High serum levels of procollagen type III N-terminal amino peptide in patients with congenital heart disease.

OBJECTIVE: The serum concentration of aminoterminal procollagen type III (PIIIP) is considered a useful marker of tissue fibrogenesis. The present study tested the hypothesis that: serum PIIIP levels are elevated in patients with congenital heart disease (CHD) and abnormal haemodynamic loading and/or hypoxaemia; PIIIP levels are associated with the severity of haemodynamic load or hypoxaemia, both of which enhance myocardial fibrosis. METHODS AND RESULTS: Serum PIIIP levels were measured in five groups of CHD patients (42 patients with ventricular septal defect (VSD), 26 with coarctation of the aorta (COA, n = 19) or aortic stenosis (AS, n = 7), 36 with atrial septal defect (ASD), 39 with pulmonary stenosis (PS) and 20 with tetralogy of Fallot (TOF)). PIIIP levels of CHD patients were significantly higher than those of 42 control subjects (p<0.05, each). Serum PIIIP levels increased in parallel with increased ventricular volume load in VSD and ASD, and with the severity of PS. In TOF patients, PIIIP levels correlated negatively with arterial oxygen saturation. Treatment with an angiotensin-converting enzyme inhibitor (ACEI) was associated with low levels of PIIIP in COA/AS patients despite the existing haemodynamic load. CONCLUSION: The increased serum PIIIP levels in proportion to the severity of ventricular load or cyanosis suggest enhanced myocardial synthesis of collagen type III in patients with CHD. Suppression of the PIIIP level by ACEI suggests the involvement of the renin-angiotensin-aldosterone system in myocardial fibrosis. These data provide the basis for the development of new diagnostic and therapeutic strategies in patients with CHD.

[Gastrointestinal hemorrhage induced by percussive ventilator in an infant with chronic lung disease complicated after surgery for corrected transposition of the great arteries].

A newborn patient (birth weight 2,332 g) with corrected transposition of the great arteries developed chronic lung disease due to a severe heart failure and post operative several complications. We applied intrapulmonary percussive ventilation (IPV) to the patient. IPV improved oxygenation concomitant with the improvement of respiratory condition and chest X-ray finding. However, the patient suffered from upper gastrointestinal bleeding 15 days after initiation of IPV therapy. The bleeding was healed several days after temporal termination of IPV, but recurred with resuming IPV therapy. The patient was irritable throughout the IPV therapy, and thus gastrointestinal bleeding of the patient could be due to stress induced by IPV therapy. IPV may be useful for the management of respiratory disturbance, often observed in low birth weight patients with congenital heart defects. However, gastrointestinal bleeding may occur and should be considered as a possible complication associated with IPV therapy.

Efficacy and safety of torasemide in children with heart failure.

OBJECTIVE: To examine the efficacy and safety of torasemide in children with chronic heart failure (HF). METHODS: 102 children with chronic HF who had received oral torasemide were analysed. Of these, 62 (de novo group) were newly diagnosed as having HF and were given torasemide as a diuretic. The remaining 40 (replacement group) had been given furosemide for >3 months before the study, and furosemide was then replaced with torasemide. Clinical signs and symptoms of HF (assessed as the HF index), humoral factors and serum potassium concentrations before torasemide treatment were compared with those obtained 3-4 weeks after torasemide treatment. Patients were also monitored for adverse effects. RESULTS: In the de novo group, torasemide significantly improved the HF index with concomitant improvement in plasma brain natriuretic peptide concentration (median (interquartile range) 52 (51) vs 43 (49) pg/ml). In a randomly selected group of 25 de novo patients with ventricular septal defect, echocardiography showed that torasemide significantly improved left ventricular geometry and function. In the replacement group, brain natriuretic peptide concentrations were also significantly decreased from 50 (104) to 45 (71) pg/ml after substitution of torasemide, but the HF index showed only a tendency for improvement (p = 0.07). Torasemide also had a potassium-sparing effect (de novo group, no change in potassium concentration; replacement group, significant increase from 4.2 (0.5) to 4.3 (0.5) mEq/l), and caused a significant rise in serum aldosterone concentration, consistent with the anti-aldosterone effect of this drug. Serum concentrations of sodium and uric acid had not changed after torasemide treatment, and there were no serious adverse events that necessitated drug withdrawal. CONCLUSION: Torasemide can be safely used, and appears to be effective for treatment of HF in children. Future clinical trials are warranted to verify the present results.

Arterial haemodynamics in patients after repair of tetralogy of Fallot: influence on left ventricular after load and aortic dilatation.

