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Biomedical subjects

D Newman

Publications and source records attributed to D Newman.

At least 73 records · Page 4Linked to original sources
PubMed1998

Peripheral blood mononuclear cells express mutated NCCT mRNA in Gitelman's syndrome: evidence for abnormal thiazide-sensitive NaCl cotransport.

Genetic analysis has demonstrated complete linkage between the human thiazide-sensitive sodium chloride cotransporter gene (NCCT or TSC) and Gitelman's syndrome (GS). Several genomic NCCT mutations have been reported. This study was performed to determine whether peripheral blood mononuclear cells (PBMC) express NCCT mRNA and whether defective PBMC NaCl cotransport could be demonstrated in GS. PBMC were isolated from two brothers with GS, their parents, and healthy control subjects. Northern analysis revealed that NCCT mRNA is expressed in PBMC. The sequence of full-length NCCT cDNA amplified from normal PBMC was identical to human renal NCCT cDNA. Two different mutations were detected in the patients' NCCT cDNA (compound heterozygote). In cDNA derived from the patient's maternal allele, exon 24 was deleted, resulting in a premature stop codon (after amino acid 920). cDNA derived from the patient's paternal allele had an additional 119-bp insertion between exons 3 and 4, generating a premature stop codon (after amino acid 187). The patient's genomic DNA had a previously described 5' splice site mutation in intron 24, GGT --> GTT (maternal allele), and a new 3' splice site mutation in intron 3, CAG --> CAA (paternal allele), which resulted in the activation of a nearby cryptic splice site in intron 3. The latter mutation was not present in 300 normal chromosomes. To determine the functional significance of these findings, chlorothiazide-inhibitable 22Na uptake was measured in PBMC from control subjects, the parents, and the patients with GS in the presence of bumetanide. In control PBMC, chlorothiazide inhibited 22Na uptake by approximately 9%. PBMC from the two patients with GS failed to respond to chlorothiazide. These results demonstrate that PBMC can be used for mutational analysis of NCCT mRNA in patients with GS. Furthermore, functional evidence is provided that the underlying cause of GS is defective NCCT NaCl cotransport.

Adult↗
PubMed1998

Implantable defibrillators and/or amiodarone: alternatives or complementary therapies.

Many patients with an implanted cardioverter defibrillator (ICD) also receive antiarrhythmic drug therapy. Although an expanding number of patients are receiving ICD therapy, many will not have received previous antiarrhythmic treatment. For patients with an ICD, infrequent arrhythmias and a low probability of inappropriate device discharges, no antiarrhythmic therapy is required. However, for those patients who require an antiarrhythmic drug, amiodarone is a reasonable first choice because of safety in patients with poor LV function. It may be particularly useful for patients with high density ventricular arrhythmias. However, the interactions between ICDs and antiarrhythmic therapy requires close monitoring in order that patient benefit can be optimised, and this review focuses on those interactions.

Aged↗
PubMed1997

A population-based method for the estimation of defibrillation energy requirements in humans. Assessment of time-dependent effects with a transvenous defibrillation system.

BACKGROUND: A weighted logistic regression analysis was developed to allow pooling of patient data for the study of the stability of defibrillation energy requirements with a new nonthoracotomy lead defibrillation system. METHODS AND RESULTS: One hundred twenty patients were prospectively studied with a single-model nonthoracotomy implantable cardioverter defibrillator (ICD) system at the time of implant and at 3 months. The pooled data of all shocks delivered to all patients were fitted to a logistic function to construct a defibrillation voltage/energy dose-response relationship. The crude logit curve was weighted in quartiles according to the average shock energy delivered per patient. Shocks at implant (n = 802; 6.6 +/- 2.5 shocks/patient) and follow-up (n = 292; 2.4 +/- 1.2 shocks/patient) were analyzed. The modeled voltage/energy required for 50% successful defibrillation (95% CI) in the pooled data was 367 V (273, 461) and 9.8 J (6.7, 12.9) at implant and 338 V (264, 412) and 10.5 J (8, 13.0) at follow-up. The conventional measure of lowest successful voltage/energy (95% CI) was 430 V (411, 449) and 12.1 J (11, 13.2) at implant and 415 V (391, 439) and 11.3 J (10, 12.6) at follow-up. There were no statistically significant differences between implant and follow-up energy requirements with either method. CONCLUSIONS: The nonthoracotomy lead system used in this study demonstrated stability of defibrillation energy requirements at implant and 3-month follow-up. A new technique for the estimation of the defibrillation energy dose-response relationship was derived by using a weighted logistic regression analysis.

