Biallelic Variants in the Nuclear Pore Complex Protein NUP93 Are Associated with Non-progressive Congenital Ataxia.

Nuclear pore complexes (NPCs) are the gateways of the nuclear envelope mediating transport between cytoplasm and nucleus. They form huge complexes of 125 MDa in vertebrates and consist of about 30 different nucleoporins present in multiple copies in each complex. Here, we describe pathogenic variants in the nucleoporin 93 (NUP93) associated with an autosomal recessive form of congenital ataxia. Two rare compound heterozygous variants of NUP93 were identified by whole exome sequencing in two brothers with isolated cerebellar atrophy: one missense variant (p.R537W) results in a protein which does not localize to NPCs and cannot functionally replace the wild type protein, whereas the variant (p.F699L) apparently supports NPC assembly. In addition to its recently described pathological role in steroid-resistant nephrotic syndrome, our work identifies NUP93 as a candidate gene for non-progressive congenital ataxia.

Correction to: Biallelic Variants in the Nuclear Pore Complex Protein NUP93 Are Associated with Non-progressive Congenital Ataxia.

The original version of this article unfortunately contained mistake in Fig. 3 image.

Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity.

The phosphoinositide-3-kinase (PI3K)/Akt signaling pathway plays an important role in cell survival and the development of cancer. Macrophage migration inhibitory factor (MIF) is a critical inflammatory cytokine that was recently associated with tumorigenesis and that potently inhibits apoptosis. This may involve inhibition of p53-dependent genes, but the initiating molecular mechanism of how MIF controls survival/apoptosis is unknown. Here, we show that MIF prevents apoptosis and promotes tumor cell survival by directly activating the Akt pathway. MIF enhanced Akt activity in primary and immortalized fibroblasts (MEF and NIH/3T3), HeLa cervix carcinoma cells and various breast cancer cell lines. Activation was abolished by kinase inhibitors Ly294002 and PP2 and in Src/Yes/Fyn(SYF)(-/-) and CD74(-/-)(MEFs), while being enhanced in CD74-overexpressing MEFs, demonstrating that the MIF-induced Akt pathway encompasses signaling through the MIF receptor CD74 and the upstream kinases Src and PI3K. Akt was activated by exogenous rMIF and autocrine MIF action, as revealed by experiments in MIF(-/-)MEFs and antibody blockade. siRNA knockdown of CSN5/JAB1, a tumor marker and MIF-binding protein, showed that JAB1 controls autocrine MIF-mediated Akt signaling by inhibition of MIF secretion. Akt activation by MIF led to phosphorylation of the proapoptotic proteins BAD and Foxo3a. Apoptosis inhibition by MIF was functionally associated with Akt activation as it was abolished by overexpression of the Akt pathway inhibitor PTEN and occurred independently of p53. This was shown by studying DNA damage-induced apoptosis in fibroblasts, the Fas death pathway in HeLa cells that do not express functional p53, and etoposide-induced apoptosis in breast carcinoma cells expressing mutant p53. Importantly, dependence of breast cancer cell survival on MIF correlated with Akt activation and the PTEN status of these cells. Thus, MIF can directly promote cell survival through activation of the PI3K/Akt pathway and this effect is critical for tumor cell survival.

Stimulation of vascular smooth muscle cell migration by macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF) is a well known proinflammatory factor that influences the migration and proliferation of various cell types, predominantly monocytes and macrophages. Recent evidence suggests an important role for MIF in the progression of atherosclerosis and restenosis. For this reason, we studied the effect of MIF on platelet-derived growth factor-BB (PDGF-BB)-induced migration and PDGF receptor protein expression in vascular smooth muscle cells (VSMCs). Furthermore, the possibility of MIF influencing the migration of VSMCs was investigated. Our results show that short-term incubation of MIF is able to enhance PDGF-BB-induced migration. Long-term incubation decreases PDGF-BB-induced migration, but preserves a short-term stimulatory effect. These effects are not regulated at the level of PDGF receptor protein expression. MIF also acts as a chemoattractant for VSMCs, with a maximum response at 15 ng/ml. In contrast, the proliferation of VSMCs was unaffected by MIF. We conclude that MIF has a biphasic effect on VSMC migration. It remains unclear whether this effect is direct or involves the secretion of unidentified promigratory factors. Exogenous MIF does not stimulate VSMC proliferation; however, a role for MIF in proliferation cannot be fully ruled out. In view of the known key contributions of macrophage-derived MIF and VSMCs, the observed effects may well play a role in the progression of atherosclerosis and restenosis.

