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Major Organs (major + organ)
Selected AbstractsPreparation and animal biodistribution of 166Ho labeled DOTA for possible use in intravascular radiation therapy (IVRT)JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 3 2003Tapas Das Owing to its favorable decay characteristics (T1/2=27 h, E,(max)=1.85 MeV, E,=81 keV) and its availability with a specific activity of 3.7,4.4 GBq/mg from a moderate flux reactor, 166Ho can be considered as a potential radionuclide for intravascular radiation therapy (IVRT) using liquid-filled balloons. In the present work, studies on the use of 166Ho labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) as a possible agent for IVRT for the prevention of restenosis has been initiated. 166Ho was obtained by irradiating natural Ho2O3 powder and DOTA was synthesized by a multistep procedure. The optimum protocol of radiolabeling of DOTA with 166Ho was achieved by varying different reaction parameters. The complex was found to retain its stability for 7 days at room temperature. Bioevaluation studies carried out in Wistar rats showed that >95% of the injected activity was excreted within 3 h p.i. with almost no retention in any major organ. Both radiochemical and biological studies showed that 166Ho labeled DOTA can be further explored as a potential agent for IVRT. Copyright © 2002 John Wiley & Sons, Ltd. [source] Hormonal and nutritional regulation of insect fat body development and functionARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY (ELECTRONIC), Issue 1 2009Ying Liu Abstract The insect fat body is an organ analogue to vertebrate adipose tissue and liver and functions as a major organ for nutrient storage and energy metabolism. Similar to other larval organs, fat body undergoes a developmental "remodeling" process during the period of insect metamorphosis, with the massive destruction of obsolete larval tissues by programmed cell death and the simultaneous growth and differentiation of adult tissues from small clusters of progenitor cells. Genetic ablation of Drosophila fat body cells during larval-pupal transition results in lethality at the late pupal stage and changes sizes of other larval organs indicating that fat body is the center for pupal development and adult formation. Fat body development and function are largely regulated by several hormonal (i.e. insulin and ecdysteroids) and nutritional signals, including oncogenes and tumor suppressors in these pathways. Combining silkworm physiology with fruitfly genetics might provide a valuable system to understand the mystery of hormonal regulation of insect fat body development and function. © 2009 Wiley Periodicals, Inc. [source] Occupational sunlight exposure and risk of renal cell carcinoma,,CANCER, Issue 8 2010Sara Karami PhD Abstract BACKGROUND: Recent findings indicate that vitamin D obtained from ultraviolet (UV) exposure may reduce the risk of several different cancers. Vitamin D is metabolized to its active form within the kidney, which is the major organ for vitamin D metabolism and activity. Because both the incidence of renal cell carcinoma (RCC) and the prevalence of vitamin D deficiency have increased over the past few decades, in the current study, the authors explored whether occupational UV exposure was associated with RCC risk. METHODS: A hospital-based, case-control study of 1097 patients with RCC (cases) and 1476 controls was conducted in 4 Central and Eastern European countries. Demographic and occupational information was collected to examine the association between occupational UV exposure and RCC risk. RESULTS: A significant reduction (24%-38%) in the risk of RCC was observed with increasing occupational UV exposure among men who participated in the study. No association between UV exposure and RCC risk was observed among women who participated. When the analyses were stratified by latitude as another estimate of sunlight intensity, a stronger reduction (71%-73%) in the risk of RCC was observed between UV exposure and cancer risk among men who resided at the highest latitudes. CONCLUSIONS: The current results suggested that, among men, there is an inverse association between occupational UV exposure and the risk of RCC. Replication studies are warranted to confirm these results. Cancer 2010. Published 2010 by the American Cancer