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Mechanisms by which efavirenz diminishes methadone plasma concentrations are unknown. This investigation determined efavirenz influence on clinical methadone disposition and miosis, intravenous and oral alfentanil clearance (hepatic and intestinal cytochrome P450 3A4/5 (CYP3A4/5) activity), fexofenadine disposition (intestinal transporters activity), and efavirenz clearance and 8-hydroxylation (CYP2B6 activity), and human hepatocyte effects. Efavirenz induced systemic and oral alfentanil clearances two- to fivefold and induced efavirenz 8-hydroxylation. Efavirenz stereoselectively decreased methadone plasma concentrations 50-70%. Methadone systemic and oral clearances, hepatic clearance and extraction ratio, N-demethylation, and metabolite formation clearance were stereoselectively increased two- to threefold. Bioavailability decreased. Efavirenz shifted methadone concentration-miosis curves leftward and upward. Efavirenz induced hepatocyte CYP2B6 and CYP3A4 expression, activity, and methadone N-demethylation. Results show that efavirenz coinduced hepatic CYP2B6 and CYP3A4/5, coinduced hepatic and intestinal CYP3A4/5, and coinduced gastrointestinal CYP3A4/5 and efflux transporters. Methadone disposition was most consistent with efavirenz induction of hepatic CYP2B6-mediated methadone N-demethylation. Efavirenz may alter methadone pharmacodynamics.

Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively.Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis).Nelfinavir decreased intravenous and oral methadone plasma concentrations 40-50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone; apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (SR) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50 and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration-effect (miosis) curve leftward and upward.Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects.

Background Methadone clearance is highly variable, and drug interactions are problematic. Both have been attributed to CYP3A, but actual mechanisms are unknown. Drug interactions can provide such mechanistic information. Ritonavir/indinavir, one of the earliest protease inhibitor combinations, may inhibit CYP3A. We assessed ritonavir/indinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A activity, and intestinal transporters (P-glycoprotein) activity. CYP3A and transporters were assessed with alfentanil and fexofenadine, respectively. Methods Twelve healthy human immunodeficiency virus-negative volunteers underwent a sequential three-part crossover. On three consecutive days, they received oral alfentanil/fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone, repeated after acute (3 days) and steady-state (2 weeks) ritonavir/indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were assessed by miosis. Results Alfentanil apparent oral clearance was inhibited more than 97% by both acute and steady-state ritonavir/indinavir, and systemic clearance was inhibited more than 90% due to diminished hepatic and intestinal extraction. Ritonavir/indinavir increased fexofenadine area under the plasma concentration-time curve four- to five-fold, suggesting significant inhibition of gastrointestinal P-glycoprotein. Ritonavir/indinavir slightly increased methadone N-demethylation, but it had no significant effects on methadone plasma concentrations or on systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Ritonavir/indinavir had no significant effects on methadone plasma concentration-effect relationships. Conclusions Inhibition of both hepatic and intestinal CYP3A activity is responsible for ritonavir/indinavir drug interactions. Methadone disposition was unchanged, despite profound inhibition of CYP3A activity, suggesting little or no role for CYP3A in clinical methadone metabolism and clearance. Methadone bioavailability was unchanged, despite inhibition of gastrointestinal P-glycoprotein activity, suggesting that this transporter does not limit methadone intestinal absorption.

