[Alcohol abuse in adolescence: a growing problem]. / Jongeren met alcoholintoxicatie: een groeiend probleem.

Alcohol intoxication appears to be a growing problem among adolescents in The Netherlands. Alcohol abuse has led to more hospitalisation over the last years. In the Reinier de GraafGasthuis, in Delft, there was a marked increase in the number of adolescents hospitalised due to alcohol intoxication in 2001-2005, with 2, 3,4, 5 and 8 admissions, respectively. Most of these patients drank in a domestic setting or during a school party. Usually, they drank many kinds of alcoholic beverages at the same time. The changes in drinking habits and the increase in hospitalisation of adolescents due to alcohol intoxication are of concern. This trend obliges physicians to do more research, possibly in co-operation with local policy makers and the government.

[A girl with breath-holding spells and anaemia, treated with iron supplementation]. / Een meisje met 'breath-holding spells' en anemie, behandeld door ijzersuppletie.

A girl aged 1.5 years was presented because of frequent breath-holding spells. Anaemia was also diagnosed. Iron supplementation reduced the frequency and severity of the spells until they fully disappeared. The pathophysiological relationship between breath-holding spells and anaemia has not been clarified, but iron supplementation appears to be effective in many patients.

[Acute generalised exanthematous pustolosis in a 2-year-old girl following treatment with amoxicillin]. / Acute gegeneraliseerde exanthemateuze pustulosis bij een 2-jarig meisje na amoxicillinegebruik.

A two-year-old girl had had fever for one week, and since the previous day general malaise, cutaneous pustolosis with swollen hands and feet. The skin condition had developed three days after the start of amoxicillin therapy. Laboratory tests at the time of admission indicated an infection. The diagnosis was 'acute generalised exanthematous pustulosis' (AGEP). During treatment with a soothing lotion, lasting one week, the patient improved and the skin condition disappeared. AGEP is characterised by acute onset of a pustular eruption in association with fever. It is usually seen after the use of drugs. This is an uncommon disease in children.

[Toxic shock syndrome in 3 children]. / Toxischeshocksyndroom bij 3 kinderen.

A 16-year-old and a 10-year-old girl were admitted with general signs of illness, and respectively a green vaginal discharge and a panaritium. They recovered following antibiotic treatment and surgical relief of the panaritium. A 2-year-old boy became ill the morning after eating tainted cold meat; he died in the course of the following night. In all 3 patients Staphylococcus aureus was incubated with the toxic-shock-toxin-1-gene and/or the enterotoxin-A-gene. These 3 cases occurred within one year in a general hospital. TSS probably occurs more frequently than is generally assumed. Given that it is a life-threatening disease, rapid diagnosis is of major importance.

[Alcohol intoxication in four adolescents]. / Vier jongeren met een alcoholintoxicatie.

Four teenagers, two boys aged 14 and almost 13 years and two girls aged 14.5 and 15 years, were hospitalised because acute alcohol intoxication was suspected. Three of them had only a single instance of excessive alcohol consumption, but the 13-year-old boy was admitted twice in three months due to alcohol intoxication. The blood alcohol concentration in these adolescents varied between 1.4 and 2.3 g/l. During admission the patients were treated symptomatically and there were no complications. Loss of consciousness occurs at lower blood alcohol concentrations in adolescents than in adults. There is also a greater risk of mild hypoglycaemia. In case of recurring excessive alcohol consumption, further psychosocial counselling is necessary.

Facilities and equipment in district general hospitals in the Netherlands: are we prepared for the critically ill paediatric patients?