Implications of mitral valve prolapse in children with rheumatic mitral regurgitation.

OBJECTIVES: This study was conducted to determine the longterm prognosis of children with mitral valve prolapse associated with isolated rheumatic mitral regurgitation. BACKGROUND: Rheumatic fever may result in mitral valve prolapse, which sometimes leads to severe mitral regurgitation requiring surgical intervention during the active stage of rheumatic fever. However, the influence of mitral valve prolapse on the prognosis of patients with rheumatic mitral regurgitation remains largely unknown. METHODS: From 1971 to 1991, 181 children who fulfilled the revised Jones criteria of rheumatic fever were identified from a rheumatic fever prevention program. Of the 181 patients, isolated mitral regurgitation was diagnosed in 123 at age 4 to 12 years. The diagnosis of mitral valve prolapse was based on echocardiographic findings. Actuarial event-free curves for persistent murmur, cardiac improvement and surgical intervention were drawn according to the Kaplan-Meier nonparametric estimation. RESULTS: Evidence of mitral valve prolapse was shown in 37 (30%) of the 123 patients. Patients with mitral valve prolapse were more likely to have a larger cardiac size than those without mitral valve prolapse during the active stage of rheumatic fever. Although the cardiac status of patients with mitral valve prolapse may improve under adequate secondary prophylaxis, an actuarial analysis indicated that patients with mitral valve prolapse had a greater likelihood of murmur persistence and surgical intervention. This trend toward murmur persistence was observed even when patients with heart failure during the active stage of rheumatic fever were excluded from analysis. CONCLUSIONS: The presence of mitral valve prolapse in children with isolated rheumatic mitral regurgitation may predict a less favorable outcome.

Balloon angioplasty for obstructed modified systemic-pulmonary artery shunts and pulmonary artery stenoses.

OBJECTIVES: The results of percutaneous balloon angioplasty for obstructed modified Blalock-Taussig (BT) or central shunts and pulmonary artery (PA) stenoses were studied to assess its role as an alternative to second shunt and surgical PA angioplasty. BACKGROUND: Obstruction of a modified shunt and PA stenosis related to the shunt or ductus are not infrequent. A second shunt with or without PA angioplastv is required if the PA size, morphology or age of the patient is suboptimal for definitive surgery. METHODS: From June 1994 to May 1999, balloon angioplasty for obstructed systemic-to-PA shunts was performed in 46 patients, with ages ranging from 1 month to 7.4 years (2.2 +/- 1.9 years). Among the 46 patients, 32 had modified BT shunts, 5 had bilateral shunts, 7 had modified central shunts, and 2 had both modified BT and central shunts. Stenoses were seen in 27 main branch PAs, and interruption was present in three. A concurrent balloon angioplasty was attempted in 28 main branch PAs, but it was performed in only 25 vessels. RESULTS: Balloon dilation for obstructed modified shunts was considered to be effective in 42 patients (91%), while angioplasty for PA stenosis was effective in 14 vessels and not effective in 11 vessels. After balloon dilation angioplastv, oxygen saturation in the aorta increased from 74.4 +/- 4.3% to 80.8 +/- 3.6% (p < 0.01) in these 46 patients. One patient died of pneumonia. Eight patients required an additional modified BT shunt soon after the procedure because of severe stenosis or interruption at main branch PA. After a mean follow-up period of 11.6 +/- 5.4 months, 29 patients underwent a repeated imaging study to evaluate the morphology and size of the PAs. Of these 29 patients, 26 underwent open-heart surgery, with two mortalities. CONCLUSIONS: When a second shunt is under consideration because of obstruction of the modified shunt, balloon angioplasty is a possible alternative procedure. Pulmonary artery stenosis, if present, can be simultaneously dilated.

Supraventricular tachycardia in patients with right atrial isomerism.

