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Biomedical subjects

T Church

Publications and source records attributed to T Church.

At least 19 recordsLinked to original sources
PubMed2005

Evidence for a multivalent interaction of symmetrical, N-linked, lidocaine dimers with voltage-gated Na+ channels.

The interaction of symmetrical lidocaine dimers with voltage-gated Na+ channels (VGSCs) was examined using a FLIPR membrane potential assay and voltage-clamp. The dimers, in which the tertiary amines of the lidocaine moieties are linked by an alkylene chain (two to six methylene units), inhibited VGSC activator-evoked depolarization of cells heterologously-expressing rat (r) Na(v)1.2a, human (h) Na(v)1.5, and rNa(v)1.8, with potencies 10- to 100-fold higher than lidocaine (compound 1). The rank order of potency (C4 (compound 4) > C3 (compound 3) > or = C2 (compound 2) = C5 (compound 5) = C6 (compound 6) >> compound 1) was similar at each VGSC. Compound 4 exhibited strong use-dependent inhibition of hNa(v)1.5 with pIC50 values < 4.5 and 6.0 for tonic and phasic block, respectively. Coincubation with local anesthetics but not tetrodotoxin attenuated compound 4-mediated inhibition of hNa(v)1.5. These data suggest that the compound 4 binding site(s) is identical, or allosterically coupled, to the local anesthetic receptor. The dissociation rate of the dimers from hNa(v)1.5 was dependent upon the linker length, with a rank order of compound 1 > compound 5 = compound 6 > compound 2 >> compound 3. The observation that both the potency and dissociation rate of the dimers was dependent upon linker length is consistent with a multivalent interaction at VGSCs. hNa(v)1.5 VGSCs did not recover from inhibition by compound 4. However, "chase" with free local anesthetic site inhibitors increased the rate of dissociation of compound 4. Together, these data support the hypothesis that compound 4 simultaneously occupies two binding sites on VGSCs, both of which can be bound by known local anesthetic site inhibitors.

Anesthetics, Local↗
PubMed2003

The formulation and evaluation of a CFC-free budesonide pressurised metered dose inhaler.

Although dry powder inhalers are well established for the delivery of corticosteroids, the pressurised metered dose inhaler remains the preferred and most cost effective presentation. To design an HFA solution formulation which matched marketed CFC products (Pulmicort and Desonac DA) two elements of the Chiesi Modulite system, the addition of a non-volatile component and the actuator orifice diameter, were varied. These variables, which were shown by in vitro tests to influence the fine particle dose and its mean particle size in different ways, could be permuted to give an aerosol cloud with size characteristics very close to the comparator products. The likelihood that this would confer clinical equivalence is reinforced by a pharmacokinetic analysis which showed that the chosen HFA solution formula gave similar systemic absorption from the lung as Pulmicort. The equivalence in aerosol characteristics was sustained when the pressurised metered dose inhalers (pMDIs) were used with spacers. The Chiesi Jet and the AstraZeneca Nebuhaler, when used with their respective pMDIs, reduced likely oropharyngeal deposition to the same extent and gave a similar increase in the fine particle dose.

Administration, Inhalation↗
PubMed2002

Using three-dimensional difference maps to assess changes in scoliotic deformities.

The three-dimensional nature of scoliosis, coupled with changes due to natural history or treatment, is often difficult to quantify and visualise. A difference map was developed to compare the sequential surface topography of subjects over their treatment period. Three-dimensional surface maps representing patients' trunk surfaces were captured with a laser scanner. Patient surface maps from two clinic visits were matched using a manual best-fit technique that accounted for growth and positioning. The surfaces were subtracted, generating a colour-coded three-dimensional difference map displaying the surface changes. The difference maps were compared with known clinical measures, indicating good agreement (78% specific) with the clinical parameters in detecting change. Full agreement or agreement with the clinical parameters occurred in the surgical, brace and no treatment groups: 76%, 80% and 85%, respectively. A difference index (average of the absolute value of differences on a point-by-point basis) was calculated from the difference map, enabling quantification of change. The difference index, with zero being a perfect match, averaged 5 +/- 1 for repeated measures 7 +/- 2 for subjects deemed to have no change, 9 +/- 2 for subjects with slight change, and 14 +/- 2 for subjects with significant change. The difference map showed the extent and location of changes and is a useful tool for assessing surface topography changes.

