Efficacy and safety of clopidogrel in children with diarrhea associated hemolytic uremic syndrome

Introduction

Hemolytic uremic syndrome is a thrombotic microangiopathy. Clopidogrel, a recently developed platelet aggregation inhibitor, has not been previously reported as a treatment for this illness. Our study's objective was to explore the efficacy and safety of clopidogrel in children with diarrhea associated hemolytic uremic syndrome.

Materials and Methods

We performed a retrospective chart review of all children (≤ 18 years) hospitalized with diarrhea associated hemolytic uremic syndrome. Outcomes in clopidogrel treated children were described. In subgroup analysis, outcomes were compared to those untreated with platelet aggregation inhibitors.

Results

Of 72 children with diarrhea associated hemolytic uremic syndrome, 88% were treated with platelet aggregation inhibitors (clopidogrel 56%, sulfinpyrazone 19%, dipyridamole 13%). The median age of clopidogrel treated children was 5 years; 40% were male. Initial median hemoglobin, platelet count, and serum creatinine were 10.1 g/dL, 53 × 10³/μL, and 2.3 mg/dL respectively. Clopidogrel (median dose 1 mg/kg/d) was given for a median of 4 days (range 1-15). Other therapies included erythropoietin (98%), red blood cell transfusions (80%), diuretics (58%), anti-hypertensive agents (45%), and dialysis (33%). The median hospital length of stay was 9 days (range 3-26). Three children had bleeding complications (epistaxis/hematemesis). The risk of chronic kidney disease was 5% and death 2.5%. In subgroup analysis, median duration of dialysis was 11 days in thirteen clopidogrel treated children compared to 21 days in five untreated patients (P = 0.04).

Conclusions

Children with diarrhea associated hemolytic uremic syndrome treated with clopidogrel have outcomes comparable to untreated patients. Bleeding complications may occur.     

Ex vivo expansion with stem cell factor and interleukin-11 augments both short-term recovery posttransplant and the ability to serially transplant marrow

The characterization of many cytokines involved in the control of hematopoiesis has led to intense investigation into their potential use in ex vivo culture to expand progenitor numbers. We have established the optimum ex vivo culture conditions that allow substantial amplification of transient engrafting murine stem cells and which, simultaneously, augment the ability to sustain serial bone marrow transplantation (BMT). Short-term incubation of unfractionated BM cells in liquid culture with stem cell factor (SCF) and interleukin-11 (IL- 11) produced a 50-fold amplification of clonogenic multipotential progenitors (CFU-A). Following such ex vivo expansion, substantially fewer cells were required to rescue lethally irradiated mice. When transplanted in cell doses above threshold for engraftment, BM cells expanded ex vivo resulted in significantly more rapid hematopoietic recovery. In a serial transplantation model, unmanipulated BM was only able to consistently sustain secondary BMT recipients, but BM expanded ex vivo has sustained quaternary BMT recipients that remain alive and well more than 140 days after 4th degree BMT. These results show augmentation of both short-term recovery posttransplant and the ability to serially transplant marrow by preincubation in culture with SCF and IL-11.     

Flashback to the 1960s: utility of archived sera to explore the origin and evolution of Plasmodium falciparum chloroquine resistance in the Pacific

The increasing frequencies of Plasmodium falciparum strains that are resistant to chloroquine (CQ) and other antimalarials are resulting in a global resurgence of malaria morbidity and mortality. CQ resistance (CQR) is associated with multiple mutations in the P. falciparum chloroquine resistance transporter (pfcrt) gene. The mode and tempo of the accumulation of substitutions leading to these complex CQR haplotypes remain speculative due to the dearth of samples temporally spanning the evolution of drug resistance. The origin and evolution of the CQR alleles of Papua New Guinea (PNG) is particularly ambiguous. It remains unclear whether the pfcrt haplotype in PNG resulted from an independent origin of a CQR haplotype identical in sequence to the South American haplotype, or if this haplotype originated in South America and recombined into a Southeast Asian-derived genome.We sequenced a segment of pfcrt exon 2 from 398 plasmid clones derived from archival human sera collected in the Pacific before and after the first reported cases of CQ treatment failure (n = 251) and modern samples (n = 147). None of the 251 pfcrt plasmid clones from nine archival samples displayed the C72S or the K76T mutations that are characteristic of CQR strains. In contrast, these two amino acid substitutions were present in all 147 pfcrt plasmid clones from five samples collected between 2001 and 2003; thus, the archival samples represent the baseline parasite genetic diversity before the evolution of CQR strains.We are currently expanding our analyses to include additional samples from the series described here and from series collected in the 1970s and the 1980s to evaluate the geographic origin of CQR strains in the Pacific and the validity of the sequential point mutation accumulation model of CQR evolution.     

