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PubMed1983

Structure-activity relationships in kynurenine, diazepam and some putative endogenous ligands of the benzodiazepine receptors.

Kynurenine, an endogenous cerebral and peripheral neuroactive metabolite of 1-tryptophan, exerts stimulant and convulsant effects in mice, rats and frogs. In mice it (intracerebroventricularly, ICV) antagonized the anticaffeine effect of diazepam and in smaller doses potentiated its sedative action. In rats 1-kynurenine (ICV) potentiated the convulsant action of caffeine. The effect of pentylenetetrazol was not altered in either species. The convulsant effect of 1-kynurenine is the most resistant among various convulsants towards the protective action of diazepam. The structure of 1-kynurenine is similar to benzophenones, metabolites of diazepam, and has four structural fragments common with diazepam. Putative endogenous and non-endogenous ligands of the benzodiazepine receptors have from one to three of these common fragments. Among the antagonists of diazepam exhibiting stimulant and convulsant action ethyl-beta-carboline-3-carboxylate has the same four fragments, Ro 5-3663 and Ro 15-1788 have three and caffeine two. The most striking dissimilarity is a diazo-moiety (N-C-C-N or N-C=C-C=N) absent in the structure of 1-kynurenine. This moiety seems to be the most important for the binding to the benzodiazepine receptors. A role of each fragment and their combinations as well as the stereoconfiguration for the pharmacological activity is considered. It is suggested that 1-kynurenine is a putative endogenous modulator or, less probably, ligand of the benzodiazepine receptor of either type (most probably that which mediates anxiolytic action of benzodiazepines) or a part of this receptor. The benzodiazepine receptor might be a phylogenetically transformed kynurenine receptor. Highly selective antagonism of purines to 1-kynurenine suggests that it can modulate the function of the benzodiazepine receptors via purinergic mechanisms. Stimulant and convulsant action of 1-kynurenine can be related to a moiety of succinic acid (O=C-C-C-C=O) which is typical of quinolinic acid, the strongest endogenous convulsant among kynurenines, and aspartic acid, an excitatory amino acid. 1-Kynurenine is suggested to be an anxiogenic and convulsigenic endogenous factor.

Animals↗
PubMed1995

Influence of culture conditions on biofilm formation by Escherichia coli O157:H7.

Biofilms of Escherichia coli O157:H7 were developed on stainless steel chips in trypticase soy broth (TSB), 1/5 dilution of TSB, 0.1% Bacto peptone (BP) and a minimal salts medium (MSM) supplemented with 0.04% of one of the following carbon sources: glucose, glycerol, lactose, mannose, succinic acid, sodium pyruvate or lactic acid. It was found that biofilms developed faster and a higher number of adherent cells (ca. 10(6) CFU/cm2) were recovered when the organisms were grown in the low nutrient media. Regardless of the carbon source, biofilms developed in MSM consisted of shorter bacterial cells and thicker extracellular matrix (ECM), with glucose as the best substrate for stable biofilm formation. Fewer bacteria in initial attachment, non-hydrophobicity of bacterial cells, lack of ECM formation and easy detachment of the biofilm bacteria may contribute to poor biofilm formation in TSB. ECM is probably important for the stability of biofilms; however, at 10 degrees C and under anaerobic conditions, ECM seems to be unnecessary.

Anaerobiosis↗
PubMed1995

Buffer composition mediates a switch between cooperative and independent binding of an initiator protein to DNA.

