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Biomedical subjects

David R Jones

Publications and source records attributed to David R Jones.

At least 91 records · Page 5Linked to original sources
PubMed2003

You're the flight surgeon. Anxiety.

Anxiety is a medical mimicker that can imitate both cardiac and neurological symptoms. Anxiety disorder research protocols regularly use hyperventilation or i.v. lactate infusion to trigger panic attacks in susceptible subjects. Susceptible patients experience panic attacks with slight decreases in CO2 or increases in lactate production seen in mild exercise such as stair climbing. To the unsuspecting physician this appears to be dyspnea on exertion. Hyperventilation during rapid eye movement (dream) sleep may trigger panic attacks in patients with panic disorder, mimicking paroxysmal nocturnal dyspnea. Syncope from panic-induced hyperventilation can mimic seizures. When panic-like anxiety is discovered in aircrew it necessitates grounding. The prognosis is frequently good after treatment with psychotherapy, with return to full flying status a strong possibility.

Adult↗
PubMed2002

Factors affecting uptake of childhood immunisation: a Bayesian synthesis of qualitative and quantitative evidence.

Falls in levels of measles, mumps, and rubella (MMR) immunisation in the UK and the continuing debate on how to respond to this situation emphasise the importance of identifying and understanding the factors that affect the uptake of recommended childhood immunisations. Both qualitative and quantitative evidence could be useful in this process. We aimed to explore the feasibility and value of an approach to formal synthesis of qualitative and quantitative evidence in the context of factors affecting the uptake of childhood immunisation in developed countries. We used a Bayesian approach to meta-analysis. Evidence from 11 qualitative and 32 quantitative studies of factors affecting uptake of childhood immunisation was combined and assessed. We conclude that use of either qualitative or quantitative research alone might not identify all relevant factors, or might result in inappropriate judgments about their importance, and could thus lead to inappropriate formulation of evidence-based policy. Further development of our methods might enable rigorous synthesis of qualitative and quantitative evidence in this and other contexts.

Bayes Theorem↗
PubMed2002

Dynamics of diacylglycerol kinase zeta translocation in living T-cells. Study of the structural domain requirements for translocation and activity.

The diacylglycerol kinases (DGK) regulate diacylglycerol-based signals by phosphorylating this key lipid intermediate to phosphatidic acid. Here, we have investigated the spatial and temporal regulation of diacylglycerol kinase zeta (DGK zeta) in living Jurkat T-cells expressing a muscarinic type I receptor. Using real time confocal videomicroscopy, we show the rapid translocation of a green fluorescent protein-tagged enzyme from the cytosol to the plasma membrane following receptor stimulation. The generation of a panel of truncations, deletions, and point mutations of the enzyme allowed us to examine the requirements of the different structural motifs for both activity and receptor-regulated translocation. The data show that DGK zeta has strict requirements for intact zinc fingers and the conserved catalytic domain for full enzymatic activity. Protein kinase C-driven myristoylated alanine-rich C kinase substrate domain phosphorylation and intact zinc fingers are in turn essential for plasma membrane translocation. DGK zeta does not translocate to the membrane following stimulation of the endogenous T-cell receptor, and our data demonstrate that the specificity in terms of receptor response is provided by the regulatory motifs present at the C-terminal domain of the protein. This is the first report that shows in vivo DGK zeta translocation in response to agonist stimulation and establishes the role of the different domains in enzymatic activity and the selectivity of the response to receptors.

Animals↗
PubMed2002

PTEN blocks tumor necrosis factor-induced NF-kappa B-dependent transcription by inhibiting the transactivation potential of the p65 subunit.

