Papers by Azaria J.j.t. Rein
International Journal of Cardiology, 2007
from poor families are dependant on financial support groups or philanthropic organizations for a... more from poor families are dependant on financial support groups or philanthropic organizations for any possible cardiac care. An estimated 10,000 pediatric cardiac surgeries are performed annually throughout the country although an estimated 220,000 newborns.are born every year with congenital heart disease. Facilities for neonatal and complex congenital heart surgery are virtually nonexistent in the neighboring countries of Pakistan, Nepal, Bangladesh, Afghanistan and Srilanka and many children from these countries travel to India or other countries for treatment if they can afford to do so. With rapid economic development it is expected that more facilities for pediatric cardiac care will come up in the near future and the outlook for the child with heart disease in this region will improve. A similar disparity exists in the Middle East. Neonatal and complex congenital heart surgery is available in Saudi Arabia, Oman and Israel. The affluent oil rich countries like Kuwait, U.A.E and Qatar can afford to provide state support for pediatric cardiac care overseas, for all their children, whenever required. This has in many ways been a disincentive for the development of advanced centers within these countries. Countries like Jordan, Yemen and Syria however cannot afford to do so and gaining access to cardiac care remains an individual effort. Political unrest has hampered progress of health care in countries like Iraq, Lebanon and Afghanistan. Children with heart disease in these countries will have to wait for political stability before they can expect any care. The status of children with heart disease in many parts of South Asia and Middle East is dismal. Improving the situation needs a concerted effort on the part of state governments, international aid agencies, international pediatric cardiac societies and industry.
PLOS Genetics
The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance... more The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality
Journal of Medical Genetics, 2016
The underlying molecular aetiology of congenital heart defects is largely unknown. The aim of thi... more The underlying molecular aetiology of congenital heart defects is largely unknown. The aim of this study was to explore the genetic basis of non-syndromic severe congenital valve malformations in two unrelated families. Whole-exome analysis was used to identify the mutations in five patients who suffered from severe valvular malformations involving the pulmonic, tricuspid and mitral valves. The significance of the findings was assessed by studying sporulation of yeast carrying a homologous Phospholipase D (PLD1) mutation, in situ hybridisation in chick embryo and echocardiography and histological examination of hearts of PLD1 knockout mice. Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in the PLD1 gene. The mutations affected highly conserved sites in the PLD1 protein and the p.His442Pro mutation produced a strong loss of function phenotype in yeast homologous mutant strain. Here we show that in chick embryos PLD1 expression is confined to the forming heart (E2-E8) and homogeneously expressed all over the heart during days E2-E3. Thereafter its expression decreases, remaining only adjacent to the atrioventricular valves and the right ventricular outflow tract. This pattern of expression follows the known dynamic patterning of apoptosis in the developing heart, consistent with the known role of PLD1 in the promotion of apoptosis. In hearts of PLD1 knockout mice, we detected marked tricuspid regurgitation, right atrial enlargement, and increased flow velocity, narrowing and thickened leaflets of the pulmonic valve. The findings support a role for PLD1 in normal heart valvulogenesis.
Pediatric Cardiology, 2010
Intracardiac echogenic foci (ECFs), probably representing microcalcifications of the papillary mu... more Intracardiac echogenic foci (ECFs), probably representing microcalcifications of the papillary muscles, are a common finding in fetal ultrasonic screening examinations. Their significance is unclear, and their value as markers for chromosomal anomalies is debatable. It also is unknown whether ECFs predict abnormal cardiac performance. This prospective study analyzed and compared the systolic and diastolic properties of the heart in 28 fetuses with ECFs and 70 fetuses without ECFs using both conventional and novel myocardial deformation methods. The findings suggest that left-sided ECFs do not predict depressed left-or right-side systolic or diastolic properties in the fetus. A longitudinal study that would follow ECF fetuses into their childhood is warranted to confirm the findings of this study.
Circulation, Oct 31, 2006
The Journal of Pediatrics, Jul 1, 2006
J Amer Coll Cardiol, 2004
Results: Indications for PVR were valvular regurgitation (n=6), obstruction (n=3), and both (n=1)... more Results: Indications for PVR were valvular regurgitation (n=6), obstruction (n=3), and both (n=1). Valve types were St. Jude (n=7), Starr-Edwards (n=2), and Bjork-Shiley (n=1). In 5 pts, the mechanical PVR was placed within a conduit. Concomitant mechanical tricuspid valve replacement (St. Jude) was performed in 6 pts. Postoperatively, all but 1 were anticoagulated with warfarin. During late follow-up (8.3 +/-7.7 yrs, max 25 yrs), 1 pt required repeat PVR for outgrowth of prosthesis 25 yrs postoperatively, and 1 pt with normal prosthetic pulmonary valve function underwent heart transplantation for severe biventricular failure 3.5 yrs postoperatively. The average mean gradient across the mechanical PVR by echocardiography in the remaining 8 pts was 11 +/-7 mmHg. There were no perivalvular leaks or vegetations, and no evidence of pannus formation or prosthesis dysfunction. There were 3 late minor bleeding events (epistaxis in 2 pts and menorrhagia in 1). There was 1 sudden late death 15 yrs after PVR, and 1 death from unknown causes in the aforementioned pt with outgrowth of the mechanical PVR, 5.5 yrs post re-PVR with a bioprosthesis. There were no cases of pulmonary emboli or PVR thrombosis. Conclusions: Mechanical PVR appears to provide excellent durability and hemodynamic results without mechanical valve failure or valve thrombosis in this small series. Mechanical prostheses should be considered for PVR in selected pts, particularly those who require chronic warfarin anticoagulation for other reasons.
