The heart of children with steroid-resistant nephrotic syndrome: is it all podocin?

Mutations in the gene NPHS2 encoding podocin are responsible for a recessive form of steroid-resistant nephrotic syndrome (SRNS). The common phenotype is of massive proteinuria in early childhood that tends to progress to end-stage renal failure. Extrarenal manifestations have not been described. Twenty-two children with SRNS from six unrelated Arab families were found to be homozygous for the R138X mutation in NPHS2. Eighteen patients underwent cardiac evaluation at diagnosis of SRNS while they had normal BP and preserved renal function. Cardiac anomalies were detected in 16 (89%) children: Left ventricular hypertrophy in eight, pulmonary stenosis in six, discrete subaortic stenosis in two, and Ebstein anomaly and ventricular septal defect in one each. The remaining four affected individuals were assessed only once they had end-stage renal failure. They had severe left ventricular hypertrophy and experienced repeated episodes of heart failure. Two control groups were equally evaluated. The first consisted of 37 siblings without nephrotic syndrome, of whom only one carrier had a cardiac defect (P < 0.001). None of the second group, which included 22 children with persistent nephrotic syndrome as a result of other causes, had a cardiac anomaly (P < 0.001). Cardiac disorders in homozygotes for mutations in NPHS2 cannot be attributed to an association by chance or to a state of persistent nephrotic syndrome. Because human podocin mRNA is expressed in fetal heart, it is speculated that it may have a role in normal cardiac development. Cardiac evaluation is recommended at the time of diagnosis of SRNS due to mutations in podocin.     

Early and Late Presentations of Graft Arterial Pseudoaneurysm Following Pancreatic Transplantation

Background

Graft pseudoaneurysm (PSA) following pancreatic transplantation (PT) is a rarely reported complication that has significant morbidity and mortality. Few case reports and small series of this complication exist.

Methods

Retrospective review of files of 106 patients who underwent PT at the Tel-Aviv Sourasky Medical center between 1995 and 2010. Accessible asymptomatic patients (n = 35) were referred for graft PSA screening using ultrasound-Doppler.

Results

Eight patients developed graft PSA (8 %). All had early posttransplant sepsis. PSA incidence among patients who had perioperative sepsis is 13 %. Three patients developed early postoperative PSA, presenting as massive abdominal bleeding requiring urgent laparotomy and graft resection. Five patients were diagnosed with late-onset graft PSA between 3 months and 11 years posttransplant: clinical presentations were massive gastrointestinal bleeding (n = 2), acute renal failure (n = 1), and asymptomatic finding on screening ultrasound-Doppler (n = 2, 6 % of screened patients).

Conclusions

PSA following PT occurs in 8 % of patients. Perioperative infection is a risk factor. Early PSAs present as massive intra-abdominal bleeding. PSA may develop years posttransplant, may be asymptomatic, but late rupture is possible and presents as gastrointestinal bleeding. We recommend screening of patients at risk with ultrasound Doppler for early detection and treatment of asymptomatic PSAs.     

Genetic analysis--a diagnostic tool for primary hyperoxaluria type I

Primary hyperoxaluria type I is an autosomal recessive metabolic disease in which excessive oxalates are formed by the liver and excreted by the kidneys, causing a wide spectrum of disease, ranging from renal failure in infancy to mere renal stones in late adulthood. The diagnosis may be suspected when clinical signs and increased urinary oxalate and glycolate excretion present, and is confirmed by the measurement of decreased alanine:glyoxylate aminotransferase activity in a liver sample. The enzymatic assay is not readily available to pediatric nephrologists in many parts of the world. We describe three families from Croatia in whom the diagnosis of primary hyperoxaluria was solely based on clinical findings that included nephrolithiasis and nephrocalcinosis accompanied by increased urinary oxalates and glycolate excretion, as enzymatic assays of liver samples could not be performed. Mutation analysis of the AGXT gene encoding the defective enzyme confirmed the diagnosis, revealing three alleles carrying the C156ins mutation and two the G630A mutation. Screening first-degree relatives for the relevant mutation disclosed an asymptomatic affected sibling. Mutation analysis of the AGXT gene is a non-invasive and accurate tool for the diagnosis of type I primary hyperoxaluria that may replace enzymatic assays of liver biopsies.     

