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Background Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immune-suppressive properties that is commonly exploited by tumors to evade immune destruction. Anti-tumor T cell responses can be initiated in solid tumors, but are immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO. In addition to these known effects on the adaptive immune system, we previously showed widespread, T cell-dependent complement deposition during allogeneic fetal rejection upon maternal treatment with IDO-blockade. We hypothesized that IDO protects glioblastoma from the full effects of chemo-radiation therapy by preventing vascular activation and complement-dependent tumor destruction. Methods To test this hypothesis, we utilized a syngeneic orthotopic glioblastoma model in which GL261 glioblastoma tumor cells were stereotactically implanted into the right frontal lobes of syngeneic mice. These mice were treated with IDO-blocking drugs in combination with chemotherapy and radiation therapy. Results Pharmacologic inhibition of IDO synergized with chemo-radiation therapy to prolong survival in mice bearing intracranial glioblastoma tumors. We now show that pharmacologic or genetic inhibition of IDO allowed chemo-radiation to trigger widespread complement deposition at sites of tumor growth. Chemotherapy treatment alone resulted in collections of perivascular leukocytes within tumors, but no complement deposition. Adding IDO-blockade led to upregulation of VCAM-1 on vascular endothelium within the tumor microenvironment, and further adding radiation in the presence of IDO-blockade led to widespread deposition of complement. Mice genetically deficient in complement component C3 lost all of the synergistic effects of IDO-blockade on chemo-radiation-induced survival. Conclusions Together these findings identify a novel mechanistic link between IDO and complement, and implicate complement as a major downstream effector mechanism for the beneficial effect of IDO-blockade after chemo-radiation therapy. We speculate that this represents a fundamental pathway by which the tumor regulates intratumoral vascular activation and protects itself from immune-mediated tumor destruction.

In recent years there have been encouraging developments in the therapy for congestive heart failure. Vasodilator therapy, as an adjunct to digitalis and diuretics, has made a major impact. Vasodilator therapy results in improved left ventricular (LV) ejection fraction, improved functional capacity, and enhanced quality of life. When an angiotensin-converting enzyme (ACE) inhibitor is used, several studies published since 1988 show that these improvements are accompanied by improved survival. Yet many questions remain. Principal among these is how to approach the patient who has significantly depressed LV function, but is asymptomatic or has only minimal symptoms. In these patients the prognosis cannot be based on New York Heart Association (NYHA) functional class, but must reflect objective measurements of ventricular function. Any intervention should be specifically designed to improve survival, since functional capacity and quality of life are apparently unimpaired. On the other hand, there are no data at present to suggest that intervention in these patients will improve survival. This article considers the evaluation of such asymptomatic patients and potential therapeutic approaches. These are the use of cardiac glycosides, the use of ACE inhibitors, or their combination. Circumstantial evidence supporting their use in this select patient population is considered. It is stressed that any decision to intervene therapeutically in the asymptomatic patient must be made by the physician on an individual basis.

The accuracy of duplex pulsed Doppler echocardiography (d-PDE) for detecting mitral regurgitation was evaluated in 35 patients undergoing d-PDE, cardiac auscultation, and left ventriculography. With three transducer positions, the overall d-PDE sensitivity was 95%, specificity was 100%, positive predictive value was 100%, negative predictive value was 94%, and diagnostic accuracy was 97% compared with ventriculography. This technique was superior to auscultation (sensitivity 74%, specificity 94%, positive predictive value 93%, negative predictive value 75%, diagnostic accuracy 83%). No false-positive d-PDE results occurred, but discordant false-negative results occurred frequently among the three transducer positions. If discordant negative results are considered to be false negatives, then d-PDE is both sensitive and specific when mitral regurgitation is defined as systolic spectral broadening in any one transducer position.