OBJECTIVES: To clarify the prevalence and mechanism of supraventricular tachycardia in patients with right atrial isomerism. BACKGROUND: Paired SA and dual atrioventricular (AV) nodes have been described in patients with right atrial isomerism. However, the clinical significance remains unclear. METHODS: From 1987 to 1996, a total of 101 patients (61 male, 40 female) and four fetuses were identified with right atrial isomerism. The diagnosis of supraventricular tachycardia exclude the tachycardia with prolonged QRS duration or AV dissociation, and primary atrial tachycardia. RESULTS: The median follow-up duration was 38 months (range 0.2-270 months). Supraventricular tachycardia was documented in 25 patients (24.8%) and one fetus (25%) (onset age ranged from prenatal to 14 years old; median 4 years old). Actuarial Kaplan-Meier analysis revealed that the probability of being free from tachycardia was 67% and 50% at 6 and 10 years of age, respectively. These tachycardias could be converted by vagal maneuvers in one, verapamil in seven, propranolol in four, digoxin in two, procainamide in one, and rapid pacing in five. Spontaneous conversion was noted in six (including the fetus). Seven cases had received electrophysiological studies. Reciprocating AV tachycardia could be induced in five and echo beats in one. The tachycardia in three patients was documented as incorporating a posterior AV node (antegrade) and an anterior or a lateral AV node (retrograde). Two of them received radiofrequency ablation. Successful ablation in both was obtained by delivering energy during tachycardia, aimed at the earliest retrograde atrial activity and accompanied by junctional ectopic rhythm. The patient with echo beats developed tachycardia soon after operation. CONCLUSIONS: Supraventricular tachycardia is common in patients with right atrial isomerism and can occur during the prenatal stage. Drugs to slow conduction through the AV node may help to terminate the tachycardia. Radiofrequency ablation is a safe and effective treatment alternative to eliminate tachycardia.

Three- versus four-week administration of benzathine penicillin G: effects on incidence of streptococcal infections and recurrences of rheumatic fever.

OBJECTIVE: To investigate the effects of 3-week versus 4-week administration of benzathine penicillin G (BPG) on the incidence of Group A streptococcal infections and the recurrences of rheumatic fever (RF). STUDY DESIGN: We started, in 1979, randomly allocating all patients with RF to a 3-week or 4-week BPG prophylaxis program. They were examined at the RF clinic, every 3 to 6 months, and at any time they did not feel well. During 1979 to 1989, throat cultures and sera for antistreptolysin O and streptozyme titers were obtained at each clinic visit. Chest radiographs, electrocardiogram, color Doppler echocardiograms, and acute phase reactants were obtained. SUBJECTS: Two hundred forty-nine patients fulfilled the revised Jones criteria and were followed until December 1991: 124 in the 3-week and 125 in the 4-week program. Their age, sex, weight, percentage with history of RF, severity of cardiac involvement, follow-up duration, and compliance to program were comparable. Eight hundred eighty throat cultures were collected in the 3-week program and 770 were collected in the 4-week program. Six hundred sixteen and 627 sera were determined in each program for antistreptolysin O, and 582 and 592 sera for streptozyme titers. RESULTS: True streptococcal infections occurred in both programs: 39 infections in the 3-week program, and 59 infections in the 4-week program (7.5 vs 12.7 per 100 patient-years). Four infections with no antibody response occurred in the 3-week program, and three such infections in the 4-week program. Nine RF recurrences occurred in 8 patients in the 3-week program, and 16 recurrences in 16 patients in the 4-week program. Prophylaxis failure occurred in 2 of 124 patients in the 3-week program, and in 10 of 125 patients in the 4-week program (0.25 vs 1.29 per 100 patient-years). The overall recurrences/infections rate in each program was comparable, 13.6% vs 15.5%, but the recurrences/ infections rate due to prophylaxis failure was higher in the 4-week program than in the 3-week program, 3.0% versus 9.7%. CONCLUSIONS: This 12-year prospective and controlled study documented that streptococcal infections and RF recurrences occurred more often in the 4-week program than in the 3-week program. The risk of prophylaxis failure was fivefold greater in the 4-week program than in the 3-week program.

Double-inlet ventricle in Chinese patients.

