Reversal of cardiac complications in thalassemia major by long-term intermittent daily intensive iron chelation.

OBJECTIVES: In patients with thalassemia major (TM) who are non-compliant with long-term deferoxamine (DFO) chelation, survival is limited mainly because of cardiac complications of transfusional siderosis. It was recently shown in a small group of TM patients with established cardiac damage that continuous 24-h DFO infusion via an indwelling intravenous (i.v.) catheter is effective in reversing cardiac toxicity. The aim of the present study was to evaluate the results with intermittent daily (8-10 h) i.v. DFO. PATIENTS: Eight TM patients with cardiac complications treated with intensive intermittent DFO were retrospectively evaluated by the mean annual serum ferritin, radionucleated ventriculography and 24-h electrocardiography recordings. RESULTS: The median age at diagnosis of cardiac disease was 17.5 yr (range 14-21), and the median follow-up time was 84 months (range, 36-120). In the majority of patients (seven of eight) high-dose DFO (mean 95 +/- 18.3 mg/kg/d) was administered via a central venous line. During follow-up, there was a significant decrease in the mean ferritin levels (5828 +/- 2016 ng/mL to 1585 +/- 1849 ng/mL, P < 0.001). Both cardiac failure (mean ejection fraction 32 +/- 5) and cardiac arrhythmias were resolved in four of five patients. One non-compliant patient died during the follow-up. Following discontinuation of the i.v. therapy, compliance with conventional DFO therapy improved. The complications of this regimen, mainly catheter-related infections and catheter-related thrombosis, were similar to those described earlier. CONCLUSIONS: These results with the longest follow-up period in the literature suggest that i.v. high-dose DFO for 8-10 h daily may be as effective as continuous 24-h infusion for the reversal of established cardiac disease in TM.

A novel thermoregulatory system maintains perioperative normothermia in children undergoing elective surgery.

BACKGROUND: Body heat loss during anaesthesia may result in increased morbidity, particularly in high-risk populations such as children. To avoid hypothermia, a novel thermoregulatory system (Allon) was devised. We tested the safety and efficacy of this system in maintaining normothermia in children undergoing routine surgical procedures. METHODS: The system consists of a computerized body, which receives continuous afferent data, i.e. core (rectal) temperature. These data are then compared with a preset temperature (37 degrees C) and a microprocessor heating/cooling unit warms/cools the temperature of circulating water in a garment that is specially designed to allow maximal coverage of body surface area, without impingement on the surgical field. Water temperature to the garment was limited to a maximum of 39.5 degrees C. Continuous perioperative monitoring of skin and rectal temperature, heart rate and blood pressure was performed. Postoperative shivering and adverse effects were also assessed. RESULTS: The Allon system was used in 38 patients aged 3 months to 14 years undergoing surgery under general anaesthesia lasting more than 30 min. Fifty to 80% body surface area was covered by the garment. Mean operative and postoperative core temperatures were 36.9 +/- 0.5 degrees C and 36.7 +/- 0.5 degrees C, respectively. Intraoperative skin temperatures were maintained at 34.4 +/- 2.7 degrees C. The average core- to-periphery intraoperative gradient was 2.9 +/- 4.9 degrees C. Postoperative shivering was absent in 36 cases and mild in two cases. No device-related adverse effects were observed. CONCLUSIONS: Perioperative thermoregulation using the Allon system is safe and effective in maintaining body temperature within a narrow range in children undergoing brief surgical procedures.

Insulin in human milk and the prevention of type 1 diabetes.

Although controversial, exclusive breast milk feeding was shown to exert a protective effect in preventing type 1 diabetes. In contrast, an early introduction of cow's milk-based formula in young infants may enhance the risk of disease, especially in genetically susceptible children, presumably by an increase of intestinal permeability to macromolecules such as bovine serum albumin and beta-casein, which may arouse autoimmunity. We have shown that human milk contains insulin in substantial concentrations, while insulin is barely detectable (if at all) in infant formulas. Orally administered insulin was demonstrated to promote gut maturation and to reduce intestinal permeability to macromolecules. Furthermore, oral insulin may induce tolerance to insulin and protect against the development of type 1 diabetes. We herewith raise a hypothesis that human milk is protective against the development of type 1 diabetes by virtue of the effects of its substantial content of insulin.

Prolidase deficiency among an Israeli population: prenatal diagnosis in a genetic disorder with uncertain prognosis.