OBJECTIVE: To evaluate the inventory for initial treatment of critically ill children. DESIGN: Prospective study. SETTING: Paediatric emergency settings in 15 major district general hospitals. METHODS: Using an "expert opinion" created by paediatric intensivists, all hospitals were visited twice to check the inventory. Firstly, to examine the initial site of emergency care for children coming from outside the hospital. Secondly, to visit other emergency sites. A total score below 75% of the optimum was considered as not optimally equipped. MAIN RESULTS: Equipment to meet "respiratory problems" was considered by the experts as most essential. Seventy five per cent of all emergency sites scored below 75% (4 of 11 paediatric departments, 1 of 15 emergency rooms. The emergency room was in all aspects significantly better equipped than the paediatric department. Major differences and variations in the inventory were identified between all hospitals. CONCLUSIONS: Emergency rooms are better equipped to meet the needs of critically ill paediatric patients coming from outside the hospital than the paediatric departments. Paediatricians involved in the treatment of children who become critically ill during their stay in the hospital (the "indoor" patients), have less equipment and medication on the paediatric department at their disposal than on their emergency room. Obviously, emergency care on the paediatric wards should be equipped at the same level as in the emergency room because for both locations the "golden hour" is critically important in final outcome.

Unlicensed and off-label drug use in a paediatric ward of a general hospital in the Netherlands.

OBJECTIVES: Many drugs used in paediatric care are not licensed for that use or are prescribed outside the terms of the product license (off-label). Studies in the UK and Europe showed a large number of unlicensed and off-label drug prescription in specialised paediatric health care centres. We determined the extent and nature of use of unlicensed drugs and off-label prescriptions in children in a general hospital in the Netherlands. METHODS: We conducted a longitudinal prospective cohort study in a dynamic population consisting of patients admitted to the paediatric ward and the neonatology unit of a general hospital during a 19-week period. Drug-licensing status of all prescriptions given to these patients was determined. RESULTS: A total of 1017 prescriptions was administered to 293 paediatric patients for 114 different drugs. The median number of prescriptions per patient was three (interquartile range 2-5). The most commonly administered drugs were acetaminophen (14%), cefotaxime (8%), amoxicillin (7%), caffeine (4%) and prednisolone (4%). Four hundred and forty-three (44%) prescriptions were off-label, and 285 (28%) were for unlicensed drugs. Ninety-two percent of patients received one or more unlicensed or off-label prescriptions, and this proportion was significantly higher in children below 6 months of age than in older children. CONCLUSIONS: This study shows that the extent of unlicensed and off-label drug prescription in a paediatric ward and neonatology unit of a general hospital is large and not smaller than in an academic paediatric setting. Lack of paediatric drug labelling is therefore not solely a problem with drugs used in university hospitals, but also in general hospitals. Efforts must be taken to change the current situation.

New developments in the treatment of acute myeloid leukemia.

Remission induction therapy fails in 20-30% of the patients with acute myeloid leukemia (AML) despite dose intensification and the use of new and more effective drugs. Primary and acquired drug resistance, metabolic or kinetic are a fundamental problem. Expression of the P-glycoprotein in AML is correlated with therapeutic outcome. Randomized clinical studies with Pgp modulators are currently on-going. Ara-C and anthracyclines, are preferentially cytotoxic to proliferating cells. Proliferation induction of leukemia blasts with growth factors in vitro resulted in an increased toxicity of Ara-C and anthracyclines. Normal hematopoietic blast cells with a high Pgp expression are noncycling and less sensitive to anthracyclines, in contrast to the more proliferating cells with a low Pgp expression. Proliferation induction by growth factors results in a down regulation of Pgp expression. Priming of leukemic cells with growth factors in vivo might be promising and randomized clinical studies are warranted.

[Drowning and near-drowning in children]. / Verdrinking en bijna-verdrinking bij kinderen.

Drowning and near-drowning are major causes of death and neurological damage, respectively, in children. The pathophysiological substrate consists of hypoxia, ischaemia, respiratory and metabolic acidosis and sometimes, hypothermia. Most cases involve aspiration of liquid; this leads to a persistent impairment of the gas exchange. Occurrence of arrhythmias and hypovolaemia is very likely. The main objective of treatment of the near-drowned is limiting cerebral damage. Treatment consists of resuscitation and stabilization, administration of oxygen with positive end-expiratory pressure, intravenous administration of liquids and central reheating. The prognosis depends in the first place on the duration of the submersion, which, however, is often difficult to establish. Submersion for over 5 minutes is prognostically unfavourable. In hypothermia due to submersion in ice cold water the prognostic factors are less clear--in these cases the treatment should always be continued until the core temperature is > or = 32 degrees C.

