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Biomedical subjects

M Schur

Publications and source records attributed to M Schur.

11 recordsLinked to original sources
PubMed2001

Genetic basis for expression of the major globotetraose-containing lipopolysaccharide from H. influenzae strain Rd (RM118).

A genetic basis for the biosynthetic assembly of the globotetraose containing lipopolysaccharide (LPS) of Haemophilus influenzae strain RM118 (Rd) was determined by structural analysis of LPS derived from mutant strains. We have previously shown that the parent strain RM118 elaborates a population of LPS molecules made up of a series of related glycoforms differing in the degree of oligosaccharide chain extension from the distal heptose residue of a conserved phosphorylated inner-core element, L-alpha-D-Hepp-(1-->2)-L-alpha-D-Hepp-(1-->3)-[beta-D-Glcp-(1-->4)-]-L-alpha-D-Hepp-(1-->5)-alpha-Kdo. The fully extended LPS glycoform expresses the globotetraose structure, beta-D-GalpNAc-(1-->3)-alpha-D-Galp-(1-->4)-beta-D-Galp-(1-->4)-beta-D-Glcp. A fingerprinting strategy was employed to establish the structure of LPS from strains mutated in putative glycosyltransferase genes compared to the parent strain. This involved glycose and linkage analysis on intact LPS samples and analysis of O-deacylated LPS samples by electrospray ionization mass spectrometry and 1D (1)H-nuclear magnetic resonance spectroscopy. Four genes, lpsA, lic2A, lgtC, and lgtD, were required for sequential addition of the glycoses to the terminal inner-core heptose to give the globotetraose structure. lgtC and lgtD were shown to encode glycosyltransferases by enzymatic assays with synthetic acceptor molecules. This is the first genetic blueprint determined for H. influenzae LPS oligosaccharide biosynthesis, identifying genes involved in the addition of each glycose residue.

Base Sequence↗
PubMed2000

Bis

The title double salt, [Ni(C(2)H(8)N(2))(3)](2)(SbS(4))(NO(3)), was crystallized under solvothermal conditions. Hydrogen bonds between the SbS(4)(3-) anions (at four sites) and the [Ni(en)(3)](2+) (en = ethylenediamine) cations (at two sites) form a three-dimensional network. The NO(3)(-) anion is disordered over four sites. The cation lies on a twofold rotation axis and the SbS(4)(3-) anion on a -4 axis.

Journal Article↗
PubMed1997

Aging effects on the organic base transporter and stereoselective renal clearance.

OBJECTIVE: The organic base transporter is responsible for stereoselective renal excretion. Changes in activity of this system secondary to aging may affect the disposition of an organic base in a stereoselective manner. METHODS: Eight young men (age range, 22 to 33 years) and seven elderly men (age range, 62 to 79 years) were given 10 mg pindolol twice daily, pindolol with 200 mg trimethoprim once daily (a known inhibitor of organic base secretion) and pindolol with 1.5 gm ammonium chloride (NH4Cl) four times daily for 3 days on three occasions. On day 4, urine and plasma were collected over 24 hours to determine renal clearance (CLR) values of pindolol isomers. RESULTS: R(+)-Pindolol CLR values in young versus elderly men were 203 +/- 82 versus 150 +/- 87 ml/min, 128 +/- 51 versus 113 +/- 35 ml/min, and 480 +/- 248 versus 247 +/- 59 ml/min during the control, trimethoprim, and NH4Cl study phases, respectively. S(-)-Pindolol CLR values in young versus elderly were 279 +/- 81 versus 207 +/- 105 ml/min, 178 +/- 70 versus 136 +/- 42 ml/min, and 593 +/- 294 versus 276 +/- 49 ml/min during control, trimethoprim, and NH4Cl phases, respectively. NH4Cl increased R(+)-pindolol CLR by 138% (p < 0.05 versus pindolol alone) in young men, which was significantly greater than that observed in elderly subjects (66%; p < 0.05 versus pindolol alone; p = 0.016 young versus old). NH4Cl affected S(-)-pindolol CLR in a similar manner. Trimethoprim decreased R(+)-pindolol CLR in the young subjects by 37% (p < 0.05 versus pindolol alone), which was similar to that observed in the elderly subjects (26%; p < 0.05 versus pindolol alone; p = 0.94 young versus elderly). Trimethoprim affected S(-)-pindolol CLR in a similar manner. Stereoselective renal excretion of pindolol was unaffected by NH4Cl and trimethoprim, where the R(+)/S(-)-pindolol CLR ratio was unchanged (p = NS) from control in the young and elderly subjects. Comparison of the pindolol CLR isomer ratio between young and elderly groups showed no significant differences. Changes in pindolol clearance values resulted in significant changes in beta-blocking activity, assessed by isoproterenol (INN, isoprenaline) testing. CONCLUSIONS: Trimethoprim and NH4Cl significantly affect pindolol renal and total clearance values. Aging does not alter renal excretion of pindolol except for the magnitude by which renal excretion can be stimulated.