BACKGROUND: Recent histological studies of the aortic wall of patients with tetralogy of Fallot (TOF) have shown massive degeneration of the tunica media of the aorta. Such changes in arterial wall structure may significantly alter arterial wall mechanical properties, and thus cause abnormal arterial haemodynamics. OBJECTIVE: To test the hypothesis that after repair of TOF, there are abnormal arterial haemodynamics which are associated with aortic dilatation and which increased after load on the left ventricle. METHODS AND RESULTS: The subjects comprised 38 patients who had undergone complete repair of TOF, and 55 control subjects. Systemic arterial haemodynamics were investigated by measuring aortic input impedance during cardiac catheterisation. The patients with TOF had significantly higher characteristic impedance (158 (43) dyne x s x cm(-5) x m(2) vs 105 (49) dyne x s x cm(-5) x m(2)) and pulse wave velocity (561 (139) cm/s vs 417 (91) cm/s) and significantly lower total peripheral arterial compliance (0.93 (0.39) ml/mm Hg/m(2) vs 1.24 (0.58) ml/mm Hg/m(2)) than the controls (for all three variables, p<0.01 vs controls), suggesting that central and peripheral arterial wall stiffness are increased after TOF repair. Additionally, patients with TOF had significantly higher arterial wave reflection than the controls (reflection coefficient: 0.21 (0.12) vs 0.16 (0.06)). These abnormalities in patients with TOF increased the pulsatile load on the left ventricle and significantly contributed to decreased cardiac output, even when right ventricular function was taken into account by multivariate regression analysis. The increase in aortic wall stiffness was closely associated with the increase in aortic root diameter. CONCLUSION: These results indicating abnormal arterial haemodynamics after TOF repair highlight the importance of regular monitoring of the systemic arterial bed and potentially relevant cardiovascular events in long-term follow-up of TOF.

The pathophysiology of coronary artery aneurysms in Kawasaki disease: role of matrix metalloproteinases.

Kawasaki disease is an acute inflammatory syndrome that takes the form of systemic vasculitis, and predominantly affects children. Important complications of this disease are coronary artery dilation and aneurysm formation. Recent studies indicate that Kawasaki disease patients have elevated expression, activity, or protein levels of matrix metalloproteinases (MMPs), and suggest that imbalances in MMPs or MMP/tissue inhibitor of MMP (TIMP) play important pathophysiological roles in the development of coronary artery lesions in this disease. However, it remains unclear whether MMP activities at the site of coronary artery lesions are indeed increased. Further studies on the effects of MMP inhibition on coronary outcome are needed to define the roles of MMPs and TIMPs in the formation of coronary artery lesions in Kawasaki disease; findings of such studies may support the use of MMP inhibitors for the prevention of coronary artery complications in patients with this disease.

Left ventricular outflow obstruction after Fontan procedure involving a patient with complete atrioventricular septal defects complicated by a small left ventricle.

We report a 1-year-old girl who developed ventricular outflow tract obstruction early after a Fontan operation, necessitating surgical relief using the Damus-Kaye-Stansel procedure. The patient had a complete atrioventricular septal defect complicated by a muscular ventricular septal defect (VSD) and a small left ventricle, a morphology that has not previously been reported in cases of systemic outflow tract obstruction after the Fontan procedure. Postoperative systemic outflow obstruction must be considered as a possible sequela following Fontan surgery in patients with an atrioventricular septal defect and a small left ventricle.

Trichilemmoma: an immunohistochemical study of cytokeratins.

BACKGROUND: The histogenesis of trichilemmoma remains unclear. OBJECTIVES: To clarify the histogenesis of trichilemmoma by evaluating its cytokeratin (CK) expression. METHODS: In three cases of trichilemmoma, CK expression was studied immunohistochemically using seven antikeratin antibodies against CK1, 10, 14-17 and 19, respectively. RESULTS: CK1 and CK10 were present in keratinizing ductal epithelium. CK14 was present in the whole layer. CK15 was present in suprabasal layers in two cases. CK16 was present in the suprabasal layer, but was absent in keratinizing ductal epithelium. CK17 was present in suprabasal layers and the sebaceous duct-like structure. CK19 was totally absent. CONCLUSIONS: These results showed that trichilemmoma may differentiate mainly towards two directions: infundibular keratinization and proliferation of the outer root sheath with undifferentiated and pluripotent characteristics.

Two cases with transient lipoprotein lipase (LPL) activity impairment: evidence for the possible involvement of an LPL inhibitor.

