Glomerular sclerosis in kidneys with congenital nephrotic syndrome (NPHS1).

Congenital nephrotic syndrome of the Finnish type (NPHS1) is a rare genetic disease caused by mutations in the NPHS1 gene encoding a major podocyte slit-diaphragm protein, nephrin. Patients with NPHS1 have severe nephrotic syndrome from birth and develop renal fibrosis in early childhood. In this work, we studied the development of glomerular sclerosis in kidneys removed from 4- to 44-month-old NPHS1 patients. The pathological lesions and expression of glomerular cell markers were studied in nephrectomized NPHS1 and control kidneys using light and electron microscopy and immunohistochemistry. An analysis of 1528 glomeruli from 20 patients revealed progressive mesangial sclerosis and capillary obliteration. Although few inflammatory cells were detected in the mesangial area, paraglomerular inflammation and fibrosis was common. The podocytes showed severe ultrastructural changes and hypertrophy with the upregulation of cyclins A and D1. Podocyte proliferation, however, was rare. Apoptosis was hardly detected and the expression of antiapoptotic B-cell lymphoma-2 and proapoptotic p53 were comparable to controls. Moderate amounts of podocytes were secreted into the urine of NPHS1 patients. Shrinkage of the glomerular tuft was common, whereas occlusion of tubular opening or protrusion of the glomerular tuft into subepithelial space or through the Bowman's capsule were not detected. The results indicate that, in NPHS1 kidneys, the damaged podocytes induce progressive mesangial expansion and capillary obliteration. Podocyte depletion, glomerular tuft adhesion, and misdirected filtration, however, seem to play a minor role in the nephron destruction.

Consistent expression of HGF and c-met in the perinatal lung.

BACKGROUND: Hepatocyte growth factor (HGF), an epithelial cell mitogen, has been shown to participate in normal lung development and in regeneration after lung injury. In human preterm infants, lower pulmonary HGF has been associated with more severe respiratory disease. OBJECTIVES: We studied the protein expression of HGF and its receptor c-met during the perinatal period in the human lung. METHODS: Immunohistochemistry for HGF and c-met was performed on lung tissues from autopsies of 4 fetuses, 5 preterm infants, 5 term infants, and 4 infants with bronchopulmonary dysplasia. RESULTS: Immunohistochemistry for HGF showed staining in all cases in mesenchymal cells (fibroblasts and cartilage cells). Additional staining was found in bronchial and distal airway epithelium. Immunohistochemistry for c-met showed staining in bronchial and distal airway epithelium, and in most cases in neutrophils. CONCLUSIONS: The consistent expression of HGF and c-met during the perinatal period supports a physiological role for HGF in human lung development.

Increased cell turnover, but no signs of increased T-cell infiltration or inflammatory cytokines in the duodenum of pediatric patients after allogeneic stem cell transplantation.

Intestinal immunopathology was studied after allogeneic stem cell transplantation (SCT) in a common clinical setup in 20 children with malignant (n=17) or nonmalignant diseases (n=3) receiving grafts from siblings (7) and unrelated donors (13). In all, 19 had total body irradiation. Duodenal biopsies at 6 and 12 weeks post transplant were evaluated by histology, immunohistochemistry, and ISEL for the detection of T-lymphocytes, inflammatory cytokines, proliferation, and apoptosis. The controls were 12 healthy children and three patients with proven intestinal graft-versus-host disease. An increased rate of apoptosis and proliferation with upregulated expression of HLA-DR antigen was detected up to 3 months post transplant in the SCT patients, even in those with a histologically normal small intestine. A low level of IFNgamma and TNFalpha was observed in the lamina propria. The initial low density of gammadelta-positive T cells had recovered to normal by the time of the second endoscopy at 12 weeks post transplant. We conclude that inflammatory activity and T cell infiltration detected by immunohistochemistry may not belong to the 'normal' recovery of the small intestine after SCT. Increased cell turnover in the intestinal crypts continues until 3 months after SCT, suggesting either an unexpectedly long-lasting effect of transplant-related toxicity or, preferably, an ongoing subclinical alloreactive process, also present in the patients without intestinal symptoms.

Sudden death associated with a multifocal type II hemangioendothelioma of the liver in a 3-month-old infant.

Sudden unexpected death in an infant caused by or associated with neoplasm is rare. We describe a case of a sudden death in an apparently healthy 3-month-old female, in which the autopsy revealed a multiple type II infantile hepatic hemangioendothelioma (IHE). This uncommon tumor has, untreated, a relatively high mortality rate, mainly due cardiac failure resulting from massive arteriovenous shunts, but the association with sudden infant death is very rare.