To further define the sarcolemmal effects of ethanol and acetaldehyde, their effects on Na pump function were studied in synchronously contracting monolayers of neonatal rat myocardial cells. The effects of ethanol (10 mg/dl to 1000 mg/dl: 2× 10 −3 M-0.2 M) and acetaldehyde (10 −6 M to 10 −4 M) on total 42 K influx, ouabain-sensitive 42 K influx, Na pump density (from specific 3 H-ouabain binding) and pump turnover rates were measured. Applied acutely ethanol had no effect on 42 K influx but after 30 min of treatment 42 K influx was decreased by 13%, 23% and 48% in 100 mg/dl, 300 mg/dl and 1000mg/dl ethanol respectively. This primarily reflected a decrease in mean ouabain-sensitive K + influx from a control of 12.54 to 9.90,8.95 and 6.68 ( p -mol/cm 2 /s) in 100, 300 and 1000 mg/dl (2×10 −2 M, 6× 10 −2 M and 0.2M) ethanol. Acetaldehyde in the concentrations tested had no effect on K + influx. Ethanol treatment produced a decrease in Na pump density, maximum within 30 min and dosedependent, at concentrations of 100 mg/dl (22%), 300 mg/dl (37%) and 1000 mg/dl (55%). Acetaldehyde had no effect on Na pump density. In the presence of ethanol (300 mg/dl and 1000 mg/dl) intracellular Na + increased significantly and the Na + efflux declined in parallel with the K + influx. From the ouabain-sensitive K + and Na + fluxes and the Na pump density individual pump turnover rates were calculated at 62.5/s in control cells and 66/s and 84/s in cells treated with 300 mg/dl (6× 10 −2 M) and 1000mg/dl (0.2 M) respectively. We conclude that ethanol, but not acetaldehyde has a depressant effect on sarcolemmal Na pump function. The results suggest this is due primarily to a decrease in the number of sarcolemmal Na pump sites.

A 50-year-old woman with chest pain and an exercise thallium-201 scintigram positive for focal ischemia was found on coronary arteriography to have a heretofore unreported variant of single left coronary artery with the right coronary artery originating as a branch from the first septal perforator. Proximally, the aberrant vessel coursed through the ventricular septum at the level of the right ventricular outflow tract. A conus artery was absent and this is a possible basis for the focal basal ventricular ischemia and the patient's symptoms.

The effect of procainamide on membrane cation exchange was investigated using monolayer cultures of Girardi heart cells. The initial effect of procainamide (10(-6) to 10(-3) mol/litre) was to produce a prompt reduction of the passive Na influx, dose-dependent along a sigmoid log dose-response curve. This effect was complete within 3 min and thereafter showed no further time-dependent increase. Mean passive Na influx (pmol-cm-2/s) decreased from 19.1 to 17.7 (P less than 0.05) and 10.4 (P less than 0.001) in 10(-5) and 10(-3) mol/litre procainamide, respectively. No effect on active Na extrusion was noted before 3 min following exposure to the drug, after which time it progressively declined reaching a minimum value for each concentration by 6 min and remaining at this level throughout a further 60 min exposure. For each concetnration this minimum value was similar to the Na influx measured under identical conditions. Na-coupled active K influx showed a parallel pattern of inhibition. K efflux was not decreased until approximately 20 min following exposure to the drug, but once present the reduction was similar in magnitude to that in the correspondingly measured K influx. Kinetic flux analysis revealed a decrease in both PNa and PK but indicated a greater effect on PNa. The results suggest that all of the above effects could be explained on the basis of one direct action of the drug, namely, the prompt initial decrease in PNa and Na influx. All other effects noted, both active and passive, could then be secondary to this phenomenon.

The Na/K-exchange characteristics, ouabain-binding kinetics, and Na pump turnover rates of synchronously contracting monolayers of neonatal rat myocardial cells were studied. The cells exchange Na rapidly (T1/2 = 35 s) with a mean Na flux of approximately 25 (pmol/cm2)/s. The half time (T1/2) of K exchange is much longer (12 min); the mean K flux is 13 (pmol/cm2)/s. Active Na/K transport, as measured by K influx, is relatively ouabain sensitive, and 10(-6) M ouabain produces half-maximal inhibition. Ouabain (10(-2)M) inhibits 60% of the Na efflux and 75% of the K influx. The cells bind [3H]ouabain rapidly (T1/2 = 8 min), but release it very slowly (T1/2 = 11 h), and both the amount bound and the rate of binding were inversely proportional to extracellular K. Specific [3H]ouabain binding demonstrates saturation reaching a maximum of 1.6 x 10(6) molecules per cell at 2 x 10(-7) M [3H]ouabain. From cell surface area and ouabain-sensitive flux measurements, the Na pump density was calculated at 720/micrometer2 with an individual pump turnover rate of 50/s. Thus the studies indicate that despite their neonatal origin, the behavior of the Na pump in these cells is very similar to that in other mammalian tissues.

