Longitudinal myelitis, aseptic meningitis, and conus medullaris infarction as presenting manifestations of pediatric systemic lupus erythematosus.

A healthy boy developed subacutely progressive quadriparesis, complicated by sudden paraplegia, fever, and meningeal signs, diagnosed as longitudinal myelitis, aseptic meningitis, and conus medullaris infarction and identified as the presenting manifestations of neuropsychiatric systemic lupus erythematosus. Rapid expansion of the conus on serial neuroimaging led to emergent decompressive laminectomy and cord biopsy showing vasculitis and cord infarction. The patient had partial recovery after treatment with high-dose steroids. Increased vigilance is required when pediatric patients develop a similar subacute presentation on the ground of active systemic lupus erythematosus because it may herald the onset of a catastrophic neurological syndrome.

Filamentous influenza A virus infection predisposes mice to fatal septicemia following superinfection with Streptococcus pneumoniae serotype 3.

Previous studies have demonstrated that animals exposed to Streptococcus pneumoniae while recovering from influenza A virus infection exhibit exacerbated disease symptoms. However, many of the current animal models exploring dual viral and bacterial synergistic exacerbations of respiratory disease have utilized mouse-adapted influenza virus and strains of Streptococcus pneumoniae that in themselves are highly lethal to mice. Here we describe a mouse model of bacterial superinfection in which a mild, self-limiting influenza virus infection is followed by mild, self-limiting superinfection with S. pneumoniae serotype 3. S. pneumoniae superinfection results in rapid dissemination of the bacterium from the respiratory tract and systemic spread to all major organs of the mice, resulting in fatal septicemia. This phenomenon in mice was observed in superinfected animals undergoing an active viral infection as well as in mice that had completely cleared the virus 7 to 8 days prior to superinfection. Neutrophils were the predominant cellular inflammatory infiltrate in the lungs of superinfected mice compared to singly infected animals. Among other cytokines and chemokines, the neutrophil activator granulocyte colony-stimulating factor (G-CSF) was found to be significantly overexpressed in the spleens, lungs, and brains of superinfected animals. High G-CSF protein levels were observed in sera and lung lavage fluid from superinfected animals, suggesting that G-CSF is a major contributor to synergistic exacerbation of disease leading to fatal septicemia.

Pediatric renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions and clinicopathologic associations.

Renal cell carcinomas (RCCs) are rare in children and studies of their subtypes and clinicopathologic associations are limited to small series. We identified 8 patients with RCC treated at our institution between 1981 and 2003, reviewed their clinicopathologic features, cytogenetics findings, and evaluated the status of TFE3 expression by immunohistochemistry and numerical chromosomal alterations by interphase fluorescent in situ hybridization on paraffin-embedded tissue. These 8 patients (5 female and 3 male) had diploidy, and 5 had morphologic features compatible with the recently described RCC associated with Xp11.2 translocations/TFE3 gene fusions and demonstrated nuclear labeling for TFE3 protein by immunohistochemistry. The translocation was confirmed in 2 of these 5 patients by conventional cytogenetics. One case was a high-grade nonpapillary RCC and the other was compatible with type 2 papillary RCC. Four patients showed at least 1 chromosomal gain including trisomy 7 and/or trisomy 17. None of the tumors from male patients showed evidence of loss of the Y chromosome, but 2 patients showed numerical abnormalities of X chromosome +add(X). Two patients had sickle cell disease, and 1 of these also had stage IV-S neuroblastoma. This study suggests that many cases of RCC in children reported under the terms "papillary" and "clear cell" likely represent Xp11.2 translocation/TFE3 gene fusion-associated RCC. It also emphasizes the unusual associations of RCC with neuroblastoma and sickle cell hemoglobinopathy, which need further study.

Robot-assisted minimally invasive Kasai portoenterostomy: a survival porcine study.

BACKGROUND: Major enhancements offered by robotic surgery for minimally invasive procedure include tremor filtration, motion scaling, and the addition of a wrist to the instrument. Minor enhancements include indexing as well as safe and rapid instrument exchange. A benefit associated with any endoscopic procedure is magnification. It was hypothesized that these enhancements would allow the performance of complex gastrointestinal surgery. METHODS: Eight survival pigs (weight, 2.5-8 kg) underwent a robotically assisted minimally invasive portoenterostomy. The procedure was analogous to the Kasai portoenterostomy for biliary atresia usually performed for human patients at the age of 4 to 12 weeks. RESULTS: Five of the eight animals survived for more than 1 month after the operation, returning to normal eating and bowel habits in 2 to 3 days. None were jaundiced. All laboratory values were normal. At 1 month, the animals were killed. There was no anastomotic stenosis at either the end-to-side enteroenterostomy or the portoenterostomy. Histologically, the anastomoses were well healed. CONCLUSION: Computer-assisted robot-enhanced technology allows complex gastrointestinal surgery to be performed using minimally invasive techniques.