The regulation of many biological processes, including DNA replication, is frequently achieved by protein-protein interactions, as well as protein-DNA interactions. Multiple protein-binding sites are often involved. For example, the replication of plasmid R6K involves binding of the initiator protein pi to seven 22-bp direct repeats (DR) in the gamma origin of replication (gamma ori). A mutant protein pi S87N has been isolated, that in Tris.borate buffer (TB) binds cooperatively to seven DR, whereas wild-type (wt) pi binds independently [Filutowicz et al., Nucleic Acids Res. 22 (1994) 4211-4215]. Surprisingly, we found that wt pi can also bind cooperatively when Tris.acetate (TA), Tris.succinate or Tris.glutamate buffers are used instead of TB. The cooperative binding of the wt pi protein was also observed in the TB buffer at high concentrations of Na2EDTA. These results suggest that pi may be able to assume two functionally distinct conformations as a result of either mutation or buffer composition. Moreover, we found that the mode of pi binding is determined not by the composition of the buffer in which the reaction was assembled, but by the composition of the electrophoresis buffer. We discuss the general implications of these findings.

Acetates↗
PubMed1993

Bioaccumulative potential and toxicity of endosulfan insecticide to non-target animals.

1. Endosulfan insecticide is a polychlorinated compound used for controlling a variety of insects; it is practically water-insoluble, but readily adheres to clay particles and persists in soil and water for several years. Its mode of action involves repetitive nerve-discharges positively correlated to increase in temperature. This compound is extremely toxic to most fish and can cause massive mortalities. In fish, it causes marked changes in Na and K concentrations, decrease in blood Ca(2+) and Mg levels and inhibits Na, K and Mg-dependent ATPase (in brain). 2. Bioaccumulation of endosulfan is reported for marine animals; however, freshwater animals (e.g., crayfish) accumulate it to some extent, but they lose the compound rapidly during depuration. Endosulfan is generally less toxic to aquatic invertebrates than fish. However, it causes decreases in adenylate energy charge, oxygen consumption, hemolymph amino acids, succinate dehydrogenase, heart-beat (mussel) and altered osmoregulation. 3. Generally, mammals are less susceptible to endosulfan's toxicity than aquatic animals. The majority of studies conducted on laboratory mammals can be summarized. (a) Neurotoxicity: male rats are more sensitive than females to endosulfan, which decreases brain and plasma acetylcholinesterase activity. Endosulfan I (a metabolite) causes a significant change in norepinephrine, 5-HT and GABA. (b) Renal toxicity: inhibition of MFOs activity was noticed in rats; other effects included changes in proximal convoluted tubules and necrosis of the tubular epithelium. (c) Hepatotoxicity: chemically-induced aminopyrine N-demethylase and aniline hydrolase were found in rat liver, and reduction in the glycogen level occurred. (d) Hematologic toxicity: endosulfan exposure resulted in a significant decrease in the level occurred. (d) Hematologic toxicity: endosulfan exposure resulted in a significant decrease in the erythrocyte glutathione reductase, hemoglobin amount, RBC number and mean corpuscular volume. 4. Respiratory toxicity: involved dyspnea, acute emphysema, cyanosis and hemorrhages in teh interalveolar portions of rat's lungs. 5. Biochemical: in rats, endosulfan caused increased glucose-6-phosphate dehydrogenase activity, blood glucose level, phospholipid contents of the microsomal and surfactant system, and profoundly induced the activity of alcohol dehydrogenase and cytosolic glutathione S-transferases. It also decreased significantly Na+, K+ and Mg(2+) ATPases, plasma calcium level and alkaline phosphatase in the intestinal epithelium. 6. Immunologic toxicity: rat serum antibody titer to tetanus toxin, IgG, IgM and gammaglobulins were significantly reduced. 7. Reproductive toxicity: degenerative changes in the seminiferous epithelium, induction of the rate-limiting enzyme in testosterone production (3beta-hydroxysteroid transferase and 17 beta-hydroxysteroid transferase), histological changes in reproductive organs, testicular atrophy and the occurrence of ovarian cysts were noticed in rat. Reduction in the weight of secondary sex organ was also observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Application of high affinity binding concept to radiolabel avidin with Tc-99m labeled biotin and the effect of pI on biodistribution.