Aged↗
PubMed1997

Human fibroblasts bind directly to fibrinogen at RGD sites through integrin alpha(v)beta3.

Fibroblast migration into the blood clot initially filling a wound requires close interaction between fibroblasts and the matrix of the fibrin clot. However, very little is known about the specific receptor-ligand interactions that mediate fibroblast attachment to fibrin. Using an attachment assay developed to measure even relatively weak interactions, we demonstrate here that normal human dermal fibroblasts can attach to substrates coated with fibrinogen, fibrin, or the fibrinogen breakdown product I-9D. Fibroblast attachment to these ligands did not require the presence of fibronectin on the cell surface or as a component of the substrate. Cells treated with cycloheximide and monensin, to limit the synthesis and secretion of endogenous fibronectin, attached as well as untreated cells. The synthetic peptide GRGDS inhibited adhesion to fibrinogen, fibrin, and fibrinogen I-9D by about 60%, while the control peptide GRGES had no substantial effect. We conclude that attachment to these ligands is mediated at least partially by direct interactions between the substrates and one specific receptor, the integrin alpha(v)beta3. Affinity chromatography demonstrated that alpha(v)beta3 from detergent lysates of fibroblasts bound to a fibrinogen matrix and was eluted with EDTA. Furthermore, antibodies against the alpha(v)beta3 complex or against the alpha(v) subunit inhibited fibroblast attachment to fibrinogen and fibrin by 50-70%. An inhibitory antibody against the integrin beta1 subunit had no effect. The observation that integrin antagonists could not produce complete inhibition suggests that there may be other fibroblast cell surface proteins that can bind directly to fibrinogen.

Cell Adhesion↗
PubMed1997

Circadian variation of sustained ventricular tachycardia in patients subject to standard adrenergic blockade.

Morning peaks in the circadian variation of sustained ventricular tachycardia (VT) may reflect the contribution of sympathetic activation to onset of VT. We hypothesized that adrenergic blockade would eliminate this morning peak. Fifty-four patients using a defibrillator had 1114 time-stamped episodes of VT requiring therapy with a device: 1012 episodes with and 102 episodes without antiadrenergic medications. Nine patients had episodes both with and without antiadrenergic medication and were examined separately. In patients taking antiadrenergic agents, data fitted to a harmonic regression model revealed a morning peak at 9:00 AM (R2= 0.542; p < 0.05), with a secondary peak at 4 PM. Those not receiving antiadrenergic therapy had a similar morning peak. Antiadrenergic agents as used in standard clinical practice do not prevent circadian variation in onset of VT. This variation may be mediated by systems other than adrenergic receptor-linked activation or may reflect inadequacy of adrenergic blockade in standard clinical dosing.

Adrenergic beta-Antagonists↗
PubMed1997

Tedisamil increases coherence during ventricular fibrillation and decreases defibrillation energy requirements.

INTRODUCTION: Drugs which primarily prolong cardiac refractoriness decrease defibrillation voltage and energy requirements in animals and man. The effect of such drugs on ventricular fibrillation itself is not well understood. We hypothesized that tedisamil, an investigational antiarrhythmic drug which blocks Ito and IK repolarizing potassium channels, would increase organization of epicardial electrograms during ventricular fibrillation while it lowered defibrillation energy requirements. METHODS: We measured magnitude-squared coherence, a measure of spatial organization, and ventricular fibrillation (VF) cycle length, ventricular effective refractory period (VERP), and monophasic action potential duration (APD90) as well as defibrillation energy threshold (E50) at baseline and after 150 micrograms/kg of tedisamil (n = 13) or saline control (n = 6) in an open chest dog model. RESULTS: After tedisamil, mean magnitude-squared coherence increased by 132 +/- 133%, from 0.15 +/- 0.08 to 0.31 +/- 0.16 (P < 0.001); VF cycle length increased from 121 +/- 24 to 190 +/- 63 ms (P < 0.001) and became more regular, with the coefficient of variation between adjacent VF intervals decreasing from 14.1 +/- 6.9 to 3.9 +/- 2.2% (P < 0.001). Mean E50 decreased from 8.9 +/- 3.8 to 6.1 +/- 2.7 joules (P < 0.001); VERP increased from 158 +/- 30 to 201 +/- 31 ms (P < 0.001), and APD90 increased from 177 +/- 25 to 244 +/- 45 ms (P < 0.001) after tedisamil. No electrophysiologic parameter was changed after saline infusion. CONCLUSIONS: Tedisamil increases both spatial coherence and temporal regularity of ventricular fibrillation. These effects on 'order' during VF may be in part responsible for the observed reduction in defibrillation energy requirements.