Prolidase deficiency is an autosomal recessive disorder that is characterized by considerable inter- and intrafamilial variability in its clinical presentation, ranging from asymptomatic to severe and fatal illness. We report here, for the first time, prenatal diagnosis of prolidase deficiency in a family whose first child was severely affected since birth and died at an early age. However, unexpectedly, the parents decided to continue the second pregnancy, which produced a full-term, healthy-appearing baby. The diagnosis of severe prolidase deficiency was confirmed in the baby's leukocytes. At age 4 months the baby is asymptomatic. Since the clinical severity of the disorder cannot be predicted, genetic counselling remains problematic despite the feasibility of prenatal diagnosis.

Familial Mediterranean fever: high gene frequency and heterogeneous disease among an Israeli-Arab population.

OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive disease that primarily affects non-Ashkenazi Jews, Armenians, Arabs, and Turks. The FMF (MEFV) gene responsible for the disease has been recently identified. Four missense mutations in exon 10 of the FMF gene seem to account for 86% of the DNA variations identified in patients with FMF. We conducted a phenotype/genotype correlation study in a homogenous population of Israeli-Moslem Arab patients with FMF and performed a mutational screening analysis on DNA samples from healthy individuals of this ethnic group. METHODS: Sixty-five patients clinically diagnosed as having FMF underwent molecular genetic studies using polymerase chain reaction and restriction endonuclease digestion methods to detect the presence of the 4 mutations (M694V, V726A, M680I, M694I). We then correlated the presence of each mutation with age of onset, clinical manifestations, and disease severity; patients whose allelic combination included M694V were then excluded from further statistical analysis, since the association of severe disease with the M694V allele has already been shown. In addition, we screened for FMF mutations the DNA samples from 318 healthy Moslem Arab individuals for the presence of these mutations. RESULTS: Among the 65 patients who were clinically diagnosed as having FMF, 78.5% had one or 2 mutation-bearing chromosomes. The most prevalent mutation was V726A, followed by M680I, M694V, and M6941. No significant difference in phenotypic characteristics was found between the patients with the diverse mutations. The total carrier frequency for the 4 mutations was 10.4% (95% confidence interval 0.07 to 0.137). CONCLUSION: A high FMF gene frequency was found among an Israeli-Moslem Arab population. Among the FMF patients from this ethnic group, several mutations were detected, none of which was found to correlate with a severe course of the disease.

Anomalous origin of the left coronary artery from the pulmonary artery: diagnosis and postoperative follow up.

BACKGROUND: Anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital malformation that presents a diagnostic challenge to the pediatrician and pediatric cardiologist. Although surgical repair is always indicated, the optimal technique has yet to be determined. OBJECTIVES: To review our experience with the diagnosis of children with ALCAPA and to assess short to midterm surgical results. METHODS: Between 1992 and 1998, 13 infants and children (2 months to 15 years) were treated for ALCAPA at our medical center. Eight were diagnosed during the first year of life; all were symptomatic and had severe dysfunction of the left ventricle. The five patients diagnosed at an older age had normal myocardial function. Diagnosis was established by echocardiography alone in seven patients; six required catheterization (one infant and all older patients). Surgery was performed in 12 patients to establish dual coronary artery system: 7 underwent the Takeuchi procedure and 5 had re-implantation of the anomalous left coronary artery. RESULTS: One infant died shortly after diagnosis before surgical repair was attempted, and one died postoperatively. Four patients required additional surgery: three for late complications of the Takeuchi procedure and one valve replacement for mitral insufficiency. Recent evaluation revealed good global left ventricle function in all patients except for one, who is still within the recovery phase and shows gradual improvement. However, most patients who presented with severe myocardial dysfunction upon diagnosis still display abnormal features such as echo-dense papillary muscles or evidence of small akinetic segments. In this group, early repair was associated with faster myocardial recovery. CONCLUSIONS: The diagnosis of ALCAPA remains a clinical challenge to the pediatrician and cardiologist. Diagnosis can be established echocardiographically, and early diagnosis and treatment may lead to faster myocardial recovery. The preferred surgical method appears to be re-implantation of the ALCA. The chance for good recovery of global ventricular function is high even in the sickest patients, nonetheless abnormal myocardial features can be identified even years after surgery.

Acute complications in the current era of therapeutic cardiac catheterization for congenital heart disease.