Monolayer cultures of myocardial cells were prepared by trypsin dispersion of neonatal rat ventricles. The cells were cultured for 4-5 days by which time a synchronously contracting monolayer of some 1.0 x 10(6) cells per 6-cm diam petri dish had formed. The contraction frequency and Na influx of the cells were unaffected by tetrodotoxin (2 x 10(-5) mg/ml) but both were markedly reduced by the addition of verapamil (10(-9) M to 10(-5) M). The effect of verapamil on both parameters occurred very rapidly. Although unresponsive to change in [Ca]0 between 0.3 mM and 3.0 mM, the contraction frequency of the cells declined rapidly as the [Ca]0 was reduced below 0.3 mM. On the other hand the beating rate of the cells was linearly related to [Na]0 below 40 mM the cells ceased to contract. It is therefore apparent that both [Ca]0 and [Na]0 contribute to the maintenance of the contraction frequency of cultured myocardial cells, but the latter is by far the more important. There also appeared to be, under all conditions, a close relationship between verapamilsensitive Na influx and contraction frequency. For the greater part this relationship was linear although at higher Na influx values it appeared to show evidence of saturation.

The effects of quinidine and temperature on Na influx and contraction frequency of synchronously contracting rat myocardial cells in monolayer cultures were studied. Quinidine (10(-6) M to 10(-1) M) produced a prompt reduction in Na influx, maximum after 30 seconds of exposure, and dose-dependent along a sigmoid log dose-response curve. At 37 degrees C, Na influx (mumol/10(11) cells per sec) decreased from 30.19 to 24.70 (P less than 0.001) and 10.49 (P less than 0.001) on exposure to quinidine, 10(-6) and 10(-2) M, respectively. Simultaneously the contraction frequency decreased from a control of 120/min to 105/min and 48/min with 10(-6) M and 5 X 10(-4) M quinidine. At higher concentrations spontaneous contractions ceased. The effects on Na influx and contraction were reversible by washing the cells free of the drug (30 seconds). A temperature-dependent decrease in the Na influx between 37 degrees C and 22 degrees C also induced a decrease in contraction frequency. Between 25 degrees C and 35 degrees C the Q10 values for Na influx and contraction frequency were 2.41 and 2.44 respectively. Under all conditions tested there was a constant linear relationship (r = 0.98) between Na influx and contraction frequency for all values of Na influx greater than 11.82 mumol/10(11) cells per sec. Na influx and contraction frequency were insensitive to tetrodotoxin (10(-5) g/ml) but very sensitive to verapamil and to changes in extracellular Na. Quinidine affected only the verapamil-sensitive Na influx. The results indicate a close relationship between verapamil-sensitive inward Na movement and automaticity in these cells and demonstrate that the quinidine-induced changes in automaticity are closely linked to the effect on Na influx.

Eight patients had cardiac manifestations that were life-threatening in five while taking psychotropic drugs, either phenothiazines or tricyclic antidepressants. Although most patients were receiving several drugs, Mellaril (thioridazine) appeared to be responsible for five cases of ventricular tachycardia, one of which was fatal in a 35 year old woman. Supraventricular tachycardia developed in one patient receiving Thorazine (chlorpromazine). Aventyl (nortriptyline) and Elavil (amitriptyline) each produced left bundle branch block in a 73 year old woman. Electrocardiographic T and U wave abnormalities were present in most patients. The ventricular arrhythmias responded to intravenous administration of lidocaine and to direct current electric shock; ventricular pacing was required in some instances and intravenous administration of propranolol combined with ventricular pacing in one. The tachyarrhythmias generally subsided within 48 hours after administration of the drugs was stopped. Five of the eight patients were 50 years of age or younger; only one clearly had antecedent heart disease. Major cardiac arrhythmias are a potential hazard in patients without heart disease who are receiving customary therapeutic doses of psychotropic drugs. A prospective clinical trial is suggested to quantify the risk of cardiac complications to patients receiving phenothiazines or tricyclic antidepressant drugs.