Spontaneous malignant transformation of human ovarian surface epithelial cells in vitro.

PURPOSE: Epithelial ovarian cancer has no reliable marker for early detection and no known specific premalignant changes. Human ovarian surface epithelial (HOSE) cells expressing human papillomavirus type 16 (HPV-16) E6/E7 genes undergo crisis, and surviving cells exhibit an immortalized phenotype. Cells show an increasingly invasive phenotype on collagen rafts over time. To ascertain the nature of this aberrant growth, we characterized this spontaneous progression of HOSE cells from a benign to an invasive phenotype using histopathology, immunophenotyping, and tumorigenesis assays. EXPERIMENTAL DESIGN: At various passages, cells were monitored for growth on collagen, response to tumor necrosis factor alpha and daunorubicin, immunohistochemistry and Western blot analysis of E-cadherin and beta-catenin, growth in soft agar, and tumor formation in immunodeficient mice. RESULTS: As passage number increased, cells became increasingly aggressive on collagen, with more pronounced focal stratification and invasion. Furthermore, late-passage cells were more resistant to the apoptotic effects of TNF-alpha and daunorubicin than earlier-passage cells. E-cadherin expression was limited to early-passage cells, whereas beta-catenin was expressed regardless of passage. Cells invading collagen formed colonies in soft agar at low efficiency but were not tumorigenic in immunodeficient mice. Some cultures recovered from colonies grew in soft agar at high efficiencies, and one was tumorigenic. CONCLUSIONS: HOSE cells expressing E6/E7, over time, develop characteristics of malignant cells and produce tumors consistent with an ovarian surface epithelium lineage. Progression of HOSE cells from a benign to an invasive phenotype in vitro may provide a model to dissect the progression of ovarian cancer.

Congenital alveolar capillary dysplasia with misalignment of pulmonary veins associated with hypoplastic left heart syndrome.

Three full-term infants died in the first month of life with hypoplastic left heart syndrome (HLH) and persistent pulmonary hypertension (PPH). At postmortem examination, they were found to have alveolar capillary dysplasia with misalignment of pulmonary veins (ACD with MPV). The association of HLH syndrome, and ACD with MPV with intestinal malrotation and/or obstruction, is unique. Decreased blood flow in the ascending aorta in fetuses with left outflow tract obstruction might cause vasoconstriction of pulmonary arterioles to maintain cerebral perfusion. Vasoconstriction early during embryogenesis might lead to decreased growth and development of alveolar capillaries and pulmonary veins. This results in pulmonary hypertension, and the arterial blood is forced to bypass the deficient capillary bed and can drain only via the anomalous bronchial veins.

Human papillomavirus-11-associated recurrent respiratory papillomatosis is more aggressive than human papillomavirus-6-associated disease.

The aim of this study was to determine whether viral type (HPV-6 vs. HPV-11) could predict the clinical course of recurrent respiratory papillomatosis in children. Viral typing, using the polymerase chain reaction, was performed on laryngeal biopsies of 61 patients treated at Children's Hospital of Michigan. HPV-6 was detected in 29 of the patients' biopsies and HPV-11 in 32 biopsies. HPV-11 was more common among the African-American patients than among Caucasians (P = 0.001). Patients with HPV-11 were diagnosed at a younger age (36.2 vs. 48.2 months; P = 0.04) and were more likely to have active disease (P = 0.0311) at the time of this study. They tended to have longer periods of disease activity (8 years vs. 5 years; P = 0.026), required more surgical procedures (42 procedures/patient vs. 13.6; P = 0.02), and more procedures per patient, per year (2.9 vs. 5.3; P = 0.0164). Three of the patients infected with HPV-11 developed invasive papillomatosis and bronchogenic squamous cell carcinoma, and two of these patients died of disease. Our findings suggest that HPV-11 infection confers a more aggressive course to recurrent respiratory papillomatosis.

Granular cell tumor of the bronchus.