OBJECTIVES To assess the cardiac auscultatory skills of health care professionals before and after an actual (not simulated) patient-centered cardiac auscultation conference and to determine the effectiveness of this clinical teaching method on improving diagnostic proficiency. SUBJECTS AND METHODS Seventy-eight participants at a conference on cardiac auscultation completed preconference and postconference examinations on their ability to diagnose a wide variety of heart sounds and murmurs. Among those tested, 46 (59%) were physicians: 17 (22%) were cardiologists, 19 (24%) were medical interns or residents, 7 (9%) were cardiology fellows, 2 (3%) were general practitioners, and 1 (1%) was a pediatrician. Thirty-two (41%) of this group of respondents were nonphysicians: 14 (18%) were nurse practitioners, 9 (12%) were nurses, 6 (8%) were physician assistants, 2 (3%) were medical students, and 1 (1%) was a nonmedical professional. All participants were tested on 14 clinically important cardiac auscultatory events directly recorded from actual (not simulated) patients and transmitted via wireless infrared stethophones. The auscultatory events tested were wide physiologic splitting of S 2 in right bundle branch block, fixed S 2 splitting and systolic murmur in atrial septal defect, midsystolic click and late systolic murmur of mitral valve prolapse, S 4 gallop, S 3 gallop, opening snap of mitral stenosis, innocent systolic murmur, systolic murmur of mitral regurgitation, systolic murmur of tricuspid regurgitation, systolic murmur of hypertrophic obstructive cardiomyopathy, continuous murmur of patent ductus arteriosus, pericardial friction rub, prosthetic valve sounds, and alternation of heart sounds, heart murmurs, and the S 3 gallop in congestive heart failure. RESULTS On the basis of the analysis of the 78 participants who completed preconference and postconference evaluations of the 14 selected cardiac auscultatory events, a preconference identification score of 26.3% and a postconference score of 44.7% were observed. This represents a statistically significant overall improvement in diagnostic proficiency ( P >.001). CONCLUSIONS Cardiac auscultatory skills among today's health care professionals are extremely poor, regardless of the level and/or type of training of the professional. An actual (not simulated) patient-centered teaching conference is an effective clinical method of improving cardiac auscultatory skills and diagnostic proficiency of health care professionals.

Lipoprotein(a) is a risk factor for cardiovascular disease composed of an apolipoprotein B-containing lipoprotein to which a second protein, apolipoprotein(a), is attached. We investigated in seven subjects with Lp(a) levels of 39--85 mg/dl the metabolism of four apo B-containing lipoproteins (VLDL(1), VLDL(2), IDL and LDL) together with that of apo B and apo(a) isolated from Lp(a). Rates of secretion, catabolism and where appropriate, transfer were determined by intravenous administration of d(3)-leucine, mass spectrometry for measurements of leucine tracer/tracee ratios and kinetic data analysis using multicompartmental metabolic modeling. Apo B in Lp(a) was secreted at a rate of 0.28 (0.17--0.40) mg/kg per day. It was found to originate from two sources -- 53% (43--67) were derived from preformed lipoproteins, i.e. IDL and LDL, the remainder was accounted for by apo B, directly secreted by the liver. The fractional catabolic rates (FCRs) of apo B and of apo(a) prepared from Lp(a) were determined as 0.27 (0.16--0.38) and 0.24 (0.12--0.40) pools per day, respectively, which is less than half of the FCR observed for LDL. Our in vivo data from humans support the view that Lp(a) assembly is an extracellular process and that its two protein components, apo(a) and apo B, are cleared from the circulation at identical rates.

Background: Dyslipidemia (predominantly hypertriglyceridemia) is frequently seen in patients receiving antiretroviral combination therapy (ART). However, the underlying mechanisms and long-term risks (e.g., cardiovascular events) are still unclear. Objectives/Methods: In 5 patients with ART-associated dyslipidemia, stable isotope labeled amino acid tracer (d3-Leu) kinetic analysis over 12 days was used to investigate the metabolism of apolipoprotein B-containing lipoproteins (very low density lipoproteins [VLDL] 1 , VLDL 2 , intermediate density lipoproteins [IDL] and low density lipoproteins [LDL]). Data were compared with those in 6 healthy normolipidemic controls. Results: The patients under ART showed significantly increased fasting triglycerides (359 vs. 77 mg/dl) and VLDL (54 vs. 15 mg/dl), compared with controls. They had significantly higher total cholesterol (213 vs. 157 mg/dl) and there was a nonsignificant trend toward higher LDL (136 vs. 93 mg/dl), and toward lower HDL (26 vs. 46 mg/dl). The ratio of large, buoyant LDL 1 over small, dense LDL 2 was markedly reduced in patients under ART (0.80 vs. 2.00). Total apo B synthesis was significantly increased (25.5 vs. 14.5 mg/kg/d) and shifted toward triglyceride rich VLDL I (18.5 vs. 8.7 mg/kg/d) in patients receiving ART. There was also a significantly reduced rate of apo B lipoprotein transfer from VLDLI to VLDL2 (3.7 vs. 20.7 pools/d). In addition, all patients revealed insulin resistance. Conclusions: These data indicate that increased triglycerides in HIV-infected patients with ART are primary due to reduced rates of VLDL transfer into denser lipoproteins implying a lower rate of lipoprotein lipase-mediated delipidation. In addition, total apo B synthesis was increased and shifted toward triglyceride-rich VLDLI. Overall, this lipoprotein profile in patients with ART-associated dyslipidemia implies an increased risk for cardiovascular events.

