Responses of biochemical markers in carp Cyprinus carpio from two field sites in Western Ukraine

The aim of this study was to compare environmental quality in two sites of the river in Western Ukraine, rural (R) and industrial (I) during three seasons via a set of biochemical markers in carp Cyprinus carpio L. Upon comparing the values of the I-site with those of the R-site, we found that Mn- and Cu, Zn-superoxide dismutase (SOD) activities decreased and O(.) production increased; metallothionein (MT) and glutathione levels increased in most cases, and acetylcholinesterase (AChE) activity decreased in summer. This confirms our hypothesis about continuous environmental press at the I-site. The higher activity of catalase and lipid peroxidation (TBARS), as well as the increased levels of vitellogenin-like proteins at the R-site, compare to the I-site in spring reflects the permitting effect of agricultural discharges. According to the results of PCA, the most sensitive biomarkers of pollution are MT, TBARS, and AChE in liver.     

Tyrosines of Human and Mouse Transferrin Covalently Labeled by Organophosphorus Agents: A New Motif for Binding to Proteins that Have No Active Site Serine

The expectation from the literature is that organophosphorus(OP) agents bind to proteins that have an active site serine.However, transferrin, a protein with no active site serine,was covalently modified in vitro by 0.5mM 10-fluoroethoxyphosphinyl-N-biotinamidopentyldecanamide, chlorpyrifos oxon, diisopropylfluorophosphate,dichlorvos, sarin, and soman. The site of covalent attachmentwas identified by analyzing tryptic peptides in the mass spectrometer.Tyr 238 and Tyr 574 in human transferrin and Tyr 238, Tyr 319,Tyr 429, Tyr 491, and Tyr 518 in mouse transferrin were labeledby OP. Tyrosine in the small synthetic peptide ArgTyrThrArgmade a covalent bond with diisopropylfluorophosphate, chlorpyrifosoxon, and dichlorvos at pH 8.3. These results, together withour previous demonstration that albumin and tubulin bind OPon tyrosine, lead to the conclusion that OP bind covalentlyto tyrosine, and that OP binding to tyrosine is a new OP-bindingresidue. The OP-reactive tyrosines are activated by interactionwith Arg or Lys. It is suggested that many proteins in additionto those already identified may be modified by OP on tyrosine.The extent to which tyrosine modification by OP can occur invivo and the toxicological implications of such modificationsrequire further investigation.     

Right ventricular systolic pressure by echocardiography as a predictor of pulmonary hypertension in idiopathic pulmonary fibrosis

RATIONALE: Pulmonary hypertension (PH) commonly complicates the course of patients with idiopathic pulmonary fibrosis (IPF). It has a significant impact on outcomes and is, therefore, important to detect. OBJECTIVES: We sought to characterize the accuracy and performance characteristics of the right ventricular systolic pressure (RVSP) as estimated by echocardiography (ECHO) alone and in conjunction with physiologic indices in predicting the presence of PH in IPF patients. METHODS: Cross-sectional study of IPF patients from two large tertiary centers in whom both ECHO and right-heart catheterization (RHC) were available. MEASUREMENTS AND MAIN RESULTS: There were 110 patients with available ECHOs and RHCs. Estimates of RVSP were reported in 60 of these patients (54.5%) of whom 22 (36.6%) had PH, while 16 of the 50 patients without RVSP estimate (32%) had PH. Twenty-four of 60 (40%) ECHOs accurately reflected the pulmonary arterial systolic pressure as measured by RHC. An optimal RVSP threshold for the screening of PH could not be detected. When assessed in combination with various thresholds of PFT and 6-minute walk test (6MWT) parameters, the performance characteristics of the RVSP were slightly improved. CONCLUSION: The RVSP is not an accurate test for the assessment of PH in IPF patients. Awareness of the various combinations of threshold values for RVSP with and without PFT and 6MWT might nonetheless assist clinicians in risk stratifying IPF patients for the presence of PH.     

Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901

The mitogenic extracellular kinase 1/2 (MEK1/2) inhibitor, PD0325901, has potent activity in a number of cancer cell types in vitro. In SKMEL-28 human melanoma cells (BRAF mutant), the drug rapidly decreased phosphorylated extracellular signal-regulated kinase 1/2, cyclin D1, and thymidine kinase 1 protein levels. We investigated if 3'-deoxy-3'-[(18)F]fluorothymidine-positron emission tomography ([(18)F]FLT-PET) could be used to image changes in cell proliferation following MEK1/2 inhibition in vivo. Mice bearing SKMEL-28 and human colon cancer HCT116 (K-RAS mutant) xenografts were treated daily with PD0325901 at 25 mg/kg and imaged by dynamic [(18)F]FLT-PET after 1 and 10 days of initiating treatment. The drug decreased tumor [(18)F]FLT uptake after 1 and 10 days of treatment compared with control animals. The normalized (maximal) [(18)F]FLT uptake in SKMEL-28 xenografts (at 60 minutes; NUV(max)) after 1 day of vehicle or PD0325901 therapy was 1.81 +/- 0.18 versus 1.23 +/- 0.10, respectively (P = 0.03). In this model, NUV(max) after 10 days was 2.07 +/- 0.40 versus 1.08 +/- 0.14, respectively (P = 0.03). The corresponding values for HCT116 tumors were 2.30 +/- 0.84 versus 1.88 +/- 0.36 (P = 0.045) after 1 day, and 1.97 +/- 0.13 versus 1.00 +/- 0.03 (P = 0.03) after 10 days. Similar changes were found for other [(18)F]FLT retention variables. The drug decreased phosphorylated extracellular signal-regulated kinase 1/2, cyclin D1, and thymidine kinase 1 protein. Tumor [(18)F]FLT-PET variables correlated with proliferation as measured by Ki67 labeling index (r >/= 0.6; P >/= 0.003). In summary, [(18)F]FLT-PET is a sensitive imaging biomarker for detecting the antiproliferative effect of MEK1/2 inhibition by PD0325901. [Mol Cancer Ther 2008;7(9):3112-21].     

22q11.2 Deletion syndrome and obstructive sleep apnea

Otolaryngologic problems are common in the 22q11.2 deletion syndrome (DS) population. Structural anomalies and retrognathia may predispose these patients to obstructive sleep apnea (OSA). The current association of OSA in this population is not defined.     

Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1

Spinocerebellar ataxia type 1 (SCA1) is the major and likely the only type of autosomal dominant cerebellar ataxia in the Sakha (Yakut) people of Eastern Siberia. The prevalence rate of SCA1 has doubled over the past 21 years peaking at 46 cases per 100,000 rural population. The age at death correlates closely with the number of CAG triplet repeats in the mutant ATXN1 gene (r = ?0.81); most patients with low-medium (39–55) repeat numbers survived until the end of reproductive age. The number of CAG repeats expands in meiosis, particularly in paternal transmissions; the average total increase in intergenerational transmissions in our cohort was estimated at 1.6 CAG repeats. The fertility rates of heterozygous carriers of 39–55 CAG repeats in women were no different from those of the general Sakha population. Overall, the survival of mutation carriers through reproductive age, unaltered fertility rates, low childhood mortality in SCA1-affected families, and intergenerational transmission of increasing numbers of CAG repeats in the ATXN1 gene indicate that SCA1 in the Sakha population will be maintained at high prevalence levels. The low (0.19) Crow’s index of total selection intensity in our SCA1 cohort implies that this mutation is unlikely to be eliminated through natural selection alone.