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PubMed1992

Permanent AV block or modification of AV nodal function by selective AV nodal artery ethanol infusion.

The acute and chronic effects of selective AV nodal artery ethanol infusion on AV nodal function was studied in 9 closed chest anesthetized dogs. Using standard percutaneous techniques of arterial catheterization, a 2.2 French infusion catheter was positioned in the AV nodal artery. Ten minute infusions into the AV nodal artery of 25%, 50%, or 100% ethanol in normal saline at rates of 0.5 mL/min acutely resulted in complete AV nodal block (AVB) in 5 dogs, 2:1 AV nodal block in 1 dog, and prolongation of AV nodal effective refractory period and/or Wenckebach cycle length in the remaining 3 dogs. One dog died with persistent complete AV block 1 week after the ethanol infusion. When restudied 4 weeks later, 7 of the 8 surviving dogs had persistent modification of AV nodal function, including complete AV block in 5 dogs and lengthening of AV nodal effective refractory period and/or Wenckebach cycle length without AV block in 2 dogs. Pathologic examination of the animals exhibiting chronic modification or ablation of AV nodal function revealed healing infarction of the AV node or its approaches. Distant myocardial necrosis was not observed and left ventricular function was normal. Slow infusion of low concentrations of ethanol into the AV nodal artery results in AV nodal modification or ablation due to localized necrosis in or around the AV node. This technique may have a role in AV nodal modification or ablation, particularly in patients who have failed DC shock or radiofrequency ablation.

Animals↗

PubMed1998

Comparison of the effects of AV nodal ablation versus AV nodal modification in patients with congestive heart failure and uncontrolled atrial fibrillation.

Radiofrequency (RF) catheter ablation of the atrioventricular node (AVN) and implantation of a ventricular pacemaker can improve cardiac performance in patients with congestive heart failure (CHF) and uncontrolled atrial fibrillation (AF). Alternatively, RF catheter modification of the AVN has been proposed to slow ventricular response during AF without requirement for permanent pacing. Among 44 consecutive patients (mean age 69.7 +/- 10.2 years) with drug resistant chronic AF, 22 (group I) had AVN ablation with permanent ventricular pacemaker implantation, while 22 patients had attempted AVN modification. Complete AV block was obtained in all group I patients while only seven (32%) AVN modification patients (group II) had permanent slowing of ventricular rate. Among patients in group I, mean left ventricular ejection fraction (EF) increased from 32.2% +/- 8.8% before ablation to 41.9% +/- 14.6% 4-weeks postablation (P < 0.01); exercise tolerance time (ETT) increased from 2.9 +/- 2.2 minutes to 4.5 +/- 2.9 minutes (P < 0.01); and quality-of-life score decreased from 66.1 +/- 22.6 to 36.9 +/- 17.1 (P < 0.01). By comparison, there was only a small increase in ETT in the seven successful group II patients (2.4 +/- 1.8 minutes to 3.0 +/- 1.9 minutes; P < 0.05) and there was no significant change in EF or quality-of-life. While AVN ablation can occasionally have transient adverse effects, it is more effective than AVN modification for improving cardiac performance in selected patients with CHF and AF.

Aged↗

PubMed1993

Modification of sodium channel inactivation by alpha-chymotrypsin in canine cardiac Purkinje cells.

