Prohepcidin concentrations and erythroid progenitors in cord blood of appropriate versus small for gestational age neonates.

OBJECTIVE: Prohepcidin (Pro-Hep), synthesized in the liver, is the prohormone of hepcidin (Hep), which reduces iron absorption in the gut; its synthesis is enhanced by inflammation and is reduced during hypoxia. We aimed to study the hypothesis that infants born small for gestational age (SGA) have reduced cord blood concentrations of Pro-Hep. STUDY DESIGN: Cord blood was collected from 20 SGA (term and near term >35 week gestation) infants and 20 appropriate for gestational age (AGA) controls. We excluded infants exposed to maternal chronic diseases, smoking, diabetes, alcohol or drug use. Both groups had a 1 min Apgar score above or equal to 7 and had normal cord blood pH (above 7.25). ELISA was used to determine serum concentrations of Pro-Hep and erythropoietin (EPO). Circulating CD71(+)/CD45(-)/SSC(low) cells were measured by flow cytometry as an index of erythroid progenitors. RESULT: There were no significant differences between groups in terms of hemoglobin concentrations, and Pro-Hep. In contrast, EPO levels and circulating CD71(+)/CD45(-)/SSC(low) erythroid progenitors were significantly higher in the SGA group. These differences remained significant even after controlling for gestational age and gravidity. CONCLUSION: Contrary to EPO upregulation during intrauterine growth restriction (IUGR), and higher concentrations of circulating erythroid progenitors, Pro-Hep concentration is not affected by IUGR.

[Talc pleurodesis in malignant pleural effusions]. / Effektivität und zugrunde liegende Mechanismen der Talkumpleurodese bei malignem Pleuraerguss.

Pleural effusions associated with malignancy--either malignant or paramalignant diseases--were found in ca. 20% of these patients. Large pleural effusions cause mainly dyspnoea but also cough and chest pain. The presence and degree of dyspnoea depend on the size of the effusion and the patient's underlying pulmonary function. In acute cases and large effusions immediate chest drainage is indicated in symptomatic patients, followed by the treatment of the underlying disease, e. g. chemotherapy. The most effective therapy for controlling reiterated malignant pleural effusions is the thoracoscopic talc poudrage (2.5-10 g) which has been shown to have a success rate of > 90%. Talc induces a broad inflammatory reaction involving mesothelial cells of the pleura, coagulation parameters, fibroblast proliferation eventually leading to symphysis of the pleura. This procedure is reserved for patients who are in good general conditions, who are expected to have a reasonably long survival, and who failed chemical pleurodesis. A good predictor for longer survival time is a Karnofsky Performance Scale > or = 40 indicating a survival time > 30 days, which therefore should be considered prior to the procedure. The adult respiratory distress syndrome (ARDS) is the most important complication initially observed in the US in up to 9% of all cases. ARDS incidence was strongly related to high number (50%) of small talc particles < 15 microm. In summary, talc poudrage or slurry (talc particle size > 10 microm) in malignant pleura effusions is a safe and effective method to induce pleura symphysis. Complaints and complications such as chest pain, transient fever, and empyema are rare or very are which are almost exclusively related to the therapeutic procedure itself.

An outbreak of echovirus 13 meningitis in central Israel.

Until recently, echovirus 13 has been a very rare cause of aseptic meningitis. We investigated an outbreak of echovirus 13 in central Israel during the summer of 2000 using a prospective case control study and a retrospective study. Echovirus 13 was isolated from 79 cerebrospinal fluid (CSF) specimens from different medical centres in central Israel. Patients' ages ranged from 10 days to 41 years (95% < 15 years, M/F ratio 62/38). A total of 128 patients with clinical aseptic meningitis were admitted to the Department of Pediatrics during the outbreak (aged 10 days to 18 years, mean 5.4 years), and 58 CSF samples were processed for viral cultures. Thirty of them did not grow any virus, 26 samples yielded echovirus 13, and 2 samples echovirus 7. The clinical features of patients with echovirus 13 in the CSF were similar to those in whom no virus was isolated or those infected with other enteroviral strains except for higher rate of fever on admission, and prolonged time with fever following the diagnosis in the echovirus 13 patients. CSF cell count varied from 4 to 2,333 cells/mm3 with polymorphonuclears (PMN) predominant in 90% of our patients. In a case-control study there was no significant difference between patients and matched controls with regard to parameters such as: day care attendance, recreation in summer camp, swimming pools and at the beach, and consumption of tap water. All the patients in our series recovered fully with no neurological abnormalities. The illness caused by echovirus 13 was benign and involved mainly patients younger than 15 year of age. Several features that characterized this outbreak include relatively high WBC in the blood and a minent CSF PMN response.