Society. [source] Oral bioavailability and toxicokinetics of 3,3,,4,4,,5-pentachlorobiphenyl in northern leopard frogs, Rana pipiensENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2000Yue-wern Huang Abstract This study is the first report on oral bioavailability, whole-body elimination, and distribution of a specific polychlorinated biphenyl (PCB) congener on an amphibian species, northern leopard frogs. Each frog was orally dosed once with either 0.35 or 5.0 mg/kg PCB 126 (based on frog wet wt), including tracer 14C-PCB 126 (3,,4,,5,-phenyl-ring- 14C) by force feeding it a cricket injected with the PCB. We found no statistical difference (t = 0.917, df = 5, p = 0.401) in the average 48-h oral bioavailabilities of 0.35- and 5.0-mg/kg dosage groups, which were 84.6 ± 5.8% (mean ± SE, n = 4) and 90.9 ± 1.5% (n = 3), respectively. Statistical analysis indicated that time was the only independent variable affecting the retention of whole-body 14C content. Kinetics were apparently first order because elimination rate was independent of dose. Assuming a single pool and one elimination rate, the t1/2 value for whole-body elimination of PCB-derived 14C was 763 d. Liver, fat bodies (corpora adiposa), carcass (head, bone, cartilage materials, and residues of other tissues), skin, and muscle were the major organs for PCB 126 retention in both dosage groups. The concentrations of 14C residue in fat bodies were relatively constant throughout the experiment. However, total residues in fat bodies declined throughout the experiment in both dosage groups in correlation with declining masses of fat bodies. Gonad, kidney, stomach, intestine, and a tissue pool including esophagus, lung, spleen, heart, and cloacal materials each accumulated <1% of the initial total 14C residue. The egg follicles in 19 females contained 1 to 23% of the initial total 14C residue, with an average of 10.0 ± 9.2% (mean ± SE, n = 19). [source] Xylem root and shoot hydraulics is linked to life history type in chaparral seedlingsFUNCTIONAL ECOLOGY, Issue 1 2010Robert B. Pratt Summary 1.,Shrubs in fire prone chaparral communities have evolved different life history types in response to fire. A key to understanding the evolution of life history type differences is to understand how physiological traits are linked to differences in life history type. Vascular adaptations are important for delivering an efficient and stable water supply to evergreen chaparral shrub leaves. This study tested for a link between vascular physiology and life history type in chaparral shrubs. 2.,Chaparral shrub species along the south-western coast of North America survive wildfire by three different life histories. Non-sprouters are killed by fire and re-establish exclusively through germination of fire-stimulated seeds, facultative sprouters re-establish by a combination of vegetative sprouting and fire-stimulated seeds, and obligate sprouters re-establish exclusively by vegetative sprouting because their seeds do not survive fire. Non-sprouters and facultative sprouters establish seedlings in the open canopy post fire environment, whereas obligate sprouters establish seedlings in the shady understory of the mature chaparral canopy. 3.,Seedlings of nine species (Rhamnaceae) representing three each of the different life history types were grown in deep containers in a common garden under treatments of sun and shade. Hydraulic conductance was measured using a high-pressure flow meter for all organs, and a vacuum technique was used to measure conductance of fine and woody roots. We predicted that non-sprouters would exhibit greater hydraulic efficiency than the sprouting species, and that facultative sprouters would be more efficient than the shade tolerant obligate sprouters. 4.,Non-sprouters had the greatest hydraulic conductance per unit leaf and sapwood area at the whole seedling level, whereas facultative and obligate sprouters were not different. Comparing hydraulic conductance across major organs (from fine roots to leaves) showed that the hydraulic system was well coordinated. At the whole seedling level, the root system was more of a bottleneck than the shoot system. This pattern was consistent with high resistance extraxylary pathways in roots and differences in root architecture. 