UNLABELLED: Two independent severe hypertriglyceridemic infants with transiently impaired lipoprotein lipase (LPL) activity were observed and the causes were explored. Both infants were female, born prematurely with low birth weight and developed hypertriglyceridemia (Fredrickson type V hyperlipidemia: high VLDL and low LDL/HDL) a few months after birth. While mass levels of their post-heparin plasma LPL and apoprotein C-II (apo C-II), a physiological activator of LPL, were normal, their post-heparin plasma LPL activities were remarkably impaired. Both of their mothers' post-heparin plasma LPL activities were slightly or moderately impaired as well, without a decrease in the LPL mass level. No mutations in the genes for LPL and apo C-II were detected in either patient. In an in vitro study with their serum at onset, we could not detect any distinct circulating inhibitors for LPL. There was no data supporting infection or autoimmune diseases, which might have an impact on LPL activity, during the follow-up period. Levels of their plasma triglyceride (TG) and total cholesterol (TC) were decreased quickly by a dietary intervention with medium-chain triglyceride (MCT) milk and kept normal even after stopping the intervention at around age 1 year. However, their low post-heparin LPL activity persisted and returned to normal at around age 2 years. Their low HDL cholesterol levels persisted even after recovery of the TG and TC levels, although lecithin:cholesterol acyltransferase (LCAT) and cholesterol-ester-transfer protein (CETP), two key enzymes of HDL metabolism, were normal throughout the course. The exact reasons why their post-heparin LPL activities were impaired for a certain period and why their HDL cholesterol levels have remained low are still unclear. CONCLUSION: Transiently impaired LPL activity with no defect in LPL enzyme induced severe hypertriglyceridemia in infants. The transient occurrence of inhibitor(s) for LPL was proposed.

Immunohistochemical study of cytokeratins in hidradenitis suppurativa (acne inversa).

In 14 cases of hidradenitis suppurativa, cytokeratin (CK) expression was studied immunohistochemically, using six antikeratin antibodies against CK1, CK10, CK14, CK16, CK17 and CK19, respectively. The draining sinus tract epithelium of hidradenitis suppurativa lesions was divided into three components: infundibular-like keratinized epithelium (type A), non-infundibular keratinized epithelium (type B), and non-keratinized epithelium (type C). In type A samples, CK17 (which is found in normal infundibulum) was not detected, suggesting fragility of this epithelial type. Keratin expression in types B and C epithelia was similar to that observed in the outer root sheath in normal hair follicles. Our results suggest that the draining sinus epithelium may possess characteristics of fragility, undifferentiation and hyperproliferation, as shown with CK expression.

Assessment of cardiovascular dynamics by pressure-area relations in pediatric patients with congenital heart disease.

OBJECTIVES: It is particularly useful to separately quantify the ventricular contractility and loading conditions for a better understanding of the cardiovascular dynamics in congenital heart disease, where abnormalities in chamber and loading properties may coexist. Furthermore, ventricular contractility and loading conditions may alter independently or simultaneously with disease progression and therapeutic intervention. The objectives of the present study were (1) to test whether ventricular pressure-area analysis can provide such quantitation among patients with various forms of congenital heart disease, (2) to reveal basal cardiovascular interaction in congenital heart disease by means of pressure-area analysis, and (3) to test the feasibility of this method in a simplified and less invasive form to further enhance its clinical value. METHODS: We constructed pressure-area loops during caval occlusion by using transthoracic echocardiographic automated border detection combined with ventricular pressure recordings in 59 pediatric patients with congenital heart disease and in 7 normal control subjects. RESULTS: Area measurements obtained by automated border detection were highly reproducible, and area changes reflected volume changes. The pressure-area data provided load-independent measures of contractility, which were consistently increased by use of dobutamine (P <.05). End-systolic and arterial elastance individually quantified simultaneous changes in ventricular contractility and loading with milrinone infusion and predicted net cardiac performance. The pressure-area analysis better characterized the ventricular contractile states under a variety of loading conditions in congenital heart disease, whereas predominant load dependence of conventional indices confounded them. Furthermore, pressure-area relations were reasonably estimated from a single beat and from aortic pressure data during abdominal compression. CONCLUSIONS: Pressure-area analysis should provide a useful modality with which to assess cardiovascular dynamics in pediatric patients with congenital heart disease in more detail and should thus help improve the management of patients with this disease.

Circulating matrix metalloproteinases and their inhibitors in patients with Kawasaki disease.

