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To assess the genetic diversity of rotavirus strains in Norway, the distribution of rotavirus genotypes was studied in children admitted to hospital with acute gastroenteritis. The detection of rotavirus in stool samples was compared using an enzyme-linked immunosorbent assay (ELISA), an immunochromatographic test and RT-PCR. Children5 years of age admitted to hospital with diarrhea in three large hospitals were enrolled prospectively from March 2006 to February 2008. Rotavirus was detected in 58% of the children by the immunochromatographic test, in 63% by ELISA and 72% by RT-PCR. A total of 219 (70%) rotavirus isolates were characterized in order to determine the genotype. The predominant G types included G1 (53%), G9 (16%), and G3 (13%), and the frequency of G3 varied more than G9 between seasons (8-20%). The P[8] genotype was identified in 188 (86%) of samples, and the globally common genotype combinations G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8] accounted together for80% of infection. No unusual rotavirus strains were detected, and only four samples contained mixed infections. This study demonstrates that ELISA has similar specificity but lower sensitivity compared to RT-PCR. The immunochromatographic test had the lowest sensitivity and specificity compared to the other assays. Rotaviruses causing severe gastroenteritis leading to hospitalization of children5 years of age in Norway include the common genotypes, however, a considerable geographical and seasonal variation was observed in the distribution of these genotypes. These data may be important for assessing the need for introducing rotavirus vaccines into immunization programs in Norway.

In a single-institution study, 23 consecutive children with acute myeloid leukemia (AML) have been treated with a protocol including doxorubicin, cytarabine and 6-thioguanine as induction therapy, followed by four courses of high-dose cytarabine as consolidation. Total duration of chemotherapy was 6-8 months from diagnosis. 21 out of the 23 children achieved complete remission. During remission, the children received 52 mumol (50,000 I.U.) retinol as retinyl palmitate per square meter daily. 14 of the 21 children are still in their first remission with a mean observation time of 36 months. In our study retinyl ester given in doses up to 30 times the recommended daily allowances has not caused any clinical or biochemical side effect for up to 4 yr of therapy.

Aim: To investigate the epidemiology and clinical characteristics of community acquired pneumonia (CAP) in children before the introduction of the 7-valent pneumococcal vaccine in the national vaccination programme. Methods: For the period 21 May 2003 to 20 May 2005 hospitalization rates for pneumonia in children were obtained from retrospective studies of medical journals. Pneumonia was also studied prospectively in children less than sixteen years old referred to Ulleval University Hospital (Oslo) in the same time period. Results: The overall observed hospitalization rate of pneumonia was 14.7/10 000 (95% CI: 12.2–17.1), for children under five it was 32.8/10 000 (95% CI: 26.8–38.8), and for children under two 42.1/10 000 (95% CI: 32.0–52.3). In the clinical study 123 children, of whom 59% (73) were boys, met the inclusion criteria and were enrolled. Only 2.4% (3) had pneumonia complicated with pleural effusion and in general few complications were observed. No patients required assisted ventilation, and none were transferred to the intensive care unit. Penicillin was effective as treatment for pneumonia. Conclusion: Pneumonia, seen in a paediatric department in Oslo, is a common but benign disease. Penicillin is effective as treatment for pneumonia in Norwegian children.

OBJECTIVE. The purpose of this work was to assess the annual incidence of arthritis in children and describe early disease and patient characteristics, microbiologic features, and immunogenetic factors in children with different subgroups of childhood arthritis.PATIENTS AND METHODS. A population-based multicenter study was performed in southeastern Norway between June 1, 2004, and May 31, 2005. The total population of children under 16 years of age was 255303. Physicians were asked to refer their patients with suspected arthritis to the local department of pediatrics or rheumatology. The children were assessed on the basis of clinical, radiologic, and laboratory examinations at inclusion and followed up at 6 weeks, 6 months, and thereafter as long as clinically indicated. A chart review was performed to identify patients with arthritis who had not been included prospectively.RESULTS. The total annual incidence of arthritis was 71 per 100000 children. Transient arthritis, juvenile idiopathic arthritis, postinfectious arthritis, and infectious arthritis were found in 43, 14, 9, and 5 of 100000 children, respectively. The incidence was higher in children under the age of 8 years than in older children (107 vs 34 per 100000). Arthritis occurred more frequently in boys than in girls before the age of 8 years but not thereafter. The median age of onset was lower in children with infectious arthritis than in those with other types of arthritis. Monarthritis was less frequent in patients with juvenile idiopathic arthritis than in the other subgroups (64% vs 83%–100%). Ten percent of the patients had poststreptococcal reactive arthritis, and only 1 had enteropathic arthritis. Autoantibodies and the presence of HLA-B27 were associated with juvenile idiopathic arthritis.CONCLUSIONS. The annual incidence of childhood arthritis was 71 per 100000 children. We found several factors that may help in differentiating between subgroups of arthritis.

