Possible involvement of regulatory T cell abnormalities and variational usage of TCR repertoire in children with autoimmune neutropenia.

Autoimmune neutropenia (AIN) in childhood is characterized by chronic neutropenia and positivity for anti-neutrophil antibodies, resulting in the excessive destruction of neutrophils. In this study, we investigated the involvement of regulatory T cells (Tregs ) in the pathogenesis of AIN in childhood. Tregs have been classified into three subpopulations based on the expressions of CD45RA and forkhead box protein 3 (FoxP3): resting Tregs , activated Tregs and non-suppressive Tregs . The frequency of activated Tregs (CD4+ CD25+ FoxP3high CD45RA- T cells) as well as that of total Tregs (CD4+ CD25+ FoxP3+ T cells) in peripheral blood was significantly decreased in patients with AIN. Analysis of the T cell receptor (TCR)-Vß repertoire of CD4+ T cells revealed skewed usages in patients with AIN compared with that observed in age-matched control subjects. Regarding T cell subsets, the use of four of 24 TCR-Vß families in Tregs and one in conventional T cells were increased in patients with AIN. The number of patients with AIN who showed skewed usages of TCR-Vß family in conventional and Tregs was significantly higher than that reported in control subjects. When the preference between Tregs and conventional T cells in each TCR-Vß family was individually compared, different use was prominently observed in the TCR-Vß 9 family in patients with AIN. These results suggest that the quantitative abnormalities of Tregs and the skew of the TCR-Vß repertoire in CD4+ T cells, including Tregs and conventional T cells, may be related to autoantibody production through a human neutrophil antigen-reactive T cell clone.

Simultaneous detection of ABL1 mutation and IKZF1 deletion in Philadelphia chromosome-positive acute lymphoblastic leukemia using a customized target enrichment system panel.

INTRODUCTION: Recent clinical outcomes of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) vastly improved owing to tyrosine kinase inhibitor (TKI). However, the genetic status would be different in each case with ABL1 gene mutation or copy number variants (CNVs) such as IKZF1 deletion. In particular, the TKI resistant clone with ABL1 kinase mutation remains problematic. The comprehensive assessment of genetic status including mutation, insertion and deletion (indel) and CNVs is necessary. METHODS: We evaluated a next-generation sequencing (NGS)-based customized HaloPlex target enrichment system panel to simultaneously detect coding mutations, indel and CNVs. We analysed approximately 160 known genes associated with hematological disorders in 5 pediatric Ph+ALL patients. RESULTS: Mono-allelic IKZF1 deletions were found in 4 patients at diagnosis. Furthermore, the mono-allelic deletions were found in exons of RB1, EBF1, PAX5 and ETV6 genes. Bi-allelic deletions were detected in CDKN2A and CDKN2B genes in 1 patient. ABL1 mutation was also detected in 1 patient at relapse. These results were almost comparable with the results of the multiplex ligation-dependent probe amplification (MLPA) method or Sanger sequence. CONCLUSION: Next-generation sequencing-based custom HaloPlex target enrichment system panel allows us to detect the coding mutations, indel, and CNVs in pediatric Ph+ALL simultaneously, and its results seem comparable with those of other methods.

Two cases of severe bronchopneumonia due to influenza A (H3N2) virus: detection of influenza virus gene using reverse transcription polymerase chain reaction.

We report two cases of severe bronchopneumonia due to influenza A (H3N2) virus. The severity of the disease necessitated initiation of empiric therapy based on the present illness and clinical data on admission. Both patients were improved by artificial ventilation with positive end-expiratory pressures and administration of broad spectrum antibiotics and corticosteroids before confirming the diagnosis of viral bronchopneumonia using viral culture and serological tests. Within 24 hours, influenza A (H3N2) virus was identified by amplification of the pathogen genes by reverse transcription polymerase chain reaction (RT-PCR) using the stored bronchoalveolar lavage (BAL) fluids of both cases. This suggests that a combination of detection methods of pathogens using RT-PCR and BAL fluid will facilitate determination of rational treatment aimed at influenza A virus.

Congestive heart failure caused by aortocaval fistula after nephrectomy.

We treated a 66-year-old man and a 69-year-old woman with high output cardiac failure due to aortocaval fistula. They underwent nephrectomy 40 and 36 years ago, respectively. They suffered from heart failure for a very long time. However, the etiology was not elucidated until recently. The aortogram revealed massive shunt from the aorta to the inferior vena cava via the right renal artery. Three-dimensional computerized tomography clearly delineated the aortocaval fistula. Surgical closure of the fistula promptly improved heart failure. We stress the importance of history taking concerning nephrectomy and the importance of abdominal auscultation in high output cardiac failure.

