Sara Szabo

Cellular Inflammatory Infiltrate in Pneumonitis Induced by a Single Moderate Dose of Thoracic X Radiation in Rats

Abstract The goal of these studies was to characterize the infiltrating inflammatory cells during pneumonitis caused by moderate doses of radiation. Two groups of male rats (WAG/RijCmcr, 8 weeks old) were treated with single 10- or 15-Gy doses of thoracic X radiation; a third group of age-matched animals served as controls. Only 25% rats survived the 15-Gy dose. Bronchoalveolar lavage fluid and whole lung mounts were subjected to cytological and histological evaluation after 8 weeks for distribution of resident macrophages, neutrophils, lymphocytes and mast cells. There was a modest increase in airway and airspace-associated neutrophils in lungs from rats receiving 15 Gy. Mast cells (detected by immunohistochemistry for tryptase) increased over 70% with 10 Gy and over 13-fold after 15 Gy, with considerable leakage of tryptase into blood vessels and airways. Circulating levels of eight inflammatory cytokines were not altered after 10 Gy but appeared to decrease after 15 Gy. In summary, there were only modest increases in cellular inflammatory infiltrate during pneumonitis after a non-lethal dose of 10 Gy, but there was a dramatic rise in mast cell infiltration after 15 Gy, suggesting that circulating levels of mast cell products may be useful markers of severe pneumonitis.

Recognition of Smith–Lemli–Opitz syndrome (RSH) in the fetus: Utility of ultrasonography and biochemical analysis in pregnancies with low maternal serum estriol

Smith–Lemli–Opitz syndrome (SLOS), or RSH, is an autosomal recessive disorder caused by mutations of the gene encoding 7‐dehydrocholesterol reductase (DHCR7). The utility of maternal serum screens and ultrasound as prenatal screening methods for SLOS is presently undetermined. We report the clinical, cytogenetic, biochemical, and molecular findings of a stillborn with SLOS. The diagnosis was made postnatally on the basis of physical findings and confirmed by biochemical and DNA analyses of fetal tissue. Although abnormalities were detected by maternal serum triple screen and prenatal ultrasonography, a diagnosis of SLOS was not suspected before delivery. This study demonstrates that patients with SLOS may escape prenatal diagnosis despite the presence of multiple anomalies and abnormal maternal serum screen results, and lends support for consideration of prenatal biochemical testing for SLOS in pregnancies with these findings. As SLOS is a severe autosomal recessive disorder with a recurrence risk of 25%, ultrasonographic, cytogenetic, and biochemical analyses in the second trimester should be considered if abnormal maternal serum screening results, specifically low levels of unconjugated estriol, are detected.

Prevalence of Dysplasia in Juvenile-Onset Recurrent Respiratory Papillomatosis

OBJECTIVES To quantify the prevalence of dysplasia and to evaluate the impact of use of cidofovir in recurrent respiratory papilloma biopsy specimens obtained from a pediatric population. DESIGN Retrospective review of patient medical records and histopathologic test results from January 1, 1998, through December 31, 2008. SETTING Childrens Hospital of Wisconsin. PATIENTS Patients with a history of operation treated for recurrent respiratory papillomatosis. MAIN OUTCOME MEASURES The presence or absence of dysplasia identified in a papilloma specimen and patient characteristics, such as age of initial presentation, number of operations, tobacco exposure, treatment for reflux, and use of cidofovir, were quantified. RESULTS Treatment for recurrent respiratory papillomatosis was identified in 21 patients. Age at initial diagnosis ranged from 8 months to 14 years. A total of 123 recurrent respiratory papillomatosis specimens in 20 patients were identified. Dysplasia was seen in less than 1% of samples (1/123), which represents 5% of total patients. Seven patients (35%) received cidofovir treatment and none of them developed dysplasia. These data demonstrate a lack of correlation between cidofovir treatment and dysplasia, with the P value being nonsignificant (Fisher exact test, P=.4). CONCLUSION Dysplasia is a rare event in pediatric recurrent respiratory papillomatosis, and there does not appear to be an association between the use of cidofovir and dysplastic changes.