Aim: To evaluate the value of radiographic follow-up of community-acquired pneumonia in children who are previously healthy. Methods: Patient records for the years 2003 and 2004 at the Ulleval University Hospital in Oslo were reviewed, and a total of 245 children were selected for the study. Radiographs were evaluated by two paediatric radiologists independently. Results: One hundred and thirty-three patients had control radiographs, of which 106 were normal and 27 were abnormal. Only three of 27 patients with abnormal findings had further clinical problems that could be related to the pneumonia. Two of 106 with normal findings had further clinical problems, despite the normal control radiograph. Of the 112 without radiographic follow-up, 10 had subsequent clinical problems, but most occurred within the first 4 weeks after discharge, before controls would have been scheduled. There were five patients who may have benefited from controls. One relapse could theoretically have been prevented. Four patients were cases for whom the pneumonias were the first manifestations of chronic lung disease. Such patients may have some benefit from control radiographs, but only in terms of detecting the chronic disease at an earlier stage, not in altering the clinical course. Such modest benefits must be weighed against the consequences of providing follow-up to a large number of healthy children, and making lots of abnormal findings with no clinical significance. Conclusion: Control radiographs are not very valuable in children who are otherwise healthy.

We aimed to evaluate rotavirus morbidity and describe rotavirus epidemiology in hospitalized children in Norway to provide information before the introduction of new rotavirus vaccines. We retrospectively reviewed 14,973 gastroenteritis hospitalizations in children aged5 y for the period 1995 to 2004, and prospectively surveyed for rotavirus in 311 children aged5 y admitted with diarrhoea to 3 hospitals in 2006-2008. The proportion of rotavirus among all gastroenteritis hospitalizations was estimated at 14.5% from the retrospective data and at 62.9% in the prospective data. The annual incidence of rotavirus hospitalizations is estimated to be 3 per 1000 children5 y of age, corresponding to approximately 900 (range 735-1092) hospitalizations each year. Children aged 6-23 months accounted for 61% of all confirmed rotavirus cases, and average duration of hospital stay for rotavirus cases was 1.3 days. We observed a predominance of rotavirus infections from March through May, similar to the seasonality of diarrhoea-associated hospitalizations with viral and unspecified aetiology. No rotavirus-associated deaths were reported. It is estimated that two thirds of all gastroenteritis hospitalizations in children5 y of age may be attributable to rotavirus in Norway. Continued surveillance and further studies are needed to assess the full burden of rotavirus disease and its economic impact in Norway.

Infantile Zellweger syndrome belongs to the group of peroxisomal disorders that lack peroxisomes. Both trihydroxycoprostanic acid (THCA), the precursor to cholic acid, and dihydroxycoprostanic acid (DHCA), the precursor to chenodeoxycholic acid, accumulate in this disease. In previous studies, we have shown that liver peroxisomes are required for the conversion of THCA into cholic acid both in vitro and in vivo by measuring a defective conversion in infants with Zellweger syndrome. In our present study, the conversion of DHCA into chenodeoxycholic acid has been measured in an infant with Zellweger syndrome to evaluate the importance of liver peroxisomes for the formation of chenodeoxycholic acid. Coprostanic acidemia was present from the second day of life with high levels of THCA and only trace amounts of DHCA. The conversion of i.v. administered [3H]DHCA into chenodeoxycholic acid was only 7% compared with the 80% conversion in an analogous study in an adult. There was, however, a rapid incorporation of 3H into biliary THCA and, after a lag phase, the 3H was incorporated into biliary cholic acid. After 72 h, 15% of [3H]DHCA was converted to cholic acid. The pool size of DHCA was 1.2 mg/m2 and the pool size of both cholic acid and chenodeoxycholic acid was markedly reduced. The renal excretion of cholic acid was more efficient than that of the less polar chenodeoxycholic acid. More polar metabolites of DHCA and THCA are formed in alternative metabolic pathways facilitating renal excretion of these toxic intermediates. We conclude that liver peroxisomes are essential for a normal conversion of DHCA into chenodeoxycholic acid.