Apolipoprotein B (apoB) metabolism was investi- gated in 20 men with plasma triglyceride 0.66-2.40 mmol/l and plasma cholesterol 3.95-6.95 mmol/l. Kinetics of VLDL 1 (S f 60-400), VLDL 2 (S f 20-60), IDL (S f 12-20), and LDL (S f 0-12) apoB were analyzed using a trideuterated leucine tracer and a multicompartmental model which al- lowed input into each fraction. VLDL 1 apoB production varied widely (from 5.4 to 26.6 mg/kg/d) as did VLDL 2 apoB production (from 0.18 to 8.4 mg/kg/d) but the two were not correlated. IDL plus LDL apoB direct production accounted for up to half of total apoB production and was inversely related to plasma triglyceride ( r 5 2 0.54, P 5 0.009). Percent of direct apoB production into the IDL/ LDL density range ( r 5 0.50, P , 0.02) was positively re- lated to the LDL apoB fractional catabolic rate (FCR). Plasma triglyceride in these subjects was determined princi- pally by VLDL 1 and VLDL 2 apoB fractional transfer rates (FTR), i.e., lipolysis. IDL apoB concentration was regulated mainly by the IDL to LDL FTR ( r 5 2 0.71, P , 0.0001). LDL apoB concentration correlated with VLDL 2 apoB pro- duction ( r 5 0.48, P 5 0.018) and the LDL FCR ( r 5 2 0.77, P , 0.001) but not with VLDL 1 , IDL, or LDL apoB produc- tion. Subjects with predominantly small, dense LDL (pat- tern B) had lower VLDL 1 and VLDL 2 apoB FTRs, higher VLDL 2 apoB production, and a lower LDL apoB FCR than those with large LDL (pattern A). Thus, the metabolic conditions that favored appearance of small, dense LDL were diminished lipolysis of VLDL, resulting in a raised plasma triglyceride above the putative threshold of 1.5 mmol/l, and a prolonged residence time for LDL. This lat- ter condition presumably permitted sufficient time for the processes of lipid exchange and lipolysis to generate small LDL particles. —Packard, C. J., T. Demant, J. P. Stewart, D. Bedford, M. J. Caslake, G. Schwertfeger, A. Bedynek, J. Shepherd, and D. Seidel. Apolipoprotein B metabolism and the distribution of VLDL and LDL subfractions. J. Lipid Res. 2000. 41: 305-317.

A simultaneous study of the metabolism of apolipoprotein B and albumin in nephrotic patients. Background The nephrotic syndrome is characterized by proteinuria, hypoalbuminemia and hyperlipidemia. Despite intensive research it is not clear at present what the causal links are between these pathological findings. Methods Stable isotope labeled amino acid tracer kinetic analysis was used to simultaneously investigate the metabolism of four apolipoprotein B-containing lipoproteins (VLDL 1 , VLDL 2 , IDL and LDL) and albumin in seven patients with nephrotic syndrome and marked hypercholesterolemia, in two additional nephrotic patients with concomitant renal failure and mixed hyperlipidemia, and in a matched group of normolipidemic controls. Results Increased concentrations of VLDL 2 , IDL and LDL were due to ( a ) impaired VLDL 2 and IDL delipidation, ( b ) reduced LDL catabolism, and ( c ) a trend towards an increased rate of total apolipoprotein B production. The rate of fractional albumin elimination was three times higher in patients than in controls and the rate of albumin synthesis was increased by 45%. No correlations were detectable between rates of apolipoprotein B production and the rate of albumin synthesis. Conclusions The results of this study suggest that hyperlipidemia in nephrotic syndrome is predominantly the result of delayed lipoprotein delipidation and catabolism. There is no evidence that it is driven by a general increase of the rate of hepatic protein synthesis.