PTEN is a lipid phosphatase responsible for down-regulating the phosphoinositide 3-kinase product phosphatidylinositol 3,4,5-triphosphate. Phosphatidylinositol 3,4,5-triphosphate is involved in the activation of the anti-apoptotic effector target, Akt. Although the Akt pathway has been implicated in regulating NF-kappaB activity, it is controversial as to whether Akt activates NF-kappaB predominantly through mechanisms that regulate nuclear translocation or transactivation potential. In this report, we utilized PTEN as a natural biological inhibitor of Akt activity to study the effects on tumor necrosis factor (TNF)-induced activation of NF-kappaB. We found that the reintroduction of PTEN into prostate cells inhibited TNF-stimulated NF-kappaB transcriptional activity. PTEN failed to block TNF-induced IKK activation, IkappaBalpha degradation, p105 processing, p65 (RelA) nuclear translocation, and DNA binding of NF-kappaB. However, PTEN inhibited NF-kappaB-dependent transcription by blocking the ability of TNF to stimulate the transactivation domain of the p65 subunit. PTEN also inhibited the transactivation potential of the cyclic AMP-response element-binding protein, but this was not observed for c-Jun. The transactivation potential of p65 following TNF stimulation could be rescued from PTEN-dependent repression by re-introducing expression constructs encoding activated forms of phosphoinositide 3-kinase, Akt, or Akt and IKK. The ability of PTEN to inhibit the TNF-induced transactivation function of p65 is important, because expression of PTEN blocked TNF-stimulated NF-kappaB-dependent gene expression, thus sensitizing cells to TNF-induced apoptosis. Maintenance of the PTEN tumor suppressor protein is therefore required to modulate Akt activity and to concomitantly control the transcriptional activity of the anti-apoptotic transcription factor NF-kappaB.

Gene Expression Regulation↗
PubMed2002

The efficacy of a novel tongue-stabilizing device on polysomnographic variables in sleep-disordered breathing: a pilot study.

The polysomnographic efficacy of a novel tongue-stabilizing device (TSD) in the treatment of snoring and sleep-disordered breathing (SDB) was evaluated in this pilot study. Six current users of the TSD with SDB underwent polysomnography with and without the TSD in situ in a randomized crossover design. The TSD significantly lowered the frequency of snores per hour slept (61- to 70-dB range) (no TSD: mean = 41/h slept +/- 52 SD; TSD: 8/h slept +/- 16 SD; P = 0.046) but did not alter snoring in the other decibel ranges (all Ps > 0.1). Trends were found for reductions in the frequency of apneas plus hypopneas (no TSD: 26/h slept +/- 17/h slept; TSD: 15/h slept +/- 13; P = 0.06) and oxygen desaturations of 4% or more (no TSD: 10/h slept +/- 10; TSD: 5/h slept +/- 5; P = 0.09). Significant improvements in microarousal frequency with the TSD were found (no TSD: 34/h slept +/- 16; TSD: 22/h slept +/- 14; P = 0.004). Significant reductions in percentage of Stage 1 sleep with the TSD were also demonstrated (no TSD: 10 +/- 3%; TSD: 8 +/- 2%; P = 0.03). The results of this small pilot study indicate that the TSD may be effective in reducing snoring severity and microarousals, with favorable trends for reducing SDB severity in selected individuals. Additional larger prospective studies are required to identify suitable candidates for TSD use in the treatment of snoring and SDB.

Humans↗
PubMed2002

The efficacy of a mandibular advancement splint in relation to cephalometric variables.

The efficacy of a titratable mandibular advancement splint (MAS) for the management of obstructive sleep apnea (OSA) was investigated in relation to supine cephalometric variables. Fourteen adults with diagnosed OSA were recruited following an initial polysomnogram. Supine cephalographic radiographs were taken at baseline and subjects wore the MAS nightly for 6 to 8 weeks. The polysomnogram and cephalogram were repeated with the MAS at maximal titration. The MAS resulted in complete or partial treatment response in all subjects as measured by the improvement in mean apnea/hypopnea index (AHI) (baseline AHI 34 +/- 22/hr, with MAS 10 +/- 5/hr; p = 0.001). The perpendicular distance between the hyoid bone and the mandibular plane (HYML) measured in awake subjects decreased with the MAS (baseline HYML 25.3 +/- 7.8 mm, with MAS 16.5 +/- 9.6 mm; p = 0.002). Baseline HYML was the only cephalometric variable associated with a successful clinical outcome. It was strongly linked to improvements in AHI (adjusted R(2) = 0.37, p = 0.012) and arousals (adjusted R(2) = 0.455, p = 0.005). We conclude that the MAS is an effective therapy for OSA and baseline HYML is an important predictor of improvement. Improvements in AHI may be explained by the MAS maintaining the new or existing relationship of the hyoid and its surrounding structures, thus preventing obstruction in the upper airway during sleep.

Adult↗
PubMed2002

Beneficial effects of inhaled nitric oxide in adult cardiac surgical patients.