INTRODUCTION: Studies of tetrodotoxin-sensitive sodium current (INa) after modification of inactivation by intracellular enzymes in mammalian cells have demonstrated a marked increase in peak INa at test potentials near current threshold causing a large, negative shift of the peak INa conductance-voltage relationship by approximately -20 mV. These findings support a kinetic model in which the unmodified Na channel has rapid and voltage-independent inactivation from the open state. However, the kinetics of cardiac Na channels differ from those of mammalian neuronal Na channels. In particular, inactivation of cardiac Na channels has been proposed to be more voltage dependent than that of tetrodotoxin-sensitive Na channels. To help understand the role of inactivation in cardiac Na channel kinetic behavior, we studied Na currents before and after modification of inactivation by the proteolytic enzyme, alpha-chymotrypsin. METHODS AND RESULTS: Whole cell INa was measured in single canine cardiac Purkinje cells that were voltage clamped and internally perfused with a large-bore suction pipette. The decay of INa in response to step depolarizations was dramatically slowed after perfusion with intracellular alpha-chymotrypsin consistent with modification of inactivation. In contrast to mammalian tetrodotoxin-sensitive Na current, Boltzmann distribution fits to peak INa conductance-voltage (GNa-V) relationships after alpha-chymotrypsin showed no change in either the potential at half maximum conductance (V 1/2), after correction for the spontaneous background shift of INa kinetics, or in the voltage-dependence of conductance (i.e., slope factor of GNa-V relationships). Maximal peak INa conductance increased by 18%. INa tail-current relaxations at potentials < or = -110 mV, after correction for spontaneous shifts in Na channel kinetics, were also similar before and after modification by alpha-chymotrypsin. CONCLUSION: alpha-chymotrypsin modified inactivation of cardiac INa with little or no change in activation, and cardiac Na channel inactivation was slow near threshold and played little role in determining V1/2 for peak INa conductance-voltage relationships.

Animals↗

PubMed1998

Radiofrequency modification of the atrioventricular node in patients with chronic atrial fibrillation: comparison between anterior and posterior approaches.

INTRODUCTION: We compared, in a prospective and randomized fashion with a cross-over design, the anterior and posterior approaches to radiofrequency (RF) modification of the AV node in patients with chronic atrial fibrillation. METHODS AND RESULTS: Thirty-three patients were randomized to receive first an anterior (group I) or posterior (group II) approach for RF modification of AV nodal conduction. Patients who did not fill the endpoint ventricular rate (< 90 beats/min) were crossed over to the alternative approach. After the anterior approach in group I patients, mean ventricular rate was significantly lower than in group II patients after the posterior approach (79.6 +/- 18.8 beats/min vs 110.8 +/- 16.2 beats/min, P < 0.001). In group I, 14 (82%) of 17 patients fulfilled the endpoint, 1 (6%) had complete AV block, and 2 (12%) were crossed over to the posterior approach fulfilling the endpoint. In group II, 4 (25%) of 16 patients fulfilled the endpoint. No transient or permanent high-degree AV block was observed. Among the 12 patients who were crossed over to the anterior approach, 8 fulfilled the endpoint, whereas 4 had permanent high-degree AV block. RF ablation carried out only in the anterior region was safer than a stepwise approach (6% vs 33% incidence of AV block), even though the difference did not reach statistical significance (P = 0.09). CONCLUSION: Posterior AV nodal modification is less effective but safer than anterior AV nodal modification. However, to reduce the incidence of AV block, the anterior approach is preferable to a stepwise approach from the posterior to the anterior zone.

Aged↗

PubMed2006

Cephalometric evaluation of condylar and mandibular growth modification: a review.

OBJECTIVE: Based on a wealth of orthodontic archives, this work aims to review the cephalometric analysis systems that can identify the changes in condylar and mandibular position as well as growth direction in response to bite jumping therapy. DESIGN: Numerous cephalometric approaches were screened to testify their feasibility and reliability in accurately depicting the growth modification of the condyle and the mandible. The critical assessment of the working mechanisms of these cephalometric methods was elaborated to help build up the rationale and justification for their clinical use. RESULTS: 1) The changes in condylar and mandibular size, position and growth direction can be identified by using lateral cephalograms with closed-mouth or open-mouth posture. 2) With superimposition methods where the anatomical structures for superimposition registration must be stable and reproducible, the growth modification of the condyle and the mandible between two time-points is qualitatively demonstrated in a diagram if reference lines are not constructed. The growth modification can be quantitatively identified if the reference lines are created. 3) With non-superimposition methods, the size and position of the condyle and the mandible are separately identified for each time-pint by relating them to the stable reference structures. The growth modification between two time-pints is evaluated by comparing the two separate measurements. CONCLUSION: The application of a standardized and well designed cephalometric evaluation system may reduce the bias that attribute to the arbitrariness of the clinical effects of bite jumping functional appliances.