Kinetics of paraquat and copper reactions with nitroxides: the effects of nitroxides on the aerobic and anoxic toxicity of paraquat

The toxicity of paraquat (PQ2+) is attributed to intracellularly formed PQ*+, O(2)*-, H(2)O(2), and secondary.OH radicals generated through Fenton-like reactions. Yet, no antidote for PQ2+ toxicity in human has been found also due to poor cell permeability of many common antioxidants that remove toxic species predominantly extracellularly. Cell-permeable nitroxides, which scavenge xenobiotic-derived deleterious radicals and detoxify redox-active metal ions, would be expected to ameliorate PQ2+ toxicity. We have studied using pulse radiolysis the kinetics of the reactions of 2,2,6,6-tetramethyl-piperidinoxyl (TPO) and 4-OH-TPO with PQ*+ and CuIIL(2) (L = 1,10-phenanthroline, 2,2'-bipyridyl) in the absence and presence of DNA. We found that the rate constant for the reaction of PQ*+ with the nitroxides is about 4 orders of magnitude lower than that with O(2). In addition, the rate of the reaction of the nitroxides with CuIL(2) decreases as [DNA] increases, which suggests that nitroxides react significantly slower with bound metal ions. These results explain the failure of 4-OH-TPO to protect bacterial and mammalian cells from PQ2+ toxicity under air. In contrast, the rate of the reaction of PQ*+ with CuIIL(2) was unaffected by DNA. Furthermore, copper toxicity has been attributed mainly to CuI and was observed predominantly for cells subjected to anoxic conditions. It implied that nitroxides would be effective protectants if PQ2+ induces toxicity also under anoxia. Surprisingly, we found that PQ2+ toxicity under anoxia was even greater than that under air, and under these conditions 4-OH-TPO protected the cells from PQ. These results indicate that the mechanism underlying the anoxic toxicity of PQ2+ differs from that operating in the presence of oxygen, and that reduced transition metal ions are most probably the species responsible for PQ2+ anoxic toxicity.     

Time course of neuromuscular blockade with rocuronium in children with intracardiac shunts

OBJECTIVE: To evaluate the time course of neuromuscular blockade after rocuronium in children with intracardiac shunts. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: Consecutive children (n = 52) with intracardiac shunts scheduled for elective cardiac surgery. Participants were allocated to 2 groups according to the direction of the shunt. INTERVENTIONS: Rocuronium, 0.6 mg/kg, was administered for muscle relaxation. The ulnar nerve was stimulated at 20-second intervals with a supramaximal 2-Hz train-of-4 stimulation (TOF-Guard nerve stimulator; Biomet International, Odense, Denmark). The onset time to maximal twitch depression and the time to clinical recovery were compared between the 2 groups. MEASUREMENTS AND MAIN RESULTS: The time to maximal block was significantly faster in children with a right-to-left shunt: 56.8 +/- 5.3 seconds versus 77.1 +/- 6.6 seconds (p = 0.01). There was a tendency to shorter recovery in children with a right-to-left shunt: 42.3 +/- 6.1 minutes versus 55.4 +/- 4.9 minutes (p = NS). CONCLUSION: This study shows a more rapid onset of rocuronium in children with cyanotic congenital heart disease. In these patients, rocuronium is indicated, particularly for rapid airway control.     

Intra-familial clinical heterogeneity: absence of genotype-phenotype correlation in primary hyperoxaluria type 1 in Israel

BACKGROUND/AIMS: Primary hyperoxaluria type 1 (PH1) is caused by the deficiency of the liver enzyme alanine:glyoxylate aminotransferase which results in increased synthesis and excretion of oxalate. The clinical manifestations of PH1 are heterogeneous with respect to the age of onset and rate of progression. The aim of this study was to investigate possible relationships between a given genotype, the biochemical profile and the clinical phenotype. METHODS: We conducted a study of 56 patients from 22 families with PH1 from Israel. The clinical and biochemical data were compiled and the genotype was determined for each family. RESULTS: The prevalent phenotype was of early onset with progression to end-stage renal disease during the first decade of life. Fifteen PH1-causing mutations were detected in 21 families: 10 were first described in this patient population. Marked intra-familial clinical heterogeneity was noted, meaning that there was no correlation between a given genotype and the phenotype. CONCLUSIONS: The clinical course of patients with PH1 is not dictated primarily by its genotype. Other genetic and/or environmental factors play a role in determining the ultimate phenotype.     

Emotional responses of children and adolescents to parents with multiple sclerosis

The effect of a chronic illness of one parent on children is determined by a complicated interaction of various emotional components. Our focus was on the children's and adolescent's emotional reactions and feelings towards their multiple sclerosis (MS)-affected parents, including: degree of responsibility, obligation and concern, yielding behaviour and active protection, fear and anxiety related to the state of illness, their sense of burden in connection with household tasks and errands, and anger. Fifty-six children, ages 10-18, each having a parent with MS, were examined. The results were compared to a control group of 156 age-matched children with healthy parents. Feelings were examined by means of a questionnaire previously constructed by us. We found that children of parents with MS felt more responsibility and obligation than children of healthy parents. They also exhibited more yielding behaviour, more fear and anxiety related to states of illness, a greater sense of burden and a greater degree of anger. We consider the interaction between the sex of the parent and the sex of the child in connection with these feelings and discuss the implications of the 'parental child' role of these children.