This study was performed to elucidate the anatomic features of double-inlet ventricle in the Chinese population. The echocardiograms of 60 Chinese patients diagnosed as having double-inlet ventricle were reviewed and analyzed. Both atria were connected to a dominant right ventricle in 36 patients (60%), to a dominant left ventricle in 17 (28%) and to an indeterminate ventricle in 7 (12%). Right atrial isomerism was present in 30 patients (83%) with double-inlet right ventricle, in 5 (29%) with double-inlet left ventricle, and in 6 (86%) with double-inlet indeterminate ventricle. Right atrial isomerism was more frequently associated with double-inlet right and indeterminate ventricles (p < 0.01; chi-square). Common atrioventricular valve was frequently present in both double-inlet right and indeterminate ventricles. Double-outlet main chamber was the predominant type of ventriculoarterial connection in double-inlet right and indeterminate ventricles. Total anomalous pulmonary venous connection was found exclusively in 9 patients with right atrial isomerism (5 with double inlet right and 4 with double-inlet indeterminate ventricles). In contrast to other reports, this series found double-inlet right ventricle to be the predominant type of double-inlet ventricle. This discrepancy may be due to a greater prevalence of right atrial isomerism that is usually associated with double-inlet right ventricle in Chinese patients.

Outcomes of transcatheter valvotomy in patients with pulmonary atresia and intact ventricular septum.

The results of transcatheter valvotomy in pulmonary atresia with intact ventricular septum (PA-IVS) patients are presented with an attempt to identify the predictive factors for pulmonary valvotomy alone as definitive treatment. Between June 1995 and December 1997, 14 PA-IVS neonates with tripartite right ventricle underwent an attempted pulmonary valvotomy. For perforation of the pulmonary valve, a guidewire was used in 4, and a radiofrequency guidewire in 10 patients. Two outcome groups were identified. Group I included those in whom transcatheter treatment achieved a definitive success; group II patients required surgery despite an initial successful valvotomy. The attempt failed in 3 patients, 1 of whom had pericardial effusion. Perforation of the pulmonary valve was achieved in 11 patients: 2 with a guidewire and 9 with a radiofrequency guidewire. A subsequent balloon valvuloplasty was performed in these 11 patients. After valvuloplasty, mean right ventricular pressure decreased from 124 +/- 24 to 60 +/- 15 mm Hg (p <0.01). One died of heart failure and infection 10 days later, despite successful weaning from prostaglandin E1. Group I patients (n = 6) were treated with transcatheter valvotomy alone. Group II patients (n = 4) required right ventricular outflow patch. Significant differences between the 2 groups (group I vs II) were identified in tricuspid valve Z value (0.52 +/- 0.37 vs -1.25 +/- 0.48, p <0.05), pulmonary valve Z value (-3.47 +/- 0.59 vs -5.43 +/- 0.94, p <0.05), and ratio of right-to-left ventricular area on the apical 4-chamber view (0.73 +/- 0.06 vs 0.49 +/- 0.03, p <0.05). There were no significant differences in hemodynamic characteristics between the 2 groups. After a follow-up period ranging from 7 to 35 months (mean 18 +/- 10.3), the most recent echocardiograms in the 10 patients showed a mean pressure gradient across the pulmonary valve of 17 +/- 15 mm Hg. All 10 patients had an oxygen saturation of >92%. Transcatheter valvotomy using a radiofrequency guidewire is a safe and effective treatment in selected patients with PA-IVS. Transcatheter valvotomy can be a definitive treatment in PA-IVS patients with a tricuspid valve Z value > or = -0.1, pulmonary valve Z value > or = -4.1 and ratio of right-to-left ventricular area > or = 0.65.

Validation of pulmonary venous obstruction by electron beam computed tomography in children with congenital heart disease.

The purpose of this study was to explore the useful imaging findings of electron beam computed tomography (EBCT) for diagnosing pulmonary venous obstruction (PVO) in children with congenital heart disease. From July 1995 to March 1998, 17 children (9 girls and 8 boys, aged 7 days to 14 years and 9 months [median 3 months]) with the diagnosis of PVO were enrolled in this study. All images were obtained by EBCT at the end-diastolic phase of the cardiac cycle after administration of intravenous iodinated contrast medium. The findings of 25 EBCT studies were retrospectively analyzed by 2 radiologists and were correlated with echocardiography, angiocardiography, and surgical findings. Main findings on EBCT for PVO were (1) structural narrowing, (2) thickened interlobular septa, (3) peribronchovascular cuffing, and (4) ground-glass opacity of the alveoli. Structural narrowing along the course of the pulmonary venous drainage was the most important finding in all examinations (25 of 25). Lung parenchymal changes secondary to PVO included thickened interlobular septa (17 of 25), peribronchovascular cuffing (15 of 25), and ground-glass opacity of the alveoli (8 of 25). Thus, the combination of these findings provides very useful data for the definitive diagnosis of PVO. Characteristic electron beam computed tomographic findings can validate suspected PVO noninvasively.

