh2-null mouse mutants rescued from early embryonic lethality to study the consequences of lack of endogenous retinoic acid (RA) in the differentiating spinal cord. Mid-gestation RA deficiency produces prominent structural and molecular deficiencies in dorsal regions of the spinal cord. While targets of Wnt signaling in the dorsal neuronal lineage are unaltered, reductions in Fibroblast Growth Factor (FGF) and Notch signaling are clearly observed. We further provide evidence that endogenous RA is capable of driving stem cell differentiation. Raldh2 deficiency results in a decreased number of spinal cord derived neurospheres, which exhibit a reduced differentiation potential. Raldh2-null neurospheres have a decreased number of cells expressing the neuronal marker β-III-tubulin, while the nestin-positive cell population is increased. Hence, in vivo retinoid deficiency impaired neural stem cell growth. We propose that RA has separable functions in the developing spinal cord to (i) maintain high levels of FGF and Notch signaling and (ii) drive stem cell differentiation, thus restricting both the numbers and the pluripotent character of neural stem cells

Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival

<p>Abstract</p> <p>Background</p> <p>The JAK2^V617Fmutation plays a major role in the pathogenesis of myeloproliferative neoplasms and is found in the vast majority of patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia or from primary myelofibrosis. The V617F mutation is thought to provide hematopoietic stem cells and myeloid progenitors with a survival and proliferation advantage. It has previously been shown that activated JAK2 promotes cell survival by upregulating the anti-apoptotic STAT5 target gene Bcl-xL. In this study, we have investigated the role of additional apoptotic players, the pro-apoptotic protein Bim as well as the anti-apoptotic protein Mcl-1.</p> <p>Methods</p> <p>Pharmacological inhibition of JAK2/STAT5 signaling in JAK2^V617Fmutant SET-2 and MB-02 cells was used to study effects on signaling, cell proliferation and apoptosis by Western blot analysis, WST-1 proliferation assays and flow cytometry. Cells were transfected with siRNA oligos to deplete candidate pro- and anti-apoptotic proteins. Co-immunoprecipitation assays were performed to assess the impact of JAK2 inhibition on complexes of pro- and anti-apoptotic proteins.</p> <p>Results</p> <p>Treatment of JAK2^V617Fmutant cell lines with a JAK2 inhibitor was found to trigger Bim activation. Furthermore, Bim depletion by RNAi suppressed JAK2 inhibitor-induced cell death. Bim activation following JAK2 inhibition led to enhanced sequestration of Mcl-1, besides Bcl-xL. Importantly, Mcl-1 depletion by RNAi was sufficient to compromise JAK2^V617Fmutant cell viability and sensitized the cells to JAK2 inhibition.</p> <p>Conclusions</p> <p>We conclude that Bim and Mcl-1 have key opposing roles in regulating JAK2^V617Fcell survival and propose that inactivation of aberrant JAK2 signaling leads to changes in Bim complexes that trigger cell death. Thus, further preclinical evaluation of combinations of JAK2 inhibitors with Bcl-2 family antagonists that also tackle Mcl-1, besides Bcl-xL, is warranted to assess the therapeutic potential for the treatment of chronic myeloproliferative neoplasms.</p

Lysine-based surfactants in nanovesicle formulations: the role of cationic charge position and hydrophobicity in in vitro cytotoxicity and intracellular delivery

Understanding nanomaterial interactions within cells is of increasing importance for assessing their toxicity and cellular transport. Here, we developed nanovesicles containing bioactive cationic lysine-based amphiphiles, and assessed whether these cationic compounds increase the likelihood of intracellular delivery and modulate toxicity. We found different cytotoxic responses among the formulations, depending on surfactant, cell line and endpoint assayed. The induction of mitochondrial dysfunction, oxidative stress and apoptosis were the general mechanisms underlying cytotoxicity. Fluorescence microscopy analysis demonstrated that nanovesicles were internalized by HeLa cells, and evidenced that their ability to release endocytosed materials into cell cytoplasm depends on the structural parameters of amphiphiles. The cationic charge position and hydrophobicity of surfactants determine the nanovesicle interactions within the cell and, thus, the resulting toxicity and intracellular behavior after cell uptake of the nanomaterial. The insights into some toxicity mechanisms of these new nanomaterials contribute to reducing the uncertainty surrounding their potential health hazards

Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders?A successful strategy for clinical research of rare diseases

BACKGROUND: To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS: Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS: Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS: The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (</= 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS: Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies