Systematic update to the mammalian relative potency estimate database and development of best estimate toxic equivalency factors for dioxin-like compounds.

The World Health Organization (WHO) assesses potential health risks of dioxin-like compounds using Toxic Equivalency Factors (TEFs). This study systematically updated the relative potency (REP) database underlying the 2005 WHO TEFs and applied advanced methods for quantitative integration of study quality and dose-response. Data obtained from fifty-one publications more than doubled the size of the previous REP database (∼1300 datasets). REP quality and relevance for these data was assessed via application of a consensus-based weighting framework. Using Bayesian dose-response modeling, available data were modeled to produce standardized dose/concentration-response Hill curves. Study quality and REP data were synthesized via Bayesian meta-analysis to integrate dose/concentration-response data, author-calculated REPs and benchmark ratios. The output is a prediction of the most likely relationship between each congener and its reference as model-predicted TEF uncertainty distributions, or the 'best estimate TEF' (BE-TEF). The resulting weighted BE-TEFs were similar to the 2005 TEFs, though provide more information to inform selection of TEF values as well as to provide risk assessors and managers with information needed to quantitatively characterize uncertainty around TEF values. Collectively, these efforts produce an updated REP database and an objective, reproducible approach to support development of TEF values based on all available data.

Lack of potential carcinogenicity for aspartame - Systematic evaluation and integration of mechanistic data into the totality of the evidence.

Despite repeated confirmation of aspartame safety in a variety of foods and beverages, there continues to be interest in researching the potential carcinogenic risk associated with its consumption. The objective of this evaluation was to conduct a systematic assessment of available mechanistic data using a framework for quantitatively integrating the key characteristics of carcinogens (KCCs). For aspartame, 1332 endpoints were appraised for quality and relevance and quantitatively integrated using an algorithm to determine the potential for individual KCC activity based on all available evidence, and subsequently assessed in the context of human and animal evidence streams. An overall lack of activity (integrated scores <0 and no "strong" categorizations) was observed for all KCCs except oxidative stressor (#5), for which activity was determined to be unlikely to be related to a carcinogenic response. Overall, the KCC-based analysis, together with the lack of consistent evidence of carcinogenicity in experimental animals, continue to support lack of carcinogenicity from aspartame consumption. This comprehensive evaluation of available mechanistic data demonstrates the need for a systematic approach to identify and appraise all avaialble data as part of weight-of-evidence determinations related use of KCC in evaluations of potential human carcinogenicity.

A hypothesis-driven weight-of-evidence analysis to evaluate potential endocrine activity of perfluorohexanoic acid.

Perfluorohexanoic acid (PFHxA) is a potential impurity and environmental degradation product of C6-based fluorotelomer products. Considering the potential endocrine activity of perfluoroalkyl acids, a hypothesis-driven weight-of-evidence (WoE) analysis was conducted to evaluate the potential endocrine disruptor activity of PFHxA, as defined by World Health Organization (WHO), across estrogen (E), androgen (A), thyroid (T), and steroidogenesis (S) pathways. A comprehensive literature search identified primary and secondary studies across species for review. The ToxCast/Tox21 database provided in vitro data. Studies identified were reviewed for reliability, and relevance, with endocrine endpoints ranked, and lines of evidence evaluated across pathways. Overall, PFHxA showed no endocrine effects in Japanese medaka, juvenile rainbow trout, chickens or reproductive parameters in northern bobwhite with no significant activity in rodent repeated-dose toxicity, lifetime cancer, or reproductive and developmental studies. In vitro, there was weak or negative activity for T transport protein or activation of E, A or T receptors. PFHxA was also negative in vitro and in vivo for disrupting steroidogenesis. Based on this WoE endocrine analysis, PFHxA exposure did not cause adverse effects associated with alterations in endocrine activity in these models, as such would not be characterized as an endocrine disruptor according to the WHO definition.

Mouse bone marrow and peripheral blood erythroid cell counts are regulated by different autosomal genetic loci.

Erythropoiesis is under fine control and genetic loci that affect it are likely to be important in a range of conditions. To assess the relative contributions of different genetic loci to parameters of erythropoiesis, we have measured RBC counts in the peripheral circulation and committed erythroid cells (RBC and small normoblasts) in the bone marrow in a cohort of (CBA/H x C57BL/6) F2 mice to map quantitative trait loci (QTL). Candidate genes were assessed using bioinformatics and DNA sequencing. Different autosomal loci affect bone marrow (chromosomes 5, 11 and 19) and peripheral blood (chromosome 4) erythroid cell counts but there may be a common chromosome X locus. Spleen weight QTL were found on chromosomes 3, 15 and 17. Surprisingly, erythropoietin (Epo) is the best candidate quantitative trait gene (QTG) in the chromosome 5 locus that affects bone marrow but not peripheral blood erythroid cell counts. Epo gene expression is known to be genetically regulated in mice, but our data suggest a tissue-specific role for epo in mouse erythropoiesis that is also genetically determined. The identity of the other QTG will be important both to further knowledge of the control of erythropoiesis and as potential modifier genes for haematological disorders.

Hair whorl as an indicator of a mediastinal plexiform neurofibroma.

We report a boy with neurofibromatosis type 1 (NF-1) who had nonspecific respiratory symptoms and a mediastinal mass. In addition to multiple caté au lait macules and subcutaneous neurofibromas, he had a hair whorl over the spine at the level of a deep mediastinal mass demonstrated by CT scan and MR examination. Thoracoscopy and biopsy of the mass revealed a plexiform neurofibroma. The clinical sign of a hair whorl may assist the clinician in early recognition of a paraspinal plexiform neurofibroma.

Primary lymphoma of bone in children.

Primary lymphoma of bone (PLB) occurs infrequently in children. Between January 1962 and November 1988, 395 children with non-Hodgkin's lymphoma (NHL) were treated at St. Jude Children's Research Hospital. Eleven of these patients (2.8%) presented with a bone primary, usually in the femur (eight of 11 patients). The median age of these seven boys and four girls at presentation was 13 years (range, 5.5 to 19 years). Seven patients had one or more additional bones involved. All patients had high-grade lymphomas based on the National Institutes of Health (NIH) Working Formulation. The histologic subtypes included six large-cell lymphomas, three lymphoblastic lymphomas, one small-noncleaved, non-Burkitt's lymphoma, and one unclassifiable lymphoma. Treatment consisted of multiagent chemotherapy combined with local radiation therapy in seven of 11 patients. Six of 10 children who received chemotherapy as a component of their initial therapy, including all who presented with localized tumor, are alive with no evidence of disease 2+ to 85+ months (median, 42.5 months) after cessation of treatment; one patient has just completed chemotherapy. Each of the four patients who died showed leukemic conversion 5 to 11 months after diagnosis, and three died of progressive disease. One patient died of sepsis during chemotherapy-induced neutropenia with no evidence of disease at necropsy. We conclude that optimal therapy for PLB, as with all other forms of NHL, should focus on the histologic subtype and stage of disease.

Significance of pulmonary computed tomography at diagnosis in Wilms' tumor.

Pulmonary lesions were found by computed tomography (CT) despite normal chest roentgenograms (CXR) at diagnosis in 11 of 124 patients with Wilms' tumor. All patients were entered on a treatment protocol at St Jude Children's Research Hospital from 1978 to 1986. The 11 patients all had favorable histology Wilms' tumor. Staging and therapy were based on interpretation of the CXR and abdominal findings. Excluding CT findings, one patient had stage I disease, two stage II, seven stage III, and one stage IV on the basis of multiple liver metastases. Four patients have relapsed: one with stage II and three with stage III. All relapses have been pulmonary. Overall, 4/11 (36%) relapsed. This relapse rate is considerably greater than the 20% overall relapse rate of patients treated according to this protocol though not statistically significant. These relapses suggest that such patients may be at increased risk for pulmonary recurrence. The results also indicate that small lesions initially noted only on CT scans of the chest in children with Wilms' tumor frequently represent metastatic tumor. Further studies of larger numbers of patients will be necessary to confirm these findings.

Diagnostic imaging in children with urinary tract infection: review of current concepts and suggested guidelines.

Symptomatic urinary tract infection (UTI) in childhood is estimated to occur with a frequency of up to 3% through adolescence. The practitioner caring for children requires both anatomic and physiologic information concerning the urinary tract to assist in diagnosis, treatment, and prognosis. Advances in diagnostic imaging have resulted in numerous methods for evaluation of the urinary system. These procedures differ in the type of information obtained, risk or discomfort to the patient, and cost. Selection of the proper test(s) requires an understanding of these factors. Based on our survey of recent pertinent literature and our clinical experience, we present guidelines for appropriate diagnostic imaging in children with UTI, and we discuss the benefits and limitations of available imaging techniques along with concepts regarding the pathogenesis of UTI and causes of renal damage from UTI.

[Glucose-6-phosphate dehydrogenase deficiency. Diagnosis during treatment of a mandibular fracture]. / Déficit en glucose-6-phosphate déshydrogénase. Découverte au cours du traitement d'une fracture mandibulaire.

The authors report a case of a 36 year old black American male, who was operated for a fracture of the mandibular angle. A second surgical procedure was necessary, because of post-operative infectious complications. An hemolytic anemia occurred which was linked to a glucose-6-phosphate dehydrogenase (G6PD) deficiency. Clinical and general aspects of the disease are discussed.

Excretory urography with iohexol: evaluation in children.

A multicenter clinical study was conducted using iohexol, a second-generation nonionic contrast medium, for excretory urography performed in 130 children. Doses of iohexol (300 mg iodine/ml) ranged between 150 and 660 mgI/kg (0.5 and 2.2 ml/kg). Iohexol was tolerated well, and no significant adverse reactions occurred. Sixty-five iohexol urograms were evaluated to determine the minimum dose for adequate visualization of the kidneys and collecting systems. A dose greater than 300 mgI/kg (1.0 ml/kg) always resulted in a urogram of diagnostic quality, while visualization was insufficient for diagnosis in 10% of studies done with doses of 150-300 mgI/kg (0.5-1.0 ml/kg). Another 65 iohexol urograms were compared in a blinded manner with a similar number of studies performed using iothalamate meglumine at comparable iodine concentration and dose. Visualization of calyces and pelvoinfundibular structures achieved with iohexol was rated better with statistical significance, but there was no difference in visualization of the renal parenchyma or ureters. Use of iohexol in excretory urography may be advantageous in children who are at greatest risk for an adverse reaction to contrast media or in those most likely to benefit from use of a low osmolality contrast agent.

Imaging of foregut duplication cysts.

There are many types of diagnostic imaging studies available for the evaluation of foregut duplication cysts. Esophagography may be helpful in confirming the presence of a mediastinal mass, explaining esophageal symptoms, or defining the location of a lesion, but it is rarely diagnostic. Digital subtraction angiography can successfully be used in place of pulmonary arteriography to define vascular anatomy. Computed tomography is often diagnostic, although the attenuation number may be slightly elevated and not that of water. Computed tomography will clarify the relationship of the mass to adjacent mediastinal structures, and may also assist in percutaneous guided aspiration. Surgical resection is often necessary in an infant because of respiratory distress with airway compromise. In asymptomatic patients with a round to oval, nonenhancing, thin walled, cystic mass demonstrated on CT, a thoracotomy may be avoided and the patients may be followed by chest radiography.

Pediatric digital subtraction angiography: intraarterial and intracardiac applications.

