Long-term severe pulmonary hypertension associated with right atrial myxoma.

An 18-year-old black woman presented with marginally compensated right heart failure, severe pulmonary hypertension, tricuspid incompetence, and right atrial myxoma. Catheterization suggested a substantial reactive component to her P-HTN, especially to nifedipine. Initial management consisted of excision of two right atrial myxomas and tricuspid annuloplasty, and postdischarge management with nifedipine, 30 mg four times daily. Emergency pulmonary thromboendarterectomy was required two weeks later for acute cor pulmonale. It is suggested that concomitant procedures are mandatory in this setting because of the otherwise accelerated adverse pathophysiology of obliterative pulmonary vascular obstructive disease.

Impaired male sexual development in perinatal Sprague-Dawley and Long-Evans hooded rats exposed in utero and lactationally to p,p'-DDE.

Although the pesticide DDT has been banned in the United States for decades, it remains at low levels in the environment. p,p'-DDE, a metabolite of DDT, was recently shown to inhibit the binding of androgens to the androgen receptor and to exert antiandrogenic effects in perinatal Long-Evans (LE) rats at a dose of 100 mg/kg/day administered to pregnant dams. In this study, we compared the effects of p,p'-DDE on male sexual development in offspring of Sprague-Dawley (SD) and LE rats. The chemical was dosed by gavage to pregnant dams at 10 or 100 mg/kg body wt from gestation day 14 to 18. The developing male rats were examined for sexual developmental landmarks, while the effects of p,p'-DDE on androgen receptor expression were evaluated in the testis and other reproductive organs. The tissue dosimetry of p,p'-DDE was also determined at different stages of development following in utero and lactational exposures. The higher p,p'-DDE dose induced a reduction in the male anogenital distance, an increase in retention of male thoracic nipples and alterations in expression of the androgen receptor in either one or both strains. A much weaker response was seen in the lower dose groups. Tissue and body fluid concentrations of p,p'-DDE were similar in the two strains in some tissues but dissimilar in others, particularly in the serum levels. Higher serum p,p'-DDE levels in the LE strain during pregnancy corresponded with an overall greater sensitivity of the LE strain to the antiandrogenic effects of p,p'-DDE. These results support the previous findings of p,p'-DDE antiandrogenicity in LE rats, extend the findings to SD rats, and suggest that the developmental effects of p,p'-DDE on male rat sexual differentiation are minimal at maternal doses below 10 mg/kg/day.

Developmental effects of dietary phytoestrogens in Sprague-Dawley rats and interactions of genistein and daidzein with rat estrogen receptors alpha and beta in vitro.

Estrogenic isoflavones, such as genistein and daidzein, are present in virtually all natural-ingredient rodent diets that use soy as a source of protein. Since these compounds are endocrine-active, it is important to determine whether the amounts present in rodent diets are sufficient to affect sexual development. The present study consisted of in vitro and in vivo parts. In the in vitro portion, human hepatoma cells were transfected with either rat estrogen receptor (ER) alpha or beta plus an estrogen-responsive luciferase reporter gene. Genistein and daidzein were complete agonists at both ERs, genistein being more potent than daidzein, and both compounds were more potent at ER beta than ER alpha. In combined studies with estradiol, genistein exerted additive effects with estradiol in vitro. In the in vivo portion of the study, groups of six pregnant Sprague-Dawley females were fed one of the following four diets, and the pups were maintained on the same diets until puberty: (1) a natural-ingredient, open-formula rodent diet (NIH-07) containing 16 mg genistein and 14 mg daidzein per 100 g of feed; (2) a soy- and alfalfa-free diet (SAFD) in which casein and corn oil were substituted for soy and alfalfa meal and soy oil, respectively, that contained no detectable isoflavones; (3) SAFD containing 0.02% genistein (GE.02); or (4) SAFD containing 0.1% genistein (GE.1). In the GE.1 group, effects of dietary genistein included a decreased rate of body-weight gain, a markedly increased (2.3-fold) uterine/body weight (U/BW) ratio on postnatal day (pnd) 21, a significant acceleration of puberty among females, and a marginal decrease in the ventral prostate weight on postnatal day (pnd) 56. However, developmental differences among the groups fed SAFD, GE.02, or NIH-07 were small and suggested minimal effects of phytoestrogens at normal dietary levels. In particular, on pnd 21, the U/BW ratio of the GE.02 and NIH-07 groups did not differ significantly from that of the SAFD group. Only one statistically significant difference was detected between groups fed SAFD and NIH-07: the anogenital distance (AGD) of female neonates on pnd 1 whose dams were fed NIH-07 was 12% larger than that of neonates whose dams were fed SAFD. The results suggest that normal amounts of phytoestrogens in natural-ingredient rodent diets may affect one developmental parameter, the female AGD, and that higher doses can affect several other parameters in both males and females. Based on these findings, we do not suggest replacing soy- and alfalfa-based rodent diets with phytoestrogen-free diets in most developmental toxicology studies. However, phytoestrogen-free diets are recommended for endocrine toxicology studies at low doses, to determine whether interactive effects may occur between dietary phytoestrogens and man-made chemicals.