To investigate the epidemiology and clinical characteristics of community acquired pneumonia (CAP) in children before the introduction of the 7-valent pneumococcal vaccine in the national vaccination programme.For the period 21 May 2003 to 20 May 2005 hospitalization rates for pneumonia in children were obtained from retrospective studies of medical journals. Pneumonia was also studied prospectively in children less than sixteen years old referred to Ullevål University Hospital (Oslo) in the same time period.The overall observed hospitalization rate of pneumonia was 14.7/10 000 (95% CI: 12.2-17.1), for children under five it was 32.8/10 000 (95% CI: 26.8-38.8), and for children under two 42.1/10 000 (95% CI: 32.0-52.3). In the clinical study 123 children, of whom 59% (73) were boys, met the inclusion criteria and were enrolled. Only 2.4% (3) had pneumonia complicated with pleural effusion and in general few complications were observed. No patients required assisted ventilation, and none were transferred to the intensive care unit. Penicillin was effective as treatment for pneumonia.Pneumonia, seen in a paediatric department in Oslo, is a common but benign disease. Penicillin is effective as treatment for pneumonia in Norwegian children.

Invasive pneumococcal disease (IPD) is an important cause of morbidity and mortality in Norwegian children.This retrospective study included all children (under 16 years) with isolates of Streptococcus pneumoniae from a normally sterile site admitted to the Department of Paediatrics at Ullevaal University Hospital in the period 1998 to 2004. We studied the epidemiology, predisposing factors, clinical picture, antimicrobial resistance, outcome of IPD and the theoretical coverage of the 7-valent conjugate pneumococcal vaccine (PCV7) in these children. The isolates were tested for antimicrobial susceptibility, serogrouped and serotyped.68 children were identified; 31 of them had one or more predisposing factors. Six children died, all of them had a predisposing factor. Six of the seven children who survived with sequelae were previously healthy. 67 of 68 isolates were fully susceptible to benzyl penicillin and 13 isolates showed intermediate susceptibility or resistance to erythromycin. Serogroups or serotypes were obtained in 66 children. 24 (36.8%) children fulfilled the criteria for PCV7. 35 (51.1%) children had serotypes covered by the vaccine. Only 12 (17.6%) fulfilled the criteria for PCV7 and had serotypes covered by it. Four of the six children who died had serotypes covered by PCV7.Invasive pneumococcal disease is a serious condition in children and vaccination can prevent disease in many children.

Background Osteomyelitis can be difficult to diagnose and there has previously not been a prospective approach to identify all children in a defined geographic area. The aim of this study was to assess the annual incidence of osteomyelitis in children, describe the patient and disease characteristics in those with acute (< 14 days disease duration) and subacute osteomyelitis (≥ 14 days disease duration), and differentiate osteomyelitis patients from those with other acute onset musculoskeletal features. Methods In a population-based Norwegian study physicians were asked to refer all children with suspected osteomyelitis. Children with osteomyelitis received follow-up at six weeks, six months and thereafter as long as clinically needed. Results The total annual incidence rate of osteomyelitis was 13 per 100 000 (acute osteomyelitis 8 and subacute osteomyelitis 5 per 100 000). The incidence was higher in patients under the age of 3 than in older children (OR 2.9, 95%: CI 2.3–3.7). The incidence of non-vertebral osteomyelitis was higher than the incidence of vertebral osteomyelitis (10 vs. 3 per 100 000; p = .002). Vertebral osteomyelitis was more frequent in girls than in boys (OR 7.0, 95%: CI 3.3–14.7). ESR ≥ 40 mm/hr had the highest positive predictive laboratory value to identify osteomyelitis patients at 26% and MRI had a positive predictive value of 85%. Long-bone infection was found in 16 (43%) patients. ESR, CRP, white blood cell count, neutrophils and platelet count were higher for patients with acute osteomyelitis than for patients with subacute osteomyelitis. Subacute findings on MRI and doctor's delay were more common in subacute osteomyelitis than in acute osteomyelitis patients. Blood culture was positive in 26% of the acute osteomyelitis patients and was negative in all the subacute osteomyelitis patients. Conclusion The annual incidence of osteomyelitis in Norway remains high. ESR values and MRI scan may help to identify osteomyelitis patients and differentiate acute and subacute osteomyelitis.