Animals↗
PubMed1997

Electrophysiologic mechanisms of antiarrhythmic efficacy of a sotalol and class Ia drug combination: elimination of reverse use dependence.

OBJECTIVES: We sought to determine the electrophysiologic mechanisms explaining the efficacy of combination therapy with DL-sotalol and a type Ia drug in the treatment of ventricular tachycardia (VT). BACKGROUND: Combination antiarrhythmic drug therapy with low dose DL-sotalol plus a type Ia antiarrhythmic agent has been shown to prevent spontaneous and induced VT. The mechanisms underlying the efficacy of this drug combination have not been fully elucidated. METHODS: We studied 32 patients with spontaneous sustained VT by using programmed electrical stimulation in the drug-free condition and after treatment with DL-sotalol (average dose [mean +/- SE] 151 +/- 8 mg/day) and a class Ia agent (quinidine, 1,337 +/- 59 mg/day, or procainamide, 2,083 +/- 327 mg/day). Sustained VT was induced in all patients at baseline study, and induction was reattempted during drug therapy. Monophasic action potential duration at 90% repolarization (APD90) and ventricular effective refractory period (ERP) were recorded with use of a contact electrode. RESULTS: Ventricular ERP increased from 258 +/- 4 ms at baseline to 310 +/- 6 ms at a 600-ms drive cycle length (DCL600) with treatment (p < 0.001). APD90 increased from 288 +/- 6 ms by +10.1% at DCL600 and from 267 +/- 7 ms by +13.3% at a 400-ms drive cycle length (DCL400) (p < 0.001). Paced QRS duration increased from 141 +/- 3 to 158 +/- 6 ms at DCL400 (p < 0.05). At baseline, the shortest achieved coupling interval between successive propagated extrastimuli decreased progressively with respect to the first extrastimulus, following double and triple extrastimuli, at both DCL600 (-14.0% and -20.0%, respectively) and at DCL400 (-16.4% and -22.4%, respectively). This "peeling back" of refractoriness was attenuated on therapy with sotalol plus a class Ia antiarrhythmic agent to -6.7% and -10.5% (DCL600, p < 0.05), and -8.1%, -9.5% (DCL400, p < 0.05), for double and triple extrastimuli, respectively. The absolute prolongation of functional refractory periods by the drug combination increased with successive extrastimuli, from 55 +/- 6 ms for the V1V2 interval to 75 +/- 6 ms for V2V3 and 67 +/- 6 ms for V3V4 at DCL600, and from 51 +/- 5 ms for V1V2 to 69 +/- 6 ms for V2V3 and 74 +/- 7 ms for V3V4 at DCL400 (p < 0.001). CONCLUSIONS: The combination of low dose sotalol and a class Ia agent greatly prolongs refractoriness. The magnitude of the effect increases at shorter coupling intervals.

Action Potentials↗
PubMed1997

Dual device therapy in the setting of changing ICD technology: device-device interaction revisited.

This case report concerns an adverse device-device interaction between a replacement ICD and a dual chamber rate responsive pacemaker. It was observed that subtle changes in the design of sensing circuits between an older first-generation ICD and the newer third-generation ICD device led to unexpected and dramatic changes in the interactive behavior of a dual device system. The new ICD was connected to chronically implanted hardware. The sensing behavior of the newer ICD included a shorter time constant in the decay of the automatic gain control function, resulting in triple sensing of both the atrial and ventricular paced stimuli and the evoked QRS complex. Physicians should be aware of new design changes in the future so as to anticipate such interactions. In the setting of rapidly changing technology, extra caution must be exercised when choosing to implant two devices in the same patient.

Aged↗
PubMed1997

Serial measures of sinoatrial and atrioventricular nodal function in ambulatory patients.

We hypothesized that the outpatient assessment of SA and AV nodal (SAN, AVN) function could be a useful tool to determine the effectiveness of drugs and other treatments. We sought to examine the reproducibility, safety and ease of acquiring serial measurements of these parameters. Ten patients with permanent pacemakers underwent low current chest wall stimulation while their device was programmed to unipolar atrial triggered mode. Measurements at multiple conditioning drive train frequencies were obtained for: sinus nodal recovery time (SNRT); corrected sinus nodal recovery time (CSNRT); SA conduction time (SACT); AVN block cycle length (AVNBCL); and AVN effective refractory period (AVNERP). AVN function curves were also constructed. All studies were repeated after 2 weeks. Measures of sinus nodal and AVN function did not show significant differences between the two studies. The following co-efficients of correlation were obtained: SNRT800, r = 0.79; CSNRT800, r = 0.71; SNRT600, r = 0.71; CSNRT600, r = 0.44; SACT, r = 0.75; AVNBCL, r = 0.98; AVNERP800, r = 0.55; and AVNERP600, r = 0.99. AVN function curves did not significantly differ between week 1 versus week 2 at conditioning drive trains of either 800 ms or 600 ms. These data suggest that serial noninvasive electrophysiological measures of AVN and SAN function are reproducible over 2 weeks. Using data in this study, estimates of the sample size necessary for the evaluation of the effects of investigational drugs on the SAN and AVN in future studies are possible.

