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Increased Dosage (increased + dosage)
Selected AbstractsIncreased Dosage during Intracoronary Irradiation Due to Overlapped Source Stepping Shows No Long-Term Adverse Changes in Vessel MorphologyJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 3 2004BONNI SYEDA M.Sc., M.D. Purpose: The purpose of this analysis was to evaluate if overdosage during intracoronary irradiation due to overlapped source stepping may result in long-term morphologic changes in vessel anatomy. Methods: Baseline angiograms of patients with in-stent restenosis undergoing coronary reintervention followed by intracoronary irradiation with source stepping were analyzed. Overlapping was considered present for the segment with overlapped reference isodose length (RIL) (RIL = segment with ,90% of reference dose at 1 mm vessel wall depth). Baseline and 6-months follow-up volumetric intravascular ultrasound (IVUS) analysis were performed for the overlapped segment and for proximal and distal segments of equal length. Results: Overlapping was found in six patients (three patients: 32P treatment; three patients: 90Sr/Y treatment); final analysis was performed in four patients. Comparison of the baseline and follow-up IVUS volumetric parameters revealed no significant change in lumen or vessel volumes at segments of overlaps in comparison to proximal and distal reference segments. Conclusion: Increased dosage due to overlapping during source stepping is not associated with morphologic changes in vessel anatomy at follow-up. (J Interven Cardiol 2004;17:143,149) [source] Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature deathAGING CELL, Issue 2 2010Mariana Pehar Summary The longevity-assurance activity of the tumor suppressor p53 depends on the levels of ,40p53 (p44), a short and naturally occurring isoform of the p53 gene. As such, increased dosage of p44 in the mouse leads to accelerated aging and short lifespan. Here we show that mice homozygous for a transgene encoding p44 (p44+/+) display cognitive decline and synaptic impairment early in life. The synaptic deficits are attributed to hyperactivation of insulin-like growth factor 1 receptor (IGF-1R) signaling and altered metabolism of the microtubule-binding protein tau. In fact, they were rescued by either Igf1r or Mapt haploinsufficiency. When expressing a human or a ,humanized' form of the amyloid precursor protein (APP), p44+/+ animals developed a selective degeneration of memory-forming and -retrieving areas of the brain, and died prematurely. Mechanistically, the neurodegeneration was caused by both paraptosis- and autophagy-like cell deaths. These results indicate that altered longevity-assurance activity of p53:p44 causes memory loss and neurodegeneration by affecting IGF-1R signaling. Importantly, Igf1r haploinsufficiency was also able to correct the synaptic deficits of APP695/swe mice, a model of Alzheimer's disease. [source] PDR16 -mediated azole resistance in Candida albicansMOLECULAR MICROBIOLOGY, Issue 6 2006Saloua Saidane Summary Many Candida albicans azole-resistant (AR) clinical isolates overexpress the CDR1 and CDR2 genes encoding homologous multidrug transporters of the ATP-binding cassette family. We show here that these strains also overexpress the PDR16 gene, the orthologue of Saccharomyces cerevisiae PDR16 encoding a phosphatidylinositol transfer protein of the Sec14p family. It has been reported that S. cerevisiae pdr16, mutants are hypersusceptible to azoles, suggesting that C. albicans PDR16 may contribute to azole resistance in these isolates. To address this question, we deleted both alleles of PDR16 in an AR clinical strain overexpressing the three genes, using the mycophenolic acid resistance flipper strategy. Our results show that the homozygous pdr16,/pdr16, mutant is approximately twofold less resistant to azoles than the parental strain whereas reintroducing a copy of PDR16 in the mutant restored azole resistance, demonstrating that this gene contributes to the AR phenotype of the cells. In addition, overexpression of PDR16 in azole-susceptible (AS) C. albicans and S. cerevisiae strains increased azole resistance by about twofold, indicating that an increased dosage of Pdr16p can confer low levels of azole resistance in the absence of additional molecular alterations. Taken together, these results demonstrate that PDR16 plays a role in C. albicans azole resistance. [source] Clozapine in schizophrenia patients with recurrent catatonia: Report of two casesPSYCHIATRY AND CLINICAL NEUROSCIENCES, Issue 2 2006YI-YUNG HUNG md Abstract, Prolonged catatonia can be a source of extremely serious morbidity and mortality. Lorazepam is effective in rapidly relieving most cases of catatonia. Reports have also shown that second-generation antipsychotic drugs are also efficacious in relieving catatonia. This report describes two schizophrenia patients who demonstrated recurrent catatonic features mutism and stupor. Both patients were treated with lorazepam, diazepam or electroconvulsive therapy (ECT). Patient 1 responded well and rapidly to lorazepam each time catatonia happened; but catatonia recurred once a year under treatment with many antipsychotic drugs. Patient 2 had catatonia features associated with discontinuing or decreasing clozapine. With each recurrent episode, the duration