Feedback: real-time delayed vision of one's own tracking behavior.

When a televised display of a person's owni behavior in pursuit tracking is delayed, his performance, as measured by time on target, is seriously degraded. Data for six subjects on two trackitng pattertns under seven delay values reveal a linear inverse relationship between the logarithm of the time on target and the magnitude of delay.

Evaluation of DualMesh for repair of large hiatus hernia in a porcine model.

BACKGROUND: Prosthetic fascial grafts are frequently used for augmentation of cruroplasty in large hiatus hernia repair to decrease the chances of recurrence. Potential complications such as intraluminal erosion may be related to the constant movement of mesh and diaphragm over the outer surface of the esophagus. This study aimed to evaluate DualMesh for repair of large hiatal defects in a porcine model. METHODS: In this study, 18 Landrace x large white x Duroc crossbred pigs underwent either primary hiatal repair or tension-free prosthetic repair using DualMesh (80 x 50 mm or 80 x 100 mm). The animals were killed at 3 or 28 weeks for macroscopic and histologic evaluation of the hiatal region and gastroesophageal junction. RESULTS: All grafts had become encapsulated at 28 weeks, and the majority had filmy adhesions only to the visceral aspect. In all models, the esophagus moved freely over the cut edge of the prosthesis. No signs of intraluminal erosion were documented. At histologic examination, significant ingrowth was noted on the porous side of the mesh, whereas no defined mesothelial layer was identified on the capsule of the nonporous side. CONCLUSION: In this animal model of large hiatus hernia repair, DualMesh showed optimal characteristics in terms of host tissue incorporation on the porous side and absence of adhesions on the visceral side of the prosthesis. The absence of adhesions and intraluminal erosion in this study may provide reassurance to surgeons using mesh at the hiatus.

Stimulus-induced critical point. Mechanism for electrical initiation of reentry in normal canine myocardium.

The hypothesis was tested that the field of a premature (S2) stimulus, interacting with relatively refractory tissue, can create unidirectional block and reentry in the absence of nonuniform dispersion of recovery. Simultaneous recordings from a small region of normal right ventricular (RV) myocardium were made from 117 to 120 transmural or epicardial electrodes in 14 dogs. S1 pacing from a row of electrodes on one side of the mapped area generated parallel activation isochrones followed by uniform parallel isorecovery lines. Cathodal S2 shocks of 25 to 250 V lasting 3 ms were delivered from a mesh electrode along one side of the mapped area to scan the recovery period, creating isogradient electric field lines perpendicular to the isorecovery lines. Circus reentry was created following S2 stimulation; initial conduction was distant from the S2 site and spread towards more refractory tissue. Reentry was clockwise for right S1 (near the septum) with top S2 (near the pulmonary valve) and for left S1 with bottom S2; and counterclockwise for right S1 with bottom S2 and left S1 with top S2. The center of the reentrant circuit for all S2 voltages and coupling intervals occurred at potential gradients of 5.1 +/- 0.6 V/cm (mean +/- standard deviation) and at preshock intervals 1 +/- 3 ms longer than refractory periods determined locally for a 2 mA stimulus. Thus, when S2 field strengths and tissue refractoriness are uniformally dispersed at an angle to each other, circus reentry occurs around a "critical point" where an S2 field of approximately 5 V/cm intersects tissue approximately at the end of its refractory period.

Activation during ventricular defibrillation in open-chest dogs. Evidence of complete cessation and regeneration of ventricular fibrillation after unsuccessful shocks.

To test the hypothesis that a defibrillation shock is unsuccessful because it fails to annihilate activation fronts within a critical mass of myocardium, we recorded epicardial and transmural activation in 11 open-chest dogs during electrically induced ventricular fibrillation (VF). Shocks of 1-30 J were delivered through defibrillation electrodes on the left ventricular apex and right atrium. Simultaneous recordings were made from septal, intramural, and epicardial electrodes in various combinations. Immediately after all 104 unsuccessful and 116 successful defibrillation shocks, an isoelectric interval much longer than that observed during preshock VF occurred. During this time no epicardial, septal, or intramural activations were observed. This isoelectric window averaged 64 +/- 22 ms after unsuccessful defibrillation and 339 +/- 292 ms after successful defibrillation (P less than 0.02). After the isoelectric window of unsuccessful shocks, earliest activation was recorded from the base of the ventricles, which was the area farthest from the apical defibrillation electrode. Activation was synchronized for one or two cycles following unsuccessful shocks, after which VF regenerated. Thus, after both successful and unsuccessful defibrillation with epicardial shocks of greater than or equal to 1 J, an isoelectric window occurs during which no activation fronts are present; the postshock isoelectric window is shorter for unsuccessful than for successful defibrillation; unsuccessful shocks transiently synchronize activation before fibrillation regenerates; activation leading to the regeneration of VF after the isoelectric window for unsuccessful shocks originates in areas away from the defibrillation electrodes. The isoelectric window does not support the hypothesis that defibrillation fails solely because activation fronts are not halted within a critical mass of myocardium. Rather, unsuccessful epicardial shocks of greater than or equal to 1 J halt all activation fronts after which VF regenerates.