Alpha/beta intraepithelial lymphocytes, serum gliadin antibodies and allergy test positivity in children.

AIM: To determine whether the amount of alphabeta-positive intraepithelial lymphocytes (IELs) is connected to allergy test positivity in children with gastrointestinal symptoms and whether elevated serum gliadin antibodies have any role in the diagnosis. METHODS: Twenty-seven children suffering from gastrointestinal-symptoms in whom intestinal biopsies had previously been obtained via endoscopy or with capsule biopsy to exclude coeliac disease were included into the study. The other inclusion criteria were increased amounts of CD3 and alphabeta-positive IELs with normal amounts of gammadelta-positive IELs in duodenal or jejunal biopsy specimens. At the control visit, the children underwent a physical examination and parents filled in a questionnaire concerning gastrointestinal- and atopic symptoms. Skin prick- and patch tests were done and serum gliadin, endomysium, transglutaminase antibodies and specific IgEs were measured. RESULTS: Only nine children (33%) had at least one positive result in the allergy tests, the rest remaining test negative. In children with digestive symptoms, IgG-class gliadin antibody titres were higher than those of the non-symptomatic children. A significant correlation was found between IgG-class gliadin antibodies and total amount of alphabeta-positive IELs (p = 0.017). CONCLUSION: No positive skin test or specific IgE positivity for cereals in children with high intestinal T-cell densities was observed. The correlation between IgG-class gliadin antibodies and the total amount of alphabeta-TCR positive-cells is likely to be a reflection of local immune response of the gut.

The natural course of gastroesophageal reflux disease in children.

BACKGROUND: The consequences of chronic gastroesophageal reflux disease (GERD) starting in childhood have not been widely studied. Our aim was to evaluate the usefulness of endoscopy in the primary diagnosis of GERD and to investigate the long-term course of this disease in children. METHODS: Between 1989 and 1999, 136 children had been endoscoped because of persisting symptoms of GER. After exclusions (neurological impairment, infant GER), 96 subjects were included, and files from 76 were available for the final evaluation. Twenty-four hour pH-monitoring had been performed primarily on 67 children and at follow-up on 28, and endoscopy to 69 subjects and at follow-up to 33, respectively. Medical therapy as well as symptoms prior to the therapy were registered. Clinical outcome was assessed at the end of the follow-up period. RESULTS: Presenting symptoms were recurrent abdominal pain, heartburn, regurgitation and vomiting. Twenty-two patients had respiratory symptoms in addition to the gastrointestinal complaints. PH-recording was normal in 17/67 subjects, slightly pathological in 33 and severe reflux was diagnosed in 13 patients. Histologically, minimal changes associated with GER were diagnosed in 22 and mild esophagitis in 7. Thirty-six patients had been treated with prokinetic drugs. H2-blockers had been used in 24 children and proton-pump inhibitors in 4. After a mean follow-up period of 28 months, only 24% of patients had become symptom-free. Control endoscopy showed no progression of the esophageal inflammation in any of the subjects. CONCLUSIONS: Pathological reflux in children is associated with no or mild esophageal inflammation, which is unlikely to deteriorate. Therefore endoscopic control could be limited to cases with severe esophagitis.

Gastroesophageal endoscopic findings and gastrointestinal symptoms in preterm neonates with and without perinatal indomethacin exposure.

BACKGROUND: The aim of this study was to investigate whether perinatal indomethacin treatment has effects on the development of esophageal and gastric lesions in preterm infants and to evaluate other potential etiologic factors behind these lesions. METHODS: Sixty-nine infants were born at less than 33 weeks' gestation. Forty-five of these infants underwent treatment with perinatal indomethacin (study group) and 24 did not (control group). All underwent upper gastrointestinal tract endoscopy and biopsy during the neonatal period. The correlation between gastrointestinal symptoms, abnormal endoscopic findings, and the factors correlating with the development of esophageal and gastric mucosal lesions was evaluated. RESULTS: Abnormal endoscopic findings were equally common in the study group (77.8%) and in controls (83.3%). There was no dependence between gastrointestinal symptoms and endoscopic findings because only 15 infants (21.7%) were symptomatic before endoscopy. The interval between endoscopy and the last perinatal indomethacin dose correlated significantly with abnormal esophageal findings and gastric mucosal lesions. Shorter duration of enteral feeding before endoscopy correlated with greater risk of abnormal esophageal findings. Older gestational age and need of ventilator treatment at the time of endoscopy remained the risk factors associated with abnormal gastric findings. CONCLUSIONS: Esophageal and gastric lesions diagnosed by endoscopy correlate poorly with the gastrointestinal symptoms of patients. Short duration of enteral feeding seems to be correlated with an increased risk of esophageal mucosal lesions, increasing gestational age and ventilator treatment with gastric mucosal lesions, and perinatal indomethacin with esophageal and gastric mucosal lesions in preterm infants. Ventilator-treated preterm infants not receiving enteral nutrition and patients with indomethacin exposure might benefit from ulcer prophylaxis.