Significant Morbidity and Mortality Attributable to Rothia Mucilaginosa Infections in Children with Hematological Malignancies or Following Hematopoietic Stem Cell Transplantation

Rothia mucilaginosa is a gram-positive coccus that poses a diagnostic challenge and often requires DNA pyrosequencing for diagnosis as it can be easily mistaken for coagulase-negative staphylococci on initial culture results. While it is often times normal human oral and upper respiratory tract microbiota, it can be a virulent pathogen in immunocompromised patients. Most commonly, it causes bacteremia (catheter and non-catheter related) and meningitis in these patients. Our objective was to report the incidence of R. mucilaginosa infections in neutropenic children with hematological malignancies or following hematopoietic stem cell transplantation at a major childrens hospital. We report 11 patients in this cohort who developed clinically significant R. mucilaginosa infections, including three deaths directly attributable to this microorganism. Three patients developed significant neurological involvement, accounting for two of the deaths, and one patient died of disseminated infection. Except for one, all patients had severe neutropenia, central line catheters, and mucosal breakdown at the time of infection. Patients who succumbed never achieved neutrophil recovery. In conclusion, R. mucilaginosa can lead to life-threatening infections in immunocompromised hosts, especially in profoundly neutropenic patients.

Nogo-B receptor deficiency causes cerebral vasculature defects during embryonic development in mice.

Nogo-B receptor (NgBR) was identified as a receptor specific for Nogo-B. Our previous work has shown that Nogo-B and its receptor (NgBR) are essential for chemotaxis and morphogenesis of endothelial cells in vitro and intersomitic vessel formation via Akt pathway in zebrafish. Here, we further demonstrated the roles of NgBR in regulating vasculature development in mouse embryo and primitive blood vessel formation in embryoid body culture systems, respectively. Our results showed that NgBR homozygous knockout mice are embryonically lethal at E7.5 or earlier, and Tie2Cre-mediated endothelial cell-specific NgBR knockout (NgBR ecKO) mice die at E11.5 and have severe blood vessel assembly defects in embryo. In addition, mutant embryos exhibit dilation of cerebral blood vessel, resulting in thin-walled endothelial caverns. The similar vascular defects also were detected in Cdh5(PAC)-CreERT2 NgBR inducible ecKO mice. Murine NgBR gene-targeting embryonic stem cells (ESC) were generated by homologous recombination approaches. Homozygous knockout of NgBR in ESC results in cell apoptosis. Heterozygous knockout of NgBR does not affect ESC cell survival, but reduces the formation and branching of primitive blood vessels in embryoid body culture systems. Mechanistically, NgBR knockdown not only decreases both Nogo-B and VEGF-stimulated endothelial cell migration by abolishing Akt phosphorylation, but also decreases the expression of CCM1 and CCM2 proteins. Furthermore, we performed immunofluorescence (IF) staining of NgBR in human cerebral cavernous malformation patient tissue sections. The quantitative analysis results showed that NgBR expression levels in CD31 positive endothelial cells is significantly decreased in patient tissue sections. These results suggest that NgBR may be one of important genes coordinating the cerebral vasculature development.

X-linked Hyper IgM Syndrome Presenting as Pulmonary Alveolar Proteinosis.

PurposeX-linked hyper IgM syndrome (XHIGM) is a combined immunodeficiency caused by mutations in the CD40 ligand (CD40L) gene that typically results in decreased or absent CD40L expression on activated T cells, leading to defective class switching and somatic hypermutation. We describe an infant who presented with respiratory failure due to pulmonary alveolar proteinosis (PAP) with a novel damaging missense mutation in the CD40L gene.MethodsWhole exome sequencing (WES) was used to identify a mutation in the CD40L gene. CD40L expression and function were determined by flow cytometry.ResultsA 5-month-old previously-healthy male presented with respiratory failure and diffuse pulmonary ground glass opacities on CT scan of the chest. Laboratory evaluation revealed an undetectable IgG, normal IgA, and elevated IgM. A bronchoalveolar lavage demonstrated pulmonary alveolar proteinosis. WES demonstrated a c.608G > C mutation in the CD40L gene resulting in p.R203T. Flow cytometry demonstrated normal CD40L expression on activated T cells but absent binding of CD40-Ig to CD40L on activated patient T cells.ConclusionsThe clinical manifestations of XHIGM in our patient had several unique features, including the presentation with PAP, normal serum IgA, and expression of non-functional CD40L on activated T cells. To our knowledge, this is the first published case of PAP in a patient with XHIGM.