Intraarterial digital subtraction angiography (IA-DSA) was performed in 80 pediatric patients. Forty-four underwent arterial injections with digital filming techniques. Of the 130 injections, DSA imaging was good or excellent in 121, often allowing resolution of vessels 1 mm in size. Thirty-six of the 80 patients underwent cardiac evaluation with intra-cardiac injections. Improved contrast resolution with IA-DSA allowed the use of smaller catheters (3-4F) and smaller amounts of contrast material. Immediate availability of subtracted images (no film processing delay) resulted in shorter total procedure time. Outpatient studies are possible. IA-DSA provides several notable advantages for the pediatric patient.

Hyperimmunoglobulinemia E syndrome: pulmonary imaging considerations.

The Hyper IgE syndrome is a rare disease consisting of recurrent sinusitis and pneumonia, pneumatoceles, chronic dermatitis, and elevated serum levels of IgE. The primary radiographic abnormalities are recurrent alveolar lung disease and pneumatoceles. Pneumothorax may occasionally occur as in one of our cases. Other causes of pneumatoceles are usually easily excluded by the history and other clinical data. Pulmonary scintigraphy and computed tomography may add information valuable to the management of these patients.

Invasive gastric candidiasis.

A case of invasive gastric candidiasis is reported. The frequency and importance of Candida sp. as a gastric pathogen is reviewed.

Ultrasonographic features of glomerulocystic disease in infancy: similarity to infantile polycystic kidney disease.

Glomerulocystic kidney disease (GCD) is an unusual condition characterized pathologically by cystic dilatation of Bowman's space and the first portion of the proximal convoluted tubule. We report the serial ultrasound findings in an asymptomatic infant with GCD which were initially confused with infantile polycystic kidney disease. We emphasize the nonspecificity of ultrasonographic findings in cystic renal disease in early infancy and suggest a protocol for the diagnostic work-up of bilateral renal cystic disease in children.

Orthognathic surgery for children. Analysis of 88 consecutive cases.

A retrospective analysis of 88 consecutive pediatric patients who underwent surgical correction of their dentofacial deformities is presented. There were twice as many female as male patients and the most common deformities were of the skeletal Class II type. The LeFort I osteotomy was the most frequently performed operation. The effect of controlled hypotensive anesthesia on the duration of both anesthesia and surgery, estimated blood loss and incidence of transfusion is discussed. Surgery for the correction of dentofacial deformities can be performed on children and adolescent patients with little morbidity and few complications.

Central nervous system hypoxia in children due to near drowning.

Fourteen children who experienced acute, profound central nervous system hypoxia secondary to near drowning, aspiration, or respiratory arrest underwent CT examination. During the first week after the episode, the most frequent finding was a loss of gray-white matter differentiation. Other findings included effacement of sulci and cisterns, focal areas of edema in the cerebral cortex or basal ganglia, and hemorrhagic infarctions of the basal ganglia. Subsequent CT scans obtained from two weeks to five months after the hypoxic episode showed progression of cerebral loss from cortical infarction with gyral hemorrhage and enhancement to global parenchymal atrophy. The prognosis is poor in these patients: seven children experienced severe neurologic deficits and seven died.

Herpes simplex encephalitis: CT findings in the neonate and young infant.

The computed tomographic (CT) findings in six cases of neonatal herpes simplex encephalitis (HSE) are reviewed and compared with previous reports. The diagnoses were made on the basis of isolation of the virus from a brain biopsy specimen in one case, from cerebrospinal fluid in two cases, from tracheal aspirate in one case, and on clinical grounds in two cases. Five infants survived; all had significant neurologic deficits. CT showed bilateral cerebral involvement with relative sparing of the lower neuraxis in all cases. Bilateral patchy low-density zones involving the periventricular white matter more than the cortical gray matter were seen initially in four of the six infants. Hemorrhage and/or calcifications in the thalamus, insular cortex, periventricular white matter, and along the corticomedullary junction were present in five infants. Severe cerebral necrosis eventually resulted in all six infants. Unlike older patients, only one infant had predominantly temporal lobe involvement. These findings agree with the CT descriptions reported by others.