Activator Appliances↗

PubMed1992

Protein synthesis, posttranslational modifications, and aging.

Posttranslational modifications of proteins are involved in determining their activities, stability, and specificity of interaction. More than 140 major and minor modifications of proteins have been reported. Of these, only a few have been studied in relation to the aging of cells, tissues, and organisms. These include phosphorylation, methylation, ADP-ribosylation, oxidation, glycation, and deamidation. Several of these modifications occur on proteins involved in crucial cellular processes, such as DNA synthesis, protein synthesis, protein degradation, signal transduction, cytoskeletal organization, and the components of extracellular matrix. Some of the modifications are the markers of abnormal and altered proteins for rapid degradation. Others make them less susceptible to degradation by normal proteolytic enzymes, and hence these accumulate during aging.

Adenosine Diphosphate Ribose↗

PubMed1987

Schirmers-I test with and without modifications (lipid extracted paper and replacement of paper).

The lacrimation rate of 12 persons was measured by the Schirmer-I test and by two modifications of the test. The modifications used were: 1. the use of lipid extracted standardized Halberg paper (in a mixture of chloroform and ethanol), 2. replacement of the test paper in the conjunctival sac if no lacrimation was observed within 2 min. We could not detect any change in the variation of results between the different modifications or set-ups, and consequently the modifications were considered as being of little clinical value compared to the original test.

Humans↗

PubMed1995

Inactivation of the cloned potassium channel mouse Kv1.1 by the human Kv3.4 'ball' peptide and its chemical modification.

1. This study used the whole-cell patch clamp technique to investigate the action of a 28-mer 'inactivation peptide' based on part of the N-terminal sequence of the human Kv3.4 K+ channel (hKv3.4 peptide) on the cloned mouse brain K+ channel mKv1.1 expressed in Chinese hamster ovary (CHO) cells, and compared this with the inactivation produced by Shaker B inactivation peptide (ShB peptide). 2. Inclusion of the hKv3.4 peptide in the patch electrode (320 microM) transformed non-inactivating mKv1.1 into a rapidly inactivating current. The voltage dependence of time constants of decay and steady-state inactivation induced by hKv3.4 peptide were characteristic of an 'A-type' K+ current. 3. The hKv3.4 peptide had no effect on the voltage dependence of activation of mKv1.1, with a mid-point of activation of -8 mV, and a slope factor of 15 mV. Steady-state inactivation curves had a mid-point of inactivation of -36 mV and a slope factor of -7 mV; the time constant of recovery from inactivation at -90 mV was 1.3 s. 4. The chemical modification reagents N-bromoacetamide (NBA, 100 microM) and chloramine-T (CL-T, 500 microM) had no effect on the fast inactivation of mKv1.1 induced by ShB peptide. In contrast, the inactivation caused by hKv3.4 peptide was removed by brief exposure to NBA and CL-T. 5. Chemical modification resulted in a hyperpolarizing shift of -8 mV (CL-T) and -11 mV (NBA) in the voltage dependence of activation of mKv1.1 in the presence of hKv3.4 peptide. 6. Chemical modification was critically dependent on the presence of a cysteine residue at position 6, and not position 24, of hKv3.4 peptide. 7. NBA and CL-T caused only a slight inhibition of unmodified mKv1.1 current with no significant effect on the voltage dependence of mKv1.1 activation, and also had no effect on channel deactivation at -90 mV. 8. Chemical modification experiments were consistent with a selective action on the hKv3.4 peptide itself, specifically at the cysteine residue at position 6.

Acetamides↗

PubMed2002

Effects of phoneme class and duration on the acceptability of temporal modifications in speech.