Clonal analysis of progenitor cells by interphase cytogenetics in patients with acute myeloid leukemia and myelodysplasia.

Interphase cytogenetics was used to investigate the clonal origin of bone marrow (BM) cells, peripheral blood (PB) cells, and in vitro cultured progenitor cells of five patients with acute myeloid leukemia (AML) and myelodysplasia (MDS). A new in situ hybridization (ISH) technique was used to examine the origin of the progenitor cells. Two patients with respectively, trisomy 8 and polyploidy as ISH marker were studied both at presentation and during remission. At presentation, the in vitro cultured clusters of both cases appeared diploid. Therefore, despite the abnormal growth patterns, the cultured progenitors could have been residual normal cells. Alternatively, they could have originated from a preleukemic clone with a normal karyotype. In both cases abnormal BM and/or PB cells (less than 6%) were detected with ISH during remission, indicating partially or completely clonal remissions in these patients. Both patients have relapsed. One patient with trisomy 10 as ISH marker was analyzed during myelodysplastic phase and after progression to AML. On both occasions, abnormally appearing clusters were cultured. However, only part of the clusters carried trisomy 10. The presence of a subclone characterized by trisomy 10 and an abnormally growing (pre)leukemic clone without trisomy 10 may explain this observation. Monosomy 1 and 17 were respectively used as ISH markers in two other AML patients. All in vitro cultured clusters carried the numerical abnormality. Long-term liquid cultures of these leukemias were performed for 10-20 days. In both cases, no residual normal clonogenic cells could be detected. Therefore, the selective growth advantage of normal progenitor cells in long-term marrow cultures could not be demonstrated in these two patients with leukemia. This paper illustrates the usefulness of ISH to study the biology of AML at the clonogenic level during preleukemic phase, active disease, remission, and under in vitro culture conditions. It is a sensitive technique which allows individual analysis of large numbers of small aggregates and single cells in culture.

Detection of incorporated iododeoxyuridine in colonies by immunoperoxidase staining: a novel method to measure the proportion of cycling colony-forming cells.

In vitro suicide by tritiated thymidine (3H-TdR), hydroxyurea (HU), or cytosine arabinoside (Ara-C) is assumed to reflect the proportion of colony-forming cells in S-phase at the time of exposure. However, these techniques are not always accurate. Nonradioactive iododeoxyuridine (IdUrd) is incorporated into DNA during S-phase and can be detected by monoclonal antibodies. In the present study, a new IdUrd application was developed to investigate the kinetics of hematopoietic progenitor cells. After incubation with IdUrd, colony-forming cells were cultured in semisolid assay. An immunoperoxidase staining protocol was developed to detect IdUrd in cells of colonies in agar. Colony-forming cells in S-phase during the IdUrd exposure were postulated to give rise to IdUrd+ colonies, whereas non-S-phase cells would generate IdUrd- colonies. Toxicity, sensitivity, and IdUrd inactivation studies indicated that progenitor cells could safely be pulse-labeled for 2 hours with 40 microM IdUrd, whereas prolonged labeling with 1 microM IdUrd was at least feasible for 5 days. Molt-4 cells and normal bone marrow cells were used to compare IdUrd pulse-labeling with 3H-TdR suicide. Part of the Molt-4 cells were enriched for G1- and S-phase cells by counterflow centrifugation. The bone marrow cells were either unstimulated or stimulated with growth factors. As a result, the accuracy of both techniques could be tested in populations with different quantities of S-phase cells. Wide confidence intervals of the suicide technique contrasted with the small confidence intervals obtained with IdUrd pulse-labeling. For instance, the fraction of Molt-4 cells with 27.8% S-phase cells contained 17.7% (confidence interval -8.2 to 43.6%) clonogenic cells in S-phase when determined with 3H-TdR suicide. Of this fraction, the percentage of clonogenic cells in S-phase was 30.6% with a confidence interval of 25.5 to 36.2% when determined with IdUrd pulse-labeling. In our hands, the IdUrd pulse-labeling was more accurate than the 3H-TdR suicide technique. Thus far, kinetic studies of progenitors have been limited to the determination of the fraction of S-phase cells by suicide techniques. By prolonged IdUrd labeling, it is now possible to determine the proliferating fraction of progenitor cells.

