Recent-onset childhood arthritis--association with Streptococcus pyogenes in a population-based study.

OBJECTIVES: To assess the frequency of Streptococcus pyogenes in children with early arthritis, compare the characteristics in patients with post-streptococcal ReA (PSReA) with those in patients with other types of arthritis, and describe the occurrence of carditis in PSRA. PATIENTS: In a population-based Norwegian study, the physicians were asked to refer all children with suspected arthritis. The arthritis patients were followed up at 6 weeks, 6 months and 18 months. The presence of S. pyogenes was based on throat smear or antibodies. Echocardiography was performed in the patients with ARF or PSRA. RESULTS: Thirty-two (18%) of the 173 children with arthritis tested positive for S. pyogenes. The percentage of positive tests rose steadily with age and peaked at ages 8-11 (35%). Six weeks after admission arthritis was present in 33% of the PSRA patients, which was less frequent than in the juvenile idiopathic arthritis (JIA) patients (P < 0.001), but more frequent than in the transient arthritis patients (P = 0.012). Hip arthritis was more frequent and knee/ankle arthritis, ANA and HLA-B27 were less frequent in PSRA than in JIA (P < 0.001, P = 0.009 and P = 0.029, respectively). The PSRA patients were older than those with transient arthritis (P = 0.007). One child with ARF had carditis. CONCLUSIONS: Streptococcus pyogenes was present in 18% of children with arthritis. The patient characteristics, clinical presentation and early disease course in PSRA was different from that of JIA and transient arthritis.

Aminoglycoside extended interval dosing in neonates is safe and effective: a meta-analysis.

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.

Evaluation of retinyl palmitate and cytarabine treatment in a slowly growing rat leukemia model.

The slowly effect of retinyl palmitate in prolonging survival time in a slowly growing rat promyelocytic leukemia model (BNML) was tested. Retinyl palmitate was given in addition to cytarabine, which has previously been shown to prolong survival time in these rats. The effect of cytarabine on liver store and plasma level of retinol was also tested. The results show that retinyl palmitate did not prolong survival time in the leukemic rats. Similarly, cytarabine did not reduce the level of retinol in liver or plasma.

Effects of antiepileptics on the hepatic storage of retinol.

The effect of various antiepileptics on the retinol storage in rat liver was tested. We observed a dose- and time-dependent reduction in the hepatic storage of retinol after the administration of several of these drugs. Administration for 11 weeks of phenobarbital, primidone and carbamazepine in doses comparable to those used in humans reduced the retinol concentration in the Liver by 17-33% compared to control rats. The plasma retinol levels remained unaffected in all the rats. Plasma retinol from 31 epileptic children had plasma levels between 0.7 and 2.4 nmol/ml, which is regarded as normal.

["Tellus", the Earth as a patient: global health status--a diagnostic approach]. / Tellus som pasient--en diagnostik tilnaerming.

The article presents important health problems in developing countries from a doctor's perspective. The poor health of people in developing countries does not exist in a vacuum. It is closely interlinked with poverty, high fertility and environmental issues. In this context, dominating medical problems are the health problems of women in connection with pregnancy and childbearing, and the results of the vicious cycle of malnutrition and infection in children. After discussing some problems in developing countries, the author considers key health problems in societies in transition. This "doctor's perspective" must be balanced with the health concerns of community itself.

[Children and HIV/AIDS--prevention, follow up and treatment]. / Barn og HIV/AIDS--forebygging, oppfølging og behandling.

At the global level, the HIV/AIDS epidemic has reached dramatic proportions. According to WHO, more than 1 million children are currently living with HIV infection. In Norway (population 4.4 million), a cumulative total of only 33 children with HIV infection have been reported, making HIV/AIDS a rare disease. In view of the limited experience with HIV/AIDS among Norwegian children, strategies for the clinical management of HIV infection are discussed in light of recent guidelines from the United States and Europe. Procedures for prophylactic treatment and follow-up of children born to HIV infected mothers, and procedures and follow-up of antiretroviral treatment of HIV infected children are proposed.

[Malnutrition and infections in children--a destructive interplay with global dimensions]. / Underernaering og infeksjoner hos barn--et destruktivt samspill med globale dimensjoner.

BACKGROUND: Seven out of ten deaths among the world's children are caused by infectious diseases. Malnutrition is a contributing cause in more than half of the children's deaths. At present, interventions against such diseases in children are the most cost-effective way of reducing the world's morbidity and mortality. MATERIAL AND METHODS: This paper discusses how nutritional status affects the immune defence, and vice versa. General protein and energy malnutrition and some specific nutrients are discussed. The paper is based on review of recent literature found in Medline, and key references in the papers identified. RESULTS: Malnutrition is the most common cause of acquired immune deficiency in children. Malnourished children are especially prone to develop persistent diarrhoea, which in turn aggravates the nutritional status. Iron deficiency may be caused or worsened by hookworm and a number of other gastrointestinal infections. There are indications that iron deficiency in itself reduces the immune defence. Vitamin A supplements have reduced the mortality of measles and other infectious diseases. Some studies have shown reduced vertical transmission of HIV when pregnant women get vitamin A supplements. Chronic diarrhoea may cause zinc deficiency which may aggravate the diarrhoea. In areas where the general population's zinc status is marginal, zinc supplementation has reduced the incidence and duration of persistent diarrhoea. INTERPRETATION: The interaction between malnutrition and common infections in children causes a considerable fraction of the global burden of disease, yet so far this is not reflected in research, which mainly targets the diseases of the rich.