5.,The greater hydraulic efficiency of the non-sprouter life history type is attributed to its post-fire pioneering habit and may partially explain the relatively high speciation in the non-sprouters. Lower hydraulic efficiency is associated with a sprouting life history and greater shade tolerance. The seedling root systems represent a hydraulic bottleneck that may place roots under especially intense selection. [source] Near-Infrared Mesoporous Silica Nanoparticles for Optical Imaging: Characterization and In Vivo BiodistributionADVANCED FUNCTIONAL MATERIALS, Issue 2 2009Chia-Hung Lee Abstract The characterization of near-infrared (NIR) mesoporous silica nanoparticles (MSN) suitable for in vivo optical imaging with high efficiency is presented. Trimethylammonium groups modified MSN (MSN-TA) with the average size of 50,100,nm was synthesized with incorporation of the TA groups into the framework of MSN. It was further adsorbed with indocyanine green (ICG) by electrostatic attraction to render MSN-TA-ICG as an efficient NIR contrast agent for in vivo optical imaging. The studies in stability of MSN-TA-ICG against pH indicated the bonding is stable over the range from acidic to physiological pH. The in vivo biodistribution of MSN-TA-ICG in anesthetized rat demonstrated a rather strong and stable fluorescence of MSN-TA-ICG that prominent in the organ of liver. Transmission electron microscopy (TEM) imaging and elemental analysis of silicon further manifested the physical and quantitative residences of MSN-TA-ICG in major organs. This is the first report of MSN functionalized with NIR-ICG capable of optical imaging in vivo. [source] Haematological, hepatic and renal alterations after repeated oral or intraperitoneal administration of monoisoamyl DMSA.JOURNAL OF APPLIED TOXICOLOGY, Issue 6 2002Abstract Monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA), a vicinal thiol chelator, is gaining recognition recently as a better chelator than meso 2,3-dimercaptosuccinic acid (DMSA) in decreasing heavy metal burden in tissues because of its lipophilic character. There is, however, little information available on the toxicological properties of this chelator after repeated administration in animals. In the present study, we investigated the dose-dependent effect of MiADMSA on various biochemical parameters suggestive of alterations in haem biosynthesis and hepatic, renal and brain oxidative stress after 21 days of repeated intraperitoneal (i.p.) or oral (p.o.) administration to rats. The concentration of essential metals in blood and soft tissues was determined along with histopathological observations of hepatic and renal tissues. The results suggest that MiADMSA administration had no effect on blood ,-aminolevulinic acid dehydratase activity. However, an increase in zinc protoporphyrin and a decrease in haemoglobin levels were noted in animals given MiADMSA i.p. A moderate increase in serum alkaline phosphatase suggested mild hepatotoxicity at the highest dose (100 mg kg,1, i.p.). This was confirmed by histopathological examinations, which identified basophilic stippling, granulation of the cytoplasm, haemorrhage and congestion. At the highest dose, levels of hepatic thiobarbituric acid reactive substance and oxidized glutathione were increased above those of control values. Levels of hepatic reduced glutathione were decreased. Taken together, these observations point to oxidative stress. In animals administered MiADMSA i.p. there was an increase in the brain malondialdehyde levels at the two higher doses (50 and 100 mg kg,1). Essential metal status revealed a significant effect of MiADMSA (p.o.) in increasing blood zinc while significantly decreasing the kidney zinc level. The most significant adverse effect of MiADMSA was on copper concentration, which showed significant depletion from almost all major organs. Magnesium levels in blood decreased but increased in liver of MiADMSA-administered rats. Histopathological observations of liver and kidneys suggest few moderate lesions. It can be concluded that repeated administration of MiADMSA is compromised with some mild toxic effect, particularly the loss of copper. The effects during oral administration are comparatively less pronounced than by the i.p. route. Copyright © 2002 John Wiley & Sons, Ltd. [source] Subchronic toxicity of chloral hydrate on rats: a drinking water studyJOURNAL OF APPLIED TOXICOLOGY, Issue 4 2002R. Poon Abstract The subchronic toxicity of chloral