Arrhythmia, Sinus↗
PubMed1997

Transcutaneous T wave shock: a universal method for ventricular fibrillation induction.

Our objective was to develop a universal noninvasive method for VF induction. ICD implantation requires VF induction. Conventional rapid ventricular stimulation may fail to induce VF. Some ICDs can deliver low energy shocks on the T wave to induce VF. We hypothesized that an external dual chamber pacemaker and an external defibrillator could be configured to allow reliable VF induction with any ICD system. A surface ECG signal was delivered to the atrial channel of an external dual chamber DDD pacemaker. The 'AV' delay was adjusted so that the ventricular output of the pacemaker was delivered to an external defibrillator synchronized to deliver 5-50 J. Twenty-six patients at ICD implant or follow-up had VF induced in native rhythm (sinus rhythm or atrial fibrillation), or during a ventricular pacing train (3-8 beats at cycle length 500-880 ms). VF was successfully induced in 14 of 25 (56%) patients in native rhythm; and in 16 of 17 (94%) patients during pacing (P = 0.013). VF induction success rate was 36% in native rhythm (31/86 attempts) and 88% during pacing (69/78 attempts) (P < 0.001). The 'R' to shock interval was 269 +/- 31 ms in native rhythm and 257 +/- 48 ms during pacing. Energy delivered from the external defibrillator was 19 +/- 3 J in native rhythm and 21 +/- 6 J during pacing. We concluded that VF induction by synchronizing a small external shock to the T wave is a fast, effective way to reliably ensure arrhythmia induction with any ICD at implant or follow-up. This method is more successful during pacing than in sinus rhythm.

Defibrillators, Implantable↗
PubMed1997

Do permanent pacemakers need an insulative coating? Results of a prospective randomized double-blind study.

During conventional manufacturing of implanted pulse generators (IPGs), an insulative coating is often applied to prevent local muscle stimulation and myopotential sensing in unipolar pacing. This can limit the orientation of the IPG into its pocket, be a potential source of muscle stimulation via coating scratches, and result in an increase in IPG production costs. We hypothesized that advances in the design and construction of current IPGs and leads obviates the need for an insulative coating of the IPG. Using a double-blind prospective randomized design, 39 patients were implanted with either coated or uncoated otherwise identical IPGs (19 dual, 20 single chamber). All testing was done in unipolar and bipolar mode in both channels. A strength-duration curve for muscle stimulation was constructed for all patients with muscle stimulation. Myopotential sensing was established during isometric exercise. At 6-month follow-up when tested in unipolar mode, 3 of 15 (20%) patients with coated IPGs and 3 of 20 (15%) with uncoated IPGs had muscle stimulation at 5.0 V/1.5 ms or lower (P = NS). No patients in either population had muscle stimulation at their normally programmed output. Myopotential sensing occurred in all patients in unipolar mode at a mean of 2.29 +/- 1.3 mV and 2.73 +/- 1.14 mV for coated versus uncoated, respectively (P = NS). The statistical power of these negative observations was 80%. An insulative coating for pacemakers does not appear to alter sensing performance or cause a significant difference in the occurrence or characteristics of muscle stimulation.

Adult↗
PubMed1996

Hyperaldosteronism and sudden cardiac death.

From a database of 130 implantable cardiac defibrillator recipients, 2 patients (1.5%) with sudden cardiac death as a presenting symptom, leading to diagnosis of primary hyperaldosteronism, are described. This is a newly described cause of sudden cardiac death, possibly more frequent than suspected, which should be considered in patients with malignant arrhythmias and hypokalemia.

Adult↗
PubMed1996

Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice.