Shawl lapel aortoplasty.

We describe a simple method of remodeling an ascending aorta that has dilated in response to a stenotic aortic valve. It provides excellent exposure for valve replacement and avoids the use of substantial prosthetic material in effecting a secure, facile closure.

Combined multiple-valve procedures: a five-year experience with 125 patients.

One hundred twenty-five patients underwent 128 operations for combined multiple-valve procedures, with an overall early mortality of 16%. Highest mortality was associated with mitral and tricuspid valve disease (28.5%), followed by triple-valve disease (18.2%) and aortic and mitral valve disease (14%). Left ventricular end-diastolic pressure, cardiac index, mean pulmonary artery pressure, pulmonary artery wedge pressure, and arteriovenous oxygen difference were all significantly different in patients with regard to early mortality. Late follow-up of 94% has been achieved in 105 early survivors, with a late mortality rate of 11.2%. Analysis of late functional results reveal that 85% of survivors improved at least one Functional Class. Actuarial 5-year survival of 75% was achieved for early survivors of operation.

Carbon dioxide field flooding minimizes residual intracardiac air after open heart operations.

Transesophageal echocardiographic studies were used to monitor the presence of air bubbles in the heart after open heart operations. After cardiac valvular procedures all 22 patients managed with careful deairing procedures had persistence of air bubbles for at least 30 minutes and usually for 45 minutes. In 56 patients with CO2 field flooding, all foam disappeared in less than 1 minute in 48 patients and the remaining 8 had complete disappearance in 1 to 24 minutes. These observations demonstrate the ineffectiveness of the usual deairing maneuvers and the effectiveness of CO2 field flooding in displacing air.

Surgical management of tetralogy of Fallot in the first year of life.

BACKGROUND: The surgical approach to tetralogy of Fallot (TOF) continues to evolve and now many centers favor early repair for TOF. METHODS: Our experience includes 82 consecutive patients less than 1 year old with TOF (n = 74) and TOF with pulmonary atresia (n = 8) who were operated on between January 1992 and March 1998. Mean age at repair was 5.2 +/- 1.2 months and mean weight was 4.5 +/- 0.4 kg. Seven patients (anomalous left anterior descending artery [n = 1], pulmonary atresia with hypoplastic pulmonary arteries [n = 6]), underwent palliative procedures in the neonatal period followed by complete repair. Forty-nine patients (59%) were symptomatic (severe cyanosis or hypoxic spells), and 33 patients (41%) were asymptomatic. A combined transatrial-transpulmonary approach was employed in 28 patients (34%), and transannular patch or conduit for reconstruction of the right ventricular outflow tract (RVOT) was required in 54 patients (66%). The mean Nakata index was 160 +/- 25 mm2/m2. RESULTS: There were no hospital deaths. Mean post-repair peak right ventricular/systemic pressure ratio was 0.48 +/- 0.1. There were no late deaths or reoperations during a mean follow-up of 23 +/- 5 months. All patients are currently asymptomatic and in New York Heart Association class 1. Postoperative evaluation by two-dimensional and Doppler echocardiography or cardiac catheterization showed minimal pulmonary artery stenosis with a mean pressure gradient of 15 +/- 6 mm Hg across the RVOT. CONCLUSIONS: Our experience suggests that early repair of TOF can yield excellent results and initial palliation does not preclude early complete repair.