Adolescent↗
PubMed2002

Modulite: a means of designing the aerosols generated by pressurized metered dose inhalers.

Although popular, the pressurized metered dose inhaler generates coarse, fast moving clouds so that the fraction reaching the lung is small. These shortcomings can be redressed by Modulite which permutes the following variables: the non-volatile components of a solution formula, the actuator orifice geometry, the volume of the metered solution and the vapour pressure of the propellants. This permits the design of aerosols with chosen particle size and plume speed. This facilitates co-ordination of dose generation with inspiration, reduces oropharyngeal deposition and provides a mechanism for targeting drug delivery to different parts of the lung. These principles are exemplified by designing an HFA-propelled beclometasone dipropionate product which closely matches existing products which use chlorofluorocarbons.

Aerosol Propellants↗
PubMed2002

Assessing changes in three dimensional scoliotic deformities with difference maps.

Topographical difference maps were used to compare the trunk surfaces of subjects over the course of their treatment. Three-dimensional points representing the trunk surfaces were aligned accounting for growth and positioning. A goodness-of-fit score was calculated and a color map used to display trunk surface changes. Fifty-one successive subjects were assessed with difference maps. Two subjects each had 10 repetitions taken on the same day to assess reliability. A blinded observer used a five-point scale that extended from full agreement to full disagrment to judge the maps according to the extent and location of changes. The observations were compared to clinical measures mapped onto the same scale by another blinded observer. Goodness of fit for repeated measures averaged 5 +/- 1, for subjects deemed to have no change 7 +/- 2, for subjects with slight change 9 +/- 2, and 14 +/- 2 for subjects with significant change. Judges were in full agreement or in agreemnt with forty of the fifty-one subjects (78%) and in slight disagreement with the remaining eleven. When the cohort was subdivided in surgical, brace and no treatment groups, the judges were in full agreement or in agreement 76%, 80%, and 85% respectively. The difference map provides a qualitative and quantitative measure of how the trunk surface has changed as a whole.

Adolescent↗
PubMed2001

Pennation angles of the intrinsic muscles of the foot.

As mathematical models of the musculoskeletal system become increasingly detailed and precise, they require more accurate information about the architectural parameters of the individual muscles. These muscles are typically represented as Hill-type models, which require data on fiber length, physiological cross-sectional area (PCSA) and pennation angle. Most of this information for lower limb muscles has been published, except for data on the pennation angle of the intrinsic muscles of the foot. Each (n=20) intrinsic muscle of three human feet was dissected free. The dorsal and plantar surfaces were photographed and a digitized color image was imported into Abobe Photoshop. The muscles were divided into "anatomical units". For each anatomical unit (n=26), a line was drawn along the tendon axis and a number of other lines were drawn along individual muscle fibers. The angle between the tendon line and each fiber line was defined as the pennation angle of that fiber. By visual inspection, an effort was made to take measurements such that they represented the distribution of fibers in various parts of the muscle. Although some individual muscles had higher or lower pennation angles, when averaged for all specimens, the second dorsal interosseous had the smallest pennation angle (6.7+/-6.81 degrees) while the abductor digiti minimi had the largest (19.1+/-11.19 degrees). Since the cosines of the angles range from 0.9932 to 0.9449, the effect of the pennation angle on the force generated by the muscle was not great.

Aged↗
PubMed2001

Health-related quality of life and cost-effectiveness studies in the European randomised study of screening for prostate cancer and the US Prostate, Lung, Colon and Ovary trial.

Decisions on policies for screening for prostate cancer require that information upon health-related quality of life (HRQL) and cost-effectiveness (CE) be available, as the lead time for some of the cases detected by screening will be very long and detriments in quality of life could have a major impact on the subjects remaining life-span. A framework within which both HRQL and cost-effectiveness of prostate cancer screening can be assessed is presented. Studies of both are ongoing in the European Randomised Study of screening for prostate cancer and the US Prostate, Lung, Colon and Ovary trial. Preliminary information confirms that it is important to study screened subjects and controls, and not to assume that inferences derived from study of prostate cancer outside screening trials can be extrapolated to the trials. However, it will require prolonged study to enable the overall effects on quality of life, and on cost-effectiveness to be determined. Such studies are ongoing for the two trials.

Colonic Neoplasms↗
PubMed2001

A modified protocol for quantitative fit testing using the PortaCount.