Shock-induced figure-of-eight reentry in the isolated rabbit heart.

The patterns of transmembrane potential on the whole heart during and immediately after fibrillation-inducing shocks are unknown. To study arrhythmia induction, we recorded transmembrane activity from the anterior and posterior epicardial surface of the isolated rabbit heart simultaneously using 2 charge-coupled device cameras (32,512 pixels, 480 frames/second). Isolated hearts were paced from the apex at a cycle length of 250 ms. Two shock coils positioned inside the right ventricle (-) and atop the left atrium (+) delivered shocks at 3 strengths (0.75, 1.5, and 2.25 A) and 6 coupling intervals (130 to 230 ms). The patterns of depolarization and repolarization were similar, as is evident in the uniformity of action potential duration at 75% repolarization (131.4¿8.3 ms). At short coupling intervals (<180 ms), shocks hyperpolarized a large portion of the ventricles and produced a pair of counterrotating waves, one on each side of the heart. The first beat after the shock was reentrant in 90% of short coupling interval episodes. At long coupling intervals (>180 ms), increasingly stronger shocks depolarized an increasingly larger portion of the heart. The first beat after the shock was reentrant in 18% of long coupling interval episodes. Arrhythmias were most often induced at short coupling intervals (98%) than at long coupling intervals (35%). The effect and outcome of the shock were related to the refractory state of the heart at the time of the shock. Hyperpolarization occurred at short coupling intervals, whereas depolarization occurred at long coupling intervals. Consistent with the "critical point" hypothesis, increasing shock strength and coupling interval moved the location where reentry formed (away from the shock electrode and pacing electrode, respectively).

PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1 arrest followed by cell death.

PTEN/MMAC1/TEP1, a tumor suppressor gene, is frequently mutated in a variety of human cancers. Germ-line mutations of phosphatase and tensin homolog, deleted on chromosome ten (PTEN) are found in two inherited hamartoma tumor syndromes: Cowden syndrome, which has a high risk of breast, thyroid, and other cancers; and Bannayan-Zonana syndrome, a related disorder. PTEN encodes a phosphatase that recognizes both protein substrates and phosphatidylinositol-3,4,5-triphosphate. The lipid phosphatase activity of PTEN seems to be important for growth suppression through inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. We established clones with stable PTEN expression controlled by a tetracycline-inducible system to examine the consequences of increased levels of wild-type and mutant PTEN expression in a well-characterized breast cancer line, MCF-7. When we overexpressed PTEN in MCF-7, growth suppression was observed, but only if PTEN phosphatase activity is preserved. The initial growth suppression was attributable to G1 cell cycle arrest, whereas subsequent growth suppression was attributable to a combination of G1 arrest and cell death. Of note, the decrease in Akt phosphorylation preceded the onset-of suppression of cell growth. Treatment of MCF-7 cells with wortmannin, a PI3K inhibitor, caused cell growth inhibition in a way similar to the effects of overexpression of PTEN in this cell. In general, the inverse correlation between PTEN protein level and Akt phosphorylation was found in a panel of breast cancer cell lines. Therefore, PTEN appears to suppress breast cancer growth through down-regulating PI3K signaling, which leads to the blockage of cell cycle progression and the induction of cell death, in a sequential manner.

Ventricular defibrillation with triphasic waveforms.