Food allergy is a matter of geography after all: sesame as a major cause of severe IgE-mediated food allergic reactions among infants and young children in Israel.

OBJECTIVE: To determine the prevalence, importance, and the order of frequency of IgE-mediated food allergens among infants and young children in Israel. STUDY DESIGN AND PATIENTS: In a cross-sectional study, the prevalence of IgE-mediated food allergy was investigated in 9070 infants and young children (0-2 years) who were followed-up at 23 Family Health Centers (FHCs) in central Israel. Patients with suspected IgE-mediated food allergic reactions, were recruited for further evaluation (detailed questionnaire and skin-prick test (SPT)). RESULTS: We identified 150 out of 9070 (1.7%) patients with suspected IgE-mediated food allergy. Among them, 102/150 (67%) [59 males, 43 females; mean age 10.3 months] completed a detailed questionnaire and underwent SPT. Evaluation revealed 131 positive SPTs in 78/102 (76.5%) patients. Twenty-seven positive SPTs in 18 patients were considered clinically irrelevant based on previous consumption of the relevant foods without clinical symptoms. Thus, there were 104 relevant positive SPTs in 78 patients. The overall prevalence of clinically relevant IgE-mediated food allergic reactions among these patients is estimated to be 1.2% (104/9070). The most common food allergens were egg, cow's milk, and sesame. Anaphylaxis was the presenting symptom in 14/78 (18%) including six sesame-induced cases. A history of other atopic diseases was reported in 27 (35%) patients. In addition, 22 (28%) had a history of atopy in first-degree family members. CONCLUSIONS: We found sesame to be a major cause of IgE-mediated food allergy in Israel. In fact, it is second only to cow's milk as a cause of anaphylaxis. We recommend that testing for food allergens be tailored to each community based on local experience and should include sesame in appropriate populations.

Carnitine-deficient myopathy as a presentation of tyrosinemia type I.

Carnitine deficiency secondary to renal Fanconi's tubulopathy has been described in only a few inborn errors of metabolism: cystinosis, galactosemia, and Fanconi-Bieckel syndrome. We report a 27-month-old infant who presented with a sudden change in gait owing to proximal muscle weakness. The laboratory evaluation showed carnitine deficiency associated with Fanconi's tubulopathy. Eventually, tyrosinemia type I was diagnosed. Carnitine deficiency can contribute to the clinical picture of hepatorenal tyrosinemia and should therefore be evaluated and treated.

Benign intracranial hypertension associated with budesonide treatment in children with Crohn's disease.

Oral budesonide in adult studies is a potent corticosteroid with decreased systemic bioavailability and an improved adverse effect profile in comparison with prednisone. It has recently been introduced for the treatment of inflammatory bowel disease in Europe, Canada, and Israel. Benign intracranial hypertension has rarely been associated with corticosteroid therapy but has not been reported in association with budesonide therapy. Three adolescents with Crohn's disease and poor nutritional status developed benign intracranial hypertension while receiving oral budesonide. All three patients had previously received multiple courses of prednisone during the course of their disease, without developing intracranial hypertension. Benign intracranial hypertension resolved after medication withdrawal and did not recur with subsequent use of prednisone. Evaluation for benign intracranial hypertension should be considered in patients with inflammatory bowel disease who develop headache while receiving oral budesonide. This side effect may be associated with poor nutritional status.