Lack of evidence for the involvement of formaldehyde in the hepatocarcinogenicity of methyl tertiary-butyl ether in CD-1 mice.

The oxygenated fuel additive methyl tertiary-butyl ether (MTBE) induced hepatocellular adenomas in female but not male CD-1 mice exposed to 8000 ppm; liver cancer was not induced in female or male mice exposed to 3000 or 400 ppm. Since MTBE is metabolized by cytochrome P450 to formaldehyde (HCHO), a potentially mutagenic intermediate capable of forming DNA-protein cross-links (DPX), the formation of DPX and of another HCHO derivative, RNA-formaldehyde adducts (RFA), from MTBE was investigated using freshly isolated hepatocytes from female CD-1 mice incubated with MTBE-(O-methyl-14C). DPX and RFA were detected, but the adduct yields were very small and were independent of the concentration of MTBE in the hepatocyte suspension over a wide concentration range (0.33-6.75 mM). Similar results were obtained using hepatocytes from male B6C3F1 mice and male F344 rats. Induction of cytochrome P450 by pretreatment of mice with MTBE prior to isolation of hepatocytes did not result in a measurable increase in the yields of either DPX or RFA. In contrast to the absence of concentration-dependent DPX and RFA formation from MTBE, there was a marked, concentration-dependent increase in the yields of both DPX and RFA when [14C]formaldehyde was added directly to the medium. These results suggest that the metabolism of MTBE to HCHO approaches saturation at concentrations below 0.33 mM, and that the rate of HCHO production from metabolism of MTBE is slow relative to the rate of HCHO metabolism. The lack of concentration dependence and the absence of species or sex differences in the formation of DPX and RFA from MTBE indicate that metabolism of MTBE to HCHO is not a critical component of its carcinogenic mechanism in mice.

The beneficial hemodynamic effects of selective patent vertical vein following repair of obstructed total anomalous pulmonary venous drainage in infants.

OBJECTIVES: Postoperative low cardiac output may persist after repair of total anomalous pulmonary venous drainage (TAPVD) because of a relatively small and non-compliant left atrium and left ventricle. We examined the effects of selective vertical vein patency on postoperative hemodynamics. METHODS: Thirty-four patients less than 3 months of age with TAPVD were operated from July 1993 to June 2000. The mean age at operation was 21+/-8 days (range, 3-62 days) and the mean weight was 3+/-0.2 kg (range, 2-4.1 kg). Supracardiac type drainage was found in 12 (35%), cardiac in three (9%), mixed in one (3%), and infracardiac in 18 (53%) patients. Twenty-two patients (65%) had obstructed venous drainage. All operations were performed with deep hypothermic circulatory arrest. Supracardiac, mixed and infracardiac types were repaired through a posterior approach, whereas, in the cardiac type, the coronary sinus was unroofed and the atrial septal defect was patched. The decision whether to keep the vertical vein open was made at the end of the operation and was based on the hemodynamic state of the patient. RESULTS: There were no operative deaths. The suture on the vertical vein was released in 22 patients who had obstructed pulmonary venous drainage (infracardiac type, n=18; supracardiac type, n=3; and mixed type, n=1), resulting in a significant drop in the left atrial pressure from 19+/-2 to 12+/-2 mmHg (P<0.05), and in the mean pulmonary artery pressure from 42+/-6 to 35+/-3 mmHg (P<0.05), associated with an immediate increase in the mean arterial blood pressure from a mean of 46+/-3 to 60+/-4 mmHg (P<0.05). During a mean follow-up of 38+/-6 months (range, 8-71 months), there were no late deaths. Follow-up, two-dimensional echocardiography with Doppler studies demonstrated good left ventricular function and trivial or no left to right shunt through the vertical vein in those patients in whom the snare was released. CONCLUSIONS: Maintaining the vertical vein patent in a selective group of patients with infracardiac total anomalous venous drainage contributes to a favorable outcome following surgery.

Microanalysis of urinary electrolytes and metabolites in rats ingesting dimethyl terephthalate.