Castleman's disease of the mesentery in a child: a case of seven years' duration without typical X-ray findings.

This report describes a 9-year-old boy with intermediate variant type of giant lymph node hyperplasia or Castleman's disease (CD) originating from the mesentery. He had symptoms and signs related to the disease for seven years before the final diagnosis. The patient's general condition remained good, except for periods of fever and abdominal pain. Pallor and slow growth were the only abnormal findings on physical examination during the follow-up. Laboratory measurements showed worsening microcytic anemia, low serum iron level, and low iron stores in bone marrow samples. The erythrocyte sedimentation rate (ESR) increased to 110 mm/h, and the serum levels of C-reactive protein varied between 80 and 120 mg/l. The level of serum albumin was low, 25-28 g/l, and serum immunoglobulin G was somewhat elevated, varying between 17-13 g/l. The radiologic examination of intenstine gave pathological results suggesting a small bowel disease, but no tumor was detected. The abnormal laboratory values and symptoms of the patient resolved completely after surgical removal of the mass.

A randomized, controlled study of prophylactic ranitidine in preventing stress-induced gastric mucosal lesions in neonatal intensive care unit patients.

OBJECTIVE: To assess endoscopically the effect of prophylactic short-term ranitidine treatment in the prevention of stress-induced gastric lesions in neonatal intensive care unit (ICU) patients. DESIGN: Prospective, randomized study. SETTING: Department of Neonatal Intensive Care, University Hospital of Tampere. PATIENTS: Fifty-three infants were enrolled in a randomized, controlled study. Forty-eight (90%) of these patients underwent endoscopic examination and were evaluated. INTERVENTIONS: A histamine-2-receptor blocker, ranitidine, was given prophylactically after birth for 4 days to infants mechanically ventilated and treated in the neonatal ICU. The gastric mucosa was both visually and histologically evaluated after 3 to 6 days, and the outcome of the infants was registered. MEASUREMENTS AND MAIN RESULTS: In the 23 infants prophylactically treated with ranitidine, the gastric mucosa was visually classified as normal in 14 (61%) infants as compared with five (20%) of 25 controls (p < .004). Histologic lesions showed parallel results (57% vs. 16%, p < .004). Eight gastric ulcers were diagnosed endoscopically in the control group vs. none in the treatment group. The ulcers were all clinically "silent" at the time of endoscopy. According to logistic regression modeling, the decreased risk for gastric mucosal lesions in infants receiving prophylactic ranitidine was 0.03 (95% confidence interval 0.003 to 0.178). Surfactant treatment for infant respiratory distress syndrome also decreased the risk for stress-induced gastric mucosal lesions (odds ratio 0.083; 95% confidence interval 0.009 to 0.788), whereas other variables (birth weight, gestational age, Apgar scores, cord blood pH, and duration of intubation) had no significant effect. No side effects could be attributed to the ranitidine treatment. CONCLUSION: We conclude that short-term prophylactic ranitidine treatment prevents gastric mucosal lesions in newborn infants under stress.

Enhanced absorption of macromolecules. A secondary factor in Crohn's disease.

We explored the function of the intestine's mucosal barrier to foreign antigen entry in Crohn's disease. Macroscopically and microscopically uninvolved areas of the small intestines of patients with Crohn's disease were examined. We studied 27 endoscopic biopsy samples from 17 patients with Crohn's disease and 14 samples from nine controls. The absorption and degradation of horseradish peroxidase (molecular weight 40,000 Da) were studied in Ussing chambers. The absorption of intact horseradish peroxidase was significantly increased in patients with moderate or severe Crohn's disease: 271 (95% confidence interval 119-616) ng/hr/cm2, but not in those with slight disease activity: 42 (18-98), compared with controls: 45 (32-64); F = 10.90, P = 0.0002. The transport rates of degraded horseradish peroxidase were comparable in the Crohn's disease samples and controls. Our results indicate that enhanced absorption of macromolecules is associated with clinical activation of Crohn's disease, and impairment of the mucosal barrier function is a secondary phenomenon in Crohn's disease.