Cardiac tumor biopsy under the guidance of intracardiac echocardiography.

Transthoracic echocardiography or transesophageal echocardiography is sometimes useful in intracardiac tumor biopsy. Intracardiac echocardiography was used as an alternative to either of these for performing a biopsy of a right cardiac tumor in a 79-year-old woman. The procedure was well tolerated and no complications occurred. Histopathological findings and immunohistological staining were compatible with the diagnosis of neurogenic sarcoma.

Transcatheter coil embolization of large-size patent ductus arteriosus in adult patients: usefulness and problems.

Transcatheter coil embolization of the patent ductus arteriosus (PDA) has been frequently used in children, especially for small lesions. It was attempted in 3 adults using Cook detachable coils. For 2 of the patients, relatively old age and heart failure were the reasons for choosing coil embolization of the PDA. In the remaining patient, who had Wolff-Parkinson-White syndrome, coil embolization was performed after radiofrequency catheter ablation of Kent's bundle. Their respective minimal PDA diameters were 5.0 mm, 4.5 mm and 4.0 mm measured by transesophageal echocardiography. Two coils were placed in 2 patients and 1 coil in the remaining patient. After the procedures, the size of the left ventricle decreased and heart failure was improved in 2 patients, although all 3 patients had a residual shunt, which caused hemolytic anemia in 2 patients. Repeat coil-embolization procedures resulted in complete occlusion and the hemolysis disappeared in these patients. In adult patients who have heart failure due to large PDA, coil embolization with detachable coils, even if residual shunt persists, is useful for improvement of the heart failure. In cases of hemolysis related to residual shunt, a second coil-embolization procedure can improve it completely.

Structural characteristics of Koch's triangle in patients with atrioventricular node reentrant tachycardia.

The aim of this study is to investigate whether patients with atrioventricular node reentrant tachycardia (AVNRT) present different structural characteristics of Koch's triangle from patients with atrioventricular (AV) reentrant tachycardia and other control patients. Fifty-eight patients with arrhythmia or chest pain underwent selective coronary sinus angiography so that the diameter of the coronary sinus could be measured. The patients with arrhythmia also underwent electrophysiological study and measurement of the height of Koch's triangle. Patients with AVNRT had large coronary sinus ostial diameters compared with patients with AV reentrant tachycardia and those with chest pain (13.6 +/- 2.2 mm vs. 10.6 +/- 2.7 mm [p < 0.005] and 10.0 +/- 2.1 mm [p < 0.002], respectively), while there were no differences in distal diameter. The ostial diameter in patients with dual AV node pathways but noninducible AVNRT (11.8 +/- 1.5 mm) tended to be smaller than that in patients with AVNRT. No differences in the height of Koch's triangle and electrophysiological characteristics, including AV node properties, were found among the study groups. In conclusion, an increased size of the coronary sinus ostium (the base of Koch's triangle) is a structural characteristic in patients with AVNRT and may be the substrate needed for the appearance of AVNRT.

Collateral flow detected by a Doppler guide wire in a case of vasospastic angina.

We could detect recruitable backward collateral flow in systole and diastole by using a Doppler guide wire during coronary artery spasm in a 42-year-old female among 20 patients with documented variant angina. The electrocardiogram (ECG) showed no ST-segment deviation, although she had chest pain and her coronary angiography showed a totally occluded right coronary artery. After administration of isosorbide dinitrate (ISDN) the collateral flow disappeared and the flow pattern recovered to normal. The good collateral flow pattern in patient with totally occluded coronary artery due to spasm was indicated to relieve myocardial ischemia, even when the patient felt chest pain.

Dependency on atrial electrophysiological properties of appearance of paroxysmal atrial fibrillation in patients with Wolff-Parkinson-White syndrome: evidence from atrial vulnerability before and after radiofrequency catheter ablation and surgical cryoablation.