Influence of aortopulmonary rotation on the anomalous coronary artery pattern in tetralogy of fallot.

Three main patterns of aortic sinus rotation were defined on 517 lateral angiograms of tetralogy of Fallot with 14 cases of anomalous coronary artery pattern occurring only in patients with a right anterior or right lateral aorta. The significant dependence of coronary artery types on the aortic sinus pattern made it possible to predict the predisposing coronary artery pattern in tetralogy of Fallot based on the aortic sinus pattern.

Usefulness of magnetic resonance imaging in the assessment of venoatrial connections, atrial morphology, bronchial situs, and other anomalies in right atrial isomerism.

Multiple complex venous and intracardiac anomalies are frequently seen in patients with right atrial isomerism, and complete anatomic information may not always be obtained from combined echocardiography and angiography. Twenty patients with right atrial isomerism were prospectively studied with use of magnetic resonance imaging (MRI); satisfactory imaging was obtained in 18 patients, aged 6 days to 12 years (median 3 months). All patients had undergone echocardiography, cardiac catheterization, and angiocardiography. The purpose of this study was to assess the usefulness of MRI in the evaluation of venoatrial connections, atrial morphology, bronchial situs, and additional anomalies. Bilateral superior venae cavae were documented in 12 patients and anomalous hepatic venous drainage in 11. The pulmonary venous system was imaged in all 18 patients, of whom 12 had total anomalous pulmonary venous connection: 9 supracardiac, 2 infracardiac, and 1 mixed type. Some obstruction to pulmonary venous return was present in 9 of the 12 patients, and the site of obstruction was demonstrated by MRI in 6. Bilateral morphologic right atrial appendages were imaged in 7 patients. Bilateral morphologic right bronchi were identified in 17 patients, asplenia was confirmed in 17 of 18 patients by the absence of splenic tissue on imaging, and hiatal hernia was imaged in 4. Compared with angiography and echocardiography, MRI more clearly defined the pulmonary venous connections in 10 patients with pulmonary venous obstruction. Anomalous hepatic venous connections were better defined by MRI in 2. Therefore, MRI provided valuable supplementary information on the cardiovascular and visceral anomalies in these patients.

Implication of aneurysmal transformation in isolated perimembranous ventricular septal defect.

Defects on the membranous ventricular septum (perimembranous ventricular septal defect [VSD]) may spontaneously close or diminish in size by "aneurysmal transformation" (i.e., adherence of the tricuspid valve or adjacent tissue onto the VSD). It was recently shown that the appearance of aneurysmal transformation may be associated with subaortic ridges, as well as left ventricular (LV)-to-right atrial (RA) shunts. In all, 877 consecutive patients with isolated perimembranous VSD were retrospectively studied. Results of actuarial analysis showed that patients with a perimembranous VSD had a 98% probability of aneurysmal transformation by the age of 240 months. Of these patients, the expected probabilities of developing LV-RA shunt, spontaneous closure and subaortic ridge were 45, 35 and 6%, respectively. Patients with LV-RA shunts had higher probabilities of developing infective endocarditis (p = 0.002) and persistent left-to-right shunts (p < 0.001). The presence of a subaortic ridge may be accompanied by LV outflow tract obstruction (10 of 25 patients), infundibular pulmonary stenosis (n = 3), or aortic valve deformity or aortic regurgitation (n = 5), and none of those with a subaortic ridge closed spontaneously. It was confirmed that a substantial proportion of aneurysmal transformation of isolated perimembranous VSD is associated with LV-RA shunts and subaortic ridges.

Malalignment-type ventricular septal defect in double-chambered right ventricle.