BACKGROUND: Pulmonary hypertension with associated right ventricular dysfunction may complicate the postoperative cardiac patient despite maximum pharmacologic and ventilatory support. The purpose of this study was to retrospectively review our experience with inhaled nitric oxide (INO) in adult postoperative cardiac patients with pulmonary hypertension. METHODS: We retrospectively reviewed the medical records of 17 adult cardiac patients treated with INO postoperatively between November 1998 and February 2000. The INO was used to manage pulmonary hypertension postoperatively in patients who had undergone coronary artery bypass graft (CABG) (n = 13), valve operation (n = 3), and combined CABG/aortic valve replacement (n = 1). Hemodynamic and respiratory measurements before INO and again 6 hours after administration were examined. Student's t test was used to analyze the data. RESULTS: Inhaled nitric oxide (20 ppm to 30 ppm) was administered for a median duration of 30.2 hours. The group, as a whole, demonstrated a significant decrease in both mean pulmonary artery pressure and right ventricular stroke work index. In addition, a significant increase in posttherapeutic cardiac index and Pao2/Fio2 ratio was observed. The vasodilatory effects of nitric oxide were specific to the pulmonary circulation as no significant change in mean arterial pressure was noted. Overall mortality was 6%. CONCLUSIONS: Inhaled nitric oxide effectively and selectively lowered right ventricular afterload and right ventricular work in critically ill adult cardiac patients with acute pulmonary hypertension.

Administration, Inhalation↗
PubMed2002

Ischemia-reperfusion injury after lung transplantation increases risk of late bronchiolitis obliterans syndrome.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the most common cause of long-term morbidity and mortality after lung transplantation. Our hypothesis was that early ischemia-reperfusion injury after lung transplantation increases the risk of BOS. METHODS: Data on 134 patients who had lung transplantation between January 1, 1990 and January 1, 2000, was used for univariate and multivariate logistic regression analysis. RESULTS: After lung transplantation, 115 patients (115 of 134, 86%) survived more than 3 months. In that group, 41 patients developed BOS, of which 23 had progressive disease. Univariate analysis revealed that ischemia-reperfusion injury (p = 0.017) and two or more acute rejection episodes (p = 0.032) were predictors of BOS onset, whereas ischemia-reperfusion injury (p = 0.011) and cytomegalovirus infection (p = 0.009) predicted progressive BOS. Multivariate logistic regression analysis showed that ischemia-reperfusion injury was an independent predictor for both BOS development and BOS progression. Two or more acute rejection episodes were also an independent predictor of BOS development, whereas cytomegalovirus infection was an independent predictor of progressive BOS. CONCLUSIONS: Ischemia-reperfusion injury increases the risk of BOS after lung transplantation.

Adolescent↗
PubMed2002

Acquired systemic-to-pulmonary arteriovenous malformation secondary to Mycobacterium tuberculosis empyema.

Pulmonary arteriovenous malformations (AVMs) with systemic arterial collateralization related to a prior tuberculosis empyema are extremely rare. We report the case of a 15-year-old boy who developed a pulmonary AVM with massive systemic arterial collateralization 5 years after being treated for a Mycobacterium tuberculosis empyema necessitans. The AVM was successfully managed with combined intraarterial embolization and surgical resection.

Adolescent↗
PubMed2002

Generalized synthesis of evidence and the threat of dissemination bias. the example of electronic fetal heart rate monitoring (EFM).

Assessment of the potential impact of dissemination bias is necessary for meta-analysis. When evidence is available from studies of different designs, the different study types may be affected by dissemination bias to differing degrees. The evidence relating to electronic fetal heart rate monitoring (EFM) for preventing perinatal mortality is used to explore the feasibility of carrying out a dissemination bias assessment in a generalized synthesis of evidence (gse) framework. Visual inspection of funnel plots, statistical tests, and methods to "adjust" the results of a meta-analysis are all used in an extensive sensitivity analysis. The potential impact of dissemination bias on gse models synthesizing all the evidence together is also reported. Detailed consideration is given to the influence of meta-analysis model choice, and outcome scale used. Using the risk difference scale, funnel plots of the observational studies appeared highly asymmetric. However, further explorations show these conclusions are not robust over use of different outcome measures or different meta-analysis models. Researchers should be aware that dissemination bias may affect different sources of evidence differently. Although assessments such as those described here are recommended, awareness of their lack of robustness to outcome scale and model choice is important. Further research into methods to assess dissemination bias that are invariant to these factors is needed.

