Renal cortical drug and xenobiotic metabolism following urinary tract obstruction

Renal cortical drug and xenobiotic metabolism following urinary tract obstruction. Renal cortical metabolism of drugs and xenobiotics was assessed with microsomes prepared from normal, contralateral and 4-day postobstructive hydronephrotic kidneys. Microsomal mixed-function oxidase and prostaglandin H synthase systems were determined in control and 3-methylcholanthrene-treated rabbits. Cytochrome P450 content and biphenyl-4-hydroxylase activity but not cytochromec reductase activity were reduced in the hydronephrotic kidney. 3-Methylcholanthrene treatment increased cytochrome P450 content and biphenyl-4-hydroxylase and acetanilide-4-hydroxylase activities in normal, contralateral, and hydronephrotic kidneys. However, even after 3-methylcholanthrene treatment, hydronephrotic kidney cytochrome P450 content and acetanilide-4-hydroxylase activity were not more than 20% of the corresponding normal kidney values. Prostaglandin H synthase metabolism of benzidine was observed in the hydronephrotic kidney but was at the limit of detection in normal or contralateral kidneys with or without 3-methylcholanthrene treatment. Characteristics of benzidine metabolism were consistent with the hydroperoxidase rather than the fatty acid cyclooxygenase activity of prostaglandin H synthase. Therefore, hydronephrosis alters the drug and xenobiotic metabolic profile of the renal cortex from a primarily mixed-function oxidase-dependent system to one with the potential for metabolism by the hydroperoxidase component of prostaglandin H synthase.Métabolisme cortical rénal des médicaments et xénobiotiques après obstruction du tractus urinaire. Le métabolisme cortical rénal de médicaments et de xénobiotiques a été étudié avec des microsomes préparés à partir des reins normaux, controlatérals, et hydronéphrotiques, 4 jours après une obstruction. Les systèmes microsomiaux de fonction oxydase mixte et de prostaglandine H synthétase ont été déterminés chez des lapins contrôles et traités par du 3-méthylcholanthrène. Le contenu en cytochrome P450 et l'activité biphényl-4-hydroxylase, mais non l'activité cytochromec réductase étaient diminués dans le rein hydronéphrotique. Le traitement par le 3-méthylcholanthrène a augmenté le contenu en cytochrome P450 et les activités biphényl-4-hydroxylase et acétanilide-4-hydroxylase chez les reins normaux, controlatérals et hydronéphrotiques. Cependant, même après traitement par le 3-méthylcholanthrène, le contenu en cytochrome P450 du rein hydronéphrotique et son activité acétanilide-4-hydroxylase n'étaient pas de plus de 20% des valeurs dans le rein normaux correspondant. Le métabolisme de la benzidine par la prostaglandine H synthétase était observable dans le rein hydronéphrotique, mais était à la limite de la détection dans les reins normaux ou controlatérals, avec ou sans traitement par le 3-méthylcholanthrène. Les caractéristiques du métabolisme de la benzidine étaient plus compatibles avec l'activité hydroperoxidase qu'avec l'activité cyclooxygénase des acides gras de la prostaglandine H synthétase. Ainsi, l'hydronéphrose altère le profil métabolique des drogues et des xénobiotiques dans le cortex rénal d'un système primitivement dépendant d'une fonction oxydase mixte à un système ayant la capacité de métabolisme par le constituant hydroperoxydase de la prostaglandine H synthétase

Transcriptome Analysis of Targeted Mouse Mutations Reveals the Topography of Local Changes in Gene Expression.

The unintended consequences of gene targeting in mouse models have not been thoroughly studied and a more systematic analysis is needed to understand the frequency and characteristics of off-target effects. Using RNA-seq, we evaluated targeted and neighboring gene expression in tissues from 44 homozygous mutants compared with C57BL/6N control mice. Two allele types were evaluated: 15 targeted trap mutations (TRAP); and 29 deletion alleles (DEL), usually a deletion between the translational start and the 3' UTR. Both targeting strategies insert a bacterial beta-galactosidase reporter (LacZ) and a neomycin resistance selection cassette. Evaluating transcription of genes in +/- 500 kb of flanking DNA around the targeted gene, we found up-regulated genes more frequently around DEL compared with TRAP alleles, however the frequency of alleles with local down-regulated genes flanking DEL and TRAP targets was similar. Down-regulated genes around both DEL and TRAP targets were found at a higher frequency than expected from a genome-wide survey. However, only around DEL targets were up-regulated genes found with a significantly higher frequency compared with genome-wide sampling. Transcriptome analysis confirms targeting in 97% of DEL alleles, but in only 47% of TRAP alleles probably due to non-functional splice variants, and some splicing around the gene trap. Local effects on gene expression are likely due to a number of factors including compensatory regulation, loss or disruption of intragenic regulatory elements, the exogenous promoter in the neo selection cassette, removal of insulating DNA in the DEL mutants, and local silencing due to disruption of normal chromatin organization or presence of exogenous DNA. An understanding of local position effects is important for understanding and interpreting any phenotype attributed to targeted gene mutations, or to spontaneous indels