Amplification of immunological functions by subcutaneous injection of intermediate-high dose interleukin-2 for 2 years after autologous stem cell transplantation in children with stage IV neuroblastoma.

BACKGROUND: Immunotherapy given post-autologous stem cell transplantation may eliminate residual tumor cells escaping the conditioning protocol. METHODS: Five children suffering from stage IV neuroblastoma were treated by recombinant interleukin-2 (IL-2) post-autologous peripheral blood stem cell transplantation. The patients' peripheral mononuclear cells were monitored for CD3+ and CD56+ levels, their proliferative response and killing of various cell lines targets. RESULTS: An increase in the level of total lymphocytes, mainly due to expansion of T cells, and enhanced proliferative response to phytohemaglutinin were observed. Elevated cytotoxicity against K562 and neuroblastoma target cells was detected in four patients and against K562 targets in one patient. Toxicity included mild thrombocytopenia, and fever in four patients and mild to moderate encephalopathy which necessitated withdrawing one patient from the protocol. Three of five patients studied are alive today, one of them whose IL-2 was stopped, is in relapse. Two patients have died. CONCLUSIONS: Immunotherapy with s.c. intermediate-high dose IL-2 is feasible and results in expansion of T cells and in stimulation of killing activity against several targets including in some cases, neuroblastoma tumor cells.

Variations in neutrophil count in preterm infants with respiratory distress syndrome who subsequently developed chronic lung disease.

Neutrophil counts were studied in 62 preterm infants receiving mechanical ventilation for neonatal respiratory distress syndrome (NRDS). Exploratory analysis indicated that the severity of NRDS, as demonstrated by fractional inspired oxygen (FiO2), mean airway pressure (MAP), arterial-alveolar PO2 ratio (a/APO2) and oxygenation index (OI), was correlated with percentage change of neutrophil counts during the first 5 days of life. Further analysis demonstrated that infants with NRDS who subsequently developed chronic lung disease (CLD) (n = 21) had statistically significant differences in variation of neutrophil counts when compared with the remainder (n = 41) without CLD (-35.0% +/- 4.3 vs. -16.9% +/- 5.8, p < 0.02). It is concluded that significant variations in neutrophil counts during the first 5 days of life may be found in infants with NRDS who subsequently develop CLD and that these changes may have predictive value regarding the development of CLD.

Gender differences in the reactogenicity of measles-mumps-rubella vaccine.

BACKGROUND: In trials comparing different formulations of measles vaccine, excess non-specific mortality occurred in female children who received high titer vaccine. These findings suggest a gender-specific effect of measles vaccine. OBJECTIVES: To determine whether gender differences exist in the rates of adverse reactions and morbidity in the month following immunization with measles-containing vaccine, and to evaluate whether there is a gender-specific association between the humoral immune response to measles vaccination and post-vaccination morbidity. METHODS: Parents completed questionnaires on the health status of 755 infants aged 15-20 months, during the month preceding and the month following the measles-mumps-rubella vaccination. Blood samples were tested for measles antibody titers in a subsample of 237 infants. RESULTS: After controlling background morbidity in the infants, the relative risk of fever and rash following vaccination was 2.35 in females and 1.36 in males. The geometric mean antibody titers against measles were similar in both sexes and there was no significant association between antibody titer and post-vaccination morbidity in either sex. CONCLUSIONS: Our findings demonstrate higher rates of adverse effects in females following vaccination with MMR vaccine, irrespective of the humoral response. This study emphasizes the need to consider possible gender differences when evaluating new vaccines.

Effective preventive central nervous system therapy with extended triple intrathecal therapy and the modified ALL-BFM 86 chemotherapy program in an enlarged non-high risk group of children and adolescents with non-B-cell acute lymphoblastic leukemia: the Israel National Study report.