Double-chambered right ventricle (DCRV) is commonly associated with ventricular septal defect (VSD). In this study, an assessment was made of the relevance of a malalignment-type VSD to hemodynamic and morphologic features in DCRV. During an 8.5-year period, 53 patients with DCRV were enrolled after study with echocardiography, catheterization, and angiography. Patients were divided into 2 groups: group I included 40 patients, aged 3.7 +/- 3.2 years, with a malalignment-type VSD; group II consisted of 13 patients, aged 8.6 +/- 2.7 years, without a malalignment-type VSD. History of congestive heart failure in infancy was present in 21 group I and 2 group II patients (53% vs 15%, respectively, p <0.05). The mean pulmonary-to-systemic flow ratio was significantly higher in group I than in group II (1.89 +/- 0.74 vs 1.14 +/- 0.21, respectively, p <0.05). The mean pressure gradient across the right ventricular outflow tract was lower in group I than in group II (41 +/- 16 vs, 73 +/- 33 mm Hg, respectively, p <0.05). Among 42 patients who had a series of echocardiograms recorded, progression of pressure gradient was evident in 35: 28 in group I and 7 in group II. A subaortic ridge was present exclusively in 29 group I patients (73%). Prolapse of the aortic valve was present in 26 (49%): 20 group I (50%) and 6 group II (46%) patients. Aneurysm formation of the septal defect was found in 17 (43%) and 7 (54%) group I and II patients, respectively. It can be concluded that a history of congestive heart failure was more common in DCRV patients with a malalignment-type VSD. Malalignment-type VSD is significantly associated with a larger pulmonary-to-systemic flow ratio and subaortic ridge.

Usefulness of electron beam computed tomography in children with heterotaxy syndrome.

Children with heterotaxy syndrome frequently have complex cardiac and noncardiac malformations requiring detailed diagnostic evaluation for management planning. Direct delineation of these structures by electron beam computed tomography (EBCT) is validated as a means of diagnosis. From July 1995 to March 1997, 32 patients (16 girls, 16 boys) with clinically impressed heterotaxy syndrome were enrolled in this study. After evaluation by echocardiography, EBCT studies were performed. Interpretation of cardiac anomalies was performed by sequential analysis based on these cross-sectional images. The diagnoses were subsequently confirmed by angiocardiography and surgical findings. Twenty-eight patients had bilateral trifurcated bronchi, and most of these (24 of 28) did not have a spleen. Four patients had bilateral bifurcated bronchi, 2 patients had polysplenia, and the other 2 patients had a lobulated single spleen. We found that laterality could be identified by EBCT in all patients. Comparison of diagnostic yield between echocardiography, catheterization, and EBCT showed that EBCT is superior to echocardiography and catheterization in demonstration of pulmonary venous anatomy and presence of a very small rudimentary ventricle. In addition, associated visceral, bronchopulmonary, mediastinal, and intracardiac anomalies could all be clearly delineated by EBCT at the same time. Thus, EBCT is a promising complementary modality for an overall understanding of heterotaxy syndrome.

Anomalous pulmonary venous pathway traversing pulmonary parenchyma. Diagnosis and implication.

STUDY OBJECTIVES: To describe four patients having total anomalous pulmonary venous connection with an intrapulmonary vertical vein, rendering difficulty in diagnosis and surgery. SETTING: a tertiary referral center. PATIENTS AND METHODS: By reviewing medical records, 4 of 25 patients with right atrial isomerism and total anomalous pulmonary venous connection were identified to have an intrapulmonary vertical vein. All four patients underwent echocardiography, catheterization, and angiography. One underwent MRI. Two underwent open-heart surgery and one received a modified Blalock-Taussig shunt. RESULTS: Right atrial isomerism was present in all four patients. On chest x-ray films, an abnormal shadow resembling scimitar syndrome was seen in two patients. Imaging the vertical vein was unsuccessful with an echocardiogram in all four patients. The intrapulmonary course of the vertical vein was depicted with a pulmonary venogram in two patients and with magnetic resonance in one patient. The intrapulmonary segment remained undetected until autopsy in one patient. All four patients died. At autopsy, the pulmonary venous confluence was hypoplastic in all four hearts. The vertical vein was buried in pulmonary parenchyma and drained to superior vena cava with significant obstruction. CONCLUSION: In the presence of right atrial isomerism and total anomalous pulmonary venous connection, there may be an intrapulmonary pulmonary venous connection that may be obstructed. Anastomosing the pulmonary venous confluence to the atrium may be difficult because of hypoplasia of the pulmonary venous confluence.