Persistent atelectasis and recurrent pneumonia in the same location should raise suspicion of congenital anomalies or obstructing lesions of the bronchus leading to the affected area. We present an 8-year-old black female with a history of recurrent fever, cough, atelectasis of the right middle and lower lobes, and weight loss for several months. Flexible bronchoscopy revealed a polypoid mass obstructing the bronchus intermedius. Biopsy of the neoplasm demonstrated a granular cell tumor (GCT). The patient had a lobectomy of the right lower and middle lobes. She had no recurrence of the tumor after several years of follow-up.

Correlation of endoscopy and histology in the gastroesophageal mucosa in children: are routine biopsies justified?

Guidelines for obtaining biopsies during endoscopy in children are needed. The endoscopic evaluation may be considered deficient on many occasions if not accompanied by a histopathologic evaluation. A retrospective review of our endoscopic records and biopsies was undertaken to determine the correlation of the visualized endoscopic appearance and the histopathologic findings in the upper gastrointestinal (GI) tract in children. Over a 1-year period, 204 patients, all of whom had esophageal biopsies and 59 of whom had gastric biopsies as well, were evaluated by an upper GI endoscopy. Endoscopic findings included erythema, granularity, abnormal vascular pattern, friability, erosions, plaques, ulceration, and strictures. Histologic evaluation of biopsies was undertaken by one pathologist according to the presence of and type of cellular infiltrate and cellular morphologic abnormalities in the mucosa and submucosa where available. In this study, the correlation of endoscopic appearance with histology was rather limited in both the esophagus and the gastric mucosa. Low specificity and sensitivity of endoscopy in both locations (41% and 81% for the esophagus; and 43% and 86% for the gastric mucosa, respectively) illustrated the discrepancy. The overall accuracy of endoscopic evaluation in matching the histologic diagnosis was not more than two out of three (63.8%). No single endoscopic finding had a reliable correlation with histologic diagnosis but some had higher predictive value than others. Of the multiple indications for endoscopy in children, recurrent abdominal pain had the least diagnostic yield. Endoscopic appearance correlates poorly with histologic diagnosis in the gastroesophageal mucosa in children. Regardless of the appearance of the mucosa, routine biopsy during upper GI endoscopy in children should be encouraged.

Diagnosis of Helicobacter pylori infection from antral biopsies in pediatric patients is urease test that reliable?

Our objectives were to determine if the urease (CLO) test alone is a reliable diagnostic test for H. pylori gastritis in children and if the density of H. pylori influences the CLO test result. We performed a combined retrospective and prospective study reviewing the results of CLO-test and histology of gastric mucosal biopsy from 67 patients (35 females) with H. pylori gastritis. Two antral biopsies were inoculated on the CLO-test and two processed for histology to grade the severity of gastritis and H. pylori density. The mean age of patients was 11 years (SD +/- 4.53). Only 50 patients tested positive for H. pylori on CLO-test, whereas all patients were positive on histology. The sensitivity of the CLO-test was 75%. There was a significant association between CLO-test positivity and the density of H. pylori organisms on histology (P < 0.01), and with the severity of gastritis (P < 0.001) by the Pearson chi-square test. However, there was no association between the density of H. pylori and severity of gastritis. In conclusion, the CLO-test is not reliable as a sole diagnostic test for H. pylori gastritis in children because of a significant number of false negatives. Histologic examination of gastric mucosal biopsy is superior to the CLO-test in diagnosing H. pylori infection.

Human papillomavirus type, proliferative activity, and p53: potential markers of aggressive papillomatosis.

CONTEXT: The predictive value of nuclear proliferation antigen (Ki-67), tumor suppressor gene product p53, and human papillomavirus type has not been evaluated for outcome of laryngeal papilloma. OBJECTIVE: This study was designed to determine whether immunohistochemical analysis of Ki-67 and p53 and human papillomavirus typing by polymerase chain reaction are able to identify patients with a more aggressive course of laryngeal papillomatosis. DESIGN: Immunohistochemistry and polymerase chain reaction were performed on archival, paraffin-embedded, laryngeal papillomatosis biopsy specimens at the time of diagnosis, at an intermediate time during treatment, and at the last procedure available. Staining indexes for Ki-67 and p53 were determined, and human papillomavirus type was analyzed for all biopsies. PATIENTS: Twelve patients with recurrent laryngeal papillomatosis for at least 5 years were selected from patients treated at our institution during the last 20 years. MAIN OUTCOME MEASURES: Separate analyses were conducted comparing average Ki-67 and p53 indexes against disease outcome, viral type, or average number of procedures per year. Associations were analyzed between virus type, average number of procedures per year, outcome, and histology. RESULTS: No statistically significant associations were noted in Ki-67 or p53 indexes and outcome. Weak associations were noted for p53 indexes and procedures per year and virus type. Weak associations also were noted between virus type and development of neoplasia. CONCLUSIONS: Our observations suggest that human papillomavirus typing may be helpful in identifying patients with aggressive recurrent laryngeal papillomatosis. The weak association between p53 indexes and procedures per year and virus type may have some predictive value in identifying aggressive lesions.