Human subjective acceptability of durational distortions in speech segments or portions is significantly affected by various segmental and sequential properties, e.g., the vowel color and temporal position in a word [Kato et al., J. Acoust. Soc. Am. 101, 2311-2322 (1997); 104, 540-549 (1998)]. The current study focused on the effects of phoneme class and original duration of speech portions in isolated words. In experiment 1, the effect of four classes of phoneme, i.e., vowel, nasal, voiceless fricative, and silent closure, on the acceptable modification range was tested. Six listeners evaluated the temporal acceptability of each of 49 words where one of the steady-state portions was subjected to durational modification from -75 ms (for shortening) to +75 ms (for lengthening) in 7.5-ms steps. The results showed that the listeners' acceptable modification ranges were narrowest for vowels, and widest for voiceless fricatives and silent closures, with nasals in between. The mean acceptable ranges for the least vulnerable phoneme class, i.e., voiceless fricative and silent closure, reached 143% or more of that for the most vulnerable class, i.e., vowel. The observed variation in the acceptable modification range due to the different phoneme class was highly correlated with the inherent loudness in each phoneme class. A larger inherent loudness yielded a narrower acceptable range. Experiment 2 tested the effect of the original, as produced, duration of steady-state speech portions using 30 words where the factors of phoneme class and original duration were designed in a factorial way. The results showed that the original durations affected the listeners' absolute acceptable ranges; the ranges were narrower for shorter original durations. There was a significant interaction between the factors of phoneme class and original duration. The effect of the original duration was larger for vowels than for fricatives. This interaction could be accounted for by the difference in the temporal structure spanning beyond the modified portion itself.

Humans↗

PubMed2005

Modification of heat shock protein 90 by 4-hydroxynonenal in a rat model of chronic alcoholic liver disease.

Lipid peroxidation during oxidative stress leads to increased concentrations of thiol-reactive alpha,beta-unsaturated aldehyde, including 4-hydroxy-2-nonenal (4-HNE) and 4-oxo-2-nonenal (4-ONE). These aldehydes have a documented ability to disrupt protein function following adduct formation with specific residues. Therefore, to identify 4-HNE-modified proteins in a model of ethanol-induced oxidative stress, a proteomic approach was applied to liver fractions prepared from rats fed a combination high-fat/ethanol diet. The results revealed that essential 90-kDa heat shock protein (Hsp90) was consistently modified by 4-HNE in the alcohol-treated animals. In vitro chaperoning experiments using firefly luciferase as a client protein were then performed to assess the functional effect of 4-HNE modification on purified recombinant human Hsp90, modified with concentrations of this aldehyde ranging from 23 to 450 microM. Modification of Hsp90 with 4-ONE also led to significant inhibition of the chaperone. Because 4-HNE and 4-ONE react selectively with Cys, a thiol-specific mechanism of inhibition was suggested by these data. Therefore, thiol sensitivity was confirmed following treatment of Hsp90 with the specific thiol modifier N-ethylmaleimide, which resulted in more than 99% inactivation of the chaperone by concentrations as low as 6 microM (1:1 M ratio). Finally, tryptic digest of 4-HNE-modified Hsp90 followed by liquid chromatography/tandem mass spectrometry peptide analysis identified Cys 572 as a site for 4-HNE modification. The results presented here thus establish that 4-HNE consistently modifies Hsp90 in a rat model of alcohol-induced oxidative stress and that the chaperoning activity of this protein is subject to dysregulation through thiol modification.

Aldehydes↗

PubMed1997

DNA modifications by antitumor trans-[PtCl2(E-iminoether)2].