hydrate, a disinfection byproduct, was studied in rats following 13 weeks of drinking water exposure. Male (262 ± 10 g) and female (190 ± 8 g) Sprague-Dawley rats, ten animals per group, were administered chloral hydrate via drinking water at 0.2, 2, 20 and 200 ppm. Control animals received distilled water only. Gross and microscopic examinations, serum chemistry, hematology, biochemical analysis, neurogenic amine analysis and serum trichloroacetic acid (TCA) analysis were performed at the end of the treatment period. Bronchoalveolar fluids were collected at necropsy and urine specimens were collected at weeks 2, 6 and 12 for biochemical analysis. No treatment-related changes in food and water intakes or body weight gains were observed. There were no significant changes in the weights of major organs. Except for a mild degree of vacuolation within the myelin sheath of the optic nerves in the highest dose males, there were no notable histological changes in the tissues examined. Statistically significant treatment-related effects were biochemical in nature, with the most pronounced being increased liver catalase activity in male rats starting at 2 ppm. Liver aldehyde dehydrogenase (ALDH) was significantly depressed, whereas liver aniline hydroxylase activity was significantly elevated in both males and females receiving the highest dose. A dose-related increase in serum TCA was detected in both males and females starting at 2 ppm. An in vitro study of liver ALDH confirmed that chloral hydrate was a potent inhibitor, with an IC50 of 8 µM, whereas TCA was weakly inhibitory and trichloroethanol was without effect. Analysis of brain biogenic amines was conducted on a limited number (n = 5) of male rats in the control and high dose groups, and no significant treatment-related changes were detected. Taking into account the effect on the myelin sheath of male rats and the effects on liver ALDH and aniline hydroxylase of both males and females at the highest dose level, the no-observed-effect level (NOEL) was determined to be 20 ppm or 1.89 mg kg,1 day,1 in males and 2.53 mg kg,1 day,1 in females. This NOEL is ca. 1000-fold higher than the highest concentration of chloral hydrate reported in the municipal water supply. Copyright © 2002 Crown in the right of Canada. Published by John Wiley & Sons, Ltd. [source] FRNK, the autonomously expressed C-terminal region of focal adhesion kinase, is uniquely regulated in vascular smooth muscle: Analysis of expression in transgenic miceJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2005Haruko Hayasaka Abstract FRNK, the autonomously expressed carboxyl-terminal region of focal adhesion kinase (FAK), is expressed in tissues that are rich in vascular smooth muscle cells (VSMCs). Here we report the generation of transgenic mice harboring the putative FRNK promoter fused to LacZ and examine the promoter activity in situ via expression of ,-galactosidase. The transgenic mice exhibited expression of ,-galactosidase predominantly in arterial VSMCs in large and small blood vessels of major organs. Upregulation of ,-galactosidase activity was observed in tunica media following carotid injury, indicating that the FRNK promoter is activated in VSMCs in response to injury. Robust expression of ,-galactosidase in blood vessels was also detected in the developing embryo. However, expression was also observed in the midline, the nose and skin epidermis, indicating distinct transcriptional regulation of the FRNK promoter in embryogenesis. To analyze FRNK expression in vitro, we identified a 116 bp sequence in the FRNK promoter that was sufficient to function as an enhancer when fused to the minimal actin promoter and expressed in cultured smooth muscle cells. Mutation of AP-1 and NF-E2 binding consensus sequences within this element abrogated enhancer activity, supporting the involvement of this promoter element in VSMC expression of FRNK. © 2005 Wiley-Liss, Inc. [source] Chronic Ethanol-Induced Insulin Resistance Is Associated With Macrophage Infiltration Into Adipose Tissue and Altered Expression of AdipocytokinesALCOHOLISM, Issue 9 2007Li Kang Background:, Chronic ethanol consumption disrupts glucose homeostasis and is associated with the development of insulin resistance. While adipose tissue and skeletal muscle are the two major organs utilizing glucose in response to insulin, the relative