Quantitative methods are described for the analysis of pH, sodium, ammonium, potassium, calcium, magnesium, chloride, phosphate, and sulfate, as well as terephthalic acid and dimethyl terephthalate, in a single urine sample as small as 20 microliter. The procedure utilizes ion chromatography and atomic absorption for electrolyte analysis, a microelectrode for pH measurement, and high-performance liquid chromatography for analysis of the organic compounds. The techniques are applied to urine samples freshly collected from rats ingesting dietary dimethyl terephthalate. Specific changes in urinary ions, including hypercalciuria and urinary acidosis, are shown to develop as a consequence of dimethyl terephthalate ingestion. The results indicate that metabolism of dimethyl terephthalate to terephthalic acid occurs extensively in Fischer-344 rats, and accounts for the ion changes that are observed.

Esophageal-aortic erosion associated with double aortic arch and tracheomalacia. Experience with 2 infants.

Patients with double aortic arch may require lengthy intubation for ventilatory support. The need for endotracheal and nasogastric intubation may be prolonged in such patients because of associated tracheomalacia. Iatrogenic tracheal or esophageal erosion with subsequent aortic fistulization is an unusual but catastrophic complication that may result from such intubation. We report the cases of 2 infants with double aortic arch and tracheomalacia who developed iatrogenic esophageal-aortic erosion. This complication was successfully managed in 1 of the infants. We conclude from our experience that the important steps in preventing this complication include 1) expediting the exclusion of upper-airway compromise in intubated infants who have a presentation characteristic of bronchospastic airway disease (hyperinflation and hypercapnia) that seems unresponsive to usual therapeutic measures; and 2) expediting the diagnosis of vascular ring in order to minimize the duration of dual tracheal and esophageal intubation. Effective management of this problem, once established, requires primary closure of the esophageal perforation, removal of the nasogastric tube, interposition of thick viable tissue between the esophagus and the aorta, and decompressive gastrostomy and feeding jejunostomy. Concomitant aortopexy may be appropriate.

Esophageal and gastroesophageal junction carcinoma: an evolved philosophy of management.

One hundred eleven patients with esophageal and gastroesophageal junction carcinoma were treated in the last 12 years. Fifty-seven (52%) underwent resection for cure (38%) or for palliation (14%). Overall operative mortality was 32% (18/57), being greatest with colon interposition (71%) or gastric tube (67%) and least with esophagogastrectomy (11%). Major complications--anastomotic leak being the most important--were strikingly more prevalent (71 and 66%) with the first two procedures than with esophgoastrectomy (14%). The mean survival time in patients resected for cure was 17 months compared to seven in those treated primarily by radiation. In addition, radiation therapy was accompanied by a 20% major complication rate and by less subjective palliation. In the surgically-resected group, there was a two, three, and five year survival of 26, 9, and 5%. Incomplete removal of tumor did not improve survival above that attained with untreated patients. Morbidity and mortality associated with use of endoprostheses in an additional 27 patients was 65%. This experience has led us to espouse the following approach: 1) The main thrust of treatment should be to resect gross tumor completely. 2) The use of the stomach in reconstruction at all levels offers the safest, most expeditious means of immediate rehabilitation. This is best accomplished by first an abdominal approach followed by a right thoracotomy, as outlined by Lewis (Br J Surg, 1946). 3) Radiation therapy should be used as post-resection adjunctive therapy or when surgery primarily is not applicable for medical reasons or refused.

Assisted circulation by phasic external lower body compression.

Assistance to the systemic venous circulation after experimental acute bypass of the right heart was provided by phasic external compression of the body. Pressure to 60 mm Hg administered to the body below the costal margin at 6--8 cycles/min augmented the circulation by translocation of blood volume from the peripheral to the central circulation, which increased right atrial pressure by 44%, mean cardiac index (61 to 74 m/kg/min) and mean arterial pressure (79 to 100 mm Hg) by 21%. The experimental study was followed by clinical trial of this method of circulatory support after anastomosis of the right atrium to the pulmonary artery (Fontan operations) in nine patients. One-minute cycles of phasic external compression of 45--50 mm Hg for 45 seconds followed by decompression for 15 seconds in patients increased right atrial pressure by 44% (mean increase 7 mm Hg) and systolic arterial pressure by 30% (average 20 mm Hg, range 13--28 mm Hg). Only two patients required inotropic medications; the others received either no medications or nitroprusside during the first 24 hours after surgery. Phasic external compression of the lower body is a simple and effective means of assisting the circulation after the Fontan operation.