Superficial hemosiderotic lymphovascular malformation (hobnail hemangioma): a report of six cases.

Hobnail hemangioma (HH), initially termed targetoid hemosiderotic hemangioma, is a rare, often solitary lesion classically characterized by a central brown or violaceous papulonodule surrounded at times by an ecchymotic halo. This lesion is typically found on the trunk or limbs of children or young to middle‐aged adults. Numerous case reports have found HHs to have a reproducible histologic appearance. Although the exact histogenesis of these lesions is unknown, multiple recent immunohistochemical studies suggest a lymphatic origin of these lesions. We present six cases of children with HHs with classic histology but with variability in their clinical appearance. Because the clinical presence of a targetoid halo is inconsistent and the hobnail phenomenon is not specific, we favor the designation of superficial hemosiderotic lymphovascular malformation instead of HH or targetoid hemosiderotic hemangioma as a more unifying term for this rare clinical entity. By eliminating confounding terminologies (in this case, incorporation of “hemangioma” in the name of this entity), we also hope to encourage a swifter change in practice to move away from erroneous diagnostic considerations.

Heterotopic salivary tissue

Salivary tissue can be present in the head and neck outside the usual locations of the major and minor salivary glands. This can be in the form of accessory salivary glands, in association with branchial cleft anomalies, or, less commonly, as heterotopic salivary gland tissue (HSGT). Heterotopic salivary gland tissue is defined as salivary tissue outside of the expected locations of major, minor, and accessory salivary glands with absence of clinical or histologic features of branchial cleft anomalies. Here we present the case of a 13-year-old girl who presented with a draining sinus of the lower neck, which was excised and, on histologic analysis, was consistent with HSGT. We include photographs and histologic images. A review of the literature on heterotopic salivary tissue in the neck is then presented including discussion of the presentation, clinical features, important considerations, and recommendations for management.

Histopathology and Pathogenesis of Vascular Tumors and Malformations

Accurate histopathological description combined with knowledgeable clinical and radiological evaluation is an absolute requisite for both study and meaningful diagnosis of vascular anomalies, both neoplastic and malformative. Unfortunately, traditional over-generic use of the hemangioma has caused inappropriate lumping of entities that we now know are both biologically as well as clinically dissimilar. This chapter provides an overview of the current clinical, histological, and immunophenotypical features that distinguish the major types of vascular tumors and malformations presenting in infancy and childhood, and summarizes the diagnostic histopathological criteria and nomenclature currently applied to these lesions in most major vascular anomalies centers around the world. The classification presented is congruent with the latest (2014) guidelines of the International Society for the Study of Vascular Anomalies. A general discussion of pathogenesis is also included for most entities, providing correlation between clinical, epidemiological, histo-immunophenotypic, and, for many, genetic features.

Autoimmune Hepatitis in a Child With Chronic Hepatitis B Virus Infection

Chronic hepatitis B virus (HBV) infection is a major health problem affecting 400 million people around the world. An estimated 200,000 new cases of HBV occur annually, and 1 to 1.25 million people are infected with chronic hepatitis B virus in the United States (1). Vertically transmitted HBV is rare in the United States and Western Europe but common in Asia and Eastern Europe. About 90% of children with vertically transmitted HBV infection become chronic carriers (2). At least 20% to 30% of carriers die from complications of cirrhosis and hepatocellular carcinoma (HCC) (3,4). Autoimmune hepatitis (AIH) is a rare disease in children, with a frequency of 11% to 23% among children with chronic liver disease (5). AIH accounts for about 6% of liver transplantations in the United States. Without treatment, approximately 50% of adult patients with severe AIH die in 5 years; children with treatment have a favorable long-term outcome, with a transplantfree survival rate of 90% over a 10-year follow-up period (6). A number of viruses have been implicated in the pathogenesis of AIH such as hepatitis A and Epstein-Barr virus (7,8). Coexistence of HBV and AIH has rarely been reported in children (9). We report a 7-year-old girl with vertically transmitted HBV infection and AIH who responded to a combination of immunosuppression and antiviral therapy and discuss the management strategies of this rare cooccurrence.