In order to label avidin with Tc-99m, we took advantage of the high affinity binding of biotin to avidin; we radiolabeled a biotin derivative with Tc-99m and then bound this Tc-99m labeled biotin derivative to avidin. For our labeling approach, N epsilon-biotinyl-L-lysine (Biocytin) was reacted with the N-hydroxy-succinimide ester of benzoylmercaptoacetyltriglycine (Bz-MAG3). The resulting Bz-MAG3-Biocytin was labeled with Tc-99m using Tc-99m glucarate as a Tc-99m transchelating agent and mixed with avidin at a 1:1 molar ratio resulting in almost a quantitative labeling yield. Tc-99m-MAG3-Biocytin/Avidin was stable in serum at 37 degrees C with 97 and 95% of the total Tc-99m activity still bound to avidin at 2 and 24 h, respectively. The biodistribution of Tc-99m-MAG3-Biocytin/Avidin in normal Balb/c mice showed a high liver and kidney uptake with 56.6 and 28.9%, respectively at 10 min. We attempted to lower the liver and the kidney activities by reducing the isoelectric point (pI) of avidin by conjugating succinic acid moieties at lysine residues of avidin (pI 10). The kidney uptake decreased to 19.0, 3.1 and 1.7% when the pI of avidin was reduced to 7.0-9.3, 5.5-6.2 and 4.0-4.8, respectively. The lowering of the pI, however, did not change the liver activity appreciably.

Animals↗
PubMed2025

Genome-wide gene-sleep interaction study identifies novel lipid loci in 732,564 participants.

BACKGROUND AND AIMS: Deviations from the population mean in sleep duration have been associated with increased risk for developing dyslipidemia and atherosclerotic cardiovascular disease, but the mechanism of effect is poorly characterized. We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. METHODS: We collected data from 55 cohorts with a combined sample size of 732,564 participants (87&#xa0;% European ancestry) with data on lipid traits (high-density lipoprotein [HDL-c] and low-density lipoprotein [LDL-c] cholesterol and triglycerides [TG]). Short (STST) and long (LTST) total sleep time were defined by the extreme 20&#xa0;% of the age- and sex-standardized values within each cohort. Based on cohort-level summary statistics data, we performed meta-analyses for one-degree of freedom tests of interaction and two-degree of freedom joint tests of the SNP-main and -interaction effect on lipid levels. RESULTS: The one-degree of freedom variant-sleep interaction test identified 10 novel loci (Pint<5.0e-9), and we additionally identify 7 loci within the two-degree of freedom analyses (Pjoint<5.0e-9 in combination with Pint<6.6e-6). Multiple loci, including those mapped to APSH (target for aspartic and succinic acid) and SLC8A1 showed biological plausibility and druggability potential based on literature. CONCLUSIONS: Collectively, the 17 (9 with short and 8 with long sleep) loci provided evidence into the biomolecular mechanisms underlying sleep-associated lipid changes, including potential involvement of the vitamin D receptor pathway. Collectively, these findings may contribute developing novel interventions for treating dyslipidemia in people with sleep disturbances.

Humans↗
PubMed2004

In situ polymerizable polyethyleneglycol containing polyesterpolyol acrylates for tissue sealant applications.

Polyesterpolyol macromers were prepared with succinic acid and polyethylene glycols (PEG) of different molecular weights. The resulting polyols were acrylated to render them photo-cross-linkable. They could be very rapidly cross-linked into non-tacky films with long-wavelength UV radiation. The resulting products were characterized by gel content, water equilibrium swell, cross-link density, Tg , tensile strength, degradation and in vitro burst strengths. Though all of them formed transparent contact lens like films, increasing the PEG molecular weight has resulted in polymers with higher hydrophilicity resulting in higher swelling, faster degradation, higher tensile strength, elongation at break and burst strength. Addition of vinyl pyrrolidinone as a reactive diluent has increased the mechanical as well as burst strength of the polymer. In vitro release of sulfamethoxazole entrapped in these cross-linked matrices was also studied.

Acrylates↗
PubMed2005

New leads of metallo-beta-lactamase inhibitors from structure-based pharmacophore design.