BACKGROUND: It has been reported that triphasic defibrillation waveforms cause less myocardial injury than biphasic waveforms. This study compared the defibrillation thresholds (DFTs) of triphasic and biphasic waveforms. METHODS AND RESULTS: ++DFTs were determined for a transvenous lead system and a 300-microF-capacitor defibrillator. In 8 pigs (group 1), DFTs were determined for 5 triphasic waveforms with tilts of 80%, 83%, and 86% and for 1 biphasic waveform. DFTs were determined in another 8 pigs (group 2) for 2 triphasic and 4 biphasic waveforms with tilts of 43%, 49%, and 56%. In both groups, a biphasic waveform from a 140-microF-capacitor defibrillator was also evaluated, and both shock polarities were tested for each waveform. In group 1, with the 300-microF-capacitor defibrillator, the leading-edge voltage and energy stored at DFT were significantly lower for triphasic waveforms with phase-duration ratios of 50/33/17 and an anode at the right ventricular electrode for phase 1 than for biphasic waveforms (P<0.001). In group 2, the stored energy of triphasic waveforms with 56% and 49% tilt was significantly lower than that of biphasic waveforms with the same tilts for anodal but not cathodal phase 1 at the right ventricular electrode. Electrode polarity significantly affected the DFT of triphasic waveforms for both studies. CONCLUSIONS: Some 80% tilt triphasic waveforms defibrillate more efficiently than biphasic waveforms with a 300-microF-capacitor defibrillator. The triphasic waveforms for both groups were not superior to 140-microF-capacitor biphasic waveforms. The efficacy of triphasic waveforms depends on phase durations and electrode polarity.

Improvement of defibrillation efficacy and quantification of activation patterns during ventricular fibrillation in a canine heart failure model.

BACKGROUND: Little is known about the effects of heart failure (HF) on the defibrillation threshold (DFT) and the characteristics of activation during ventricular fibrillation (VF). METHODS AND RESULTS: HF was induced by rapid right ventricular (RV) pacing for at least 3 weeks in 6 dogs. Another 6 dogs served as controls. Catheter defibrillation electrodes were placed in the RV apex, the superior vena cava, and the great cardiac vein (CV). An active can coupled to the superior vena cava electrode served as the return for the RV and CV electrodes. DFTs were determined before and during HF for a shock through the RV electrode with and without a smaller auxiliary shock through the CV electrode. VF activation patterns were recorded in HF and control animals from 21x24 unipolar electrodes spaced 2 mm apart on the ventricular epicardium. Using these recordings, we computed a number of quantitative VF descriptors. DFT was unchanged in the control dogs. DFT energy was increased 79% and 180% (with and without auxiliary shock, respectively) in HF compared with control dogs. During but not before HF, DFT energy was significantly lowered (21%) by addition of the auxiliary shock. The VF descriptors revealed marked VF differences between HF and control dogs. The differences suggest decreased excitability and an increased refractory period during HF. Most, but not all, descriptors indicate that VF was less complex during HF, suggesting that VF complexity is multifactorial and cannot be expressed by a scalar quantity. CONCLUSIONS: HF increases the DFT. This is partially reversed by an auxiliary shock. HF markedly changes VF activation patterns.

Reduction of atrial defibrillation threshold with an interatrial septal electrode.

BACKGROUND: The standard lead configuration for internal atrial defibrillation consists of a shock between electrodes in the right atrial appendage (RAA) and coronary sinus (CS). We tested the hypothesis that the atrial defibrillation threshold (ADFT) of this RAA-->CS configuration would be lowered with use of an additional electrode at the atrial septum (SP). METHODS AND RESULTS: Sustained atrial fibrillation was induced in 8 closed-chest sheep with burst pacing and continuous pericardial infusion of acetyl-ss-methylcholine. Defibrillation electrodes were situated in the RAA, CS, pulmonary artery (PA), low right atrium (LRA), and across the SP. ADFTs of RAA-->CS and 4 other lead configurations were determined in random order by use of a multiple-reversal protocol. Biphasic waveforms of 3/1-ms duration were used for all single and sequential shocks. The ADFT delivered energies for the single-shock configurations were 1.27+/-0.67 J for RAA-->CS and 0. 86+/-0.59 J for RAA+CS-->SP; the ADFTs for the sequential-shock configurations were 0.39+/-0.18 J for RAA-->SP/CS-->SP, 1.16+/-0.72 J for CS-->SP/RAA-->SP, and 0.68+/-0.46 J for RAA-->CS/LRA-->PA. Except for CS-->SP/RAA-->SP versus RAA-->CS and RAA-->CS/LRA-->PA versus RAA+CS-->SP, the ADFT delivered energies of all of the configurations were significantly different from each other (P:<0. 05). CONCLUSIONS: The ADFT of the standard RAA-->CS configuration is markedly reduced with an additional electrode at the atrial SP.