The acute complications of therapeutic cardiac catheterization for congenital heart disease as performed currently in a small unit were reviewed. In recent years, there has been a significant increase in the number of lesions thought amenable to catheter therapy. Only a few reports, however, have addressed the overall incidence of acute complications of therapeutic cardiac catheterization, all representing the experience of centres performing moderate-to-large numbers of procedures. A retrospective review was performed of 425 therapeutic catheter procedures performed at our institution between May 1993 and November 1997. Acute complications were retrieved from the database. This included all adverse events that were clinically recognized at the time of or within 2 weeks after the procedure and which, to the best of the authors' clinical judgement, were related to the catheterization and not part of the natural history of the child's illness. All patients were observed overnight following the procedure, and stayed in hospital if a complication developed. There were 49 acute complications (11.5%), of which 43 (10.1%) were deemed minor and 6 (1.4%) were considered major. The rate was low in patients with valvar pulmonary stenosis, including three neonates (3/45, 6.7%), for those undergoing angioplasty of native co-arctation (1/15, 6.7%) and pulmonary arteries (2/27, 7.4%); and for coil embolization of systemic to pulmonary collateral arteries (1/16, 6.3%). The rate was high in patients with valvar aortic stenosis, including 12 neonates (9/37, 24.3%), and for angioplasty of re-coarctation (4/23, 21.7%). There were more overall complications in neonates (25.6%) than in older patients (10.1%) (p < 0.01). Two patients died (0.5%), but no patient required emergency surgical intervention. In spite of the introduction of many new therapeutic modalities with greater intrinsic risk, and the fact that patients with more complex lesions and who are more acutely ill are being treated, the overall rate of complications remains relatively low. This probably reflects improvements in pericatheterization medical management, in selection of patients, in procedural techniques, and in the experience of operators.

Familial Mediterranean fever: clinical and genetic characterization in a mixed pediatric population of Jewish and Arab patients.

OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease which primarily affects non-Ashkenazi Jews, Armenians, Arabs, and Turks. The gene responsible for the disease (MEFV/FMF) has been recently identified. Four common mutations in exon 10 of the MEFV gene seem to account for 86% of the DNA variations identified in patients with FMF. We conducted a phenotype/genotype correlation study in a mixed population of Jewish and Arab children with FMF. STUDY DESIGN: Seventy patients clinically diagnosed as having FMF underwent molecular genetic studies using polymerase chain reaction and restriction endonuclease digestion methods to detect the presence of the four mutations (M694V, M680I, V726A, M694I). We then correlated the presence of each mutation with ethnic origin, age of onset, clinical manifestations, disease severity, and occurrence of amyloidosis. RESULTS: The M694V mutation, which is predominant in non-Ashkenazi Jews, was found in 92% of our Jewish patients and in only 30% of the Arab patients. All four mutations were identified among 94% of the Arab patients, but with no particular prevalence for any one of them. The presence of a homozygous M694V mutation was significantly associated with a more severe form of the disease: the clinical onset of the disease manifested at an earlier age; the number of attacks per month was higher; the global assessment by the treating physician and the severity of pain scored higher; and arthritis was more frequent. Only patients with the M694V mutation had a family history of amyloidosis. No association was found between the type of mutation and the predominance of fever, abdominal pain, pleuritis, skin eruption, or response to colchicine in the clinical picture. CONCLUSIONS: Homozygosity for the M694V mutation, predominant among North African Jews, is associated with a severe course and prognosis for FMF. This mutation is less common among Arabs and, when present, occurs almost only in heterozygous form. In Arab patients, the disease tends to run a milder course and seems to bear a better prognosis. The phenotype/genotype patterns that are evident from our study of a mixed series of Jewish and Arab children with FMF might provide a rational basis for counseling about the natural history of the disease and for clinical treatment of FMF patients and their families.

A comparison of arterial versus venous-activated clotting time in patients with congenital heart disease undergoing cardiac catheterization.

Studies in adult patients undergoing percutaneous coronary angioplasty have demonstrated differences in measured activated clotting time (ACT) in venous vs. arterial blood samples. Ninety-two patients with congenital heart disease undergoing cardiac catheterization were prospectively evaluated to compare venous vs. arterial ACT values in monitoring heparin effect in this population. Simultaneous venous and arterial ACT samples were drawn at baseline, 10 min, 60 min, and every 30 min thereafter until each case was finished. ACT values were determined simultaneously with a dual-chambered Hemochron 801 instrument. At baseline and throughout the study up to 90 min, venous and arterial ACT values were not significantly different. They were also no different in the subgroup of cyanotic patients. Therefore, venous and arterial ACT values can be safely used alternatively to guide heparin dosing during cardiac catheterization in patients with congenital heart disease without the risk of undercoagulation.

Developmental dysplasia of the hip: a new approach to incidence.