contribution of these two tissues to impaired glucose homeostasis during chronic ethanol feeding is not known. As other models of insulin resistance, such as obesity, are characterized by an infiltration of macrophages into adipose tissue, as well as changes in the expression of adipocytokines that play a central role in the regulation of insulin sensitivity, we hypothesized that chronic ethanol-induced insulin resistance would be associated with increased macrophage infiltration into adipose tissue and changes in the expression of adipocytokines by adipose tissue. Methods:, Male Wistar rats were fed a liquid diet containing ethanol as 36% of calories or pair-fed a control diet for 4 weeks. The effects of chronic ethanol feeding on insulin-stimulated glucose utilization were studied using the hyperinsulinemic-euglycemic clamp technique, coupled with the use of isotopic tracers. Further, macrophage infiltration into adipose tissue and expression of adipocytokines were also assessed after chronic ethanol feeding. Results:, Hyperinsulinemic-euglycemic clamp studies revealed that chronic ethanol feeding to rats decreased whole-body glucose utilization and decreased insulin-mediated suppression of hepatic glucose production. Chronic ethanol feeding decreased glucose uptake in epididymal, subcutaneous, and omental adipose tissue during the hyperinsulinemic-euglycemic clamp, but had no effect on glucose disposal in skeletal muscle. Chronic ethanol feeding increased the infiltration of macrophages into epididymal adipose tissue and changed the expression of mRNA for adipocytokines: expression of mRNA for monocyte chemoattractant protein 1, tumor necrosis factor ,, and interleukin-6 were increased, while expression of mRNA for retinol binding protein 4 and adiponectin were decreased in epididymal adipose tissue. Conclusions:, These data demonstrate that chronic ethanol feeding results in the development of insulin resistance, associated with impaired insulin-mediated suppression of hepatic glucose production and decreased insulin-stimulated glucose uptake into adipose tissue. Chronic ethanol-induced insulin resistance was associated with increased macrophage infiltration into adipose tissue, as well as changes in the expression of adipocytokines by adipose tissue. [source] Inhibition of the progression of type 2 diabetes in the C57BL/6J mouse model by an anti-diabetes herbal formulaPHYTOTHERAPY RESEARCH, Issue 6 2003Wendell D. Winters Abstract The effects of a speci,cally prepared anti-diabetic herbal formula (ADHF) on the course of established diet-induced type 2 diabetes in animal subjects has been studied. In a C57BL/6J mouse model for diet induced type 2 diabetes, intervention for 12 weeks using ADHF as a diet supplement resulted in a signi,cant inhibition of diabetes related changes in major organs usually targeted by type 2 diabetes and a signi,cant reduction in circulating levels of glucose and insulin. Young male mice were randomly assigned to receive ad libitum exposure to either a standard rodent chow diet or to a high fat, high simple sugar, low ,bre diet (diabetes induction diet), respectively for 8 weeks. All mice fed the induction diet developed abnormally high blood glucose levels at 8 weeks. Animals with con,rmed diet induced diabetic blood glucose levels were again randomly assigned into one of three groups (10 subjects per group), one group was thereafter fed only the diabetes induction diet and the other two groups were thereafter fed the diabetes induction diet into which ADHF had been mixed at 4% or at 8% ,nal concentrations. Normal mice were also randomized into two groups that were fed either a regular diet alone or 8% ADHF mixed in the regular diet. Blood glucose levels markedly increased over the 20 weeks of study in the diabetic mice fed the diabetes induction diet only. In contrast, diabetic mice fed induction diet into which 4% or 8% ADHF had been incorporated showed signi,cantly decreased blood glucose and insulin levels over the time of the study. Additional parameters signi,cantly reduced in diabetic mice fed ADHF included insulin resistance and histopathological changes in the pancreas and liver. This is the ,rst report to our knowledge to show in vivo evidence for signi,cantly decreased circulating glucose and insulin levels and a signi,cant reduction of progressive damage to major target organs