To evaluate the value of radiographic follow-up of community-acquired pneumonia in children who are previously healthy.Patient records for the years 2003 and 2004 at the Ullevål University Hospital in Oslo were reviewed, and a total of 245 children were selected for the study. Radiographs were evaluated by two paediatric radiologists independently.One hundred and thirty-three patients had control radiographs, of which 106 were normal and 27 were abnormal. Only three of 27 patients with abnormal findings had further clinical problems that could be related to the pneumonia. Two of 106 with normal findings had further clinical problems, despite the normal control radiograph. Of the 112 without radiographic follow-up, 10 had subsequent clinical problems, but most occurred within the first 4 weeks after discharge, before controls would have been scheduled. There were five patients who may have benefited from controls. One relapse could theoretically have been prevented. Four patients were cases for whom the pneumonias were the first manifestations of chronic lung disease. Such patients may have some benefit from control radiographs, but only in terms of detecting the chronic disease at an earlier stage, not in altering the clinical course. Such modest benefits must be weighed against the consequences of providing follow-up to a large number of healthy children, and making lots of abnormal findings with no clinical significance.Control radiographs are not very valuable in children who are otherwise healthy.

Objectives: To review the evidence from controlled clinical trials of neonates given equal daily aminoglycoside doses as extended interval dosing (dosage interval typically 24 hours in term and 36–48 hours in immature neonates) compared with traditional dosing (dosage interval typically 8–12 hours in term and 12–24 hours in immature neonates). Design: Systematic review and meta-analysis of controlled trials found in electronic databases, trial registers, and references in reviews and selected trials. Settings: The selected trials were blinded and assessed for methodological quality. Each trial’s own predefined criteria for treatment failure, nephrotoxicity, ototoxicity, and therapeutic serum drug concentrations were used. Subjects: Controlled trials of neonatal aminoglycoside treatment in which equal aminoglycoside daily doses were given at traditional and extended dosage intervals. Main outcome measures: Serum drug concentrations outside the therapeutic range. Treatment failure and toxicity. Results: Sixteen trials involving 823 neonates met the inclusion criteria for the systematic review. Twelve trials involving 698 neonates were included in the meta-analysis of the pharmacokinetics. Compared with traditional dosing, extended interval dosing was associated with a significantly lower risk of both peak (summary risk ratio 0.50, 95% confidence interval 0.26 to 0.94) and trough (0.36, 0.25 to 0.56) serum drug concentrations outside the therapeutic range. Accurate information on treatment failure was obtained in nine trials involving 555 neonates. One trial reported treatment failure. In this trial two neonates in the traditional dosing group did not respond to treatment within 72 hours. Nephrotoxicity was investigated in 589 neonates in 12 trials and ototoxicity in 210 neonates in four trials, with no significant differences between the two dosing regimens. Conclusions: Extended interval dosing of aminoglycosides in neonates is safe and effective, with a reduced risk of serum drug concentrations outside the therapeutic range.

Febrile illness without focal symptoms in a child who has visited tropical or sub-tropical areas is an increasing health problem in western countries. In the department of paediatrics at Ullevaal University Hospital, malaria, typhoid and paratyphoid fever are the most frequent infectious diseases acquired in tropical or sub-tropical areas.We describe all 31 children under 16 admitted between 1998 and 2003 who had blood cultures positive for Salmonella typhi or Salmonella paratyphi A or B.Nearly all the children were second or third generation immigrants from the Indian subcontinent. Fever was the main symptom at onset. Out of 31 salmonella strains, 8 showed reduced sensitivity to quinolones, which are the drugs of choice. Clinical poor response to treatment is associated with reduced sensitivity to nalidixic acid in vitro.Blood cultures prior to administration of antibiotics are important in providing correct diagnosis and appropriate treatment. Before visiting endemic areas, groups at risk should be informed that there are vaccines available against typhoid fever.