BACKGROUND: Accelerated matrix breakdown caused by the increased activity of matrix metalloproteinases (MMPs) and/or the quantitative imbalance between MMP and tissue inhibitor of MMP (TIMP) have been implicated in several pathological conditions. MMP and TIMP may also be involved in the destruction of the coronary arterial wall and the resultant coronary arterial lesions in Kawasaki disease. METHODS AND RESULTS: Plasma levels of MMPs, neutrophil elastase, and TIMPs were measured by enzyme-linked immunoassay in 57 patients with Kawasaki disease and no coronary arterial lesions (group 1) and in 8 patients with Kawasaki disease and coronary arterial lesions (group 2). Blood samples were obtained before and after intravenous gamma globulin therapy and in the convalescent stage. Levels of MMPs, neutrophil elastase, and TIMPs were significantly higher in Kawasaki disease patients before gamma globulin therapy than in 18 age-matched afebrile control subjects and 17 age-matched febrile disease control subjects (P<0.01). More importantly, the pre-gamma globulin MMP9 level and MMP9/TIMP2 ratio and post-gamma globulin MMP3 level and MMP3/TIMP1 ratio were significantly higher in group 2 than in group 1 patients (P<0.05). Although MMP levels in febrile disease controls were significantly higher than those of afebrile controls, the MMP/TIMP ratios of febrile disease controls and afebrile controls were comparable. CONCLUSIONS: These data suggest that patients with Kawasaki disease and high levels of MMP and/or MMP/TIMP are susceptible to coronary arterial lesions. Studies of the effects of MMP inhibitors on coronary outcome may provide evidence that MMP is a viable therapeutic target for the prevention of coronary arterial lesions due to Kawasaki disease.

Bone morphogenetic protein-2 and type IV collagen expression in psammoma body forming ovarian cancer.

Psammoma bodies (PBs), characterized as calco-spherules with concentric laminations, are common in serous tumors of the ovary. However, there is no agreements as to how the PBs are formed. Bone morphogenetic protein-2 (BMP-2) has recently been proposed to be involved in the calcification of tumor cells and recent electron microscopic studies demonstrated the presence of type IV collagen in PBs. Based on this evidence, we postulated a possibe role for BMP-2 and type IV collagen in the formation of PBs in ovarian cancer. We examined the expression of BMP-2 and typle IV collagen by immunohistochemistry and reverse transcription PCR (RT-PCR) in PBs-forming (NK-211) and -non-forming (SHIN-3, KF-1, A2780, KK-92, KOC-2S, SKOV-3, OMC-3, MN-1, EC, and KEN-3) ovarian cancer cell lines in vitro and in surgical specimens of serous adenocarcinoma (SA) with/without PBs and mucinous adenocarcinoma (MA) of the ovary. Cellular growth of cell lines was also evaluated by their doubling time in vitro. Transcripts for BMP-2 mRNA were detected by RT-PCR in all cell lines. By immunohistochemistry, BMP-2 protein expression was positive in 45% (5 out of 11) of cell lines. 36.4% (4 out of 11) were positive for type IV collagen. PBs-forming NK-211 was intensively positive for both BMP-2 and type IV collagen. In addition, NK-211 demonstrated extremely slow growth with a doubling time of 450 hours. In surgical specimens, BMP-2 vs. type IV collagen positivities in tumor cells were 100% (20 out of 20) vs. 40% (8 out of 20) in SA with PBs, 61.1% (11 out of 18) vs. 0% (0 out of 18) in SA without PBs and 75% (9 out of 12) vs. 0% (0 out of 12) in MA. In PBs themselves, 100% (20 out of 20) positivity for BMP-2 and 80% (16 out of 20) for type IV collagen was shown. These results raise the possibility that BMP-2 and type IV collagen-producing slow growing tumor cells form PBs in ovarian cancer.

Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure.

Recent studies implicate increased cGMP synthesis as a postreceptor contributor to reduced cardiac sympathetic responsiveness. Here we provide the first evidence that modulation of this interaction by cGMP-specific phosphodiesterase PDE5A is also diminished in failing hearts, providing a novel mechanism for blunted beta-adrenergic signaling in this disorder. In normal conscious dogs chronically instrumented for left ventricular pressure-dimension analysis, PDE5A inhibition by EMD82639 had modest basal effects but markedly blunted dobutamine-enhanced systolic and diastolic function. In failing hearts (tachypacing model), however, EMD82639 had negligible effects on either basal or dobutamine-stimulated function. Whole myocardium from failing hearts had 50% lower PDE5A protein expression and 30% less total and EMD92639-inhibitable cGMP-PDE activity. Although corresponding myocyte protein and enzyme activity was similar among groups, the proportion of EMD82639-inhibitable activity was significantly lower in failure cells. Immunohistochemistry confirmed PDE5A expression in both the vasculature and myocytes of normal and failing hearts, but there was loss of z-band localization in failing myocytes that suggested altered intracellular localization. Thus, PDE5A regulation of cGMP in the heart can potently modulate beta-adrenergic stimulation, and alterations in enzyme localization and reduced synthesis may blunt this pathway in cardiac failure, contributing to dampening of the beta-adrenergic response.