In vitro response of blasts to IL-3, GM-CSF, and G-CSF is different for individual AML patients: factors that stimulate leukemic clonogenic cells also enhance Ara-C cytotoxicity.

In vivo, growth factors are currently investigated for their capacity to trigger leukemic stem cells into cycle and thus overcome kinetic drug resistance. In this study, the susceptibility of leukemic clonogenic cells to individual growth factors was related to cytosine-arabinoside (Ara-C) sensitivity. The effects of interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (G-CSF), granulocyte colony-stimulating factor (G-CSF), and combinations of these recombinant hematopoietic factors were tested on blast cells of nine acute myeloid leukemia (AML) patients. Growth factor responses were assessed in semi-solid clonogenic assay and in a 10-day liquid culture followed by clonogenic assay. Heterogeneity in growth factor response was observed in both test systems, resulting in a variable pattern for individual leukemias. In the majority of cases (six of nine) the response patterns in the semi-solid and liquid cultures were divergent. To test the Ara-C sensitivity, leukemic blasts were exposed in liquid to various concentrations of Ara-C in the absence and presence of preselected growth factors. After 10 days, the number of surviving leukemic colony-forming cells (CFU-L) was assessed. Exposure to Ara-C in the presence of optimal stimulatory factor(s) resulted in a 3- to 1000-fold increase of the Ara-C toxicity in seven patients. The Ara-C concentrations resulting in 50% inhibition of clonogenicity (ID50) were 0.48-123 x 10(-8) M Ara-C in the absence of stimulatory growth factors, versus only 0.12-0.40 x 10(-8) M Ara-C in the presence of these factors. In two patients, addition of one or more factors neither increased the number of CFU-L in liquid nor enhanced the Ara-C toxicity. Even in the absence of growth factors the ID50 values in these cases were as low as 0.20 and 0.28 x 10(-8) M Ara-C and in the same range as the ID50 values observed with maximum growth factor stimulation in the other seven patients. These results indicate that Ara-C cytotoxicity can be enhanced by individually selected, clonogenic cell growth-promoting hematopoietic factors.

Cell cycle kinetics of hematopoiesis before and after in vivo administration of GM-CSF in refractory anemia: evidence for a shortening of the granulocyte release time.

GM-CSF administration to patients with refractory anemia (RA) induces an increase in neutrophils and eosinophils. We studied cell kinetic mechanisms underlying this observation using clonogenic assays and in vivo iododeoxyuridine labeling of bone marrow cells. Cell cycle kinetics were studied in three patients before and during GM-CSF administration (two daily subcutaneous injections of 54 or 108 micrograms). No consistent effect on the relative number of bone marrow CFU-GM was noticed. The DNA synthesis time and potential doubling time of low-density bone marrow cells remained essentially the same. A slight decrease (1.5-3.7%) in labeling index was found, originating from the myelo(-mono)cytic lineage. In all three patients the release time of labeled granulocytes from the bone marrow into the peripheral blood was shortened (before GM-CSF treatment 5-7 days and during GM-CSF 3-4 days). Cell cycle kinetics of CD34+ cells were studied in order to obtain kinetic information on immature precursor and progenitor cells. The DNA synthesis time of the CD34+ cells was shortened during GM-CSF therapy, resulting in a shorter potential doubling time. GM-CSF administration to patients with RA results in a rise in granulocytes that might be due partly to an accelerated release of granulocytes from the bone marrow compartment into the circulating blood and partly to an increased proliferative activity of the immature precursor and progenitor cells.