We have applied pharmacophore generation, database searching, docking methodologies, and experimental enzyme kinetics to discover new structures for design of di-zinc metallo-beta-lactamase inhibitors. Based on crystal structures of class B1 metallo-beta-lactamases with a succinic acid and a mercapto-carboxylic acid inhibitor bound to the enzyme, two pharmacophore models were constructed. With the Catalyst program, these pharmacophores were used to search the ACD database, which provided a total of 74 hits representing four different chemical classes of compounds: Dicarboxylic acids, phosphonic and sulfonic acid derivatives, and mercapto-carboxylic acids. All hits were docked into different metallo-beta-lactamases (from classes B1 and B3) using the GOLD docking program. A selection scheme based on the GOLD scores, the Catalyst fit and shape values, and the size of the compounds (molecular weight, surface area, and number of rotatable bonds) was developed and thirteen compounds representing all four chemical classes were selected for experimental studies. Three compounds with new scaffolds hitherto not present in metallo-beta-lactamase inhibitors have IC50 values less than 15 microM and may serve as starting points in the design of metallo-beta-lactamase inhibitors.

Enzyme Inhibitors↗
PubMed2005

The synthesis and aqueous superoxide anion scavenging of water-dispersible lutein esters.

Xanthophyll carotenoids of the C40 series, which includes commercially important compounds such as lutein, zeaxanthin, and astaxanthin, have poor aqueous solubility in the native state. Hawaii Biotech, Inc. (HBI) and others have shown that the aqueous dispersibility of derivatized carotenoids can be increased by varying the chemical structure of the esterified moieties. In the current study, the published series of novel, highly water-dispersible C40 carotenoid derivatives has been extended to include (3R,3'R,6'R)-lutein (beta,epsilon-carotene-3,3'-diol) derivatives. Two novel derivatives were synthesized by esterification with inorganic phosphate and succinic acid, respectively, and subsequently converted to the sodium salts. Red-orange, clear, aqueous suspensions were obtained after addition of these novel derivatives to USP-purified water. Aqueous dispersibility of the disuccinate sodium salt of lutein was 2.85 mg/mL; the diphosphate salt demonstrated a >10-fold increase in dispersibility at 29.27 mg/mL. As reported previously, these aqueous suspensions were obtained without the addition of heat, detergents, co-solvents, or other additives. The direct aqueous superoxide scavenging abilities of these novel derivatives were subsequently evaluated by electron paramagnetic resonance (EPR) spectroscopy in a well-characterized in vitro isolated human neutrophil assay. The novel derivatives were nearly identical aqueous-phase scavengers, demonstrating dose-dependent suppression of the superoxide anion signal (as detected by spin-trap adducts of DEPMPO) in the millimolar range. These lutein-based soft drugs will likely find utility in those commercial and clinical applications for which aqueous-phase singlet oxygen quenching and direct radical scavenging may be required.

Anions↗
PubMed2006

Factor VIIa inhibitors: a prodrug strategy to improve oral bioavailability.

We have developed a series of potent and selective factor VIIa inhibitors based on the 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6-hydroxy-biphenyl-3-yl]-succinic acid scaffold. These amidine-containing compounds have low oral bioavailability. Herein, we describe our efforts to improve the oral bioavailability of the parent amidine via a prodrug strategy where the amidine basicity and polarity were reduced with either an alkoxy-amidine or a carbamate prodrug.

Administration, Oral↗
PubMed2005

In vivo modification of adriamycin-induced apoptosis in L-5178Y lymphoma cell-bearing mice by (+)-alpha-tocopherol and superoxide dismutase.

Apoptosis was followed in L5178Y lymphoma cell-bearing mice at different times after intraperitoneal injections of adriamycin (ADM). Apoptosis was determined morphologically and confirmed by DNA laddering on electrophoresis. Apoptosis was observed 36h after injection of 5mg/kg ADM (apoptotic cell index 64.2+/-5.6 vs. 1.5+/-2.1 from the untreated group) and confirmed by DNA electrophoresis. However, when the animals were pretreated with (+)-alpha-tocopherol acid succinate or superoxide dismutase before ADM administration apoptotic index significantly diminished (P<0.05) and the DNA electrophoresis did not show fragmentations. We conclude that in ADM-treated mice, tumour cell death occurs in two ways: first by necrosis, then later by apoptosis. These observations are likely to be associated with or caused by the generation of reactive oxygen species.