[Children and tuberculosis--diagnosis, treatment and follow-up]. / Barn og tuberkulose--diagnostikk, behandling og oppfølging.

BACKGROUND: Since the 1980s, there has been an increase in the incidence of tuberculosis (TB) world-wide. Mainly due to immigration, the number of new TB cases in the Norwegian child population is also increasing. In March 2000, a selected group of Norwegian paediatricians interested in infectious diseases held a meeting to discuss the clinical management of tuberculosis in children, and develop recommendations. MATERIAL AND METHODS: The recommendations are based on current British, European and American recommendations. Two recent Norwegian recommendations on the management of tuberculosis in the general population were also reviewed. RESULTS: Epidemiological data from Norway and the clinical characteristics of tuberculosis in children are briefly presented, followed by recommendations regarding diagnostic procedures, chemoprophylaxis, treatment of latent tuberculosis and disease. Local health services play a crucial role in the follow-up of children with tuberculosis, and the importance of co-operation between the hospital paediatrician and the primary health care service is emphasised. INTERPRETATION: Early diagnosis and adequate treatment of tuberculosis is necessary to reduce mortality and morbidity from tuberculosis. Clinical guidelines may aid in management.

[Global child health--interventions that work]. / Global barnehelse--tiltak som virker.

BACKGROUND: Over the last decades, better drinking water and hygiene, improved nutrition and vaccines and antibiotics have greatly reduced child mortality and morbidity. Still, 11 million children under the age of five die every year, many of them from diseases that could have been prevented or treated, given existing knowledge and technology. MATERIALS AND METHODS: On the basis of a review of recent literature, this paper discusses current strategies to reduce childhood morbidity and mortality. RESULTS: Sufficient knowledge and technology exist to further improve the health of the worlds' children. Poverty and its consequences--weak implementation and organisation of health services--is a major obstacle. INTERPRETATION: In order to improve health services in developing countries, additional resources are needed. There is also a need for better quality of service. This will require increased efforts in the field of health policy and systems research.

[Varicella in children]. / Varicella hos barn.

Chickenpox in childhood is a milder condition than in older patients, but serious and even fatal complications may occur. Complications occur especially in immunosuppressed individuals, but can also be seen in previously healthy children. In Norway, children with varicella and complications have traditionally been hospitalized in departments of medicine. After the new Department of Paediatrics was opened at Ulleval University Hospital in 1998, we have been able to isolate them there. This article describes our experience with these children and discuss our current policy guidelines. We review issues relating to isolation, contagiousness, prevention, complications and treatment, and recommendations from the literature.

Effect of cytostatics on liver retinol store in rat.

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.

[Acute osteomyelitis in young children--a diagnostic challenge]. / Akutt osteomyelitt hos små barn--en diagnostisk utfordring.

BACKGROUND: Acute osteomyelitis in young children poses a diagnostic challenge. Signs and symptoms are often not well defined and blood tests (SR, CRP etc.) are often of limited value. Standard roentgenograms do not preclude the diagnosis. MATERIALS AND METHODS: We present eight cases of acute osteomyelitis in children under the age of two, seen at the Child Centre, at Ullevaal University Hospital during the last year. RESULTS: Scintigraphic interpretation failed to reveal the diagnosis in two cases. Magnetic resonance imaging (MRI) was shown to be a more reliable method. Only a few biopsies were done. INTERPRETATION: Examination of children suspected of suffering from an osteomyelitis should include both a bone scintigraphy, MRI, and to the extent possible a needle biopsy.

Uptake of retinyl ester in HL-60 cells via the low-density-lipoprotein-receptor pathway.

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.

[Tuberculosis in Norwegian children--diagnostic challenges]. / Tuberkulose hos barn i Norge--diagnostiske utfordringer.

BACKGROUND: Each year, 20-25 Norwegian children below the age of 18 are diagnosed with tuberculosis in Norway. MATERIAL AND METHODS: As a demonstration of various difficulties in the work-up and diagnosis of tuberculosis, we present eight infected children aged 15 months to 10 years. RESULTS: Children often contract the infection from adults and may develop serious manifestations including miliary tuberculosis and meningitis. The symptoms are often not specific and tuberculosis may be mistaken for other diseases. Delay and inappropriate diagnostics may have deleterious consequences. INTERPRETATION: The main message is to start treatment upon clinical suspicion of tuberculosis. It is mandatory to sample the necessary biological material for microbiological tests before starting treatment.

Importance of peroxisomes in the formation of chenodeoxycholic acid in human liver. Metabolism of 3 alpha,7 alpha-dihydroxy-5 beta-cholestanoic acid in Zellweger syndrome.

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.

Retinol bound to physiological carrier molecules regulates growth and differentiation of myeloid leukemic 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.

Retinyl esters in chylomicron remnants inhibit growth of myeloid and lymphoid leukaemic cells.

We have studied the effects of retinyl esters in chylomicron remnants on cell growth and differentiation of myeloid and lymphoid leukaemic cells. Ten mumol 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 mumol 1-1 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 monomyelocytic, 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.

Effect of retinoids and 1,25(OH)2 vitamin D3 bound to their plasma transport proteins on growth and differentiation of HL-60 cells.

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.

High-dose retinol in children with acute myelogenous leukemia in remission.

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.