Fatal thrombocytopenic coagulopathy after cardiopulmonary bypass: clinicopathologic correlations implicating heparin.

Heparin-associated thrombotic thrombocytopenia after cardiopulmonary bypass is frequently lethal. The propensity for this syndrome generally goes unrecognized because thrombocytopenia is common in the early postoperative period and because testing for heparin-induced platelet antibody may not distinguish between patients with thrombocytopenia alone and those in whom associated thrombi (the white clot syndrome) may develop. Moreover, differentiation between heparin-associated thrombotic thrombocytopenia and a consumptive coagulopathy may be difficult, and intervention may be inappropriate because of diametrically opposite treatments. Our experience with three cases and the necropsy findings in two of them demonstrate that postbypass thrombocytopenic coagulopathy may be a clinical and pathologic spectrum of consumptive coagulopathy, with heparin as the major premorbid factor. This report further emphasizes the need for vigilance in assessing certain patients preoperatively to lessen the high risk of morbidity and mortality associated with this syndrome.

DNA-protein cross-links and cell replication at specific sites in the nose of F344 rats exposed subchronically to formaldehyde.

Chronic exposures to high concentrations (> or = 6 ppm) of formaldehyde (HCHO) induce cell proliferation, squamous metaplasia, and squamous cell carcinomas in F344 rats. To assess the cancer risk associated with HCHO exposure, DNA-protein cross-links (DPX) formed in a single exposure of naive (previously unexposed) rats and monkeys have been used as a surrogate for the internal dose. Since the quantity of DPX may differ in subchronically exposed animals, the effects of preexposure to HCHO on the acute DPX yield (concentration of DPX following a single exposure) and the cumulative DPX yield (concentration of DPX following repeated exposures) were determined. Male F344 rats were preexposed (PE) to 0.7, 2, 6, or 15 ppm of HCHO (6 hr/day, 5 days/week, 11 weeks + 4 days). Naive (N) rats were exposed to room air. On the 5th day of the 12th week, PE and N rats were simultaneously exposed (3 hr) to H14CHO at the same concentrations used for preexposure. Acute DPX yields and cell replication (incorporation of 14C into DNA) were determined in the mucosal lining of the nasal lateral meatus (LM) (high tumor site in HCHO bioassay) and the medial and posterior meatuses (M:PM) (low tumor site in bioassay). DPX yields in the LM were approximately sixfold higher than in the M:PM. At 0.7 and 2 ppm, no differences between PE and N rats were detected in either tissue. At 6 and 15 ppm, acute DPX yields in the LM of PE rats were approximately half those of N rats, but no differences were detected in the M:PM. Cell proliferation was induced in PE rats at 6 ppm (LM only) and especially at 15 ppm (LM and M:PM). Cumulative DPX yields were measured indirectly by determining the decrease in extractability of DNA from proteins. PE rats were preexposed to 6 or 10 ppm as above, while N rats were exposed to room air. Both groups (PE and N) were then exposed (3 hr) to the same concentration of unlabeled HCHO. DPX yields increased in a concentration-dependent manner in both groups, but the yields were smaller in PE than N rats, suggesting that no accumulation of DPX occurred in PE rats. The results demonstrate that at concentrations < or = 2 ppm, N and PE rats are equivalent with respect to the formation of DPX.(ABSTRACT TRUNCATED AT 400 WORDS)

Fatty acid block of the transient outward current in adult human atrium.