Toxicity of idarubicin and doxorubicin towards normal and leukemic human bone marrow progenitors in relation to their proliferative state.

The effect of growth stimulation on the sensitivity of normal and leukemic human bone marrow progenitors to idarubicin and doxorubicin was studied. Clonogenic assays from colony-forming units of the granulocyte-macrophage lineage (CFU-GM) and leukemic clonogenic cells (CFU-L) were applied using human placenta conditioned medium (HPCM) as source of growth factors. Before seeding cells in clonogenic assay they were exposed to the anthracyclines for 2 h without preincubation, or following a 48 h preincubation period in the presence of HPCM. Drug concentrations used ranged from 0.001-0.1 microgram/ml for idarubicin and from 0.1-1.5 microgram/ml for doxorubicin. In addition, a limited number of bone marrow samples were exposed to the cytostatically active metabolite of idarubicin; idarubicinol (Idol; range 0.001-0.1 microgram/ml). Proliferation of CFU-GM and CFU-L during 48 h was measured by iododeoxyuridine (IdUrd) incorporation. Spontaneous proliferation of CFU-GM increased from 38 to 88% after 48 h stimulation by HPCM. The mean number of proliferating CFU-L increased from 40 to 77% when stimulated with HPCM. Doxorubicin inhibited colony formation of CFU-GM and CFU-L to 50% (IC50CFU-GM, IC50CFU-I) at mean concentrations of 0.355 microgram/ml and 0.103 microgram/ml when applied before preincubation with HPCM, and 0.108 microgram/ml and 0.055 microgram/ml when applied after preincubation. Idarubicin appeared the most potent drug in all experiments regardless of the preincubation procedure or sample origin, with average IC50CFU-GM and IC50CFU-L of 0.008 microgram/ml and 0.006 microgram/ml, respectively, when applied before preincubation with HPCM, and 0.006 microgram/ml and 0.005 microgram/ml when applied after preincubation with HPCM. Idarubicinol showed intermediate potency with average IC50CFU-GM of 0.022 microgram/ml and 0.023 microgram/ml when applied before and after preincubation with HPCM, respectively. In order to assess the effect of growth stimulation on drug sensitivity, samples were evaluated pair-wise (sensitivity of the same sample before vs. after preincubation with HPCM) and were submitted to the Wilcoxon test for matched pairs. Statistically significant enhancement of cytotoxicity was demonstrated for Doxorubicin vs. CFU-GM (p < or = 0.021) and a strong trend versus CFU-L (p = 0.06). The data further demonstrate that proliferation-dependency of doxorubicin toxicity is more pronounced for CFU-GM than for CFU-L. These data also show that idarubicin and idarubicinol toxicity is proliferation-independent. Idarubicin is relatively more potent than doxorubicin in suppressing the growth potential of low or nonproliferating progenitors.(ABSTRACT TRUNCATED AT 400 WORDS)

[A child with Chlamydia trachomatis pneumonia]. / Een kind met een Chlamydia trachomatis-pneumonie.

A six week old boy is presented with a Chlamydia trachomatis pneumonia. This pneumonia is seldom diagnosed because of the mild clinical symptoms and the good prognosis, even without therapy. Diagnosing the Chlamydia trachomatis infection of the neonate is of importance for the mother and the child. Chlamydia trachomatis infections in neonates are an underestimated problem.

Interphase cytogenetics on agar cultures: a novel approach to determine chromosomal aberrations in hematopoietic progenitor cells.