Prognostic significance of left ventricular diastolic indexes in beta-thalassemia major.

OBJECTIVE: To define the prognostic significance of left ventricular diastolic function in patients with beta-thalassemia major by noninvasive M-mode echocardiography and Doppler measurements. DESIGN: Cohort analytic study. SETTING: A university hospital in Taipei, Taiwan. PATIENTS: Forty-five patients (age range, 4 to 25 years) with transfusion-dependent beta-thalassemia major followed up for 5 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: M-mode and Doppler echocardiography were used to determine the left systolic time interval; ejection fraction; left atrium emptying index; isovolumetric relaxation period; diastolic total period; the duration, slope, and height of the early diastolic flow-velocity peak; and the ratio between the heights of early and atrial diastolic flow-velocity peaks. All patients had normal systolic ventricular function initially, but impaired diastolic function developed, especially in the older age group who had more evidence of iron loading. In nine of those with abnormal diastolic total period (n = 10) and duration of the early diastolic flow-velocity peak (n = 12) values, regardless of age, congestive heart failure developed during the period of follow-up. Of these nine, four died within 2 years after the advent of heart failure and five remained compensated after anticongestive treatment and use of deferoxamine mesylate. The presence of an abnormal diastolic total period and duration of the early diastolic flow-velocity peak values correlated well with the prognosis. CONCLUSIONS: Left ventricular diastolic filling variables by echocardiography are important predictors of the outcome of patients with transfusion-dependent beta-thalassemia major and could provide useful measures in determining the effects of medication during long-term follow-up.

Modified arterial switch operation by spiral reconstruction of the great arteries in transposition.

BACKGROUND: Spiral relationship of the normally related great arteries (SRGA) has never been reconstructed in an arterial switch operation. METHODS: From March 1998 to April 1999, 9 consecutive cases of transposition of the great arteries (TGA) family (from 2 days to 1.6 years old) underwent arterial switch operations with SRGA at our hospital. Two had a congenitally corrected TGA (plus atrial redirection). Lecompte maneuver was not used in all. The posterior wall of pulmonary trunk was not divided but three were reattached, two of whom had had previous pulmonary trunk banding. Thus the wall was shared between the great arteries facing each other. RESULTS: All survived the operation. Supraaortic stenosis was balloon-dilated in 2 cases of early series, but technical modifications later were able to avoid it. Angiogram showed smooth flow into SRGA without upward and anterior tilting of the pulmonary bifurcation. All great and coronary arteries were patent. All were doing well on follow-up (16.5 +/- 4.2 months). CONCLUSIONS: We concluded that the techniques to relocate the coronary arteries using common wall and in situ switch could also be applied to pulmonary arterial reconstruction, so that SRGA can be resumed in TGA.

Paramedian reticular nucleus--sympathetic inhibition in spontaneously hypertensive rats.

The cardiovascular reactivity of various areas in the medulla related to sympathetic or parasympathetic activation, or to sympathetic inhibition, was compared in spontaneously hypertensive rats (SHR) and in normotensive rats Wistar-Kyoto (WKY) or Sprague-Dawley (SD). In SHR, which has an elevated resting systemic arterial blood pressure (SAP), the sympathetic pressor responses elicited from electrical stimulation of the dorsomedial medulla (DMM), parvocellular lateral nucleus (PVC) or ventrolateral medulla (VLM) were more profound than those in WKY and SD. The depressor and bradycardia responses elicited from electrical stimulation of the paramedian reticular nucleus (PRN) (which exerts both sympathetic and parasympathetic inhibitions) or from the area of the solitary nucleus/dorsomotor nucleus of vagus (NTS/DMV) (where stimulation leads to both parasympathetic activation and sympathetic inhibition) were also more intensive in SHR than in WKY and SD. The elicited pressor and depressor responses, however, were not significantly different between WKY and SD. Our results are consistent with previous findings (15) that in SHR an increased sympathetic activity of the pressor areas of medulla contributes to the pathogenesis of hypertension. Sympathetic inhibition (PRN and NTS/DMV areas) and parasympathetic activation (NTS/DMV area) from these areas, however, may not be critically involved.