by the addition of an herbal diet supplement to a diabetes induction diet proven to be capable of causing and maintaining type 2 diabetes. Copyright © 2003 John Wiley & Sons, Ltd. [source] Transfer of maternally administered fusogenic liposome-DNA complexes into monkey fetuses in a pregnancy modelTHE JOURNAL OF GENE MEDICINE, Issue 5 2002Makoto Hirano Abstract Background Materno-fetal transfer of intravenously administered liposome-plasmid DNA complexes has been demonstrated only in mice. Studies on its materno-fetal transfer in the pregnant monkey model is needed because of critical differences in placental structure between primates including humans and rodents. Methods The reporter plasmid pEGFP-C1 was formulated in cationic lipid containing polybrene and vesicular stomatitis virus G protein. The fusogenic liposome-plasmid DNA complexes were intradermally injected into pregnant common marmosets (N=2), a New World monkey, near term. DNA extracted from fetal tissues was subjected to PCR for detection of the egfp gene. Confocal microscopy and immunostaining were performed to determine the sites of transgene expression in the fetal organs. Results The egfp gene was detected in fetal blood and major organs (heart, liver, lung). The encoded protein was mainly produced in the endothelial cells of blood vessels in the fetal lungs. Conclusions This is the first report on materno-fetal transfer of intradermally administered fusogenic liposome-plasmid DNA complexes and fetal expression of a transgene in primates. Copyright © 2002 John Wiley & Sons, Ltd. [source] Development of a Disposable Magnetically Levitated Centrifugal Blood Pump (MedTech Dispo) Intended for Bridge-to-Bridge Applications,Two-Week In Vivo EvaluationARTIFICIAL ORGANS, Issue 9 2010Eiki Nagaoka Abstract Last year, we reported in vitro pump performance, low hemolytic characteristics, and initial in vivo evaluation of a disposable, magnetically levitated centrifugal blood pump, MedTech Dispo. As the first phase of the two-stage in vivo studies, in this study we have carried out a 2-week in vivo evaluation in calves. Male Holstein calves with body weight of 62.4,92.2 kg were used. Under general anesthesia, a left heart bypass with a MedTech Dispo pump was instituted between the left atrium and the descending aorta via left thoracotomy. Blood-contacting surface of the pump was coated with a 2-methacryloyloxyethyl phosphorylcholine polymer. Post-operatively, with activated clotting time controlled at 180,220 s using heparin and bypass flow rate maintained at 50 mL/kg/min, plasma-free hemoglobin (Hb), coagulation, and major organ functions were analyzed for evaluation of biocompatibility. The animals were electively sacrificed at the completion of the 2-week study to evaluate presence of thrombus inside the pump, together with an examination of major organs. To date, we have done 13 MedTech Dispo implantations, of which three went successfully for a 2-week duration. In these three cases, the pump produced a fairly constant flow of 50 mL/Kg/min. Neurological disorders and any symptoms of thromboembolism were not seen. Levels of plasma-free Hb were maintained very low. Major organ functions remained within normal ranges. Autopsy results revealed no thrombus formation inside the pump. In the last six cases, calves suffered from severe pneumonia and they were excluded from the analysis. The MedTech Dispo pump demonstrated sufficient pump performance and biocompatibility to meet requirements for 1-week circulatory support. The second phase (2-month in vivo study) is under way to prove the safety and efficacy of MedTech Dispo for 1-month applications. [source] Positron emission tomography of [18F]-big endothelin-1 reveals renal excretion but tissue-specific conversion to [18F]-endothelin-1 in lung and liverBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2010Peter Johnström Background and purpose:, Big endothelin-1 (ET-1) circulates in plasma but does not bind to ET receptors until converted to ET-1 by smooth muscle converting enzymes. We hypothesized that tissue-specific conversion of [18F]-big ET-1 to [18F]-ET-1 could be imaged dynamically in vivo within target organs as binding to ET receptors. Methods:, [18F]-big ET-1 conversion imaged in vivo following infusion into rats using positron emission tomography (PET). Key results:, [18F]-big ET-1 was rapidly