Revised Phase Diagram of the Gross-Neveu Model

We confirm earlier hints that the conventional phase diagram of the discrete chiral Gross-Neveu model in the large N limit is deficient at non-zero chemical potential. We present the corrected phase diagram constructed in mean field theory. It has three different phases, including a kink-antikink crystal phase. All transitions are second order. The driving mechanism for the new structure of baryonic matter in the Gross-Neveu model is an Overhauser type instability with gap formation at the Fermi surface.Comment: Revtex, 12 pages, 15 figures; v2: Axis labelling in Fig. 9 correcte

Emergence of Skyrme crystal in Gross-Neveu and 't Hooft models at finite density

We study two-dimensional, large $N$ field theoretic models (Gross-Neveu model, 't Hooft model) at finite baryon density near the chiral limit. The same mechanism which leads to massless baryons in these models induces a breakdown of translational invariance at any finite density. In the chiral limit baryonic matter is characterized by a spatially varying chiral angle with a wave number depending only on the density. For small bare quark masses a sine-Gordon kink chain is obtained which may be regarded as simplest realization of the Skyrme crystal for nuclear matter. Characteristic differences between confining and non-confining models are pointed out.Comment: 27 pages, 11 figures, added reference, corrected sig

Phonon-Like Excitations of the Instanton Liquid

The phonon-like excitations of (anti)-instanton liquid ($\bar II$) due to adiabatic variations of vacuum wave functions are studied in this paper. The kinetic energy term is found and proper effective Lagrangian for such excitations is evaluated.The properties of their spectrum, while the corresponding masses are defined by $\Lambda_{QCD}$ with prevailing chromoelectric component, are investigated based on the phenomenology of QCD vacuum already developed.Comment: 7 page

Positional identification of variants of Adamts16 linked to inherited hypertension

A previously reported blood pressure (BP) quantitative trait locus on rat Chromosome 1 was isolated in a short congenic segment spanning 804.6 kb. The 804.6 kb region contained only two genes, LOC306664 and LOC306665. LOC306664 is predicted to translate into A Disintegrin-like and Metalloproteinase with Thrombospondin Motifs-16 (Adamts16). LOC306665 is a novel gene. All predicted exons of both LOC306664 and LOC306665 were sequenced. Non-synonymous variants were identified in only one of these genes, LOC306664. These variants were naturally existing polymorphisms among inbred, outbred and wild rats. The full-length rat transcript of Adamts16 was detected in multiple tissues. Similar to ADAMTS16 in humans, expression of Adamts16 was prominent in the kidney. Renal transcriptome analysis suggested that a network of genes related to BP was differential between congenic and S rats. These genes were also differentially expressed between kidney cell lines with or without knock-down of Adamts16. Adamts16 is conserved between rats and humans. It is a candidate gene within the homologous region on human Chromosome 5, which is linked to systolic and diastolic BP in the Quebec Family Study. Multiple variants, including an Ala to Pro variant in codon 90 (rs2086310) of human ADAMTS16, were associated with human resting systolic BP (SBP). Replication study in GenNet confirmed the association of two variants of ADAMTS16 with SBP, including rs2086310. Overall, our report represents a high resolution positional cloning and translational study for Adamts16 as a candidate gene controlling B

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Positional identification of variants of Adamts16 linked to inherited hypertension

A previously reported blood pressure (BP) quantitative trait locus on rat Chromosome 1 was isolated in a short congenic segment spanning 804.6 kb. The 804.6 kb region contained only two genes, LOC306664 and LOC306665. LOC306664 is predicted to translate into A Disintegrin-like and Metalloproteinase with Thrombospondin Motifs-16 (Adamts16). LOC306665 is a novel gene. All predicted exons of both LOC306664 and LOC306665 were sequenced. Non-synonymous variants were identified in only one of these genes, LOC306664. These variants were naturally existing polymorphisms among inbred, outbred and wild rats. The full-length rat transcript of Adamts16 was detected in multiple tissues. Similar to ADAMTS16 in humans, expression of Adamts16 was prominent in the kidney. Renal transcriptome analysis suggested that a network of genes related to BP was differential between congenic and S rats. These genes were also differentially expressed between kidney cell lines with or without knock-down of Adamts16. Adamts16 is conserved between rats and humans. It is a candidate gene within the homologous region on human Chromosome 5, which is linked to systolic and diastolic BP in the Quebec Family Study. Multiple variants, including an Ala to Pro variant in codon 90 (rs2086310) of human ADAMTS16, were associated with human resting systolic BP (SBP). Replication study in GenNet confirmed the association of two variants of ADAMTS16 with SBP, including rs2086310. Overall, our report represents a high resolution positional cloning and translational study for Adamts16 as a candidate gene controlling BP