In nonobese diabetic (NOD) mice, beta-cell reactive T-helper type 1 (Th1) responses develop spontaneously and gradually spread, creating a cascade of responses that ultimately destroys the beta-cells. The diversity of the autoreactive T-cell repertoire creates a major obstacle to the development of therapeutics. We show that even in the presence of established Th1 responses, it is possible to induce autoantigen-specific anti-inflammatory Th2 responses. Immune deviation of T-cell responses to the beta-cell autoantigen glutamate decarboxylase (GAD65), induced an active form of self-tolerance that was associated with an inhibition of disease progression in prediabetic mice and prolonged survival of syngeneic islet grafts in diabetic NOD mice. Thus, modulation of autoantigen-specific Th1/Th2 balances may provide a minimally invasive means of downregulating established pathogenic autoimmune responses.

Adoptive Transfer↗
PubMed1996

Management of intracardiac device recalls: a consensus conference. Participants of the Consensus Conference. North American Society of Cardiac Pacing and Electrophysiology (NASPE)

The incidence of cardiac device recalls seems to be increasing, in part due to increasing complexity, but also due to greater public awareness and regulatory overview. Manufacturers are responsible for postmarket surveillance of their implanted products; evidence for poor performance is usually evaluated by a Physician Advisory Committee (PAC) and unacceptable failure rates or modes prompt the issuance of a recall. A Consensus Conference was held March 6, 1995, in Toronto, Ontario, to discuss the management of cardiac device recalls after the provincial Ministry of Health issued unique guidelines regarding a recent lead problem. Various stakeholders expressed their views and concerns: the federal regulatory body, the provincial Ministry of Health and hospital association, manufacturers, hospital legal counsel, patient and media advocates, and physicians from the United Kingdom, the United States, and Canada. Specific recommendations included: the establishment of a National (or regional) Pacemaker (device/lead) Registry interposed between the manufacturer and the federal authority; the creation of a Recall Task Force (RTF) to deal with specific problems distinct from the manufacturers' PAC; emphasis on patient responsibility for obtaining regular follow-up and maintaining contact by a pacemaker passport system as exists in Europe; and the fair assignment of costs involved in a recall with specific emphasis on appropriate compensation for physicians and clinic personnel.

Defibrillators, Implantable↗
PubMed1996

d-Sotalol decreases defibrillation energy requirements in humans: a novel indication for drug therapy.

INTRODUCTION: We assessed the effect of d-sotalol on defibrillation voltage and energy requirements in patients undergoing automatic defibrillator implantation. Drugs that primarily prolong cardiac refractoriness generally decrease the energy requirements for defibrillation in animal models. Despite the widespread use of antiarrhythmic drugs in patients with implanted cardioverter defibrillators, the effect of such drugs on defibrillation energy requirements in humans has not been well studied. Sotalol (in the d,l racemic form) is an antiarrhythmic with beta-blocking and cardiac refractoriness prolonging effects. The d-isomer of sotalol is largely devoid of beta-blocking effects; both forms decrease defibrillation energy requirements in animals. We hypothesized that d-sotalol would decrease defibrillation voltage and energy requirements in humans. METHODS AND RESULTS: Fifteen patients undergoing implanted cardioverter defibrillator implantation were studied before and 20 minutes after d-sotalol infusion (2 mg/kg IV in 15 min, followed by 1 mg/kg per hour). The estimated energy (E50) and voltage (V50) for 50% success in defibrillation (estimated from two successive defibrillation "threshold" measurements), ventricular effective refractory period, monophasic action potential duration, and mean cycle length of ventricular fibrillation were measured, along with heart rate, blood pressure, and plasma concentration of d-sotalol. There was a significant decrease in defibrillation energy (E50 = 12.4 +/- 5.0 J before and 8.4 +/- 4.0 J after d-sotalol, P < 0.003) and voltage (V50 = 440 +/- 77 V before and 354 +/- 93 V after d-sotalol, P < 0.001). Consistent with the Class III effect of d-sotalol, ventricular effective refractory period increased from 284 +/- 21 to 330 +/- 24 msec (P < 0.001), and action potential duration was prolonged from 296 +/- 28 to 340 +/- 22 msec (P < 0.001). Following d-sotalol, there was a tendency for induced tachyarrhythmia to self-terminate (23/102 episodes before vs 74/150 after sotalol, P < 0.001), and ventricular fibrillation cycle length was increased from 216 +/- 20 msec before to 274 +/- 23 msec (P < 0.001) after d-sotalol, despite the persistence of a rapid, disorganized rhythm of the surface ECG. No patient suffered adverse effects. CONCLUSIONS: d-Sotalol lowers defibrillation energy by a mean 32% +/- 27% at concentrations producing a 16% +/- 7% increase in ventricular effective refractory period. Along with its other antiarrhythmic effects, d-sotalol may increase the safety margin for defibrillation or allow lower programmed energies in patients with implanted defibrillators.

Adrenergic beta-Antagonists↗