Adrenergic beta-Antagonists↗
PubMed1997

Hypertonic saline does not reverse the sodium channel blocking actions of lidocaine: evidence from electrophysiologic and defibrillation studies.

Studies have shown that increasing extracellular sodium concentration can partially reverse sodium channel blockade. However, there is conflicting in vitro evidence in this regard for lidocaine. The effects of lidocaine on cardiac electrophysiology and defibrillation were studied in a basal and hypernatremic state to determine reversibility of sodium channel blockade. Electrophysiologic studies measured right ventricular effective refractory period at 350 ms pacing cycle length and QRS interval, JT interval, and monophasic action potential duration during sinus rhythm and right ventricular pacing (350 ms cycle length) in 14 pentobarbital-anesthetized swine (25-30 kg). Defibrillation threshold (DFT) was measured by quantitating successful conversion of sustained ventricular fibrillation to normal sinus rhythm. Each pig was randomly assigned to a treatment group with three study phases; group 1 = baseline, lidocaine (20 mg/kg/h), and lidocaine plus placebo (D5W; n = 7); and group 2 = baseline, lidocaine, and lidocaine plus hypertonic saline (2-3 mM/kg/h; n = 7). In groups 1 and 2, lidocaine infused alone significantly (p < 0.01) increased DFT values from baseline (9.8 +/- 3.9 to 15.7 +/- 5.8 J and 8.9 +/- 2.9 to 14.7 +/- 5.4 J, respectively) and increased QRS duration from baseline during right ventricular pacing (89 +/- 6 to 109 +/- 10 ms; p < 0.01; and 87 +/- 6 to 103 +/- 12 ms; p < 0.01). Lidocaine alone reduced right ventricular action potential duration (APD) in groups 1 and 2 (214 +/- 18 to 206 +/- 20 ms; p < 0.10; and 228 +/- 8 to 212 +/- 8 ms; p < 0.05), respectively, and it reduced paced JT interval in both groups (194 +/- 20 to 184 +/- 18 ms; p < 0.10; and 200 +/- 12 to 183 +/- 16 ms; p < 0.05), respectively. When hypertonic saline was added to lidocaine, DFT and QRS duration values were unaffected (14.7 +/- 5.4 to 16.1 +/- 3.7 J and 103 +/- 12 to 100 +/- 11 ms, respectively). However, APD and JT intervals returned to basal values when hypertonic saline was added to lidocaine (212 +/- 8 to 225 +/- 13; p < 0.05; and 183 +/- 16 to 192 +/- 18; p < 0.05, respectively). When D5W was added in the control group, no changes occurred in DFT or electrophysiologic values. Lidocaine slowed ventricular conduction velocity and reduced APD. The administration of hypertonic saline to increase extracellular sodium concentrations failed to reverse the effect of lidocaine on conduction-velocity slowing or elevated DFT values. Hypertonic saline did reverse the effects of lidocaine on repolarization parameters. These data suggest that shortening of repolarization is not a mechanism by which lidocaine makes it more difficult to defibrillate the heart.

Action Potentials↗
PubMed1996

Mechanism of antiarrhythmic drug-induced changes in defibrillation threshold: role of potassium and sodium channel conductance.