OBJECTIVE: The controversy over the incidence of developmental dysplasia of the hip (DDH) stems mainly from an ambiguity of criteria for defining a genuinely pathologic neonatal hip. In this study, we evaluate an algorithm we devised for the treatment of DDH, for its ability to identify those neonatal hips which, if left untreated, would develop any kind of dysplasia and, therefore, are to be included in the determination of DDH incidence. METHODS: Clinical and ultrasonographic examinations for DDH were performed on 18 060 consecutive neonatal hips at 1 to 3 days of life. Newborns with skeletal deformities, neurologic/muscular disorders, and neural tube defects were excluded. Hips that featured any type of sonographic pathology were reexamined at 2 or 6 weeks, depending on the severity of the findings. Only hips in which the initial pathology was not improved or had deteriorated were treated; all others were examined periodically until the age of 12 months. RESULTS: Sonographic screening of 18 060 hips detected 1001 instances of deviation from normal, indicating a sonographic DDH incidence of 55.1 per 1000. However, only 90 hips remained abnormal and required treatment, indicating a true DDH incidence of 5 per 1000 hips. All the others evolved into normal hips, and no additional instances of DDH were found on follow-up throughout the 12 months. CONCLUSIONS: The implementation of our protocol enables us to distinguish two categories of neonatal hip pathology: one that eventually develops into a normal hip (essentially sonographic DDH); and another that will deteriorate into a hip with some kind of dysplasia, including full dislocation (true DDH). This approach seems to allow for a better-founded definition of DDH, for an appropriate determination of its incidence, for decision-making regarding treatment, and for assessment of the cost-effectiveness of screening programs for the early detection of DDH.

[Percutaneous closure of patent arterial ducts with occluding spring coils].

In recent years percutaneous closure of small and medium-sized patent arterial ducts has been achieved using occluding spring coils. We describe our experience in 93 patients with this technique, using a snare to facilitate the procedure in most. All patients had a clinically apparent patent arterial duct and had undergone attempts at transcatheter closure at a mean age of 6.8 years. In 1, the duct was a residual lesion following surgical ligation, and in 5 it was a residual following attempted closure with the Rashkind double-umbrella. The mean narrowest diameter of the ducts was 2.1 mm. In our 93 patients implantation was successful in 92 (99%), using 1 coil (82 patients), or 2 (10 patients), and in 1 by a combination of a double-umbrella device and an occluding spring coil. The mean fluoroscopic screening time for the whole group was 22.8 minutes, which decreased to 16.8 minutes in the last 50 patients. The coil embolized in 7 patients, but was retrieved in 6 and the ducts were subsequently occluded with another coil. In 1 patient the coil was left in a distal small branch of the left pulmonary artery and the duct was successfully occluded with a double-umbrella. Color-Doppler echocardiogram performed the morning after placement of the coils showed residual leaks in 18%. At mean follow-up of 24.6 months repeat imaging showed residual leaks in only 3 of these patients (3%). We conclude that occlusion of small to medium-sized ducts using coils appears to be effective and is the treatment of choice. The use of a snare to hold and manipulate the coil as it is delivered improves control of the coil, the accuracy of its placement, as well as giving complete occlusion of the ducts.

[Balloon angioplasty of native coarctation of the aorta].

The use of balloon dilatation to treat native coarctation of the aorta is gaining acceptance among interventional pediatric cardiologists, but is still controversial. We describe our experience with this procedure in 21 children, mean age 5.6 years and mean weight 21.1 kg. Most had an additional congenital heart defect, most commonly a bicuspid aortic valve. 17 were asymptomatic, 3 had tachypnea and 1 infant had severe congestive heart failure and was ventilated. The mean systolic blood pressure was 129.7 mm Hg. Balloon dilatation was successful in 90% (19), decreasing the mean maximal systolic gradient from 35.3 to 9 mm Hg (p < 0.001), and increasing the narrowest area from 3.9 to 8.2 mm (p < 0.001), with a mean balloon-to-coarctation width-ratio of 2.8. There were no complications. Of 15 who underwent repeat cardiac catheterization at a mean interval of 10.6 months, 2 had a maximal systolic gradient of more than 20 mm Hg. 1 of these underwent successful repeat angioplasty and the other, who also had a small aneurysm, underwent surgical repair successfully. 2 others had small aneurysms and they are being followed clinically. All patients were seen again after a mean interval of 31 months. The mean systolic blood pressure was 104 mm Hg, significantly lower than before intervention (p < 0.002). 1 had an increased pressure gradient between right arm and leg of 35 mm Hg at later follow-up, and repeat cardiac catheterization demonstrated a good result 13 months after the initial procedure. She is awaiting a third catheterization. Overall, 90% had good mid-term results. Based on our experience and recent reports, balloon angioplasty is safe and effective in most children older than 7 months and should be considered a viable alternative to operation for discrete aortic coarctation. Further long-term evaluation is needed.