Background We analysed incidence, predictors, histological features and specific treatment options of anti-tumour necrosis factor α (TNF-α) antibody-induced psoriasiform skin lesions in patients with inflammatory bowel diseases (IBD). Design Patients with IBD were prospectively screened for anti-TNF-induced psoriasiform skin lesions. Patients were genotyped for IL23R and IL12B variants. Skin lesions were examined for infiltrating Th1 and Th17 cells. Patients with severe lesions were treated with the anti-interleukin (IL)-12/IL-23 p40 antibody ustekinumab. Results Among 434 anti-TNF-treated patients with IBD, 21 (4.8%) developed psoriasiform skin lesions. Multiple logistic regression revealed smoking (p=0.007; OR 4.24, 95% CI 1.55 to 13.60) and an increased body mass index (p=0.029; OR 1.12, 95% CI 1.01 to 1.24) as main predictors for these lesions. Nine patients with Crohn9s disease and with severe psoriasiform lesions and/or anti-TNF antibody-induced alopecia were successfully treated with the anti-p40-IL-12/IL-23 antibody ustekinumab (response rate 100%). Skin lesions were histologically characterised by infiltrates of IL-17A/IL-22-secreting T helper 17 (Th17) cells and interferon (IFN)-γ-secreting Th1 cells and IFN-α-expressing cells. IL-17A expression was significantly stronger in patients requiring ustekinumab than in patients responding to topical therapy (p=0.001). IL23R genotyping suggests disease-modifying effects of rs11209026 (p.Arg381Gln) and rs7530511 (p.Leu310Pro) in patients requiring ustekinumab. Conclusions New onset psoriasiform skin lesions develop in nearly 5% of anti-TNF-treated patients with IBD. We identified smoking as a main risk factor for developing these lesions. Anti-TNF-induced psoriasiform skin lesions are characterised by Th17 and Th1 cell infiltrates. The number of IL-17A-expressing T cells correlates with the severity of skin lesions. Anti-IL-12/IL-23 antibody therapy is a highly effective therapy for these lesions.

Background Methadone disposition and pharmacodynamics are highly susceptible to interactions with antiretroviral drugs. Methadone clearance and drug interactions have been attributed to cytochrome P4503A4 (CYP3A4), but actual mechanisms are unknown. Drug interactions can be clinically and mechanistically informative. This investigation assessed effects of the protease inhibitor indinavir on methadone pharmacokinetics and pharmacodynamics, hepatic and intestinal CYP3A4/5 activity (using alfentanil), and intestinal transporter activity (using fexofenadine). Methods Twelve healthy volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone. This was repeated after 2 weeks of indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by miosis. Results Indinavir significantly inhibited hepatic and first-pass CYP3A activity. Intravenous alfentanil systemic clearance and hepatic extraction were reduced to 40-50% of control, apparent oral clearance to 30% of control, and intestinal extraction decreased by half, indicating 50% and 70% inhibition of hepatic and first-pass CYP3A activity. Indinavir increased fexofenadine area under the plasma concentration-time curve 3-fold, suggesting significant P-glycoprotein inhibition. Indinavir had no significant effects on methadone plasma concentrations, methadone N-demethylation, systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Methadone plasma concentration-effect relationships were unaffected by indinavir. Conclusions Despite significant inhibition of hepatic and intestinal CYP3A activity, indinavir had no effect on methadone N-demethylation and clearance, suggesting little or no role for CYP3A in clinical disposition of single-dose methadone. Inhibition of gastrointestinal transporter activity had no influence of methadone bioavailability.

Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined short-term (2-day) and steady-state (2-week) ritonavir effects on intestinal and hepatic CYP3A4/5 (probed with intravenous (IV) and oral alfentanil (ALF) and with miosis) and P-glycoprotein (P-gp) (fexofenadine), and on methadone pharmacokinetics and pharmacodynamics in healthy volunteers. Acute ritonavir increased the area under the concentration-time curve (AUC)(0-infinity)/dose ratio (ritonavir/control) for oral ALF 25-fold. Steady-state ritonavir increased the AUC(0-Infinity)/dose ratio for IV and oral ALF 4- and 10-fold, respectively; reduced hepatic extraction (from 0.26 to 0.07) and intestinal extraction (from 0.51 to 0); and increased bioavailability (from 37 to 95%). Acute ritonavir inhibits first-pass CYP3A > 96%. Chronic ritonavir inhibits hepatic CYP3A (> 70%) and first-pass CYP3A (> 90%). Acute and steady-state ritonavir increased the fexofenadine AUC(0-infinity) 2.8- and 1.4-fold, respectively, suggesting P-gp inhibition. Steady-state compared with acute ritonavir caused mild apparent induction of P-gp and hepatic CYP3A, but net inhibition still predominated. Ritonavir inhibited both intestinal and hepatic CYP3A and drug transport. ALF miosis noninvasively determined CYP3A inhibition by ritonavir.

Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined ritonavir effects on stereoselective methadone pharmacokinetics and clinical effects (pupillary miosis) in healthy human immunodeficiency virus-negative volunteers. Subjects received intravenous plus oral (deuterium-labeled) racemic methadone after no ritonavir, short-term (3-day) ritonavir, and steady-state ritonavir. Acute and steady-state ritonavir, respectively, caused 1.5- and 2-fold induction of systemic and apparent oral R- and S-methadone clearances. Ritonavir increased renal clearance 40-50%, and stereoselectively (S > R) increased hepatic methadone N-demethylation 50-80%, extraction twofold, and clearance twofold. Bioavailability was unchanged despite significant inhibition of intestinal P-glycoprotein. Intestinal and hepatic CYP3A was inhibited > 70%. Ritonavir shifted methadone plasma concentration-miosis curves leftward and upward. Rapid ritonavir induction of methadone clearance results from increased renal clearance and induced hepatic metabolism. Induction of methadone metabolism occurred despite profound CYP3A inhibition, suggesting no role for CYP3A in clinical methadone metabolism and clearance. Ritonavir may alter methadone pharmacodynamics.

Kinetics of apo B and apo AI were assessed in 8 patients with mixed hyperlipidemia at baseline and after 8 weeks of atorvastatin 80 mg q.d. and micronised fenofibrate 200 mg q.d. in a cross-over study. Both increased hepatic production and decreased catabolism of VLDL accounted for elevated cholesterol and triglyceride concentrations at baseline. Atorvastatin significantly decreased triglyceride, total, VLDL and LDL cholesterol and apo B concentrations (-65%, -36%, -57%, -40% and -33%, respectively, Ptextless0.05). Kinetic analysis revealed that atorvastatin stimulated the catabolism of apo B containing lipoproteins, enhanced the delipidation of VLDL1 and decreased VLDL1 production. Fenofibrate lowered triglycerides and VLDL cholesterol (-57% and -64%, respectively, Ptextless0.05) due to enhanced delipidation of VLDL1 and VLDL2 and increased VLDL1 catabolism. Changes of HDL particle composition accounted for the increase of HDL cholesterol during atorvastatin and fenofibrate (18% and 23%, Ptextless0.01). Only fenofibrate increased apo AI concentrations through enhanced apo AI synthesis (45%, Ptextless0.05). We conclude that atorvastatin exerts additional beneficial effects on the metabolism of apo B containing lipoproteins unrelated to an increase in LDL receptor activity. Fenofibrate but not atorvastatin increases apo AI production and plasma turnover.

PLoS one 8(11), e77773 (2013). doi:10.1371/journal.pone.0077773, Published by PLoS [u.a.], Lawrence, Kan.