OBJECTIVES: We sought to determine which ion current predominantly affects defibrillation outcomes by using specific pharmacologic probes (lidocaine [a sodium channel blocking agent] and cesium [an outward potassium channel blocking agent]) in 26 swine. BACKGROUND: The effect of a drug on sodium or potassium channel conductance, or both, may affect defibrillation threshold values. However, it is unknown which ion channel predominates. METHODS: Each pig was randomly assigned to one of four treatment groups with two treatment phases: group 1 = placebo (D5W) in treatment phase I followed by placebo plus cesium in treatment phase II (n = 6); group 2 = lidocaine followed by lidocaine plus placebo (n = 7); group 3 = lidocaine followed by lidocaine plus cesium (n = 7); group 4 = placebo followed by placebo plus placebo (n = 6). Defibrillation threshold values and electrocardiographic measurements were obtained at baseline and at treatment phases I and II. RESULTS: Lidocaine increased defibrillation threshold values from baseline by 71% in group 2 (p = 0.02) and by 92% in group 3 (p < 0.01). There were no changes in defibrillation threshold values from baseline to D5W in groups 1 and 4. When D5W was added to lidocaine in group 2 and D5W in group 4, there were no significant changes in defibrillation threshold values. However, when cesium was added to lidocaine in group 3, the elevated defibrillation threshold values (mean +/- SD) returned to baseline values (from 15.7 +/- 3.46 to 7.55 +/- 3.19 J, p < 0.01). Cesium added to D5W in group 1 also significantly reduced defibrillation threshold values from 7.10 +/- 1.27 to 4.14 +/- 1.75 J (p < 0.01). The effect of cesium on defibrillation threshold values was similar between groups 1 and 3, regardless of lidocaine, such that these values were reduced by 40 +/- 14% and 51 +/- 18%, respectively (p = 0.28). CONCLUSIONS: Cesium, through potassium blockade, reverses lidocaine-induced elevation in defibrillation threshold values. The magnitude of defibrillation threshold reduction when cesium was added to lidocaine was similar to the defibrillation threshold reduction when cesium was added to placebo. Thus, inhibiting outward potassium conductance and prolonging repolarization decreases defibrillation threshold values independent of sodium channel blockade.

Animals↗
PubMed1996

Influence of hypertonic saline solution infusion on defibrillation efficacy.

Hypertonic saline solution may enhance cardiac conduction via the fast inward sodium channel and alter transmembrane Ca+2 conductance via the sodium-calcium exchanger. Evidence suggests that both Ca+2 conductance and myocardial conduction velocity may affect ventricular defibrillation. Since hypertonic saline solution solutions (ie, sodium bicarbonate) may be administered to patients who have conditions that often require ventricular defibrillation (ie, cardiac arrest or hypovolemic shock), we studied the effect of hypertonic saline solution on the defibrillation threshold (DFT) in 16 pentobarbital-anesthetized domestic farm swine (20 to 30 kg). Defibrillation was performed using two interfaced epicardial electrode patches. DFTs were determined at baseline and during treatment phase. Pigs were randomly assigned to treatment consisting of either hypertonic saline solution (6 mmol/kg load, 2.0 to 3.0 mmol/kg infusion) to maintain serum sodium concentrations 10 to 15 mmol/L above baseline or control (D5W given in equal volume). DFT values (joules) that predicted 50% success were modeled from a best-fit histogram. Hypertonic saline solution did not change DFT values from baseline values (10.2 +/- 4.3 vs 10.8 +/- 7.0, respectively). Likewise, placebo (D5W) did not change DFT values from baseline values (10.1 +/- 4.5 vs 11.3 +/- 4.3). During treatment phase, DFT values were 99 +/- 28% of baseline values in the hypertonic saline solution group and 116 +/- 23% of baseline values in the D5W groups (p = 0.21). The administration of hypertonic saline solution also did not affect ventricular conduction velocity, right ventricular action potential duration, or right ventricular effective refractory period. These data indicate that hypertonic saline solution does not appreciably affect defibrillation efficacy or electrical treatment of ventricular fibrillation.

Animals↗
PubMed1996

Urine acidification affects the activity of the organic base transporter in a nonstereoselective manner.