The 48,XXYY syndrome: a case detected by maternal serum alpha-fetoprotein screening.

A 17-year-old woman was referred for amniocentesis due to a low maternal serum alpha-fetoprotein (AFP) concentration in a voluntary screening test. The fetal karyotype was 48,XXYY, and the pregnancy was terminated. Autopsy of the fetus disclosed agenesis of the corpus callosum and unusual facial features.

Helicobacter pylori gastritis in dyspeptic children. A long-term follow-up after treatment with colloidal bismuth subcitrate and tinidazole.

The connection between dyspeptic symptoms and Helicobacter pylori infection was studied prospectively in 21 children treated for verified H. pylori infection with bismuth subcitrate and tinidazole. Gastroscopy with biopsy was performed before and a mean of 4 months after discontinuation of the treatment. A second post-treatment check with determination of H. pylori antibodies and serum pepsinogen 1 level was made a mean of 1.5 years after cessation of treatment. The therapy given cleared the bacteria in 67% of the patients. No significant difference in symptoms was observed between treatment successes and failures. The histopathologic diagnosis of H. pylori infection was accompanied by positive IgG serology in 15 (75%) of the 20 patients tested, and a decrease in antibody levels was observed in children with successful eradication. Serum pepsinogen 1 seemed to be even a better marker in the follow-up. The healing of acute and also to some extent of chronic gastritis took place closely after successful eradication. Our results suggest that healing of H. pylori-induced gastritis should be confirmed at reendoscopy only, independent of the symptoms.

Gastric mucosal cell densities in Helicobacter pylori-positive and -negative dyspeptic children and healthy controls.

The densities (cells/mm2) of gastric inflammatory cells were determined. Fifty-four dyspeptic children, of whom 12 had proven Helicobacter pylori infection, were compared with 13 healthy children. The mean antral lymphocyte density for healthy children was 604 cells/mm2 (95% confidence interval [95% CI], 414-793); for plasma cells, 411 (95% CI, 274-548); for neutrophils, 0; and for eosinophils, 4 (95% CI, -4-13). H. pylori-positive children had significantly higher mean densities of all cell types: lymphocytes, 1,738 (p < 0.001); plasma cells, 1,640 (p = 0.001); neutrophils, 371 (p = 0.023); and eosinophils, 263 (p < 0.01). Successful eradication of H. pylori resulted in reduced numbers of all cells. The gastric body cell densities paralleled those of the antrum. Of the dyspeptic children negative for H. pylori, 43% had antral gastritis, 43% had body gastritis, and 29% had pangastritis, as determined morphometrically. Gastritis in these patients was defined as mononuclear cell densities > 2,016 cells/mm2 in the antrum and > 1,994 cells/mm2 in the gastric body (mean + 2 SD for controls) or the presence of neutrophils. A poor correlation was observed between routine histologic description and morphometric evaluation of gastritis in H. pylori-negative dyspeptic children. Standardized morphometric cell-density determination of gastritis may be the method of choice in evaluating chronic superficial gastritis in children.

X-linked laterality sequence in a family with carrier manifestations.

X-linked laterality sequence (XLLS) consists of situs inversus, complex cardiac defects, and alterations in the development of the spleen. We describe a family in which two male cousins had XLLS with caudal manifestations. In our family, the obligate carrier females had uterine septum and hypertelorism, which may be gene carrier manifestations.

Abnormal embryogenesis in the etiology of ectopic pregnancy.

Flow cytometric measurements of DNA using paraffin-embedded retrospective material were performed on 42 samples of ectopic conceptuses to see whether there were any aberrations from normal DNA. It was found that DNA aneuploidy was associated with tubal implantation in 14 (33%) cases. The range of DNA indices of the DNA aneuploid peaks was from 1.14 to 2.17. Near-diploid karyotype changes were seen in 8 (19%) cases. Six cases were found to be tetraploid. In 18 abortions with known cytogenetic status, all 3 cytogenetically normal cases showed DNA diploidy in flow cytometry. It was also found that 3 out of 10 cases of trisomy 21 were DNA aneuploid. Flow cytometric DNA reflects only chromosomal changes where a significant number of cells have either lost or acquired several chromosomes. DNA aneuploidy of ectopic pregnancies suggests a grave chromosomal aberration in one third of the cases. Abnormal embryogenesis may contribute significantly to the occurrence of ectopic implantation.