The pathogenesis of paroxysmal atrial fibrillation in patients with Wolff-Parkinson-White syndrome and the effects of elimination of accessory pathways on the appearance of atrial fibrillation are still controversial. Fifty-four patients with Wolff-Parkinson-White syndrome were classified into three groups: a No AF group (n = 24), patients without paroxysmal atrial fibrillation; an RF-AF Group (n = 12), patients with paroxysmal atrial fibrillation whose accessory pathways were eliminated using radiofrequency catheter ablation; and a Cryo-AF Group (n = 18), patients with paroxysmal atrial fibrillation whose accessory pathways were eliminated with surgical cryoablation. The electrophysiological characteristics of each group were evaluated prior to and following the elimination of their accessory pathways. As indices of atrial vulnerability, the presence of fragmented atrial activity and repetitive atrial firing zones were assessed. Inducibility of atrial fibrillation was significantly reduced following ablation of accessory pathways in the Cryo-AF group (83.3%-5.6%, P < 0.0001), while it was unchanged in the RF-AF group (83.3%-75%). In preablation studies, the effective refractory periods of the atrium in the RF-AF group and the Cryo-AF group were significantly shorter compared with the No AF group (204 +/- 18 ms, 197 +/- 16 ms vs 246 +/- 44 ms, respectively, P < 0.0001). Following ablation, the effective refractory period for patients in the Cryo-AF group was significantly prolonged compared with before ablation (197 +/- 16 ms to 232 +/- 24 ms, P < 0.0001). As a result of this prolongation of the effective refractory period of the atrium, the fragmented atrial activity and repetitive atrial response zones narrowed following ablation in the Cryo-AF group, but not in the RF-AF group. Therefore, the pathogenesis of atrial fibrillation in patients with Wolff-Parkinson-White syndrome may depend on the refractory period of the atrium rather than on the presence of accessory pathways.

Effects of volume loading on pulmonary venous flow and its relation to left atrial functions.

Although pulmonary venous (PV) flow is closely related to left atrial (LA) pressure dynamics, few investigators have discussed it in relation to LA functions, i.e., reservoir, conduit, and booster pump functions. We examined changes in PV flow rate, LA dimension, and left ventricular filling volume in 11 dogs, and assessed the effects of multistaged volume loading on PV flow and LA functions. Systolic PV flow rate (S) increased significantly and reached a plateau, reflecting a limited LA reservoir function. Diastolic PV flow rate (D) increased significantly with an increase in LA pressure. S/D ratio increased non-significantly from 0.87 +/- 0.07 before volume loading to 0.96 +/- 0.08 until S reached a plateau and then decreased to 0.76 +/- 0.08 (p < 0.05) because of a significant increase in D without an increase in S at the higher stages of volume loading. During atrial contraction, increases in LA active shortening and left ventricular filling volume were limited, indicating a limited LA forward ejection. The difference between PV flow rate just before and at the end of atrial contraction increased and correlated positively with left ventricular end-diastolic pressure (r = 0.57, p < 0.01). PV flow varies according to the degree of volume loading and reflects LA functions, which exhibit limited increases in response to volume loading.

Postprandial atrioventricular block in a patient with diabetes mellitus.

Postprandial atrioventricular (AV) block and hypotension occurred in an 80-year-old man with a 13-year history of diabetes mellitus. Two weeks before admission, he experienced syncope on two occasions after lunch. Master's two-step test induced second degree AV block (2:1 block). Four days after admission, syncope recurred while walking 1 hour after eating; electrocardiogram (ECG) showed complete AV block following 2:1 block. PP interval analysis suggested phase 3 block as the mechanism of AV block. Electrophysiologic study revealed 2:1 HV block. Postprandial syncope ceased after permanent pacemaker implantation. Postprandial AV block and hypotension merit close attention in diabetics.

Time interval determination from left atrial appendage ejection flow in patients with mitral stenosis.

The feasibility of determining the time interval from left atrial appendage (LAA) flow was examined using transesophageal Doppler echocardiography. Time intervals were compared between LAA flow and mitral flow patterns during late diastole in 8 patients with mitral stenosis and in 12 controls. The start of ejection flow from the LAA was later than the initiation of mitral flow, but the termination was same in both flows, indicating the contribution of LAA ejection to the latter half of the left atrial booster pump function. The pre-ejection time and the time interval from P-wave to end-ejection correlated significantly with left atrial dimensions (r = 0.55, and r = 0.70, respectively). The pre-ejection time, duration of the ejection flow from the LAA, and duration of mitral flow in the atrial contraction phase were significantly longer in patients with mitral stenosis (126 +/- 14 msec, 131 +/- 36 msec, and 167 +/- 28 msec, respectively) than in the controls (109 +/- 13 msec, 108 +/- 15 msec, and 141 +/- 17 msec, respectively). These results indicate that electrical conduction time from the right atrium to LAA can be estimated from the LAA ejection flow, and the time is related to the left atrial size. In patients with mitral stenosis, LAA contraction may contribute to left ventricular filling in the latter half of the atrial contraction phase.

Effects of heart rate on left atrial contractile performance and left ventricular filling during atrial systole in dogs.