This investigation determined 1) the effect of urine acidification on renal clearance (Clrenal), total systemic clearance (Cltotal) and nonrenal clearance (Clnonrenal) of pindolol, 2) whether urine acidification affected the stereoselectivity of pindolol excretion and 3) the pharmacodynamic effects that may result from changes in the activity of the organic base transporter. The Clrenal, Cltotal and Clnonrenal values of pindolol isomers were determined during pindolol administration (10 mg twice daily; control phase) and during pindolol administration (10 mg twice daily) with NH4Cl, a systemic and urinary acidifier, (1.5 g every 6 hr). Eight healthy males (22-33 yr) randomly received this therapy for 3 days on two occasions. On day 4, urine and plasma were collected over 24 hr. R-(+) pindolol Clrenal values during control and NH4Cl were 203 +/- 82 and 480 +/- 248 ml/min, respectively (P = .03). S-(-) pindolol Clrenal values during control and NH4Cl were 279 +/- 81 and 593 +/- 294 ml/min, respectively (P = .005). NH4Cl increased R-(+) pindolol Clrenal by 173% +/- 136% (P = .003) and S-(-) pindolol Clrenal by 127% +/- 105% (P = .03). Stereoselective renal excretion of pindolol was unaffected by NH4Cl; the R(+)/S(-) pindolol Clrenal ratio was unchanged from control to NH4Cl (0.74 +/- 0.23 to 0.81 +/- 0.10, P = NS, respectively). NH4Cl, however, affected pindolol Clnonrenal in a stereoselective fashion; R-(+) pindolol Clnonrenal values increased (641 +/- 241 to 851 +/- 251 ml/min; P = .02), whereas S-(-) pindolol Clnonrenal values remained constant (354 +/- 116 vs. 370 +/- 213 ml/min). Changes in pindolol clearance values resulted in a significant reduction in beta-blocking activity assessed by isoproterenol testing. We conclude that increasing the urine proton gradient can increase the Clrenal value of organic bases by 2-fold in a manner that is not stereoselective. NH4Cl, however, did increase the Clnonrenal value of pindolol in a stereoselective manner. These data, therefore, indicate that the administration of a urine-acidifying agent can greatly enhance the elimination of organic bases and ultimately reduce the pharmacologic activity of the organic base.

Adult↗
PubMed1995

Differential effects of lidocaine on defibrillation threshold with monophasic versus biphasic shock waveforms.

BACKGROUND: Defibrillation waveforms and antiarrhythmic drugs have disparate effects on myocardial excitability and refractoriness, making it likely that antiarrhythmic drugs will interact with one waveform differently than with another. The aim of the present study was to determine if the increase in defibrillation threshold (DFT) induced by lidocaine is similar for electrical shocks with monophasic and biphasic waveforms. METHODS AND RESULTS: Twenty-six pentobarbital-anesthetized farm-raised pigs were instrumented with pacing catheters and epicardial defibrillation electrodes. Each pig was assigned to one of four groups: (1) monophasic shock waveform and placebo (5% dextrose in water [D5W]) (n = 7), (2) monophasic shock waveform and lidocaine (n = 7), (3) biphasic shock waveform and placebo (D5W) (n = 5), or (4) biphasic shock waveform and lidocaine (n = 7). DFT was measured at baseline and subsequently during treatment (D5W or lidocaine). In the monophasic waveform groups, DFT increased from baseline in response to lidocaine by 92% (P < .0001), whereas DFT values in response to D5W did not change. In the biphasic waveform groups, DFT values did not change from baseline in response to lidocaine (P = NS), whereas DFT values from baseline in response to D5W significantly decreased by 29% (P = .04). In the monophasic waveform groups, the change in DFT from baseline in response to lidocaine was significantly different than the change from baseline in response to D5W (92 +/- 29% versus -0.5 +/- 29%, respectively) (P < .0002). In the biphasic waveform groups, however, the change in DFT from baseline in response to lidocaine was similar to the change from baseline in response to D5W (-5.66 +/- 15% versus -29 +/- 17%, respectively) (P = .48). Furthermore, the change in DFT from baseline in response to lidocaine differed significantly between monophasic and biphasic waveform groups (92 +/- 29% versus -5.66 +/- 15%) (P < .0002), whereas the change from baseline in response to D5W did not differ between monophasic and biphasic waveforms (-0.5 +/- 29% versus -29 +/- 17%) (P = .34). CONCLUSIONS: Compared with placebo groups, DFT values increased during lidocaine treatment to a much greater degree in the monophasic waveform group than in the biphasic waveform group receiving lidocaine. These data support our hypothesis that antiarrhythmic drugs can affect the defibrillation efficacy of monophasic waveforms differently than that of biphasic waveforms.

Animals↗