A prospective trial of lansoprazole triple therapy for pediatric Helicobacter pylori infection.

BACKGROUND: Triple therapy with a proton-pump inhibitor and two antibiotics is widely used in the treatment of Helicobacter pylori infection in adults. Experience with such therapy in the pediatric population is limited. This was a prospective, nonrandomized, open-label trial to evaluate safety and efficacy of a combination of lansoprazole, clarithromycin, and amoxicillin in symptomatic children with H. pylori infection. METHODS: Children with H. pylori gastritis diagnosed by endoscopy performed for persistent nausea, vomiting, recurrent abdominal pain, and diarrhea with consistent histology were treated with the regimen of 0.45 mg/kg per day lansoprazole divided into two doses (maximum dose, 15 mg twice daily), amoxicillin 40 mg/kg per day in two doses (maximum dose, 1.0 g twice daily), and 250 mg clarithromycin twice daily (<10 years old) or 500 mg twice daily (>10 years old) for 2 weeks. Pre- and posttreatment endoscopic biopsy specimens were graded for the severity of gastritis and H. pylori density by a blinded pathologist. A questionnaire for assessing the severity of symptoms at the time of initial and second endoscopy were completed by patient and/or parent. RESULTS: Thirty-two children (age range, 1-25 years; mean age, 11 years; 19 females, 13 males) were treated with this regimen during an 18-month period. H. pylori organisms with varying grades of gastritis were present in tissue specimens of all patients. Only 28 children had follow-up endoscopy, which showed eradication of H. pylori in 15 (54%) children. Histologic symptoms of gastritis improved after therapy in the whole group. Overall, symptoms of vomiting, abdominal pain, diarrhea, anorexia, and halitosis significantly improved (P < 0.05). Minor adverse effects of therapy occurred in 25% of patients. CONCLUSIONS: Symptoms, histologic, and endoscopic findings improved after triple therapy in children with H. pylori gastritis; however, eradication of bacteria was achieved in only 56% of children.

Hepatic pulmonary fusion in neonates.

OBJECTIVE: This report discusses the relationship of supradiaphragmatic hepatic tissue that is fused to the lung (through a diaphragmatic defect) with pulmonary hypoplasia-a new constellation of findings. CONCLUSION: Hepatic pulmonary fusion should be suspected in instances of apparent diaphragmatic hernia characterized by mediastinal shift towards the hypoplastic lung or when the mediastinum does not shift away from the mass.

Blau syndrome (familial granulomatous arthritis, iritis, and rash) in an african-american family.

Blau syndrome (familial granulomatous arthritis, iritis, and rash) was originally described in 1985, in 11 members of a family of Dutch ancestry. Inheritance is autosomal dominant. Several more Caucasian families have been described since. Skin and synovial biopsy specimens show noncaseating sarcoid like granulomas, but the lung is not involved as in classic sarcoidosis. This report describes 3 members of an African American family with Blau syndrome. It is important to differentiate this genetic disorder from other childhood arthritides, such as, juvenile rheumatoid arthritis, juvenile spondyloarthropathies, and early-onset sarcoidosis, because of the need for genetic counseling, treatment and differing potential for selective involvement of other organs (eye, skin, and tendons/joints). All children of an affected individual have a 50% chance of inheriting the disease. Unaffected children do not have to be concerned about subsequent generations being affected. The response to conventional treatments used in juvenile rheumatoid arthritis and to etanercept in our patients has not been satisfactory. Joint disease responds to corticosteroids, but these agents are not suitable for a disease that is lifelong. The eye involvement is aggressive and can lead to blindness. These patients need close follow-up by an ophthalmologist.

Altered cardiac histology following apical right ventricular pacing in patients with congenital atrioventricular block.