A modified quantitative fit testing method has been developed for testing half masks using the TSI PortaCount respirator fit tester. This approach focuses on shortening the time for each exercise during fit testing; however, the shortened protocol is applied only to the very good-fitting masks. For marginal-fitting masks, the testing is carried out according to the full Occupational Safety and Health Administration (OSHA) respiratory protection standard (29CFR1910.134).(1) The shortened protocol (currently not approved by OSHA) still uses all the exercises required by the OSHA standard but for a shorter time (30 seconds [s] for each exercise instead of the usual 60 s). How good the fit has to be to qualify for a shortened exercise is determined by the statistical analysis of a large data set containing pass and fail fit-test data. The statistical analysis involves calculating the sensitivity and specificity of the pass and failed fit tests on half masks. From this analysis, a multiplication factor (K) to the OSHA pass/fail criterion was developed. For a respirator to undergo the shortened protocol, the fit factor obtained during any exercise must be K times the OSHA pass/fail criterion of 100 for half masks. Hence, this approach is more conservative than fit testing protocols that involve shortened exercises regardless of the fit. Nevertheless, this approach still saves time without compromising the accuracy of the fit test expressed in terms of sensitivity and specificity. For the existing data, 85 percent of the fit tests would have been performed according to the faster test protocol while only 15 percent of the tests would have been tested according to the full-length OSHA test protocol.

Decision Trees↗
PubMed2001

Selected contribution: synergism between TNF-alpha and IL-1 beta in airway smooth muscle cells: implications for beta-adrenergic responsiveness.

In human cultured airway smooth muscle cells, interleukin (IL)-1 beta increases cyclooxygenase (COX)-2 expression and PGE(2) release, ultimately resulting in decreased beta-adrenergic responsiveness. In this study, we aimed to determine whether tumor necrosis factor-alpha (TNF-alpha) synergizes with IL-1 beta in the induction of these events. TNF-alpha alone, at concentrations up to 10 ng/ml, had no effect on COX-2 protein expression; at concentrations as low as 0.1 ng/ml, it significantly enhanced the ability of IL-1 beta (0.2 ng/ml) to induce COX-2 and to increase PGE(2) release. IL-1 beta and TNF-alpha in combination also significantly enhanced COX-2 promoter activity, indicating that synergism between the cytokines is mediated at the level of gene transcription. Although IL-1 beta and TNF-alpha each increased nuclear factor-kappa B activation and induced extracellular regulated kinase and p38 phosphorylation, combined administration of the cytokines did not enhance either nuclear factor-kappa B or mitogen-activated protein kinase activation. Combined administration of IL-1 beta (0.2 ng/ml) and TNF-alpha (0.1 or 1.0 ng/ml) reduced the ability of isoproterenol to decrease human airway smooth muscle cell stiffness, as measured by magnetic twisting cytometry, even though individually these cytokines, at these concentrations, had no effect on isoproterenol responses. Treatment with the selective COX-2 inhibitor NS-398 abolished the synergistic effects of TNF-alpha and IL-1 beta on beta-adrenergic responsiveness. Our results indicate that low concentrations of IL-1 beta and TNF-alpha synergize to promote beta-adrenergic hyporesponsiveness and that effects on COX-2 expression and PGE(2) are responsible for these events. The data suggest that the simultaneous release in the airway, of even very small amounts of cytokines, can have important functional consequences.

Adrenergic beta-Agonists↗
PubMed1999

Contribution of head-up tilt testing and ATP testing in assessing the mechanisms of vasovagal syndrome: preliminary results and potential therapeutic implications.