BACKGROUND: Preventive cranial radiotherapy (CRT) in childhood acute lymphoblastic leukemia (ALL), although effective, may be associated with neurologic sequelae and second malignancies. Attempts to replace CRT with intensified intrathecal therapy (IT) have shown promise in lower risk subgroups. In the Israel National Study (INS) 89 trial, the efficacy of extended triple IT (TIT) alone for cranial prophylaxis in an enlarged non-high risk group (Non-HRG) was assessed in the context of a modified ALL-Berlin-Frankfurt-Munster (BFM) systemic chemotherapy program. METHODS: Non-HRG patients included the standard-risk group (SRG) and the risk group (RG), as defined in ALL-BFM 86. In the INS 89 protocol, all Non-HRG patients were treated with extended TIT x 18 times and systemic therapy based on the BFM 86 protocol, with the addition of etoposide x 4 times. The HRG patients, classified according to BFM 86 criteria, were treated with the BFM 90 HRG protocol including CRT. RESULTS: A total of 250 patients were enrolled. At a median follow-up of 58 months (range, 2-8.5 years), the overall 5-year event free survival (EFS) was 73.5% +/- 3% (standard error ¿SE), and the cumulative central nervous system (CNS) recurrence rate was 4.3% +/- 1.4% (SE) (isolated, 2.3%; combined, 2%). Of the 220 eligible children, 189 (86%) were in the Non-HRG group, and their 5-year EFS was 77.8% +/- 3% (SE). The cumulative CNS recurrence rate for patients without CNS disease at presentation was 3.1% +/- 1% (SE) (isolated, 1.7%; combined, 1.4%). Within the risk subsets defined by the BFM 86 of the Non-HRG, the 5-year EFS rates of the RG (148 patients) and the SRG (41 patients) were 74.8% +/- 4% (SE) and 89.5% +/- 5% (SE), respectively, and the rates of CNS recurrence (isolated and combined) were 4% and 0%, respectively. For the HRG (31 patients), the 5-year EFS and CNS recurrence rates were 47.9% +/- 9% (SE) and 8. 5% +/- 6% (SE), respectively. CONCLUSIONS: Early extended TIT therapy in the context of modified BFM 86 systemic chemotherapy was found to provide adequate CNS protection and systemic leukemia control in patients with non-high risk ALL. However, no benefit for etoposide could be proven in this study.

Differential effects of CD4+ and CD8+ cells on lymphocyte development from human cord blood cells in murine fetal thymus explants.

The possibility that mature lymphocytes play a role in the regulation of human T cell development was studied in the experimental model of fetal thymus organ cultures (FTOC), by reconstituting lymphocyte-depleted murine fetal thymus (FT) lobe with cells isolated from human umbilical cord blood (CB). Cultures were incubated with human cytokines (IL-7, FLT-3 ligand and Steel Factor), or remained untreated. When CD4+, or CD8+ CB cells, were co-cultured with FT explants, they expanded and maintained their original phenotypic markers, with no significant effect of the cytokines. Cultures of human hematopoietic stem cells (CD34+) gave rise to CD4+CD8- cells, which were mainly CD3-, with no indication of further intermediate developmental stages. However, a limited number of CD4+CD8+ (double positive [DP]) cells were detected when the CD34- cells were co-cultured with CD4+ cells from the same CB samples. In contrast, FT with unseparated CB cells resulted in the different CD4/CD8 subsets, and their numbers increased in the presence of cytokines. The appearance of DP cells depended on the presence of either CD4+ or CD8+ cells in the cultured CB samples. Hence, DP cells were not detected when the CB was depleted of CD4+ and CD8- cells ("depCB") before culture, and they appeared when depCB were co-cultured with either CD4+ or CD8+ cells. In contrast, CD4+ cells inhibited the development of CD8+CD3+ cells, and this was most pronounced in the absence of the cytokines. There was no symmetrical down-regulatory effect of CD8+ cells on the development of CD4+CD3+ cells. Addition of IL-15 to the cytokine mixture led to an increased proportion of CD56+ cells in cultures of CD34+ cells. The presence of CD4+, and not CD8+ cells, interfered with this process. Our results thus imply differential effects of CD4+ and CD8+ cells on thymocytopoiesis.