[A case of very rare tuberculosis of the testis].

A 61-year old man visited our hospital with a painless swelling of right scrotal contents as the chief complaint. Transillumination test of the right scrotal contents was negative, and a quail's egg sized, elastic hard and smooth induration in the right testis was palpable. The laboratory data were normal except for slightly elevated E.S.R and CRP. Urine examination was normal. Although not only tumor marker, beta-hCG, AFP and LDH but also Plain lung X-ray, DIP and CT were normal, ultrasonography and MRI revealed a well-defined nodule in the right testis. Under the diagnosis of right testicular tumor, right high orchiectomy was performed. A yellowish white nodule of 2.5 cm in diameter was found in the slightly enlarged right testis. Pathologically, the patient was diagnosed as having tuberculotic granuloma with necrotic caseation. However, the epididymis was histologically normal. After operation, an antitubercular medication was started. Subsequently, E.S.R and CRP became normalized. At present, 12 months after surgery, the recurrence is not found. Tuberculosis of testis which shows no lesion in the epididymis is very rare, and ours is the first reported case in the Japanese literature. The importance of tuberculosis as a revival infection should be recognized in social circumstance in which tuberculosis is beginning to spread again.

Inferior vena cava occlusion catheter for pediatric patients with heart disease: for more detailed cardiovascular assessments.

Traditional evaluation of cardiac function is too often limited by reliance on measurements with complex interdependence between cardiac properties and loading factors. Analysis by ventricular pressure-volume (P-V), -area (P-A), or -dimension (P-D) relations during inferior vena caval (IVC) occlusion independently quantifies ventricular properties and loading conditions, providing detailed information about cardiovascular dynamics. However, there has been no appropriate size of balloon catheter that can effectively occlude IVC of pediatric patients, hindering the application of P-V (P-A, or P-D) analysis to children with heart disease despite its potential benefit. To address this problem, we have developed a new balloon catheter for IVC occlusion in children. The catheter effectively occluded IVC in 92 pediatric patients with varying forms of heart disease who underwent cardiac catheterization, yielding end-systolic pressure-area relations. Thus a newly developed balloon catheter would contribute to establishing more accurate and detailed cardiovascular assessments in children with heart disease. Cathet Cardiovasc Intervent 2001;53:392-396.

Novel cell lines established from a human myxoid malignant fibrous histiocytoma arising in the uterus.

Two cell lines (Nara-H and Nara-F) with different phenotypes were established from a myxoid MFH of the uterus. In vitro, Nara-F grew in sheets showing a storiform arrangement and Nara-H in raised colonies. Although tumors generated in nude mice shared similar morphological features of abundant myxoid tumor in Nara-H and -F, the pleomorphic component was conspicuous in Nara-F. Both cell lines produced hyaluronic-acid but CD44 was expressed only in Nara-H. Estrogen receptor alpha (ER alpha) and progesterone receptor (PgR) were detected in Nara-H. Nara-F was positive for ER beta and PgR. Among hormonal agents, the response to the anti-estrogen tamoxifen was more sensitive than progesterone agents. This report illustrates the characteristics of these newly established cell lines, and presents the possibility of an adjuvant hormonal therapy for MFH.

Intraglomerular metastasis from pancreatic cancer.

Few case reports have shown the presence of metastatic tumor cells in renal glomeruli. We report one case with intraglomerular metastasis proved at renal biopsy. A 60-year-old man suffered from weight loss and fever of unknown origin. Urinalysis revealed proteinuria with cellular and granular casts. Because vasculitis was suspected, renal biopsy was performed. Presence of tumor cells occupying the glomerular capillary lumina was shown by means of light microscopy and electron microscopy. Laboratory findings revealed elevated leukocyte count (28.9 x 10(3)/mm(3)), serum granulocyte colony-stimulating factor (G-CSF) (77 pg/mL), and serum CA 19-9 (21,885 U/mL). The patient soon developed disseminated intravascular coagulation and died. Autopsy findings revealed pancreatic cancer showing positive staining for G-CSF and CA 19-9. Tumor cells in the glomerular capillary lumina showed positive staining for CA 19-9 and proliferating cell nuclear antigen (PCNA). These results suggest that the pancreatic tumor cells producing G-CSF were entrapped in the glomerular capillary lumina where they proliferated. This may have been the first step in renal metastasis.