Localization of septal pacing sites in the dog heart by epicardial mapping.

To examine whether different septal pacing sites could be distinguished by their epicardial activation patterns, six to eight stimulating electrodes were placed throughout the septum in seven open chest dogs. Unipolar electrograms were obtained from 52 epicardial electrodes during pacing from each stimulating electrode and isochronous epicardial maps were constructed. The location of each stimulating electrode was found by dissection, and its distance from the overlying epicardium was measured. To allow comparison among epicardial maps, the septum was conceptually subdivided into nine regions to which stimulating electrodes were assigned. Epicardial activation patterns from the same region were similar and these patterns allowed the region containing a stimulating electrode to be identified in many cases. Three other variables were found to have additional localizing value. There were: 1) the time from the stimulus to epicardial breakthrough, 2) the duration of epicardial activation, and 3) the area of epicardium activated in the first 5 ms after epicardial breakthrough. For those stimulating electrodes that could not be localized by their epicardial activation patterns, the distance of the stimulating electrode beneath the epicardium was well fit from these three variables by multiple regression (correlation coefficient [r] = 0.97). Thus, using all the previous factors, localization of septal pacing sites was possible in the noninfarcted dog heart by epicardial mapping.

The effects of ventricular fibrillation duration and site of initiation on the defibrillation threshold during early ventricular fibrillation.

OBJECTIVES: The purpose of this study was to determine if the defibrillation threshold (DFT) is lower during the first few cycles of ventricular fibrillation (VF) than after 10 s of VF and, if so, if the effect is caused by local or global factors. BACKGROUND: The DFT may be low very early during VF because: (1) for the first few cycles VF arises from a localized region close to a defibrillation electrode where the shock field is strong (local factors), or (2) during early VF the effects of ischemia and sympathetic discharge have not yet fully developed and the heart has not yet completely dilated (global factors). METHODS: Protocol 1 included seven pigs in which a defibrillation electrode and a pacing catheter were both placed in the right ventricular apex. VF was induced by delivering a high current premature stimulus from the pacing catheter that should have caused reentry confined to the right ventricular apex for the first few cycles of VF. A bipolar electrogram was recorded from the tip of the defibrillation catheter. Using a three reversal up-down protocol, the DFT was determined for biphasic shocks delivered after 1, 2, 3, 4, 5, 7, 10, 15, 20 and 25 activations in this electrogram and after 10 s (control). Protocol 2 included seven pigs undergoing the same procedure as in protocol 1 except that an additional pacing catheter was placed in the left ventricle. Defibrillation thresholds were determined after 1, 2, 3, 4 and 5 VF activations following VF induction from the right ventricle (RV) or the left ventricle (LV) and after 10 s (control). RESULTS: In protocol 1, the mean +/- SD DFrs were lower during the first three cycles than after 10 s of VF (3.0 +/- 4.1 J for the first VF cycle vs 15.8 +/- 6.6 J after 10 s of VF, p < 0.05). In protocol 2, the DFF for the first few cycles of VF induced away from the defibrillation electrode in the LV (6.9 +/- 1.4 J for the first VF cycle) was significantly lower than that after 10 s of VF (16.0 +/- 2.2 J), whereas the DFF for the first few cycles induced near the defibrillation electrode in the right ventricular apex was significantly lower (2.3 +/- 2.7 J for the first VF cycle) than that induced from the LV. CONCLUSIONS: This study demonstrates that the DFT is significantly lower during the first few VF cycles of VF than after 10 s of VF and that this decrease may be caused by both local factors and global factors. These results provide an impetus for exploring earlier shock delivery in implantable devices.

Ventricular defibrillation using biphasic waveforms: the importance of phasic duration.