Animals↗
PubMed2006

Birnessite mediated debromination of decabromodiphenyl ether.

Decabromodiphenyl ether (BDE-209) is a major component of a commercial flame retardant formulation; however, there is limited information on the fate of BDE-209 in the environment, including metal oxide mediated degradation. Laboratory experiments were conducted to investigate the birnessite (delta-MnO(2))-promoted debromination of BDE-209 in tetrahydrofuran (THF)-water systems as well as catechol solutions. Up to 100% (0.1044 micromol initial charge) of BDE-209 disappeared upon reaction with birnessite in THF/H(2)O (4:6-9:1). The formation of aqueous Br(-) from BDE-209 reduction was determined and up to 16 mole% of initial bromine was released over the course of the reaction indicating approximately 1.7 Br-C bonds were reduced per BDE-209 molecule. The distribution of debrominated congeners, however, indicated a much greater extent of debromination for some products than what was inferred from an average bromine mass balance. The produced congeners varied from tetra- to nona-bromodiphenyl ether, including BDE-47 and -99, during the 24 h reaction. Experiments with deuterated water indicated that water was not the major hydrogen donor in the reduction but rather THF provided the reducing power. This conclusion was supported by the presence of succinic acid, which was produced from oxidation of THF. The reactions with aqueous catechol, rather than THF-water mixtures, were performed to assess the possible role that compounds found in natural environments, such a tannin-like phenols, might have on the chemistry. These experiments indicated that birnessite mediated debromination of BDE-209 might occur in natural settings.

Bromine↗
PubMed2005

Langmuir monolayers of the long-chain alkyl derivatives of a nucleoside analogue and the formation of self-assembled nanoparticles.

The long-chain alkyl derivatives of a nucleoside analogue-acyclovir were prepared in the paper. One is stearyl-glycero-succinyl-acyclovir (SGSA) with a single 18-carbon length (C18) alkyl chain. Another is dioctadecyl-aspartate-succinyl-acyclovir (DASA) with double C18 alkyl chains. They were prepared by the esterification of succinyl-acyclovir with the lipids, and sodium salts of them were also prepared. Guanine moieties and alkyl moieties bring the derivatives intermolecular hydrogen bonding and hydrophobic interaction in water separately. The forces are influenced by the number of alkyl chains and the charged state, and determine the solubility and the self-assembly behavior of the derivatives. The double alkyl-chain derivatives (DASA and DASA-Na) formed rigid Langmuir monolayers on air/water surface, while the single alkyl chain derivatives (SGSA and SGSA-Na) did not. However, cholesterol (Chol) could assist SGSA to form rigid monolayers through inserting into the alkyl chains of SGSA to mimic the second alkyl chain. SGSA self-aggregates in water were prepared by the injection method with tetrahydrofuran as solvent. Cuboid-like shape and nanoscale size demonstrated that SGSA self-aggregates were self-assembled nanoparticles. Shape, particle size, zeta potential and phase transition of the nanoparticles were characterized. And they showed an average size of 83.2 nm, a negative surface charge of -31.3-mV zeta potential and a gel-liquid crystalline phase transition of 50.38 degrees C. The formation mechanism of self-assembled nanoparticles was analyzed. Hydrophobic interaction of alkyl chains improves SGSA molecules to form bilayers, and then cuboid-like nanoparticles were obtained by layer-by-layer aggregation based on inter-bilayers hydrogen bonding. However, the charged guanine moieties make SGSA-Na lose the function of hydrogen bonding so that SGSA-Na only forms vesicles in water based on hydrophobic interaction. Strong hydrophobicity and wide-open rigid double alkyl chains of DASA and DASA-Na restrict self-assembly in water media, and no homogeneous suspensions were obtained. Therefore, the molecular self-assembly behavior of the long-chain alkyl derivatives of nucleoside analogues on water surface or in water media is determined by the number of alkyl chains and the charged state.