Left ventricular (LV) diastolic filling and left atrial (LA) contribution have been investigated in patients with heart disease. However, many of these studies were not conducted at a constant heart rate, and the effects of heart rate remain unclear. The purpose of this study was to clarify the effects of the heart rate on left atrial contractile performance and left ventricular filling during atrial systole. The changes in LA and LV dimensions and pulmonary venous (PV) flow were determined in 9 open-chest dogs by a sonomicrometer and an electromagnetic flowmeter. With a stepwise decrease in the pacing rate from 110 beats/minute to 70 beats/minute, the LA dimension just before atrial contraction increased from 21.4 +/- 0.6 mm to 23.1 +/- 0.7 mm (p < 0.01), and the LA systolic shortening increased from 1.6 +/- 0.1 mm to 2.1 +/- 0.1 mm (p < 0.01). However, the calculated LV filling volume during atrial systole decreased from 1.9 +/- 0.3 ml to 1.4 +/- 0.2 ml (p < 0.01). The PV flow during atrial systole was directed toward the LA, and the LA influx volume from PV decreased from 0.6 +/- 0.1 ml to 0.2 +/- 0.04 ml (p < 0.01). With a decrease in the pacing rate, the LA Frank-Starling mechanism operated. However, LV filling during atrial systole decreased because of the decrease in PV flow to the LV via the LA. Thus, LA contractile performance cannot always be evaluated from LV filling.

The role of the left atrial appendage. A volume loading study in open-chest dogs.

Although the left atrial appendage has a quite unique structure, its function remains unclear. To clarify the function of the left atrial appendage, changes in its anteroposterior, transverse and longitudinal dimensions, and in the anteroposterior dimension of the left atrial body were measured by a sonomicrometer during volume loading in open chest dogs. In the control state, fractional shortening of the transverse dimension of the appendage was greater than that of the atrial body. After dextran infusion, each dimension of the appendage and body, measured just before atrial contraction, increased curvilinearly. The percent increase in appendage dimensions was greater than that of the atrial body dimension (p < 0.05). Systolic shortenings of the appendage increased until mean left atrial pressure reached approximately 15 mmHg but after further pressure elevation, it decreased. In postmortem isolated hearts, the appendage volume was 17.2 +/- 4.4% of the whole left atrial volume. These findings indicate that the appendage has a considerable volume with a greater compliance and assists left ventricular filling during atrial contraction by a Frank-Starling mechanism.

The role of the accessory pathway in the onset of atrial fibrillation in Wolff-Parkinson-White syndrome--electrophysiological examination before and after surgical ablation.

To determine the role of the accessory pathway in the pathogenesis of atrial fibrillation, we compared electrophysiological findings in 17 patients (44.7 +/- 10.2 years) with a history of atrial fibrillation before and after surgical ablation of the accessory pathway. The PA interval was shortened, and the atrial refractory periods and the potential minimal wavelength of an atrial impulse (FRPA/PA) were significantly increased, after surgery. Fragmented atrial activity (an increase of 150% or more in the duration of the high right atrial electrogram) was observed in 80% of the patients before surgery and in 25% after surgery. Its zone was significantly decreased after surgery. Repetitive atrial firing was defined as the occurrence of 3 or more successive atrial electrograms induced by a premature stimulation. This was observed in 60% of the patients before surgery, but in none after surgery. Atrial fibrillation was induced in 16 patients during the preoperative study, but in only 1 patient postoperatively. In conclusion, these results suggest that accessory pathways affect atrial vulnerability and play an important role in the onset of atrial fibrillation in WPW syndrome.

Differential effect of pharmacological autonomic blockade on some electrophysiological properties of the human ventricle and atrium.