Recent findings that an analogue of clinically ineffective transplatin, trans-[PtCl2(E-iminoether)2], exhibits antitumor activity has helped reevaluation of the empirical structure-antitumor activity relationship generally accepted for platinum(II) complexes. According to this relationship, only the cis geometry of leaving ligands in the bifunctional platinum(II) complexes, should be therapeutically active. Global modifications of natural DNAs in cell-free media by trans-[PtCl2(E-iminoether)2] were studied through various molecular biophysical methods and compared with modifications by cis-[PtCl2(E-iminoether)2], transplatin, cisplatin, and monofunctional chlorodiethylenetriamineplatinum(II) chloride. Thus, the results of this study have extended our recent finding, indicating that the prevalent lesion occurring in double-helical DNA on its modification by trans-[PtCl2(E-iminoether)2] is a monofunctional adduct at guanine residues. The modification by trans-[PtCl2(E-iminoether)2] has been found to induce local distortions in DNA, which have a character differing fundamentally from those induced by both clinically ineffective or antitumor platinum complexes tested in this study. The different character of alterations induced in DNA by the adducts of trans-[PtCl2(E-iminoether)2] and transplatin has been suggested to be relevant to the unexpected observation that the new complex with leaving chloride groups in trans position exhibits antitumor efficacy. In addition, the results support the idea that platinum drugs that bind to DNA in a manner fundamentally different from that of cisplatin can exhibit altered biological properties, including differing spectra and intensities of antitumor activity.

Animals↗

PubMed1987

A physiological basis for a theory of synapse modification.

The functional organization of the cerebral cortex is modified dramatically by sensory experience during early postnatal life. The basis for these modifications is a type of synaptic plasticity that may also contribute to some forms of adult learning. The question of how synapses modify according to experience has been approached by determining theoretically what is required of a modification mechanism to account for the available experimental data in the developing visual cortex. The resulting theory states precisely how certain variables might influence synaptic modifications. This insight has led to the development of a biologically plausible molecular model for synapse modification in the cerebral cortex.

Action Potentials↗

PubMed1986

Protein modification by amino acid addition is increased in crushed sciatic but not optic nerves.

Rat optic and sciatic nerves were crushed, and 10 minutes to 3 days later nerve segments between the crushed site and the cell body were removed and assayed for posttranslational protein modification by amino acid addition. Protein modification was comparable in intact optic and sciatic nerves, but in sciatic nerves increased to 1.6 times control levels 10 minutes after crushing and reached a maximum of ten times control levels by 2 hours. In optic nerves activity was decreased throughout the time course studied. The results indicate that, in a nerve which is capable of regeneration (sciatic), protein modification by the addition of amino acids increases immediately after injury, but a nerve incapable of regeneration (optic) is incapable of activating the modification reaction. These findings may be important in understanding the reasons for the lack of a regenerative response after injury to central mammalian nerves.

Amino Acids↗

PubMed1993

Germ-line gene modification and disease prevention: some medical and ethical perspectives.

There has been considerable debate about the ethics of human germ-line gene modification. As a result of recent advances in the micromanipulation of embryos and the laboratory development of transgenic mice, a lively discussion has begun concerning both the technical feasibility and the ethical acceptability of human germ-line modification for the prevention of serious disease. This article summarizes some of the recent research on germ-line gene modification in animal models. Certain monogenic deficiency diseases that ultimately might be candidates for correction by germ-line intervention are identified. Several of the most frequently considered ethical issues relative to human germ-line gene modification are considered in the context of professional ethics, parental responsibility, and public policy. Finally, it is suggested that there is merit in continuing the discussion about human germ-line intervention, so that this technique can be carefully compared with alternative strategies for preventing genetic disease.

Animal Experimentation↗

PubMed1973

Host specificity of Salmonella typhimurium deoxyribonucleic acid restriction and modification.

The restriction and modification genes of Salmonella typhimurium which lie near the thr locus were transferred to a restrictionless mutant of Escherichia coli. These genes were found to be allelic to the E. coli K, B, and A restriction and modification genes. E. coli recombinants with the restriction and modification host specificity of S. typhimurium restricted phage lambda that had been modified by each of the seven known host specificities of E. coli at efficiency of plating levels of about 10(-2). Phage lambda modified with the S. typhimurium host specificity was restricted by six of the seven E. coli host specificities but not by the RII (fi(-) R-factor controlled) host specificity. It is proposed that the restriction and modification enzymes of this S. typhimurium host specificity have two substrates, one of which is a substrate for the RII host specificity enzymes.