Acyclovir↗
PubMed2006

Thermostabilization of Bacillus amyloliquefaciens alpha-amylase by chemical cross-linking.

Chemical cross-linking of a mesophilic alpha-amylase from Bacillus amyloliquefaciens (BAA) was carried out. Intra-molecular cross-links between lysine residues upon treatment of the enzyme with ethylene glycol bis(succinic acid N-hydroxy succinimide ester) resulted in enhancement of thermostability as indicated by irreversible thermoinactivation experiments. Enhancement of thermostability coincided with a dramatic protection against aggregation, combined with a decrease in surface hydrophobicity. Deamidation, another important mechanism of irreversible thermoinactivation, was also diminished upon modification. While no significant changes in the kinetic parameters are evident, rigidification of the protein structure is suggested by circular dichroism (CD) and fluorescence studies.

Bacillus↗
PubMed2004

Biologically relevant tetraazamacrocyclic complexes of manganese: synthetic, spectral, antimicrobial, antifertility and antiinflammatory approach.

The testicular sperm density, sperm morphology, sperm motility, density of cauda epididymis spermatozoa and fertility in mating trials and biochemical parameters of reproductive organs have been examined and discussed for [Mn(N(4)MacL(n))(NO(3))(2)] (where N(4)MacL(n) represents the tetraazamacrocyclic ligand molecule with n=1-4) type of complexes. An attempt also has been made to correlate the structural aspects of the compounds with their anti-inflammatory activity. The 14-18 membered tetraamide macrocyclic ligands N(4)L(1)-N(4)L(4) used during these investigations have been prepared by the condensation of 1,2-diaminoethane or 1,3-diaminopropane with malonic or succinic acid in the presence of condensing reagents, dicyclohexylcarbodiimide and 4-dimethylaminopyridine. On reduction, these macrocyclic ligands give a new series of tetraazamacrocyles [N(4)MacL(n)] and their complexes with manganese(II) nitrate. The ligands and their complexes were characterized by elemental analyses, molecular weight determinations, infrared, electronic, mass and X-ray structural analyses. An octahedral geometry for these complexes has been confirmed by spectral studies. On the basis of the chemical composition, the representation of the complexes as [Mn(N(4)MacL(n))(NO(3))(2)] has been established. The ligands and their complexes have been screened in vitro against a number of pathogenic fungi and bacteria to assess their growth inhibiting potential.

Animals↗
PubMed2006

Review of 86 patients with myelodysplasia and neurogenic bladder who underwent sigmoidocolocystoplasty and were followed more than 10 years.

PURPOSE: We reviewed the long-term outcome of sigmoidocolocystoplasty. MATERIALS AND METHODS: The records of 86 patients who underwent sigmoidocolocystoplasty with a followup of more than 10 years were reviewed, focusing on histopathology, renal function, vesicoureteral reflux, bladder stones and urinary continence. We developed a urinary continence evaluation score, calculated as the postoperative minus the preoperative urinary continence score, including 0-incontinence, 1-severe leakage, 2-moderate leakage, 3-mild leakage, 4-almost dry and 5-dry, for patient self-assessment of urinary continence. A score of 2 or more meant improvement and a score of less than 2 meant no improvement. RESULTS: Mean followup was 13.1 years (range 10 to 21). Histopathology showed inflammation in all cases, hyperplasia in 9 and metaplasia in 4. In 80 of 86 cases creatinine clearance was normal. Ureteral reimplantation had been performed before sigmoidocolocystoplasty in 9 cases (13 kidneys) for grades III to V vesicoureteral reflux, which recurred as grade I in 1 (1 kidney). Ureteral reimplantation was performed during sigmoidocolocystoplasty in 31 cases (58 kidneys) and grades I to II vesicoureteral recurred in 5 (6 kidneys). Of the remaining 44 sigmoidocolocystoplasty cases there were 2 (2 kidneys) of grade I vesicoureteral reflux. On (99m)technetium-dimercapto-succinic acid scintigraphy there was increased renal scarring in 8 cases. Bladder stones were identified in 18 of 86 cases during followup but they were absent at review. The urinary continence evaluation score showed improvement in 61 cases and no improvement in 25. CONCLUSIONS: Our results suggest that sigmoidocolocystoplasty is safe and effective in the long term.