BACKGROUND: In patients with vasovagal syndrome, head-up tilt testing may reproduce symptoms generally associated with vasodepression. Recent research suggests ATP testing identifies patients with abnormal vagal cardiac inhibition. This preliminary study examined the joint contribution of both tests in identifying underlying mechanisms in the general population with vasovagal syndrome. METHODS AND RESULTS: Both tests were performed in random order during 1 session and outside of predominant sympathetic periods in 72 patients hospitalized for syncope (n=56) or presyncope (n=16) for whom no cardiac or extracardiac cause was found. For passive and isoproterenol-provocative tilt testing by standard protocol, reproduction of symptoms defined a positive test. The ATP test consisted of injecting ATP 20 mg IV at bedside, continuously monitoring ECG and blood pressure; a vagal cardiac pause >10 seconds defined a positive test. For most patients (64%), >/=1 test was positive. Of the 41 patients (57%) with a positive tilt test (either passive or provoked by isoproterenol), 32% had cardiac disease; none had significant bradycardia (<50 bpm). Of the 8 patients (11%) with a positive ATP test, 62% had cardiac disease; the probability of a positive result increased with age (P=0.015). Both tests were positive in 3 patients and negative in 26 patients; the tilt and ATP test results were uncorrelated (P=0.28). CONCLUSIONS: Results suggest tilt and ATP tests individually and jointly determine the mechanism of vasovagal symptoms in most patients and that vagal cardiac inhibition increases with age.

Adenosine Triphosphate↗
PubMed1999

Is a pacemaker indicated for vasovagal patients with severe cardioinhibitory reflex as identified by the ATP test? A preliminary randomized trial.

BACKGROUND: A previous observational study suggested that, in syncopal elderly patients with vasovagal syndrome, a test using adenosine-5'-triphosphate (intravenous ATP 20 mg. 2 ml-1) could identify a subgroup of patients at high risk of severe cardioinhibitory response and guide the therapeutic strategy. To test one aspect of these results prospectively, we designed a small study focusing only on vasovagal patients with abnormal response to ATP testing. METHODS: Twenty patients hospitalized for syncope, which was considered to be vasovagal, and exhibiting an abnormal ATP test--defined by a longer than 10 s cardiac pause--were randomized to two groups: half to implantation with a dual-chamber pacemaker and half to usual medical care. All patients who were not hospitalized for recurrences were assessed every 6 months in the clinic or by telephone. RESULTS: At baseline, the randomized patient groups were similar in their demographic and health characteristics and in the results of their ATP tests, for example the mean cardiac pause (21.4 +/- 9.3 vs 15.9 +/- 3.7 s) and the mean interval between escape beats during the pause (7.29 +/- 4.2 vs 7.48 +/- 3.3 s). During a mean follow-up of 52 months, recurrences appeared in six of the 10 usual-care patients (range 0.2-29 months) but in none of the implanted patients (P < 0.02). CONCLUSIONS: This limited trial (1) supports the conclusion that patients with an abnormal ATP test who receive a dual-chamber pacemaker suffer fewer recurrences than those who are monitored only; and (2) consequently further supports the hypothesis that, among vasovagal patients, a cardiac pause of longer than 10 s in patients administered ATP identifies those at high risk of symptomatic vagal cardiac inhibition.

Adenosine Triphosphate↗
PubMed1998

Comparison of results in two implantable defibrillators. Jewel 7219D Investigators.

The Jewel 7219D was the first non-thoracotomy implantable cardioverter-defibrillator (ICD) with biphasic shock capability small enough to be placed in the prepectoral subcutaneous position. Size reduction of ICDs is desirable, but safety and efficacy of smaller devices must be demonstrated. Outcomes of patients treated with the Jewel 7219D defibrillator (n = 1,781) and with its precursor model PCD 7217B (n = 2,637) were compared. To use PCD patients (n = 2,637) as historical (n = 2,574) and concurrent controls (n = 63), statistical adjustments using the Cox proportional-hazards regression model were made. Jewel recipients (n = 1,781) treated in 106 US and 32 non-US centers exhibited similar characteristics including a mean age of 59 years, 78% men, ejection fraction of 34%, history of aborted sudden cardiac death in 41%, and coronary artery disease in 70%. Implantation was completed in 1,777 of 1,781 (99.9%) attempts and success with the first electrode configuration and polarity was 89.5%. Kaplan-Meier cumulative first-year survivals for cardiac and all-cause mortality were 98.5% and 93.3%. Complication-free first-year survival for Jewel implants in prepectoral subcutaneous (n = 582), subpectoral submuscular (n = 366), and abdominal (n = 449) positions did not differ (p > 0.05). First-year survival free of pocket-related complications exceeded 98% in all locations. Adjusted cardiac and all-cause first-year mortality, and efficacy in terminating spontaneous tachyarrhythmias did not differ between the 2 device groups. In conclusion, the safety and efficacy of Jewel model 7219D in the prepectoral subcutaneous position are at least equal to either those of Jewel models implanted in different positions or to those of the previously extensively characterized PCD 7217B.