OBJECTIVE: This study investigated the dominance of each limb of the autonomic nervous system and tested sympathetic-vagal interactions in the human ventricle and atrium after administration of propranolol and atropine. PATIENTS AND METHODS: The 90% monophasic action potential duration (MAPD90) and the effective refractory period (ERP) at the right ventricular apex (RV) and the right lateral atrium (RA) were measured in 14 patients. The MAPD90 was measured during constant RV and RA pacing (cycle length 600 ms) and the ERP was measured at a driven cycle length of 600 ms. Electrophysiological variables were measured during a control period, after propranolol (0.15 mg/kg loading dose followed by 0.1 mg/min infusion), and after autonomic blockade (atropine 0.04 mg/kg). RESULTS: Both RV MAPD90 and RV ERP increased after propranolol (RV MAPD90 from 268 (26) ms to 275 (26) ms, p < 0.005; RV ERP from 252 (25) ms to 258 (26) ms, p < 0.0005) and then decreased to below the control values after autonomic blockade (RV MAPD90 256 (24) ms; RV ERP 239 (25) ms, p < 0.0005 v propranolol, p < 0.0005 v control). In contrast, both RA MAPD90 and RA ERP increased after propranolol (RA MAPD90 from 242 (19) ms to 260 (19) ms; RA ERP from 216 (21) ms to 230 (18) ms, p < 0.0005), and then increased slightly more after autonomic blockade (RA MAPD90 265 (16) ms, p = 0.09; RA ERP 235 (16) ms, p = 0.07), thus remaining above control values (p < 0.0005). CONCLUSIONS: The results indicate (a) that in the human ventricle vagal stimulation and sympathetic beta stimulation are antagonistic and that direct vagal stimulation predominates over beta stimulation, with sympathetic-vagal interaction being minimal and (b) that in the human atrium vagal stimulation and beta stimulation are synergistic and beta stimulation predominates over vagal stimulation, with direct vagal stimulation having a minimal effect.

Long-term results of catheter ablation for idiopathic ventricular tachycardia originated from the right ventricular outflow.

We performed catheter ablation in 10 consecutive patients with idiopathic monomorphic right ventricular tachycardia and studied the long-term outcome. All ventricular tachycardias had a left bundle branch block configuration with an inferior axis, and originated from right ventricular outflow. Antiarrhythmic drugs (3-6 drugs) had been ineffective in controlling ventricular tachycardia. The 2 patients who underwent direct-current ablation (2 shocks of 150 J) had no recurrence of ventricular tachycardia and did not require antiarrhythmic drugs during a follow-up of 56 and 51 months, respectively. Of the 8 patients who underwent radiofrequency ablation (30-40 watt, 20-40 sec, 2-15 application, using Inter Nova RA 50, 13.56 MHz), 1 patient had no recurrence of ventricular tachycardias and did not require antiarrhythmic drugs, 4 patients had no recurrence of ventricular tachycardias but did require anti-arrhythmic drugs, and 3 patients experienced recurrence of non-sustained ventricular tachycardia despite the use of antiarrhythmic drugs during a follow-up of 15-40 months. There were no complications except for cardiac perforation which occurred immediately after direct-current ablation in 1 patient. In conclusion, long-term success in preventing ventricular tachycardia was achievable with direct-current ablation, but this success was associated with serious risks, such as cardiac perforation. Radiofrequency ablation was safer than direct-current ablation, but had a lower long-term success rate.

Early afterdepolarizations in a patient with idiopathic monomorphic right ventricular tachycardia.

To identify the role of afterdepolarizations in the induction of idiopathic monomorphic right ventricular tachycardia (VT), monophasic action potentials (MAPs) were recorded in a patient with this type of VT. The VT had a left bundle branch block configuration and inferior axis, and originated in the right ventricular outflow tract (RVOT). MAPs were recorded with a contact electrode at the origin of the VT, as well as other ventricular sites. The VT was induced by the intravenous administration of isoproterenol and/or rapid ventricular pacing and was preceded by short-long-short sequences of RR intervals. Early afterdepolarizations (EADs) in MAPs were recorded at the origin of VT (RVOT), but not recorded at other ventricular sites. These data suggest that catecholamine sensitive triggered activity seems to be the mechanism of idiopathic monomorphic right VT and EADs can be recorded in association with the occurrence of this type of VT.

[The effects of pharmacological autonomic blockade on the conduction system in patients with and without sinus node dysfunction].

Electrophysiological studies were performed in 26 patients with sick sinus syndrome (SSS) and 12 controls before and after pharmacologic autonomic blockade (PAB) with propranolol (0.15 mg/kg) and atropine (0.04 mg/kg). Sinus cycle length (SCL) shortened significantly after PAB in both groups. PA and HV intervals did not change after PAB. AH interval shortened and Wenckebach period increased after PAB in SSS group. Maximum corrected sinus node recovery time shortened in the control group but did not change in the SSS group after PAB. Calculated sinoatrial conduction time shortened after PAB in both groups. Refractory periods of the atrioventricular (AV) node and the ventricle shortened significantly, but those of the atrium did not change after PAB. Linear relations existed between the change of SCL and the change of AH interval and of the Wenckebach period. These results suggested that the autonomic nervous system had the same effects on the sinus and the AV nodes in patients with SSS, and that parasympathetic tone was predominant on the sinus node, the perinodal tissue and the AV node under resting conditions.