Histamine has been shown to have both positive inotropic and chronotropic effects. To evaluate the chronotropic effects, spontaneously contracting monolayers of cultured rat myocardial cells were treated with histamine, 10(-7) M-10(-4) M. This resulted in a dose-dependent increase in contraction frequency reaching a maximum in 10(-5) M histamine. Contraction frequency (mean +/- SEM) increased from a control of 121 +/- 5 contractions per minute to 153 +/- 4.5, 181 +/- 9, 212 +/- 4, and 216 +/- 1 in 10(-7) M, 10(-6) M, 10(-5) M, and 10(-4) M histamine, respectively (for each n = 10, p less than 0.001). The effect was time-dependent, taking 30 minutes to develop fully. Changes in contraction frequency were accompanied by parallel dose- and time-dependent increases in the verapamil-sensitive sodium influx. Verapamil-sensitive sodium influx (pmol/cm2/sec) increased from a control of 10.45 +/- 1.44 (mean +/- SEM) to 24.34 +/- 2.41 and 32.57 +/- 2.35 at 10- and 30-minute treatment with 10(-6) M histamine (n = 5, p less than 0.001). These data fit the previously described relation between verapamil-sensitive sodium influx and contraction frequency in these cells. Cimetidine (10(-4) M) but not diphenhydramine (10(-4) M) abolished both the contraction frequency and sodium influx response to histamine. Subsequent studies showed a dose- and time-dependent elevation of cyclic adenosine monophosphate (cAMP) with histamine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The kinetics of thallium exchange in cultured rat myocardial cells were studied and compared to those of potassium in the same tissue. Studies were carried out using low concentrations (10 nM to 5 microM) of thallium-204, approximating those likely to be encountered during clinical myocardial scintigraphy. Both thallium uptake and release could be described by a single exponential with a half-time of exchange which was approximately half that of potassium and which was largely independent of extracellular thallium concentration. Some 60% of thallium uptake occurred via an "active" or ouabain-inhibitable mechanism which, in the absence of extracellular potassium, could be activated by low concentrations (10 nM to 5 microM) of thallium. The apparent Km for thallium on this active transport mechanism was 2-7 microM. Increasing extracellular potassium from 0-10 mM caused significant, concentration-dependent decreases in both the total and the active component of the thallium influx. Similarly nonradioactive thallium (0.10 microM to 0.10 mM) caused a concentration-dependent decrease in active potassium influx. Analysis of these results by both Lineweaver-Burk plots and Dixon plots confirmed competitive inhibition, potassium on thallium influx and vice versa, for the active component of the fluxes, and noncompetitive in the remainder. These findings indicate that active transport accounts for the greater portion of the influx of thallium and potassium, and that this active transport occurs via a common mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of procainamide and lignocaine, in concentrations from 10(-6) to 10(-2) mol.litre(-1), on the Na influx and contraction frequency of cultured heart cells were studied. Both drugs produced a prompt, dose-dependent reduction in Na influx which was significant (P less than 0.01) for all concentrations tested. Lignocaine affected only that portion of the Na influx which was also verapamil-sensitive, whereas procainamide suppressed in addition, the verapamil-insensitive influx. In addition both drugs produced a concomitant decrease in the spontaneous contraction frequency of the cells. A close linear correlation (r = 0.99) between verapamil-sensitive Na influx and contraction frequency, in the presence of both procainamide and lignocaine was found. From this, and previous studies indicating a dependency of contraction frequency on the inward verapamil-sensitive Na influx, it is suggested that the drugs modify the automaticity of this preparation by a primary influence on membrane Na exchange.

We report a 25-year-old female with characteristic features of eosinophilic heart disease on clinical presentation, echocardiography, cardiac catheterization, and LV endomyocardial biopsy. Concomitant physical examination and echocardiographic findings suggesting hypertrophic obstructive cardiomyopathy resolved during treatment with anticoagulation and prednisone therapy.

Methods of precordial counting of radio-active isotopes in the detection of left-to-right intracardiac shunts are presented. Both iodine-131 labelled albumin and technetium-99m were used but the latter is preferred, especially for children, since it has a short physical half-life and emits a single gamma ray. Investigations were done to establish normal values and those in patients who had either rheumatic or congenital heart disease. All left-to-right shunts were confirmed at cardiac catheterization. False negative results were rare but false positive results can occur in the presence of congestive cardiac failure. It is possible to detect left-to-right shunts with a pulmonary to systemic flow ratio as low as 1·2:1 and an estimate of this ratio can be made from the precordial curve. The main value of the method is as a preliminary investigation in the detection of intracardiac shunts.

SUMMARY The effects of a new steroid anaesthetic agent (CT1341) were studied in twenty volunteers divided into three groups. In group I, serial measurements were made of heart rate, blood pressure and respiratory rate. In group II, detailed haemodynamic studies were made in patients undergoing diagnostic cardiovascular investigations. These studies included measurement of cardiac output, stroke volume and arterial blood gases. In group III, time from induction to “true recovery” was measured following a single intravenous injection of the drug. This agent produced a stable anaesthetic state in all cases. Anaesthesia was characterized by a rise in respiratory rate and pulse rate with a slight fall in systolic and diastolic blood pressure. A significant fall in Pao2 occurred in those patients breathing air. The mean recovery time in six patients was 24.3 min. CT1341 produced safe and stable anaesthesia in all twenty cases and is worthy of further clinical trial.