Cardiotocography↗
PubMed2002

Coronary risk stratification in patients with end-stage lung disease.

BACKGROUND: Significant coronary artery disease (CAD) has been a contraindication for listing patients for lung transplantation. We hypothesize that coronary risk stratification can help identify a sub-set of patients who need additional diagnostic tools and intervention. METHODS: We performed a retrospective review of 72 consecutive patients who underwent lung transplantation at our institution from 1995 to 2000. Further, a review of patients who are currently listed for transplantation yielded 48 patients. We then identified the various risk factors for CAD, the diagnostic tools used, and pre-operative intervention. Risk factors identified included smoking history, diabetes, hypertension, hypercholesterolemia, CAD, congestive heart failure, age >50, and arrhythmias. Based on these risk factors, the patients were then classified into 2 groups: low risk (< or =1 risk factors) and high risk (> or =2 risk factors). We identified the patients in each group who underwent coronary angiography (CA), those with angiographic evidence of CAD, and those who received pre-operative intervention. RESULTS: Of the 72 patients who underwent lung transplantation, 48 were identified as at high risk for CAD. Of these, 5 patients had CAD diagnosed before surgery using CA, and 1 patient received pre-operative intervention. Of the 48 patients currently on the lung transplant list, we identified 28 patients as high risk for CAD, 12 of whom were noted to have CA, and 2 of whom received pre-operative intervention. CONCLUSIONS: Although CAD was once a contraindication for lung transplantation, pre-operative risk stratification allows identification of CAD with CA in a high-risk group. We believe that by using appropriate pre-operative cardiac intervention, patients with severe CAD could successfully undergo lung transplantation.

Adolescent↗
PubMed2002

T lymphocyte nuclear diacylglycerol is derived from both de novo synthesis and phosphoinositide hydrolysis.

Novel phospholipid metabolism in T lymphocytes and the generation of biologically active lipid second messengers (LSMs) has attracted much attention in recent years. Despite this interest, no reports have attempted to characterise such events in the nuclei of these cells. In order to gain insight into the structural relationships between the lipids diglyceride (DG) and phosphatidic acid (PtdOH) and their structural precursors phosphatidylcholine (PtdCho) and phosphatidylinositides (PtdIns) in the nuclei of CTLL-2 T lymphocytes, an analysis of their molecular species was performed. The results clearly indicated that there were two pools of DG. The major pool consisted primarily of saturated and monunsaturated structures whereas the minor pool consisted of more unsaturated species, most likely derived from PtdIns. Only the latter pool was found to be accessible to endogenous nuclear diacylglycerol kinase (DGK) activity which showed partial inhibition with the recognised DGK inhibitor R59949. Molecular species analysis of the endogenous nuclear PtdOH revealed it to be distinct from that generated by the endogenous DGK, but instead resembled that of PtdCho species. We were unable to detect enzymatic activities which targeted PtdCho (PtdCho-phospholipase C (PtdCho-PLC), PtdCho-phospholipase D (PtdCho-PLD) and sphingomyelin synthase (SMS)) but instead a detectable PtdOH phosphatase (PAP) activity. We propose that, in exponentially growing CTLL-2 cells, synthesis de novo represents one of the routes for the biosynthesis of structural phospholipids which may be the source of biologically active LSMs in the nucleus.

Adenosine Triphosphate↗
PubMed2002

Inhibition of nuclear factor kappaB chemosensitizes non-small cell lung cancer through cytochrome c release and caspase activation.