Biphasic waveforms can be used to defibrillate the heart with less energy than that used by monophasic waveforms. In 14 anesthetized open chest dogs with large contoured defibrillation electrodes, the effect on defibrillation efficacy of varying the duration of the two phases of biphasic waveforms was studied. All combinations of 0, 1, 3.5, 6 and 8.5 ms duration were used for both the first and the second phase except for the meaningless case in which both durations were 0 ms. The 3.5-2 waveform (3.5 ms first phase and 2 ms second phase) was also tested. All the hearts were defibrillated with less than or equal to 5 joules using any of the 25 waveforms. However, biphasic waveforms with the second phase shorter than or equal to the first had significantly lower defibrillation thresholds than did those with the second phase longer than the first or than did monophasic waveforms of approximately the same total duration. A plot of defibrillation threshold current strength versus second phase duration for all biphasic waveforms with a 3.5 ms first phase did not produce a hyperbolic strength-duration curve as seen with monophasic waveforms. To verify these findings, defibrillation dose-response curves were obtained for the 3.5-2, 6-6 and 3.5-8.5 biphasic waveforms in another six dogs. The 50 and 80% successful voltage doses of the 3.5-8.5 waveforms were significantly higher than those of the other two waveforms, which were not different from one another.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the internal defibrillation thresholds for monophasic and double and single capacitor biphasic waveforms.

Implantable cardiac defibrillators are now an accepted form of therapy for patients with life-threatening ventricular arrhythmias that cannot be controlled by antiarrhythmic drugs. These devices could be made even more acceptable if they were smaller, had increased longevity and the surgical procedure for implantation was less invasive. Reducing the energy requirements for internal defibrillation with use of a nonthoracotomy system would make all of these goals achievable. Monophasic and double and single capacitor biphasic waveforms were compared in 14 anesthetized dogs (25.5 +/- 2.2 kg) with use of a nonthoracotomy lead system that has previously been shown to distribute the delivered voltage throughout the heart more equally. Cathodal catheter electrodes were placed in the right ventricular apex and outflow tract. The anodal electrode was a large cutaneous R2 patch placed over the left side of the chest. The mean energy requirement for defibrillation when a single capacitor biphasic waveform was used was significantly less (6.4 +/- 2.6 J) than that for either the double capacitor biphasic or the monophasic waveform (18.0 +/- 8.0 and 17.4 +/- 8.0 J, respectively) of the same duration. Unexpectedly, the leading edge voltage for the phase I of the single capacitor biphasic waveform was significantly less (266 +/- 51 V) than that for either the double capacitor biphasic or the monophasic waveform (336 +/- 76 and 427 +/- 117 V, respectively). In conclusion, in large dogs, defibrillation is possible at low energy levels with a single capacitor biphasic waveform.

Comparison of defibrillation probability of success curves for an endocardial lead configuration with and without an inactive epicardial patch.

OBJECTIVES: This study sought to assess the effect of passive "bystander" epicardial electrodes on defibrillation efficacy. BACKGROUND: We hypothesized that an inactive epicardial patch placed in an area of low potential gradient from an endocardial electrode shock might affect defibrillation efficacy through its effects on the shock field and the underlying potential gradient. METHODS: We studied the effects of an inactive 18-cm2 titanium mesh patch placed on the anterolateral left ventricular epicardium on the 50% probability of successful defibrillation. A biphasic shock with both phases 6 ms in duration was delivered between superior vena cava and right ventricular catheter electrodes 10 s after the electrical induction of ventricular fibrillation. Six dogs underwent an up/down defibrillation protocol randomized with or without the patch on the heart. RESULTS: Mean 50% (+/-) probability point for energy doubled with the conductive patch on the heart, from 8.0 +/- 3.2 to 16.8 +/- 7.0 J (p < 0.01), and leading-edge voltage increased from 334 +/- 64 to 477 +/- 98 V (p < 0.01). Mean 50% probability points for energy and leading-edge voltage were not significantly changed when the procedure was repeated using a nonconductive patch in another six dogs as a control group. In a saline-saturated foam model, measurements from electrodes placed around and under the patch revealed a 72% mean decrease in the potential gradient in the foam under the conductive patch. CONCLUSIONS: A passive defibrillator patch can markedly increase the energy requirements for defibrillation, probably by decreasing the potential gradient under the patch. These results suggest the use of caution when passive electrodes are present, for example, when a patient receives a nonthoracotomy defibrillator system while epicardial electrodes from a previously implanted system are left in place.

Comparison of time domain and frequency domain variables from the signal-averaged electrocardiogram: a multivariable analysis.