European Journal of Heart Failure Supplements, 2003
The Israel Medical Association journal : IMAJ, 2007
Surgical repair of tetralogy of Fallot may leave the patient with pulmonary regurgitation, causin... more Surgical repair of tetralogy of Fallot may leave the patient with pulmonary regurgitation, causing eventual right ventricle dilatation and dysfunction. Predicting clinical deterioration may help to determine the best timing for intervention. To assess whether the clinical and humoral status of patients in the second decade after repair of ToF is worse than that of patients in the first decade after repair. Twenty-one patients with repaired ToF underwent clinical assessment, electrocardiogram, echocardiogram and measurement of plasma B-type natriuretic peptide and N-terminal pro-BNP as well as the 6 minute walk distance test. Patients were divided into two groups: group A - less than 10 years after repair (n=10, age < 12 years old), and group B - more than 10 years after repair (n=11, age > 12 years old). The age at repair was similar in both groups. In all but one patient the distance in the 6 min walk test was less than the minimum for age. RV end-diastolic volume and the 6 m...
Harefuah, 1996
Aortopulmonary (AP) window is an uncommon cardiac anomaly which is frequently associated with oth... more Aortopulmonary (AP) window is an uncommon cardiac anomaly which is frequently associated with other cardiac anomalies. Concomitant repair of all intra- and extracardiac anomalies is usually recommended. Between October 1993 and July 1994, 4 patients aged 37 days, 4 weeks, 3.5 and 1.5 years, respectively, underwent repair of AP window and associated malformations. The associated anomalies consisted of interrupted aortic arch (IAA), and atrial and ventricular septal defects in the 1st patient, patent ductus arteriosus in the 2nd, inlet ventricular septal defect in the 3rd and congenital narrowing of the right pulmonary artery and a patent foramen ovale in the 4th. Extreme metabolic acidosis after repair of IAA in the 1st, dictated ligation of the AP window before repair of the intracardiac anomalies at 2 months of age. In the 2nd and 3rd, repair of the window and associated anomalies was performed in a single stage. In the 4th, left pulmonary artery banding preceded complete repair. A...
Cardiology, 1992
The most serious side effects of recombinant interleukin-2 (rIL-2) and recombinant interferon-alp... more The most serious side effects of recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFN alpha) immunotherapy are cardiovascular disturbances, including systemic hypotension, left-ventricular dysfunction and pulmonary edema. We present a 25-year-old female who developed reversible cardiogenic shock during intermediate dose rIL-2 and low dose rIFN alpha therapy. Rapid clinical improvement occurred after intravenous fluid and dopamine support. A serial echocardiographic evaluation, which has not been described previously in this setting, is reported.
European Journal of Human Genetics, 2014
The laterality in the embryo is determined by left-right asymmetric gene expression driven by the... more The laterality in the embryo is determined by left-right asymmetric gene expression driven by the flow of extraembryonic fluid, which is maintained by the rotary movement of monocilia on the nodal cells. Defects manifest by abnormal formation and arrangement of visceral organs. The genetic etiology of defects not associated with primary ciliary dyskinesia is largely unknown. In this study, we investigated the cause of situs anomalies, including heterotaxy syndrome and situs inversus totalis, in a consanguineous family. Whole-exome analysis revealed a homozygous deleterious deletion in the WDR16 gene, which segregated with the phenotype. WDR16 protein was previously proposed to play a role in cilia-related signal transduction processes; the rat Wdr16 protein was shown to be confined to cilia-possessing tissues and severe hydrocephalus was observed in the wdr16 gene knockdown zebrafish. The phenotype associated with the homozygous deletion in our patients suggests a role for WDR16 in human laterality patterning. Exome analysis is a valuable tool for molecular investigation even in cases of large deletions.
Biomarkers in Medicine, 2012
Thanks to improved treatment of congenital heart disease early in life, many such patients reach ... more Thanks to improved treatment of congenital heart disease early in life, many such patients reach adulthood. Adults with congenital heart disease are an increasing population, which will continue to grow in the future. The clinical state of these patients is affected by their complex heart diseases, as well as the consequence of past corrective or palliative interventions. The natriuretic peptides are important markers for the presence, severity and prognosis of heart disease. The majority of the current knowledge is on patients with acquired heart disease. This article reviews the present knowledge regarding the role of the natriuretic peptides in adults with various forms of congenital heart disease.
PEDIATRICS, 2006
The authors have indicated they have no financial relationships relevant to this article to discl... more The authors have indicated they have no financial relationships relevant to this article to disclose.
Open Journal of Pediatrics, 2014
Objective: Acute heart failure due to heart muscle disease is potentially fatal in pediatric pati... more Objective: Acute heart failure due to heart muscle disease is potentially fatal in pediatric patients. Heart transplantation (Tx) is utilized to improve survival. However, spontaneous recovery may occur. The outcome of patients treated in centers with no Tx option was studied. Patients and Methods: A retrospective review of infants and children (≤16 years) who presented with heart muscle disease (left ventricular shortening fraction, LVSF ≤ 25%) between 1992 and 2007, in two medical centers in Jerusalem, was performed. Results: There were 62 patients, mean age 2.5 years, mean LVSF 16.3%. The 5-year survival was 73%. Lower LVSF at presentation (p = 0.006) was independently associated with mortality. Recovery (normalization of LVSF) occurred in 56% of survivors. Of the 38 patients who were eligible for Tx at their presentation, according to the AHA guidelines, 22 (58%) survived and 13 (34%) recovered. Conclusions: This study shows the long term outcome of pediatric patients with acute heart muscle disease treated with no Tx option. These findings may reflect the impact of improved medical management of these patients in recent years.
Interventional Cardiology, 2011
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Papers by Azaria J.j.t. Rein