High rate of asthma among immigrants.

Articles dealing with the epidemiological aspects of asthma were carefully reviewed in order to support or reject our clinical impression of increased rate of asthma among immigrants. Particular emphasis was put on data on very high or very low rates of asthma. The proposed theories to explain these differences were critically examined. The prevalence of asthma in China and in Africa is 1-2% and 0.5-5%, respectively. The prevalence of the disease in other indigenous populations ranges between 0.5% and 12%. On the other hand, asthma is much more frequently seen in Australia and in New Zealand (approximately 20-25%), where peoples' ancestors immigrated from distant areas. Statistical meta-analysis found a significant difference between the rates of asthma in the two groups of populations (P < 0.001). Immunoglobulin E levels of immigrants in Sweden are higher than those of native Swedes. Similarly, cord blood immunoglobulin E concentrations are more elevated in neonates whose mothers emigrated to Germany from Eastern countries than in those of native German mothers. There is an increased rate of IgE-mediated asthma among immigrant populations.

Translocation (1;20)(q32;q13.3) in myelofibrosis following polycythemia vera.

We report a novel chromosomal translocation (1;20)(q32;q13.3) in a patient with myelofibrosis following polycythemia vera. This 73-year-old woman developed myelofibrosis 6 years after the initial diagnosis of polycythemia vera (PV). The course of PV was uneventful. Subsequent to the diagnosis, the patient was treated with phlebotomy and low doses of hydroxyurea for 4 years. No therapy was delivered during the remaining 2 years. A bone-marrow biopsy and a karyotype analysis performed because of evolving anemia demonstrated myelofibrosis and a chromosomal aberration-t(1;20)(q32;q13.3). Aberrations in chromosomes 1 and 20 have been reported in myeloproliferative disorders, but a t(1;20) translocation has not been reported. Because a karyotype analysis was not performed at the time PV was diagnosed, whether this translocation is linked to the primary disease (PV) or to the transition to myelofibrosis is not known.

Increased number of peripheral blood CD34+ cells in lithium-treated patients.

Eight adult patients with bipolar disorder were prospectively examined to find whether lithium carbonate increased their peripheral blood CD34+ haemopoietic stem cells. Following lithium therapy for 3-4 weeks their neutrophil counts increased by a mean of 88% (from 4625 +/- 1350 x 10(9)/l, mean +/- SD pretreatment, to a peak of 8300 +/- 3910 x 10(9)/l). Concommitantly, there was a significant increment in their CD34+ cells (from 0.11 +/- 0.01% to a peak of 0.18 +/- 0.08%). There was a significant correlation between the rise in neutrophil count and that of the CD34+ cells (r = 0.795, P = 0.019). Lithium therapy may be used to mobilize peripheral blood CD34+ cells for marrow transplantation.

Pure red cell aplasia responsive to interferon-alpha in a patient with hepatitis C virus infection.

A 51-year-old man presented with severe anemia, mild splenomegaly and elevated serum aspartate aminotransferase and serum alanine aminotransferase levels. The bone marrow findings were consistent with pure red cell aplasia (PRCA) with a 'maturation arrest' at the level of pronormoblast. The patient has been transfusion-dependent for 8 months. Following diagnosis of chronic active hepatitis due to hepatitis C virus (HCV), therapy with interferon-alpha was initiated. Two weeks later, the hemoglobin level stabilized, and he has not required any transfusion ever since. In spite of ongoing HCV viremia, cessation of interferon therapy, and deterioration of the liver function tests, the patient, followed for 2 years, maintains a high-normal hemoglobin level. To the best of our knowledge, this is the first report of prolonged PRCA corrected by interferon-alpha therapy, with or without an ongoing HCV infection. We speculate that the 'maturation arrest' of the erythroid lineage seen in the bone marrow was the result of an immune mechanism, possibly induced by the HCV, and that the elimination of this mechanism, rather than the elimination of the HCV, provided the opportunity for regeneration of erythropoiesis.