Intracoronary adenosine infusions in conscious dogs produced half-maximal coronary vasodilation at 0.57 +/- 0.18 (SD) microns and at 1.01 +/- 0.25 microns in open-chest dogs. In both preparations, adenosine at concentrations in the range found in cardiac muscle by direct analysis produced coronary vasodilation equal to that attained during a maximum reactive hyperemic response. The quantitative structure-activity relationship technique was applied to data on the coronary vasoactivity of 68 adenosine analogs to identify the chemical features of this molecule that determine its vasoactivity. These are: (1) the size of the purine base; (2) the inductive effect of C-2 substituent; (3) the electron-withdrawing effect of the C-6 substituent; (4) the glycosylic torsion angle; (5) the ability of the C-2' and C-3' hydroxyls to participate in hydrogen bonding; (7) the absence of sterically hindering groups in the vicinity of C-2' and, more importantly, C-3'; and (8) the inductive effect of the C-5' substituent. The hydrophobicity of these analogs did not correlate with vasoactivity, suggesting that the hydrophilicity of the ribose moiety overshadows any hydrophobic influence of the very weakly aromatic purine base.

An implantable beta-radiation detector suitable for the measurement of reginal blood flow in the experimental animal by the indicator clearance principle is described. A lithium-drifted silicon diode encapsulated in a stainless steel case is sutured over the site of interest. A suitable beta-emitting isotope, such as 85Kr in saline solution, is injected into the arterial supply and its calibrated against a mechanical system and showed excellent agreement up to 600 ml/100 g per min. At very high rates beyond the physiological range, flow was underestimated by a maximum of 10%. In vivo comparisons of myocardial blood flow assessed by the beta detector did not agree well with estimates of flow from a precordial counter or by the microsphere technique. Possible reasons are spatial heterogeneity of regional myocardial blood flow, the greatly different masses of tissue involved, or our inability to achieve sufficient numbers of spheres for accuracy in a 50-mg mass of tissue. The unit was still functional after 50 days in a chronic animal.

Clinical, hemodynamic, and anatomic data were analyzed in 50 cases of sinus venosus atrial septal defect (SVASD) that underwent surgery. SVASD comprised 12 per cent ( 50 470 ) of ASD's over a 12 year period. All patients had a mid-systolic murmur and fixed splitting of the second sound. Analysis of 48 preoperative ECG's revealed that 46 per cent had a P wave axis of less than 30 degrees. Cardiac catheterization data were not distinctive for SVASD although the demonstration of anomalous pulmonary venous connection (APVC) was highly suggestive. At surgery a persistent left superior vena cava was present in 8 per cent ( 4 50 ). APVC was found in 86 per cent ( 43 50 ). In the 38 patients with APVC in whom accurate anatomic description was available, all had APVC from the right upper lobe. Twenty-five patients also had APVC from the right middle and inferior lobes or from the middle lobe. Distal connections of the anomalous veins were as follows: 27 to the SVC, 6 to the SVC-right atrial junction 7 to the right atrium, 3 to the SVC and to the right atrium, and 1 to the inferior vena cava.

A case of left atrial myxoma is reported. Some newly recognized clinical characteristics of this tumor are emphasized, and hemodynamic and surgical findings are discussed. The hypergammaglobulinemia in this case was shown to be due to a polyclonal elevation of IgA. Tissue culture of the tumor ceils was successful and revealed the presence of fusion giant cells in the cell culture. Electron microscopy suggested that the endothelial or subendocardial reserve cell was the cell of origin.

EXTERNAL direct-current and alternating-current countershock has proved effective in terminating ventricular tachycardia. Various medications have also been used to control this arrhythmia. This paper describes the successful use of frequent intermittent, intravenous administration of lidocaine (Xylocaine) hydrochloride to control recurrent ventricular tachycardia after the failure of other commonly available drugs. Report of a Case A 31-year-old white woman was admitted to the hospital for elective pelvic surgery. There was a history of eight normal full-term deliveries, two spontaneous abortions, and dilation and curettage had been done five times. She had had two brief episodes of palpitations, 13 and 9 months previously. Evaluation after the latter episode revealed an innocent cardiac murmur. On this admission a grade II (of VI), basal, systolic ejection murmur was heard and considered to be innocent. Results of urinalysis and serological study were normal, and a hemogram and chest roentgenogram were normal. An electrocardiogram was not