Adolescent↗
PubMed2006

Renal scarring in familial vesicoureteral reflux: is prevention possible?

PURPOSE: Detailed knowledge about risk factors for renal scarring in familial reflux is necessary to decide whether these factors could be influenced by early screening and treatment of siblings. We evaluated the prevalence of and risk factors influencing renal scarring in familial vesicoureteral reflux. MATERIALS AND METHODS: We reviewed the medical records and dimercapto-succinic acid scans of 306 children with familial vesicoureteral reflux. Scarring was classified as mild, moderate and severe. The impact of urinary tract infections, patient sex, reflux grade and age at diagnosis on renal scarring was evaluated. RESULTS: The prevalence of renal scarring was identical at 36% in 142 index patients and 74 siblings presenting with urinary tract infection but it was only 10% in 87 asymptomatic siblings (p <0.001) The difference between siblings with and without urinary tract infection was only statistically significant for mild scarring (23% vs 4.6%, p <0.001). It did not attain significance in those with moderate to severe scarring (13.5% vs 5.7%). Moderate to severe scarring was significantly more common in grade V than in grade IV refluxing units (43% vs 10%, p <0.0001) and in male than in female siblings (15.8% vs 3.4%, p = 0.012). Mild scarring was not significantly associated with reflux grade or patient sex. Children diagnosed before age 3 years showed significantly less scarring than patients diagnosed later (23% vs 41%, p <0.002). CONCLUSIONS: The development of mild renal scarring seems to mainly depend on urinary tract infections, while moderate and severe scarring are also associated with high grade reflux and male sex. Early detection and treatment may prevent further urinary tract infections as well as reflux related kidney damage.

Child, Preschool↗
PubMed2004

Inhibition of experimental tobacco carcinogen induced head and neck carcinogenesis.

Oral cancer models have attempted to demonstrate inhibition of oral carcinogenesis. These models used synthetic carcinogens, lacked a specific mechanism of activity or used non-physiologic doses for carcinogen or inhibitor. To correct these problems the tobacco and environmental carcinogen, dibenzo[a,l]pyrene (DB[a,l]P) (0.25%, 0.010 microM/application) was painted on the tongue and/or vitamin E acid succinate (VE(as)) (0.43 I.U./0.136 (microM/treatment) administered by gavages to Syrian hamsters (14 animals per group) using physiologic low doses, 5X/week. Oral cytology supplied keratinocytes after 1, 10, or 25 weeks of treatment. Cells were analyzed by flow cytometry/laser scanning cytometry. Initiation (1-6 weeks) was suppressed by reducing DNA damage (oxidation lesions: 8-oxo-dG), and repair (comet, fpg, OGG1, NTH1). Reduction in promotion (6-10 weeks) was identified by depressed proliferation (cell cycle, bromodeoxyuridine incorporation (BrdU)) and aneuploidy (propidium iodide stain). p53 and apoptosis expressions were increased (Sub G(1), mitochondrion activation: Apo 2.7, and nucleosomal formation: mebstain (TUNEL)). VE(as) administration reduced dysplasia (10 weeks) and oral cancer formation at 25 (0/7 vs. 5/7 DB[a,l]P) and 30 weeks (3/7 vs. 6/7 DB[a,l]P). Inhibition of oral carcinogenesis by VE(as) involved reversal of several cellular events that contribute towards oral cancer.

Aneuploidy↗