cleared from the circulation (t1/2= 2.9 ± 0.1 min). Whole body microPET images showed highest uptake of radioactivity in three major organs. In lungs and liver, time activity curves peaked within 2.5 min, then plateaued reaching equilibrium after 10 min, with no further decrease after 120 min. Phosphoramidon did not alter half life of [18F]-big ET-1 but uptake was reduced in lung (42%) and liver (45%) after 120 min, consistent with inhibition of enzyme conversion and reduction of ET-1 receptor binding. The ETA antagonist, FR139317 did not alter half-life of [18F]-big ET-1 (t1/2= 2.5 min) but radioactivity was reduced in all tissues except for kidney consistent with reduction in binding to ETA receptors. In kidney, however, the peak in radioactivity was higher but time to maximum accumulation was slower (,30 min), which was increased by phosphoramidon, reflecting renal excretion with low conversion and binding to ET receptors. Conclusions and implications:, A major site for conversion was within the vasculature of the lung and liver, whereas uptake in kidney was more complex, reflecting excretion of [18F]-big ET-1 without conversion to ET-1. This article is part of a themed section on Imaging in Pharmacology. To view the editorial for this themed section visit http://dx.doi.org/10.1111/j.1476-5381.2010.00685.x [source] Oligonucleotide N3,,P5, Phosphoramidates and Thio -Phoshoramidates as Potential Therapeutic AgentsCHEMISTRY & BIODIVERSITY, Issue 3 2010Sergei Abstract Nucleic acids analogues, i.e., oligonucleotide N3,,P5, phosphoramidates and N3,,P5, thio -phosphoramidates, containing 3,-amino-3,-deoxy nucleosides with various 2,-substituents were synthesized and extensively studied. These compounds resist nuclease hydrolysis and form stable duplexes with complementary native phosphodiester DNA and, particularly, RNA strands. An increase in duplexes' melting temperature, ,Tm, relative to their phosphodiester counterparts, reaches 2.2,4.0° per modified nucleoside. 2,-OH- (RNA-like), 2,- O -Me-, and 2,- ribo -F-nucleoside substitutions result in the highest degree of duplex stabilization. Moreover, under close to physiological salt and pH conditions, the 2,-deoxy- and 2,-fluoro-phosphoramidate compounds form extremely stable triple-stranded complexes with either single- or double-stranded phosphodiester DNA oligonucleotides. Melting temperature, Tm, of these triplexes exceeds Tm values for the isosequential phosphodiester counterparts by up to 35°. 2,-Deoxy-N3,,P5, phosphoramidates adopt RNA-like C3,- endo or N -type nucleoside sugar-ring conformations and hence can be used as stable RNA mimetics. Duplexes formed by 2,-deoxy phosphoramidates with complementary RNA strands are not substrates for RNase H-mediated cleavage in vitro. Oligonucleotide phosphoramidates and especially thio -phosphoramidates conjugated with lipid groups are cell-permeable and demonstrate high biological target specific activity in vitro. In vivo, these compounds show good bioavailability and efficient biodistribution to all major organs, while exerting acceptable toxicity at therapeutically relevant doses. Short oligonucleotide N3,,P5, thio -phosphoramidate conjugated to 5,-palmitoyl group, designated as GRN163L (Imetelstat), was recently introduced as a potent human telomerase inhibitor. GRN163L is not an antisense agent; it is a direct competitive inhibitor of human telomerase, which directly binds to the active site of the enzyme and thus inhibits its activity. This compound is currently in multiple Phase-I and Phase-I/II clinical trials as potential broad-spectrum anticancer agent. [source] Early-onset Group B streptococcal sepsis in a preterm infant with Kostmann syndromeACTA PAEDIATRICA, Issue 12 2002T Fujiu A preterm infant died of group B streptococcal sepsis 7 h after birth. The infant's complete blood count showed total agranulocytosis. Histopathology of the major organs showed significant bacterial invasion without infiltration of polymorphonuclear leucocytes. Examination of the bone marrow revealed normal cellularity of the granulocyte precursors with arrested maturation. These findings are consistent with Kostmann syndrome. Conclusion: It is suggested that in patients with deteriorating early-onset infection, underlying congenital abnormalities in host defence, such as Kostmann syndrome, should be considered. [source] | ||||||||||||||||