of catatonia increased, requiring an increased dosage of benzodiazepine. The patient's response to lorazepam and ECT gradually decreased, until the patient had almost no response to lorazepam, diazepam or ECT. Both patients had no recurrence during a period of 2-year follow up with continuous clozapine therapy. [source] Early prediction of anthracycline induced cardiotoxicityACTA PAEDIATRICA, Issue 4 2007Bedirhan Erkus Abstract Aim: The purpose of this study is to evaluate echocardiographically determined cardiac functions with serum levels of brain natriuretic peptide (BNP), cardiac troponin I (cTnI) and total antioxidant status (TAOS) in childhood leukemia treated with chemotherapeutics containing anthracyclines. Methods: A study group of 29 patients who have been followed for acute lymphoblastic leukemia (ALL) and administered a treatment protocol containing chemotherapy of anthracyclines were included in the analysis. Levels of BNP, cTnI and TAOS were studied in serum samples of the patients. Results: We demonstrated that as the drug dosage increased, systolic ejection fraction (EF) and shortening fraction (FS) values decreased (EF r2= 0.2327, FS r2= 0.251). On the other hand, increased dosage of anthracycline therapy was associated with significant raise in plasma BNP levels (r2= 0.246) and significant decrease in serum TAOS levels (r2= 0.317) without any change in serum cTnI levels. Conclusion: Our study suggest that serum TAOS and BNP levels may be useful as an early and sensitive indicator of anthracycline induced cardiotoxicity. [source] Stringent testing identifies highly potent and escape-proof anti-HIV short hairpin RNAsTHE JOURNAL OF GENE MEDICINE, Issue 6 2009Karin J. von Eije Abstract Background RNA interference (RNAi) is a cellular mechanism that can be induced by small interfering RNAs to mediate sequence-specific gene silencing by cleavage of the targeted mRNA. RNAi can be used as an antiviral approach to silence the human immunodeficiency virus type 1 (HIV-1) through stable expression of short hairpin RNAs (shRNAs). Previously, we used a co-transfection assay in which shRNA constructs were transfected with an HIV-1 molecular clone to identify 20 shRNA inhibitors that target highly conserved HIV-1 sequences. Methods In the present study, we selected the most potent shRNAs to formulate a combinatorial shRNA therapy and determine the best and easiest method for antiviral shRNA selection. We performed transient inhibition assays with either a luciferase reporter or HIV-1 molecular clone and also infected shRNA-expressing T cell lines with HIV-1 and monitored virus replication. The latter assay allows detection of viral escape. In addition, we also tested shRNA-expressing T cells upon challenge with increasing dosages of HIV-1, and measured the dose required to result in massive virus-induced syncytia formation in this 2-week assay. Results Extended culturing selected three highly effective shRNAs that do not allow viral replication for more than 100 days. This difference in potency was not observed in the transient co-transfection assays. The use of increased dosages of HIV-1 selected the same highly potent shRNAs as the laborious and extended escape study. Conclusions These highly potent shRNAs could be used for a clinical vector and the comparison of the developed assays might help other researchers in their search for antiviral shRNAs. Copyright © 2009 John Wiley & Sons, Ltd. [source] Ex Vivo Biocompatibility of Avidin-Agarose: A New Device for Direct Adsorption of Biotinylated Antibodies from Human Whole BloodARTIFICIAL ORGANS, Issue 9 2000T. Bosch Abstract: Radioimmunotherapy using radiolabeled antitumor antibodies (RAA) is limited by the toxicity of unbound antibodies in the circulation. Removal of excessive antibodies by affinity-adsorption could therefore allow the administration of increased dosages of RAA while decreasing their adverse effects. Recently, avidin-agarose (AA) minicolumns were used in animal experiments for the removal of biotinylated antibodies from whole blood exploiting the high affinity binding of biotin to avidin (pK 1015 M,1). This study was performed to evaluate the ex vivo biocompatibility of AA minicolumns with human blood. Ten ml AA minicolumns were perfused online ex vivo in the single pass mode with fresh blood from 8 healthy donors at a flow rate of 6.25 ml/min. The anticoagulation consisted of 0.5 IU heparin plus 0.0,2.1 mg citrate per ml of blood. In Part 1 of the study (40 min perfusion, n = 4), the optimal anticoagulation was found to be 0.5 IU heparin plus about 1 mg citrate per ml of blood. In Part 2 of the study, four 80 min test-runs were performed. No signs of hemolysis were found, and the thrombogenicity of the AA gel was negligible. Cell counts and column inlet pressures remained constant; toward the end of the 80 min test-runs, some activation of blood cells (elastase, ,-thromboglobulin), the complement system (C3a, C5a) and the plasmatic coagulation (thrombin-antithrombin complex) was detectable. A moderate initial bradykinin release rapidly subsided to very low levels. In summary, AA minicolumns showed good biocompatibility upon contact with human whole blood and merit further investigation in a closed-loop system for a potential application of direct tumor antibody removal by hemoperfusion. [source] | |||||||||||||