Children undergoing transplantation or treatment for cancer have periods with severe immunosuppression; hence they are very susceptible to infections. A bacterial infection can rapidly become life threatening, and it is crucial to promptly start antibiotic treatment.The background for this article is a two-day discussion among Norwegian paediatricians about infections in immunosuppressed children. In addition we have reviewed the literature by searches in PubMed, reference books and international guidelines.When a neutropenic patient becomes febrile, one should quickly do a thorough clinical examination, secure relevant microbiological samples, and start treatment with broad-spectrum antibiotics. As standard treatment for Norwegian children we recommend a combination of intravenous ampicillin and gentamicin. Patients who have clinical signs of septic shock should be given cefotaxime and gentamicin. If they get worse or show no signs of recovery after 3 to 5 days, a change to monotherapy with cefotaxime is recommended. Patients already treated with cefotaxime should be switched to meropenem, possibly in combination with vancomycin. Antifungal and/or anti-anaerobic treatment should also be considered.

Serious systemic infections represent a major challenge to all paediatric departments, hence the importance of having treatment guidelines available.Based on a review of the literature and a meeting of Norwegian paediatricians with an interest in the field, guidelines for the treatment of serious infectious diseases are proposed.The two main new proposals include once daily dosage of aminoglycosides and increased dosage of aciclovir in the treatment of herpes simplex encephalitis.The main objective of the meeting was to maintain a conservative and environmental-friendly antibiotics policy in order to contribute to the prevention of antibiotic resistance.

Hepatitis C-virus infection is relatively infrequent among children in the western world. Although most hepatitis C infections in children evolve to chronicity, liver damage is usually mild. In April 2001, a selected group of Norwegian paediatricians interested in infectious diseases convened to discuss the clinical management of hepatitis C in children. So far, no consensus reports concerning follow-up of hepatitis C infected mothers and their children or clinical management of chronic hepatitis C infection in childhood have been published. In view of the limited experience with hepatitis C among Norwegian children, strategies for the clinical management of hepatitis C infection are discussed based upon available literature and experience from England and Sweden. We present epidemiological data, the risk of vertical transmission and the clinical characteristics of hepatitis C in children. Procedures for follow-up of hepatitis C infected mothers and their children and guidelines for treatment of hepatitis C infected children are proposed. Long term follow-up to identify those who require treatment is important.

350 million people worldwide are chronic carriers of the hepatitis B virus. Mainly because of immigration, the number of children with chronic hepatitis B infection in Norway is also increasing, although the absolute number is still small. In April 2001, a group of Norwegian paediatricians interested in infectious diseases held a meeting to discuss the clinical management of chronic hepatitis B in children and develop recommendations. The recommendations are based on current European and American guidelines, experience from England and Sweden, and a review of the literature. International epidemiological data and data from Norway are briefly presented, followed by recommendations regarding diagnosis, follow-up and treatment of chronic hepatitis B infection in children. Children at risk of contracting hepatitis B from their mothers should be immunized shortly after birth. Paediatricians should follow up children with chronic hepatitis B infections in order to identify those who may be eligible for treatment.

We have studied the effects of retinyl esters in chylomicron remnants on cell growth and differentiation of myeloid and lymphoid leukaemic cells. Ten μmol l-1 retinyl ester in chylomicron remnants effectively reduced proliferation of the myeloid leukaemic cell lines HL60, U937 and KG-1, and induced differentiation of 68% and 53% of the HL60 and U937 cells, respectively, in 5 days. While no effect on cell growth of the lymphoid cell lines Daudi, Raji and SOS was observed, 10 μmol l-1 retinyl esters in chylomicron remnants reduced the growth of the B lymphoid cell line Reh by more than 50%. Primary cell cultures from six patients with acute leukaemia (four non-lymphocytic and two lymphocytic) were incubated with chylomicron remnant retinyl esters and proliferation was measured by means of thymidine incorporation. Among the myeloid leukaemic cells, the mono-myelocytic, the two promyelocytic and the monoblastic leukaemic cells were growth inhibited. Chylomicron remnants had no effect on the growth of the c-ALL primary culture, but reduced proliferation of the T-ALL primary culture by approximately 20% after 48 h. These data suggest that high doses of retinol may be used in the treatment of some forms of acute leukaemia.