We describe a novel approach to determine the presence of chromosomal aberrations in progenitor cells by in situ hybridization (ISH) on agar cultures. Bone marrow cells of 3 patients suffering from acute myeloid leukemia (AML) were selected to develop the method. In all 3 cases, numerical aberrations for chromosome 1 and/or 8 were detected by karyotyping and ISH using chromosome-specific centromeric-associated DNA probes. These aberrations were used as markers in this study. After in vitro culture of the bone marrow samples in agar, the cells were pretreated to perform ISH. This approach retains the cytological architecture of the agar assay, allowing discrimination between chromosomal aberrations detected in the clonogenic and non-clonogenic cells in culture. With this new technique, the presence of the cytogenetic aberration in clonogenic cells can be shown at the interphase level.

A randomized phase-I/II multicenter study of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy for patients with myelodysplastic syndromes and a relatively low risk of acute leukemia. EORTC Leukemia Cooperative Group.

To assess the effects of GM-CSF in patients with myelodysplasia, a total of 101 patients with refractory anemia (RA), RA with ringed sideroblasts (RARS), and RA with an excess of blasts provided that the percentage of blasts in the bone marrow did not exceed 10% (RAEB) were enrolled in the EORTC Leukemia Cooperative Group study 06885. They were randomized to receive two daily subcutaneous injections of rhGM-CSF (mammalian, glycosylated, Sandoz/Schering-Plough) at a daily dose of either 108 micrograms glycoprotein (group I) or 216 micrograms glycoprotein (group II) for 8 weeks. Response was defined as an increase in Hb (greater than 2.5 g%), neutrophil count (more than 100%), or platelet count (more than 100%) without progression of the disease. After exclusion of 19 patients who did not meet the entry criteria, 82 were evaluated. Fifty-four patients (66%) responded (27 of 42 patients in group I and 27 of 40 in group II). Progressive disease was seen in two patients of group I and in four of group II. Two of the latter developed leukemia. All responses were reflected in the granulocytic series. In two patients platelet numbers also increased. Cytogenetic analysis, successfully performed in 43 cases, showed that 14 of 16 patients with normal karyotypes responded, compared with 14 of 27 patients with abnormal karyotypes (p = 0.008). In some cases GM-CSF was reduced in dose or discontinued prematurely due to side effects so that only 35% of all evaluable patients finished 8 weeks of treatment without a change of dose.

Recombinant human granulocyte-macrophage colony-stimulating factor accelerates neutrophil and monocyte recovery after allogeneic T-cell-depleted bone marrow transplantation.

In a prospective randomized study, five European transplant centers compared recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; mammalian glycosylated) with placebo. rhGM-CSF was administered in a dose of 8 micrograms glycoprotein (5.5 micrograms protein)/kg/d, as a continuous intravenous (IV) infusion for 14 days, starting 3 hours after bone marrow infusion. Fifty-seven patients entered and completed the study. Median age of the recipients was 34 years (range, 17 to 51 y). All donors were HLA-identical, MLC-nonreactive siblings. Marrow grafts were depleted of T lymphocytes either by counterflow centrifugation (n = 42) or by immunological methods (n = 15). Twenty-nine patients received rhGM-CSF and 28 patients placebo. The leukocyte count and the absolute neutrophil count were significantly higher in the rhGM-CSF-treated group from day +9 to day +14 after bone marrow transplantation (BMT). This was also true for the monocyte count from day +12 to day +21. Early neutrophil (greater than 0.1 and greater than 0.3 x 10(9)/L) and early leukocyte (greater than 0.3 and greater than 0.5 x 10(9)/L) recovery was significantly faster for the patients given GM-CSF. The incidences of graft-versus-host disease (GVHD) and transplant-related mortality were not different in both groups. However, the number of bronchopneumonias was significantly lower in the rhGM-CSF-treated group (P = .03). Long-term follow-up showed a trend to better overall disease-free survival at 2 years and a trend to a lower relapse risk in patients treated with rhGM-CSF. This study shows that rhGM-CSF significantly increases neutrophil and monocyte counts during periods of 6 to 10 days in the second and third week after BMT. This shortened period until myeloid cell recovery after transplantation resulted in a decreased number of pneumonias, without an increase in incidence of GVHD or relapse.