OBJECTIVE: Although we have previously shown that inhibition of nuclear factor kappaB sensitizes non-small cell lung cancer cells to chemotherapy-mediated cell death, the apoptotic pathways mediating this process are unknown. The purpose of this study was to determine whether chemosensitivity after the inhibition of nuclear factor kappaB in non-small cell lung cancer cells is a mitochondrial and caspase-mediated process and whether it is dependent on nuclear factor kappaB transcriptional activity. METHODS: Previously described H157 non-small cell lung cancer cells were treated with gemcitabine, and DNA fragmentation was determined. Caspase 3, 6, 7, 8, and 9 activity in cytoplasmic extracts was determined fluorometrically. The mitochondrial permeability index and cytosolic cytochrome c levels were also determined. The caspase inhibitor Boc-D, as well as nuclear factor kappaB-regulated gene products A1, c-IAP-2, and Bcl-X(L), were added to H157 cells lacking nuclear factor kappaB and the degree of apoptosis assessed. All experiments were performed in triplicate, and data significance was determined by means of analysis of variance. RESULTS: Non-small cell lung cancer cells lacking functional nuclear factor kappaB (H157I) underwent more apoptosis after chemotherapy than vector control cells (H157V). There was an increase in the mitochondrial permeability index and cytochrome c release after chemotherapy in the H157I cells. H157I cells also had more activation of caspases 3 and 9 than control cells. Inhibition of caspase activity or transfection with nuclear factor kappaB-regulated gene products rescued cell death after the inhibition of nuclear factor kappaB. CONCLUSION: Chemosensitization by means of inhibition of nuclear factor kappaB in non-small cell lung cancer cells occurs through increased cytochrome c release and caspase 3 and 9 activation. Inhibition of nuclear factor kappaB or its gene products in addition to chemotherapy warrants further study as a treatment strategy in patients with advanced-stage non-small cell lung cancer.

Antimetabolites, Antineoplastic↗
PubMed2002

Expression of a catalytically inactive form of diacylglycerol kinase alpha induces sustained signaling through RasGRP.

Regulating the generation and clearance of lipid second messengers, such as diacylglycerol (DAG), is critical for the correct propagation of intracellular signaling pathways. DAGK type alpha acts as a negative modulator of the DAG levels generated during T cell activation, which is initiated by triggering of the endogenous T cell receptor (TCR), as well as by stimulation of an ectopically expressed human muscarinic type 1 receptor. Here we show that stimulation of either of these receptors causes rapid, transient membrane translocation of the recently discovered Ras guanyl nucleotide release protein (RasGRP), followed by activation of mitogen-activated protein kinase (MAPK). When cells expressing a catalytically inactive form of DAGKalpha were analyzed, however, similar agonist stimulation resulted in sustained signaling through RasGRP and MAPK. Biochemical analysis showed that expression of kinase-dead diacylglycerol kinase a (DGKalpha) led to a greater, more sustained, DAG accumulation following receptor stimulation. These results suggest that, in T cells, agonist-stimulated DAG generation is the key factor controlling activation of the Ras/MAPK signaling pathway through membrane translocation of RasGRP. Moreover, we demonstrate that through the modulation of the intracellular level of agonist-stimulated DAG, DGKalpha alters Ras activation and downstream signaling dramatically, a process of utmost importance for sound immunological function.

Carbachol↗
PubMed2002

Differential modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1)-catalyzed estradiol-3-glucuronidation by the addition of UGT1A1 substrates and other compounds to human liver microsomes.

Previous results demonstrating homotropic activation of human UDP-glucuronosyltransferase (UGT) 1A1-catalyzed estradiol-3-glucuronidation led us to investigate the effects of 16 compounds on estradiol glucuronidation by human liver microsomes (HLM). In confirmation of previous work using alamethicin-treated HLM pooled from four livers, UGT1A1-catalyzed estradiol-3-glucuronidation demonstrated homotropic activation kinetics (S(50) = 22 microM, Hill coefficient, n = 1.9) whereas estradiol-17-glucuronidation (catalyzed by other UGT enzymes) followed Michaelis-Menten kinetics (K(m) = 7 microM). Modulatory effects of the following compounds were investigated: bilirubin, eight flavonoids, 17alpha-ethynylestradiol (17alpha-EE), estriol, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), anthraflavic acid, retinoic acid, morphine, and ibuprofen. Although the classic UGT1A1 substrate bilirubin was a weak competitive inhibitor of estradiol-3-glucuronidation, the estrogens and anthraflavic acid activated or inhibited estradiol-3-glucuronidation dependent on substrate and effector concentrations. For example, at substrate concentrations of 5 and 10 microM, estradiol-3-glucuronidation activity was stimulated by as much as 80% by low concentrations of 17alpha-EE but was unaltered by flavanone. However, at higher substrate concentrations (25-100 microM) estradiol-3-glucuronidation was inhibited by about 55% by both compounds. Anthraflavic acid and PhIP were also stimulators of estradiol 3-glucuronidation at low substrate concentrations. The most potent inhibitor of estradiol 3-glucuronidation was the flavonoid tangeretin. The UGT2B7 substrates morphine and ibuprofen had no effect on estradiol 3-glucuronidation, whereas retinoic acid was slightly inhibitory. Estradiol-17-glucuronidation was inhibited by 17alpha-EE, estriol, and naringenin but was not activated by any compound. This study demonstrates that the interactions of substrates and inhibitors at the active site of UGT1A1 are complex, yielding both activation and competitive inhibition kinetics.