Previous studies have demonstrated that right ventricular apical pacing inherently alters ventricular contraction, regional blood flow, wall stress, and predisposes to diminished function. However, histological consequences of chronic apical pacing potentially contributing to the observed ventricular dysfunction remain conjectural. Previous canine studies have demonstrated histopathological cellular abnormalities with apically initiated ventricular pacing that may result in the observed diminished ventricular function. To determine if comparable adverse changes also occur in the clinical setting, 16 endomyocardial biopsies were obtained from 14 age-matched patients with congenital complete atrioventricular block (CCAVB) and otherwise normal anatomy, divided into two groups: eight biopsies (median patient age 15.5 years) from patients prior to pacemaker implant and another eight biopsies (median patient age 16 years) from patients following 3-12 years (median 5.5) of chronic ventricular pacing. In one patient, biopsy samples were obtained before and after pacing. Results demonstrated a significant (P<0.05) increase in histopathological alterations among the patient biopsy samples following pacing, consisting of myofiber size variation, fibrosis, fat deposition, sclerosis, and mitochondrial morphological changes. These findings indicate that chronic apical right heart ventricular pacing may adversely alter myocellular growth, especially among the young, on the cellular and subcellular level, potentially contributing to the diminished function observed clinically.

Increased colonic ornithine decarboxylase activity in inflammatory bowel disease in children.

The risk of colorectal carcinoma is increased in pediatric-onset inflammatory bowel disease (IBD). There is little information available regarding the colonic mucosal proliferative state in children with IBD. The aim of this study was to assess colonic ornithine decarboxylase (ODC) activity, a marker of cell proliferation, in pediatric IBD patients. ODC activity was assessed in colonic mucosa from 23 children (7 with ulcerative colitis, 9 with Crohn's disease, and 7 controls) undergoing colonoscopic examination. ODC activities were then compared with degree of inflammation of biopsied samples. ODC activities in patients with and without corticosteroid treatment were also analyzed. The mucosal ODC activities of sigmoid colon and rectum were significantly higher (2.5- to 4-fold) in both ulcerative colitis and Crohn's disease. The higher ODC activity was associated with increased mucosal inflammation. Moreover, treatment with corticosteroids decreased the ODC activity. In conclusion, using ODC activities as a marker of cell proliferation, our results suggest that there is a higher colonic mucosal proliferative state in children with IBD. The increased ODC activities were associated with increased colonic mucosal inflammation. Colonic mucosal ODC activity may provide an additional parameter to access the therapeutic efficacy of corticosteroid treatment in pediatric IBD patients.

Generalized infantile myofibromatosis in a patient with Turner's syndrome: a trial of interferon-alpha.

A patient with Turner's syndrome was found to have generalized infantile myofibromatosis with visceral involvement at birth. The infant was treated with interferon-alpha because of the size of the lesions. Two months after treatment, the lesions appeared to have decreased in size and showed evidence of maturation with decreased apoptosis on histologic examination. Interferon-alpha treatment might induce regression of myofibromatosis.

Arteritis and fatal subarachnoid hemorrhage complicating occult Candida meningitis: unusual presentation in pediatric acquired immunodeficiency syndrome.

We report the case of an 11-month-old child with acquired immunodeficiency syndrome, who despite treatment for systemic candidiasis developed undetected Candida meningitis. This uncommon manifestation of candidiasis was accompanied by basilar granulomatous inflammation and fibrosis of meninges with arteritis, vascular invasion by fungi, and terminal subarachold hemorrhage. To our knowledge, this constellation of findings has not been reported previously in pediatric acquired immunodeficiency syndrome.

Organotypic culture of human ovarian surface epithelial cells: a potential model for ovarian carcinogenesis.

The objective of this work was to establish an in vitro multidimensional culture system for human ovarian surface epithelial (HOSE) cells as a model for ovarian carcinogenesis. The epithelial origin of cell outgrowth from cells obtained from the ovarian surface was confirmed by keratin staining. Two cultures from two different patients were established, HOSE-A and HOSE-B. Cultures were infected with a retrovirus expressing human papillomavirus genes E6 and E7 to extend their life span. HOSE cells were seeded onto collagen gels containing NIH3T3-J2 fibroblasts as feeder cells and grown to confluence submerged in growth medium. The collagen bed was then raised to the air-medium interface for 7 d (organotypic culture). Microscopically, fixed cultures revealed a single layer of flat cells growing on the collagen surface, reminiscent of HOSE cells in vivo. Infected HOSE-A and HOSE-B cells exhibited aberrant growth because they stratified. In addition, established ovarian cancer lines grown in this fashion stratified and showed malignant phenotypes. Thus, cells grown in organotypic culture resemble their in vivo counterparts, providing a basis for establishing a system to study growth, proliferation, differential gene expression, and perhaps malignant transformation of HOSE cells.