Fatty acids represent an essential source of fuel for the heart and play an important role in the mechanical, electrical, and synthetic activities of cardiac cells. Under pathological conditions, such as ischemia followed by reperfusion, the myocardium is exposed to very high levels of fatty acids, in particular the monounsaturated fatty acid, oleic acid. Elevated plasma fatty acids have been linked to an increased risk for cardiac arrhythmias. In other species, fatty acids have been shown to modulate several cardiac ion channels, most notably potassium channels. Virtually nothing is known about the actions of oleic acid on potassium channels in human heart. We therefore characterized the effects of oleic acid on the transient outward current, sustained current, and inwardly rectifying current, some of the major potassium channels present in human atrium, using the whole-cell patch clamp method. Exposure of cells to oleic acid (5 microM) reduced the transient outward potassium current to 3.7 +/- 0.8 pA/pF (n = 4) compared with 7.0 +/- 0.7 pA/pF (n = 4) (P <. 05) for cells not exposed. In contrast, oleic acid had little effect on either the sustained current (4.3 +/- 0.3 pA/pF, n = 4 for oleic acid versus 4.8 +/- 0.5, n = 5 for control) present after the decay of the transient outward current or on the amplitude of IK1 measured at -100 mV (1.4 +/- 0.4 pA/pF, n = 4 for oleic acid versus 1.3 +/- 0. 4 pA/pF, n = 6 for control). In addition, oleic acid significantly slowed the rate of recovery of the transient outward current, which is predicted to result in a use-dependent reduction in current amplitude in the beating heart. These results suggest a possible contributing role for oleic acid block of the transient outward current in the pathological consequences of myocardial ischemia.

Determination of imipramine in plasma by high pressure liquid chromatography and field ionization mass spectrometry: increased sensitivity in comparison with gas chromatography mass spectrometry.

A quantitative method is reported for the determination of imipramine in plasma samples in the low nanogram and subnanogram range. The sensitivity and precision of the technique, which involves high pressure liquid chromatography and direct probe field ionization mass spectrometry, are approximately an order of magnitude greater than are offered by gas chromatography mass spectrometry with selected ion monitoring using deuterated or other types of internal standards. [2H6]Imipramine, labeled in the ethylene bridge and in the aromatic rings, serves as the isotopic diluent. The method has been used for the determination of the comparative bioavailabilities of two different commercial preparations of imipramine. In these tests, subjects ingested a 25 mg tablet of one or the other drug preparation together with a solution containing an equivalent amount of imipramine deuterated in the ethylene bridge ([2H2]imipramine). The latter served as an internal check for intrasubject variability in absorption of the imipramine tablets. Typical results from one of the subjects are presented.

Transplacental and lactational transfer of p,p'-DDE in Sprague-Dawley rats.

p,p'-DDE (hereafter DDE), a persistent metabolite of p,p'-DDT, is a widespread environmental contaminant that can induce antiandrogenic developmental effects in rats. Quantitative measurements of the transfer of DDE from pregnant or lactating dams to the fetus or suckling neonate were performed, and physiologically based pharmacokinetic (PBPK) models for the transplacental and lactational transfer of DDE were developed. Pregnant Sprague-Dawley rats were dosed by gavage in corn oil with either 10 or 100 mg DDE per kg body wt per day from Gestation Day (gd) 14 to 18. DDE was analyzed in several maternal tissues as well as in fetal and neonatal tissues from gd 15 to Postnatal Day (pnd) 21. Fetal DDE concentrations were about threefold lower than corresponding placental concentrations. By adopting a cross-fostering design, the contributions of transplacental and lactational transfer were compared. In the pup liver, where DDE was detectable in the 100 mg/kg groups on pnd 10, the lactationally exposed group had DDE concentrations about 50 times higher than those of the in utero only exposure group; the lactation only exposure groups had DDE tissue dose profiles very similar to those of the in utero plus lactation exposure groups, indicating that the lactational route is far more important than the in utero route quantitatively. The PBPK models postulated initial absorption of DDE into both the blood circulation and lymphatic system with the primary storage sites being maternal and neonatal adipose tissues. Mobilization of DDE from its storage sites is postulated to occur via its association with mobilized fatty acids and lipoproteins. The results provide an overall framework for evaluating the tissue dosimetry of DDE and for understanding how maternal exposure to DDE could affect perinatal sexual development in utero or in the early postnatal period.

Bioavailability of imipramine tablets relative to a stable isotope-labeled internal standard: increasing the power of bioavailability tests.

A new methodology for comparative bioavailability testing is described in which each drug formulation is compared with a stable isotope-labeled variant of the drug that is consumed orally in solution at the same time the tested formulation is ingested. The methodology is used to determine the comparative bioavailabilities of two commercially available brands of imipramine hydrochloride. The power of the new methodology to detect differences between drug formulations, when, in fact, such differences exist, is shown to be superior to that of conventional bioavailability tests.