Algorithms↗
PubMed2002

Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7.

The human cytochromes P450 (P450) CYP3A contribute to the biotransformation of 50% of oxidatively metabolized drugs. The predominant hepatic form is CYP3A4, but recent evidence indicates that CYP3A5 contributes more significantly to the total liver CYP3A than was originally thought. CYP3A7 is the major fetal form and is rarely expressed in adults. To compare the metabolic capabilities of CYP3A forms for 10 substrates, incubations were performed using a consistent molar ratio (1:7:9) of recombinant CYP3A, P450 reductase, and cytochrome b5. A wide range of substrate concentrations was examined to determine the best fit to kinetic models for metabolite formation. In general, K(m) or S(50) values for the substrates were 3 to 4 times lower for CYP3A4 than for CYP3A5 or CYP3A7. For a more direct comparison of these P450 forms, clearance to the metabolites was determined as a linear relationship of rate of metabolite formation for the lowest substrate concentrations examined. The clearance for 1'-hydroxy midazolam formation at low substrate concentrations was similar for CYP3A4 and CYP3A5. For CYP3A5 versus CYP3A4, clearance values at low substrate concentrations were 2 to 20 times lower for the other biotransformations. The clearance values for CYP3A7-catalyzed metabolite formation at low substrate concentrations were substantially lower than for CYP3A4 or CYP3A5, except for clarithromycin, 4-OH triazolam, and N-desmethyl diltiazem (CYP3A5 - CYP3A7). The CYP3A forms demonstrated regioselective differences in some of the biotransformations. These results demonstrate an equal or reduced metabolic capability for CYP3A5 compared with CYP3A4 and a significantly lower capability for CYP3A7.

Alprazolam↗
PubMed2002

Delayed depolarization of the cog-wheel valve and pulmonary-to-systemic shunting in alligators.

Alligators and other crocodilians have a cog-wheel valve located within the subpulmonary conus, and active closure of this valve during each heart beat can markedly and phasically increase resistance in the pulmonary outflow tract. If this increased resistance causes right ventricular pressure to rise above that in the systemic circuit, right ventricular blood can flow into the left aorta and systemic circulation, an event known as pulmonary-to-systemic shunting. To understand better how this valve is controlled, anaesthetized American alligators (Alligator mississippiensis) were used to examine the relationships between depolarization of the right ventricle, depolarization/contraction of the cog-wheel valve muscle and the resultant right ventricular, pulmonary artery and systemic pressures. Depolarization swept across the right ventricle from the apex towards the base (near where the cog-wheel valve muscle is located) at a velocity of 91+/-23 cm s(-1) (mean +/- S.E.M., N=3). The cog-wheel valve electrocardiogram (ECG) (and thus contraction of the valve) trailed the right ventricular ECG by 248+/-28 ms (N=3), which was equivalent to 6-35 % of a cardiac cycle. This long interval between right ventricular and valve depolarization suggests a nodal delay at the junction between the base of the right ventricle and the cog-wheel valve. The delay before valve closure determined when the abrupt secondary rise in right ventricular pressure occurred during systole and is likely to strongly influence the amount of blood entering the pulmonary artery and thus to directly control the degree of shunting. Left vagal stimulation (10-50 Hz) reduced the conduction delay between the right ventricle and cog-wheel valve by approximately 20 % and reduced the integrated cog-wheel ECG by 10-20 %. Direct application of acetylcholine (1-2 mg) also reduced the integrated cog-wheel ECG by 10-100 %; however, its effect on the conduction delay was highly variable (-40 to +60 %). When the cog-wheel valve muscle was killed by the application of ethanol, the cog-wheel ECG was absent, right ventricular and pulmonary pressures remained low and tracked one another, the secondary rise in right ventricular pressure was abolished and shunting did not occur. This study provides additional, direct evidence that phasic contraction of the cog-wheel valve muscle controls shunting, that nervous and cholinergic stimulation can alter the delay and strength of valve depolarization and that this can affect the propensity to shunt.

Acetylcholine↗