Construction of modern Australian first trimester ultrasound dating and growth charts

Accurate pregnancy dating is vital to obstetric management. However, first trimester fetal charts commonly used in Australia rely on data reported more than three decades ago. This study reports first trimester dating and growth charts for crown‐rump length between 5 and 14 weeks of gestation and biparietal diameter between 9 and 14 weeks of gestation on an Australia population using modern real‐time ultrasound equipment. All consenting eligible women attending a large Sydney clinic for first trimester ultrasound between March 2005 and December 2006 were recruited. Measurements were carried out to Australasian Society for Ultrasound in Medicine standard protocols. Statistical analyses were undertaken using polynomial regression models and thorough diagnostic checks made. Overall 396 eligible women consented to the study, with 268 between 9 and 14 weeks of gestation. The average participant age was 34 years (range 22–45 years), 371 and all yielded valid biometry measurements. Equations, means and 90% reference intervals for crown‐rump length measurements and biparietal diameter measurements were derived using polynomial regression models. Thorough residual and diagnostic checks were made. Once validated by others, we believe they will warrant consideration for use by Australasian Society for Ultrasound in Medicine.     

Cerebrospinal fluid exchange after intrathecal methotrexate overdose. A report of two cases

Two patients aged 11 and four years, were accidentally given a 10-fold overdose of intrathecal methotrexate while being treated for malignant disease. Neither patient developed any signs of neurotoxicity and exchange of lumbar cerebro-spinal fluid was started 3 and 5 h later, respectively. In one of the patients, who received 120 mg of methotrexate intrathecally, 31% of the given dose was recovered during 2 h of cerebrospinal fluid exchange that was started 3 h after the accidental overdosage. No sequelae were observed in any of the patients. Cerebrospinal fluid exchange is safe and can be recommended in all cases of intrathecal methotrexate overdosage. Ventriculo-cisternal perfusion is not necessary in cases of a 10-fold overdose if the patient has no signs of acute neurotoxicity.     

Home parenteral nutrition in chronic intestinal failure

In children with severe failure of intestinal function, intravenous nutrition is at present the only treatment able to maintain adequate nutrition for prolonged periods of time. Over the last five years we have discharged 10 patients home on parenteral nutrition for a total of 25 patient years and here the outcome of these children is presented. Of the 10 patients, one has discontinued home parenteral nutrition (HPN), seven patients remain well, one patient has recently moved to the USA, and one patient has died after major abdominal surgery. All children had either normal or an accelerated rate of growth on HPN and developmentally all have progressed well. All the children over 5 years attend normal schools. The major complication of treatment was line sepsis with an overall rate of one episode in 476 days and a total of nine central lines (five patients) have required replacement giving an average line life of 680 days. For those children unfortunate enough to suffer from severe intestinal failure, HPN is preferable to prolonged hospital treatment and offers the chance of a good quality of life with prolonged survival.     

Immunity to hepatitis B, poliomyelitis and measles in fully vaccinated Aboriginal and Torres Strait Island children

Objective: To determine the immunity to hepatitis B, poliomyelitis and measles in fully vaccinated Aboriginal and Torres Strait Island children in north Queensland.
Methodology: A cross-sectional survey of immunity in a sample of children; 101 fully vaccinated Aboriginal and Torres Strait Island children, with a median age of 24.5 months, from 10 communities in North Queensland participated in this study. The main outcome measures were the prevalence of adequate antibody levels against hepatitis B, poliomyelitis and measles.
Results: Only 54% (95% Cl 44–63%) of the children had adequate immunity (10 m iu/mL) to hepatitis B, and one child had been infected despite vaccination. Although all the children (95% Cl 96–100%) had adequate immunity (i.e. neutralizing antibodies at a dilution of 1:8) to poliovirus 2, only 93% (95% Cl 86–96%) and 60% (95% Cl 50–69%) had adequate immunity to polioviruses 1 and 3, respectively. Nearly all (96%; 95% Cl 90–98%) of the children had adequate immunity (i.e. detectable IgG antibody) to measles.
Conclusions: Although a relatively low proportion of the children had adequate antibody levels against hepatitis B the clinical significance of this observation is uncertain. Further studies are needed to determine whether fully vaccinated Torres Strait Island children have been adequately protected and whether they require a booster dose of hepatitis B vaccine. A substantial proportion of fully vaccinated Aboriginal and Torres Strait Island children are inadequately protected against poliomyelitis, and therefore any such child with acute flaccid paralysis should be investigated fully for poliomyelitis. Vaccinated Aboriginal and Torres Strait Island children are well protected against measles, as are other Australian children.     

Magnetic resonance angiography findings in the early post-carotid endarterectomy period

This preliminary study was designed to investigate the ability of multiple axial volume three-dimensional fourier transform (3DFT) time-of-flight (TOF) magnetic resonance angiography (MRA) to depict the carotid bifurcation in the early post-carotid endarterectomy period. Five patients underwent intra-operative digital subtraction angiography (DSA) and carotid MRA within 5 days of carotid endarterectomy. An axial volume fast imaging in steady-state precession (FISP) gradient-echo 3DFT TOF carotid MRA technique in this limited series appeared to display accurately the surgically significant abnormalities at the carotid bifurcation after endarterectomy. However, in normal or near-normal intra-operative DSA studies, overestimation of internal carotid artery stenoses was encountered. Postoperative MRA demonstrates potential as a useful non-invasive investigation after carotid endarterectomy but should be interpreted with caution until larger studies become available.