The relative values of the unprocessed signal-averaged electrocardiogram (ECG) and time domain analysis and frequency domain analysis of the signal-averaged ECG were compared in 36 patients with sustained monomorphic ventricular tachycardia and a remote myocardial infarction, in 29 asymptomatic patients with a remote myocardial infarction and in 23 normal subjects. Area ratios of the energy spectra derived from fast Fourier transform analysis were calculated using six separate 140 ms intervals starting at 0, 40, 50 and 60 ms after QRS onset; 40 and 50 ms before QRS end and a variable length interval starting 40 ms before QRS end and extending to the T wave. Total filtered QRS duration, late potential duration and root mean square voltage of the terminal QRS complex were measured from the filtered vector magnitude signal-averaged ECG. The total QRS duration was also measured from the X, Y, Z leads of the unfiltered signal-averaged ECG. Seven variables were significantly different in univariate tests between myocardial infarction patients with and without ventricular tachycardia: three fast Fourier transform area ratios with the sampling interval starting at 1) QRS onset (p = 0.007), 2) 40 ms after QRS onset (p = 0.02), and 3) 60 ms after QRS onset (p less than 0.0001); and all four time domain variables at 1) total filtered QRS duration (p less than 0.0001), 2) late potential duration (p = 0.0001), 3) root mean square terminal QRS voltage (p = 0.0001), and 4) QRS duration from the unprocessed signal-averaged ECG (p less than 0.0001). Of these seven variables, only the fast Fourier transform area ratio starting at QRS onset was significantly different between patients with myocardial infarction without ventricular tachycardia and normal subjects. In multi-variable analysis, the total filtered vector magnitude QRS duration, a time domain variable that includes the late potential, was the only independent factor that separated patients with myocardial infarction with and without associated ventricular tachycardia.

Effect of a passive endocardial electrode on defibrillation efficacy of a nonthoracotomy lead system.

OBJECTIVES: We investigated the impact of an inactive endocardial lead on the 50% effective dose (ED50%) for successful ventricular defibrillation. BACKGROUND: The presence of abandoned epicardial mesh patch electrodes detrimentally affects the defibrillation efficacy of an endocardial lead system. It is not known whether abandoned endocardial electrodes produce a similar effect. METHODS: An endocardial lead system (ENDOTAK, model 0062, Cardiac Pacemakers, Inc.) was implanted in eight dogs (mean +/- SD weight 23.7 +/- 1.0 kg). The ED50% for each of seven lead configurations was determined by a three-reversal point protocol in a balanced-randomized order with and without a second electrically passive endocardial lead system in the right ventricle (power 0.97 to detect a 50-V difference). Biphasic shocks with 80% tilt were delivered 10 s after the induction of ventricular fibrillation. In one configuration the active electrode made contact with the passive electrode in the right ventricular (RV) apex. In another configuration the active electrode was placed in a more proximal position to avoid contact. Additionally, the ED50% was determined for the endocardial lead system with a passive pacing lead positioned in the RV apex. RESULTS: ED50% values for peak voltage, peak current and delivered energy were not significantly different with or without a passive RV electrode, and this was true whether or not the active electrode touched the passive electrode. However, ED50% values were significantly higher when the active electrode was slightly proximal than when it was positioned at the apex. CONCLUSIONS: Physical contact between active and passive endocardial electrodes does not significantly alter defibrillation efficacy in this dog model. An increase in ED50% energy was caused by a slightly proximal position. Therefore, a good electrode position within the right ventricle is a more important determinant of defibrillation efficacy than is avoidance of the electrode touching a passive electrode.

Over-representation of PPARgamma sequence variants in sporadic cases of glioblastoma multiforme: preliminary evidence for common low penetrance modifiers for brain tumour risk in the general population.

PPARgamma, the gamma isoform of a family of peroxisome proliferator activated receptors, plays a key role in adipocyte differentiation. Recently, its broad expression in multiple tissues and several epithelial cancers has been shown. Further, somatic loss of function mutations in PPARgamma have been found in primary colorectal carcinomas. We sought to determine if somatic high penetrance mutations in this gene might also play a role in glioblastoma multiforme (GBM). We also examined this gene to determine if common low penetrance polymorphic alleles might lend low level susceptibility to GBM in the general population. No somatic high penetrance mutations were detected in 96 sporadic GBMs. However, polymorphic alleles at codons 12 and 449 were significantly over-represented among the 27 unrelated American patients with sporadic GBM compared to 80 race matched controls. While nine (33%) were heterozygous for the P12A variant, c.34C/G (cytosine to guanine change at nucleotide 34), 12 (15%) controls were heterozygous for P12A (p<0.05). Similarly, 13 of 26 (50%) glioblastoma patients compared to 10 of 80 (12%) normal controls were found to have the heterozygous H449H polymorphism (p<0.001). The over-representation of H449H in glioblastoma patients was confirmed with a second validation set of American patients. When both American series were combined, polymorphic H449H was over-represented among cases versus controls (p<0.001) and there was a similar trend (p=0.07) for P12A. The precise mechanism for this association is unknown but these PPARgamma polymorphisms may be acting in a low penetrance predisposing manner. However, these associations were not found in a German population, possibly arguing that if these variants are in linkage disequilibrium with a third locus, then this effect is relatively new, after the settlement of the American colonies.