[1000 cardiac catheterizations in congenital heart disease].

Over the past 15 years, percutaneous therapeutic cardiac catheterization has become increasingly important in the treatment of congenital heart disease. We describe our experience in 1000 such catheterizations between 1993-1997. 55% were in 1-12-year-olds; only 20% were in patients younger than 1 year old and 11.3% were in adults with congenital heart defects. In about 50% it was at least a second cardiac catheterization. Overall, there were 425 therapeutic cardiac catheterizations, increasing from 33% in the first 200 procedures, to 63% in the last 200. We performed 30 different types of therapeutic catheterizations: 23.3% were valvular dilations, 21.4% vessel angioplasties, 36.9% closure procedures, 9.2% electrophysiological procedures, and 9.2% miscellaneous. In 31.3% of therapeutic catheterizations we used 12 new procedures. Minor complications occurred in 8.5% and major in 0.6%; most complications were successfully treated or were self-limited and there was no residual damage. In this report the current role of each type of major catheterization is discussed on the basis of our experience. Further development of technology for lesions not amenable to currently available transcatheter methods, and longer follow-up for current techniques will consolidate the role of therapeutic cardiac catheterization in congenital heart disease.

Plasmalogen phospholipids are involved in HDL-mediated cholesterol efflux: insights from investigations with plasmalogen-deficient cells.

Plasmalogens are ether-glycerophospholipids that exist in all mammalian cells, but their physiological function remains thus far an enigma. It has been previously suggested that the association of high-density lipoprotein (HDL) with cellular phospholipid is a pre-requisite for the process of HDL-mediated cholesterol efflux (HDL-MCE). To investigate our hypothesis that plasmalogens might play a role in HDL-MCE, we used a model composed of plasmalogen-deficient cells including RAW mutant macrophages and fibroblasts from patients with rhizomelic chondrodysplasia punctata type II. In mutant macrophages, HDL-MCE was reduced by 57% compared to control macrophages, after 16 hours. A similar phenomenon was observed in plasmalogen-deficient patients fibroblasts. Incubation of plasmalogen-deficient fibroblasts with 1-0-hexadecyl-sn-glycerol, which restored plasmalogen levels to that of control cells, resulted in a 35% increase in HDL-MCE, compared to a 10% increment in controls. The novel finding that HDL-MCE is reduced in plasmalogen-deficient cells and increases following plasmalogen restoration leads us to suggest that plasmalogen has an important function in the mediation of cellular cholesterol efflux.

Interventional catheterization decreases plasma levels of atrial natriuretic peptide (ANP) in children with congenital heart defects.

Atrial natriuretic peptide (ANP) is one of the cardiac peptides implicated in volume and sodium homeostasis. We investigated the effect of interventional catheterization on plasma levels of ANP, aldosterone, and cortisol in 28 children with various congenital heart defects (CHD). Patients were divided by age into two groups: group A--infants and children over 3 months of age (n = 22), and group B--newborns (n = 6). These were compared to age-matched control groups. In group A, interventions included pulmonic valvotomy (n = 8), aortic valvotomy (n = 4), balloon angioplasty of native coarctation of the aorta (n = 3), balloon dilatation of the mitral valve (n = 1), and Rashkind double umbrella closure of patent ductus arteriosus (n = 6). Group B interventions included pulmonic valvotomy (n = 3), aortic valvotomy (n = 1), and balloon atrial septosomy (n = 2). In group A, mean ANP levels were markedly higher than in age-matched controls (125.2+/-15.8 vs. 24.6+/-4.6 pg/ml) (P <0.0001), and decreased immediately after intervention (75.6+/-11.4 pg/ml, P <0.02), and more markedly on follow-up (42.9+/-5.0 pg/ml, P < 0.0001). In group B (newborns), mean basal plasma levels were high before and after intervention and were not different from age-matched controls (243+/-42.1 vs. 220.8+/-16.2 pg/ml). There was a significant decrease on follow-up measurement (62.1+/-12.7 pg/ml, P < 0.005). In both groups, plasma cortisol levels increased significantly immediately following catheterization (P < 0.02), and normalized on follow-up. Basal aldosterone levels were normal in group A and high in Group B (9.9+/-3.8 vs. 167.6+/-16.9 ng/dl) (P < 0.001). It is suggested that plasma ANP levels are increased in children with CHD, without overt heart failure, and decrease significantly following successful intervention. In newborns with CHD, the physiological high ANP levels obscure the effect of the CHD.