Alleles↗

PubMed1974

Temperature-sensitive modification and restriction phenotypes of an Escherichia coli dnaD mutant.

A mutant of Escherichia coli temperature-sensitive for deoxyribonucleic acid synthesis, dnaD, was found to have temperature-sensitive modification and restriction phenotypes. In contrast to the original observation by Carl (1970), the mutant could support the growth of lambda phage at 41 C. However, the lambda phages thus produced were able to form plaques with normal plating efficiency only on E. coli C, a restriction-less strain, but not on E. coli K. Since the lambda phages produced in the mutant at 30 C could form plaques equally well on both E. coli strains, it was concluded that the dnaD mutant has a temperature-sensitive modification phenotype. Furthermore, since the dnaD mutant allowed some growth of unmodified lambda.C phages at 41 C but less at 30 C, the mutant is also temperature sensitive in restriction. The relationship, if any, between temperature-sensitive deoxyribonucleic acid synthesis and temperature-sensitive modification-restriction in the dnaD mutant is not known. Similar experiments were done with three dnaC mutants and one dnaA mutant. Two dnaC mutants were found to have altered restriction phenotypes at 41 C, but none of the mutants were defective in modification.

Coliphages↗

PubMed1974

Mutants of the N-3 R-factor conditionally defective in hspII modification and deoxyribonucleic acid-cytosine methylase activity.

The N-3 drug resistance (R) factor specifies a deoxyribonucleic acid (DNA)-cytosine methylase and a DNA restriction-modification (hspII) system. We have isolated three independent mutants that are conditionally defective in their ability to modify bacteriophage lambda and to methylate DNA-cytosine residues. The ratio of 5-methylcytosine to N(6)-methyladenine in bacterial DNA and in the DNA of phages lambda and fd was determined after labeling with [methyl-(3)H]methionine at various growth temperatures. Although the ability of the wild-type N-3 factor to modify phage lambda and to methylate DNA-cytosine residues was unaffected with increasing temperature, two of the mutants exhibited a parallel loss in modification and cytosine methylation ability. The ability of the third mutant to carry out these functions was dependent on the presence or absence of an amber suppressor mutation in the host genome. These results offer further support for the notion that hspII modification is mediated by a DNA-cytosine methylase. Evidence is also presented that the modification methylase is responsible for the in vivo methylation of phage fd DNA (which is not subject to hspII restriction in vivo).

Alanine↗

PubMed1981

Deoxyribonucleic acid modifications and restriction endonuclease production in Neisseria gonorrhoeae.

Modification of gonococcal deoxyribonucleic acid (DNA) was investigated, and the relationship with endonuclease production was explored. Both chromosomal and plasmid DNA from different gonococcal strains, irrespective of their plasmid content, was poorly cleaved by the restriction endonucleases HaeII, HaeIII, SacII, and BamHI. The fragment pattern of the Tn3 segment present on the 7.2-kilobase gonococcal resistance plasmid, when compared to its known DNA sequence, allowed us to conclude that the HaeIII and BamHI resistance was due to modification of these sites. A comparison of the fragment pattern of the resistance plasmid, when isolated from Escherichia coli or Neisseria gonorrhoeae, revealed that the resistance of HaeII must also be due to modification of its recognition sequence. Isoschizomers of HaeII and HaeIII can be found in isolates of N. gonorrhoeae (NgoI and NgoII, respectively). A new restriction endonuclease in gonococci, NgoIII, with a specificity similar to SacII, is reported here. High-pressure liquid chromatography of gonococcal DNA showed the presence of 5-methylcytosine. It is suggested that the methylation of cytosine residues in the HaeII (NgoI), HaeIII (NgoII), and SacII (NgoIII) recognition sites is the basis for the resistance of gonococcal DNA to cleavage by these enzymes. This methylation may be part of a host restriction modification system. In two out of five gonococcal strains the sequence -GATC- was modified. One strain unable to modify this sequence was a spontaneous mutant of a strain carrying such a modifying function.

Base Sequence↗