A computer-derived treadmill exercise score that quantifies the electrocardiographic response to exercise has been reported to have a high sensitivity (87 per cent) and specificity (92 per cent) in patients with a high prevalence of coronary artery disease. To test its accuracy in young, asymptomatic men with a low prevalence of coronary artery disease, we evaluated the responses of 377 military officers (mean age, 36.6 years) by two independent methods. According to standard electrocardiographic criteria, 45 of the subjects (12 per cent) had positive tests, whereas the treadmill exercise score indicated that only 3 (less than 1 per cent) had positive tests. Since two of these three had left ventricular hypertrophy and met only the criteria for the latter without associated coronary artery disease, the treadmill exercise score predicted that only 1 of 377 subjects would have clinically important coronary artery disease. Coronary arteriography, performed in 10 persons with the most positive scores on standard treadmill tests and the highest scores for risk factors, showed that nine subjects did not have coronary artery disease and that one had single-vessel disease (the same subject who the treadmill score predicted would have mild disease). The treadmill exercise score appears to improve the diagnostic specificity of exercise electrocardiography and may be more useful than values on standard stress tests in screening asymptomatic populations for coronary artery disease.

CLINICAL SUMMARY: This 67-year-old man was well until 3 weeks prior to admission when he experienced chest pain and shortness of breath. Nine days prior to admission, after an episode of chest pain that lasted an hour and a half, the patient reported to a community hospital for evaluation. An electrocardiogram was interpreted as normal (Fig. 1). The patient returned home and went about his daily activities which included yard work and lifting heavy objects. Three days prior to admission, the patient experienced severe shortness of breath and malaise. This increased until the day of admission when he again went to the community hospital. At this time a new systolic murmur was heard. The electrocardiogram was unchanged and was now interpreted as compatible with an acute anteroseptal myocardial infarction. The patient was transferred to Walter Reed Army Medical Center for evaluation. He denied any cardiac awareness, palpitations, paroxysmal nocturnal dyspnea, orthopnea, or edema. He had no fever or chills. The patient had adult onset diabetes mellitus, controlled with diet, and a vague history of hypertension which was never treated. There was no family history of heart disease. The patient denied having rheumatic or scarlet fever, gout, or hyperlipoprotein

A newly developed agarose gel electrophoretic technique which separates the pre-β-lipoproteins into subfractions, has been applied in the determination of serum lipoprotein patterns in patients undergoing coronary catheterization. A correlation is established between the presence of one or two lipoprotein pre-β bands with the presence or absence of coronary atherosclerosis by coronary cineangiography. It was found that two pre-β bands were present in 47% of patients without demonstrable coronary atherosclerosis and in 90% of patients with coronary atherosclerosis. The agarose gel electrophoretic technique is recommended as a screening test prior to coronary cineangiography.

Hematologic data in previous cases of eosinophilia with fibrosing endocarditis have been too limited to firmly establish a relation to the myeloproliferative disorders. A patient with the ...

A 17-year-old patient is discussed who had the tachycardia-bradycardia syndrome following closure of a sinus venosus atrial septal defect. Cardiac standstill up to 7.2 seconds long occurred, but placement of a permanent demand pacemaker was avoided. This unique case demonstrates that permanent pacemaker may not always be necessary in the tachycardia-bradycardia syndrome, especially when it occurs in a young postsurgical patient.

A retroesophageal innominate artery is a rare congenital anomaly theoretically occurring if there is a break in either aortic arch proximal to the origin of the common carotid artery. The resulting vessel is the last off the arch and gives origin to a subclavian and common carotid artery (Fig. 1). In reality a persistent dorsal aortic root (5), this vessel may then be considered an innominate artery. The purpose of this paper is to report an angiographically documented, right aortic arch with retroesophageal left innominate artery and to indicate an error that has been made in the diagnosis of this anomaly. S. G., a 19-year-old white male, was referred for evaluation because of a heart murmur and dyspnea on strenuous exertion. His past history was interesting in that he had been hospitalized for four and a half months during the first year of his life with a diagnosis of “mucoviscidosis and aspiration pneumonia.” There had been difficulty with feedings associated with intermittent periods of cough, cyanos...

Four patients had deviation of the mean QRS axis as an electrocardiographic manifestation of hyperkalemia. Two patients had a leftward and superior axis shift and two had a rightward and inferior axis shift. These findings are reported so that the spectrum of electrocardiographic changes associated with hyperkalemia will be appreciated.