Cardiac Surgical Procedures↗
PubMed1997

Can adenosine 5'-triphosphate be used to select treatment in severe vasovagal syndrome?

BACKGROUND: Selection of treatment in vasovagal syndrome should be guided by the mechanism of symptoms. This study determined whether a simple drug test may assess one mechanism. METHODS AND RESULTS: To identify patients at risk of severe cardioinhibitory response of vagal origin, we infused 20 mg ATP into 316 patients hospitalized for recurrent syncope (n=195) or presyncope (n=121) of unknown origin and into normal subjects (n=51). We then assessed the ECG and clinical responses to the drug, recommended therapy, and followed up the subjects chronically. A cardiac pause > 10 seconds was seen in only 3 normal subjects (6%). Therefore, a pause < or = 10 seconds yielded the approximately 95th percentile of the normal range. ATP provoked a pause > 10 seconds in 130 symptomatic patients (41%) and a pause < or = 10 seconds in 186 symptomatic patients (59%). Thus, symptomatic patients with pauses > 10 seconds were proposed for pacemaker implantation; all other patients and normal subjects were simply monitored. Among long-pause patients with follow-up, the observed recurrence rate for the 104 with pacemakers was one-third that for the 21 who were only monitored (P<.0001). Among followed-up short-pause patients, the rate in the 153 monitored-only patients did not differ from the 20 implanted patients (P=.432). CONCLUSIONS: The vagal effect of ATP may identify the subgroup of patients at high risk of severe cardioinhibitory response of vagal origin who likely will benefit from pacemaker therapy. This fast, uncomplicated test should be considered for further use in screening patients with vasovagal syndrome.

Adenosine Triphosphate↗
PubMed1997

A multicenter, randomized trial comparing an active can implantable defibrillator with a passive can system. Jewel Active Can Investigators.

Replacing one defibrillation electrode lead by the defibrillator can may simplify implantation of the ICD. In this multicenter study, 304 patients were randomized to receive either the biphasic active can (AC) (model 7219C system, Medtronic, Inc.) or the passive can (PC) (model 7219D system). The AC and PC systems were compared with respect to their ability to meet the implant defibrillation criterion and to defibrillate VF, and to DFTs, implant time, patient adverse events, and survival rates. A higher percentage fulfilled the implant defibrillation criterion on the first configuration with the AC (86.3% vs 75.9% for PC; P = 0.023), and the first shock success for terminating induced VF was 94% for AC compared to 89% for PC (P = 0.026). DFTs were significantly lower (10.9 vs 12.7 J; P = 0.031), and implant time was significantly shorter for the AC patients (99.2 vs 112.0 min; P = 0.002). The two groups showed no significant differences in 3-month adverse event rates, 3-month survival, and hospital stay.

Adolescent↗
PubMed1988

A model to evaluate alternative methods of defibrillation threshold determination.

The voltage (or, equivalently, energy) at which defibrillation occurs for a specific episode of fibrillation can be represented by specifying or estimating the probability of successful defibrillation for each voltage or energy. This relation of voltage to probability is the probability function. For a series of attempts, the probability function predicts the frequency with which defibrillation will occur at a given voltage. By defining the defibrillation threshold (DFT) as the voltage at which the probability function takes on a specific value, say 50%, a method of defibrillation threshold determination can be evaluated by how accurately and precisely it estimates the "true" defibrillation threshold. By utilizing estimated probability functions from animals and humans, the relative performance of different methods of defibrillation threshold determination can be evaluated. Three methods were evaluated using published animal data and human clinical data: (1) stepping down to the first voltage that fails; (2) stepping up to the first voltage that succeeds; and (3) doing both 1 and 2 and averaging. In all cases, Method 3 has lower total error. Definitions of defibrillation threshold other than the 50% level can also be evaluated in this fashion.

Animals↗
PubMed1986

Ten-year experience with implanted polyurethane lead insulation.

Polyurethane leads have been implanted in humans since 1977. Because of cases of stress cracking found in 1981, changes in the manufacturing process were made. Subsequent performance was excellent. There remains concern regarding the ability to predict accurately long-term performance. However, the advent of reliable, statistically accurate actuarial data coupled with accelerated tests predictive of human performance has restored confidence in the newer polyurethane lead technology.

Electrodes, Implanted↗