Hypertension management in the Multiple Risk Factor Intervention Trial (MRFIT). Six-year intervention results for men in special intervention and usual care groups.

The Multiple Risk Factor Intervention Trial was a large collaborative primary prevention trial designed to test the effects of lowering cardiovascular risk factors (ie, diastolic blood pressure [DBP], serum cholesterol, and cigarette smoking) on mortality rate from coronary heart disease in 12,866 high-risk men aged 35 to 57 years. Men were randomly assigned to either special intervention (SI) or usual care (UC) groups. Usual care men were referred to their regular source of medical care. Special intervention men were seen frequently and underwent intensive intervention initially followed by maintenance intervention in 22 different clinical centers. Hypertension intervention in SI men primarily consisted of a stepped-care pharmacologic approach designed to lower blood pressure (BP). After six years, 58.2% of SI men and 47.0% of UC men were given antihypertensive medication. In both study groups, mean systolic and diastolic BPs decreased from baseline; after six years, overall DBP was 3.2 mm Hg lower in SI men compared with UC men. In hypertensive men (DBP greater than or equal to 90 mm Hg or those taking antihypertensive medication at baseline), after six years, DBP was 4.4 mm Hg lower in the SI group compared with the UC group. Use of specific antihypertensive agents differed substantially between the two groups. Self-reported complaints while taking antihypertensive drugs were minimal in both groups. Weight loss was associated with BP lowering in both study groups, regardless of treatment status.

Rapid construction of a patient-specific torso model from 3D ultrasound for non-invasive imaging of cardiac electrophysiology.

One of the main limitations in using inverse methods for non-invasively imaging cardiac electrical activity in a clinical setting is the difficulty in readily obtaining high-quality data sets to reconstruct accurately a patient-specific geometric model of the heart and torso. This issue was addressed by investigation into the feasibility of using a pseudo-3D ultrasound system and a hand-held laser scanner to reconstruct such a model. This information was collected in under 20 min prior to a catheter ablation or pacemaker study in the electrophysiology laboratory. Using the models created from these data, different activation field maps were computed using several different inverse methods. These were independently validated by comparison of the earliest site of activation with the physical location of the pacing electrodes, as determined from orthogonal fluoroscopy images. With an estimated average geometric error of approximately 8 mm, it was also possible to reconstruct the site of initial activation to within 17.3 mm and obtain a quantitatively realistic activation sequence. The study demonstrates that it is possible rapidly to construct a geometric model that can then be used non-invasively to reconstruct an activation field map of the heart.

Pharmacodynamics and pharmacokinetics of oral pirmenol.

The efficacy, pharmacokinetics, and pharmacodynamics of pirmenol, a class Ia antiarrhythmic agent, were studied in patients with frequent symptomatic premature ventricular complexes (PVCs). Pirmenol was given every 12 hours to eight patients in a dose-ranging protocol, and median PVC suppression of 94% (range 72% to 100%) was achieved. The median effective pirmenol dose was 300 mg/day (range 200 to 500 mg/day), and mean (+/- SD) trough plasma pirmenol concentration at the effective dose was 0.98 +/- 0.29 micrograms/ml. The mean half-life of elimination was 10.5 +/- 2 hours. There was considerable overlap among patients with respect to plasma pirmenol concentration and times at which PVC frequency returned to 25%, 50%, and 75% of baseline during drug washout trials. Altering pirmenol's dose interval (while maintaining a constant daily dose) from 12 to 6 hours did not improve drug efficacy. Pirmenol was given to seven patients for long-term therapy (24 to 44 months). Median PVC suppression at 24 months was 70%. Pirmenol is safe and well tolerated, and it can be administered twice daily for PVC suppression.