We have compared the effect of physiological and pharmacological concentrations of retinoids and 1,25(OH)2 vitamin D3 bound to their plasma transport proteins upon the proliferation and differentiation of HL-60 cells. Concentrations of chylomicron remnant retinyl ester similar to that obtained in plasma after a vitamin A-rich meal reduced the proliferation in more than 50% of HL-60 cells. Pharmacological concentrations of chylomicron remnant retinyl ester completely blocked the proliferation of the cells, and induced differentiation in 60% of the cells after 5 days. Physiological and pharmacological concentrations of retinoic acid bound to albumin had comparable effects. In contrast to earlier published data, which have been obtained with retinoids dissolved in ethanol, our results suggest that physiological and pharmacological concentrations of retinol (i.e. retinyl esters in chylomicron remnants) are as active as retinoic acid in reduction of proliferation and induction of differentiation of HL-60 cells. Physiological concentrations of 1,25(OH)2 vitamin D3 bound to vitamin D-binding protein (DBP) and retinol bound to retinol-binding protein had only a small effect on differentiation and proliferation of HL-60 cells.

We have tested effects of retinol bound to its physiological carrier molecules, i.e. low density lipoprotein chylomicron remnants, and retinol binding protein (RBP) on differentiation and proliferation of myeloid leukemic cells in concentrations that can be obtained in vivo. Data presented in this study show that physiological concentrations of retinyl ester in chylomicron remnants induce differentiation and inhibit proliferation of the cell line HL-60 and promyelocytic leukemic cells in primary culture. Retinyl ester in low density lipoprotein showed no effect either on cell differentiation or proliferation of any of the myeloid cells tested. Retinol bound to RBP induced differentiation of HL-60 cells only in concentrations above those that can be found in vivo. However, cell proliferation was reduced both in HL-60 cells and in primary culture of leukemic cells using physiological concentrations of holo-RBP. These results suggest that retinyl ester in chylomicron remnants is the most effective vehicle for transport of retinol into leukemic cells in vivo.

Newly absorbed retinol is transported in association with chylomicrons and their remnants. In addition, after intake of high doses of retinol, significant amounts are also found in low-density lipoprotein (LDL). As both chylomicron remnants and LDL may be taken up by cells via the LDL receptor, and retinoids inhibit proliferation of some leukaemic cells, we have studied the uptake of retinol in leukaemic cells via the LDL-receptor pathway. HL-60 cells contain saturable binding sites for LDL. The binding of LDL to its receptor has a dissociation constant of about 3.2 x 10(-9) M, and the number of receptors per cell was calculated to be about 2700. Uptake of 125I-LDL by HL-60 cells was increased 2-fold by preincubating the cells with mevinolin. The presence of specific receptors for LDL on HL-60 cells was further confirmed by the finding that exogenous LDL cholesterol was able to up-regulate the ACAT (acyl-CoA: cholesterol acyltransferase) activity of HL-60 cells. We then tested the uptake of retinyl ester in leukaemic cells via the LDL-receptor pathway. HL-60 cells were incubated with LDL or chylomicron remnants labelled with [3H]retinyl palmitate. Uptake of retinyl ester associated with both LDL and chylomicron remnants was observed. Furthermore, the presence of excess LDL decreased the uptake by 75-100%, supporting the hypothesis that the uptake of retinyl ester occurred via the LDL receptor in HL-60 cells.

The effect of the cytostatics doxorubicin, 6-thioguanine and cytarabine on retinol store in rat liver was examined. When rats were treated with pharmacological doses of the combination of doxorubicin and 6-thioguanine for 10 days, the content of retinol in the liver was reduced by about 33%. In a longer term experiment, doxorubicin and cytarabine given separately reduced the retinol store by 33% and 11%, respectively, while doxorubicin and 6-thioguanine given in combination reduced retinol in liver by 31%. For one of the cytostatics (doxorubicin) the effects on plasma retinol and on acyl CoA:retinol acyltransferase (ARAT) activity in small intestine were also examined. Both were transiently reduced during the experiment.