The burden of pneumococcal meningitis in Austrian children between 2001 and 2008.

UNLABELLED: The present study was conducted to evaluate the burden of pneumococcal meningitis in Austrian children between 2001 and 2008. Clinical outcome was retrospectively analyzed both on discharge and on follow-up investigations. This study was based on a prospective multicentre surveillance study on hospitalized invasive pneumococcal infections in Austrian children with a total annual "study population" of about 399,000 children aged below 5 years per year. Between 2001 and 2008, 74 cases of pneumococcal meningitis were identified in children aged below 5 years. The mean annual incidence rate for pneumococcal meningitis was 2.3 per 100,000 children in this age group. In 57/74 children (mean age on admission 14.5 ± 13.3 months), outcome data on hospital discharge were available: 5 deaths (8.8%), 20 children (35.1%) with sequelae and 32 children (56.1%) without sequelae were observed. Sequelae on discharge included motor impairment in 8 children (14.0%), hearing impairment in 9 children (15.8%) and/or other complications in 14 children (24.6%). In 7/8 children with motor deficits, matching cerebral lesions were identified by neuroimaging: cerebral infarction in five children, cerebral vasculitis and cerebral abscess in one child each. In 40/57 children, long-term outcome (18.9 ± 20.2 months after discharge) could be assessed: 1 child (2.5%) died 9 months after hospital discharge, 11 children (27.5%) had one or two long-term sequelae and 28 children (70.0%) had no sequelae. Long-term sequelae included motor impairment in three children (7.5%), hearing impairment in nine children (22.5%) and other deficits in two children (5.0%). CONCLUSION: Our study confirms that pneumococcal meningitis causes high mortality and severe long-term sequelae. On long-term follow-up, we observed improvements of motor impairment, but not of hearing impairment.

156Pro-->Gln substitution in the light chain of cytochrome b558 of the human NADPH oxidase (p22-phox) leads to defective translocation of the cytosolic proteins p47-phox and p67-phox.

Src homology 3 (SH3) domains have been suggested to play an important role in the assembly of the superoxide-forming nicotinamide adenine dinucleotide phosphate (NADPH) oxidase upon activation of phagocytes, which involves the association of membrane-bound and cytosolic components. We studied the translocation of the cytosolic proteins to the plasma membrane in neutrophils of a patient with a point mutation in the gene encoding the light chain of cytochrome b558. This mutation leads to a substitution at residue 156 of a proline into a glutamine in a putative SH3 binding domain of p22-phox (Dinauer, M., E. A. Pierce, R. W. Erickson, T. Muhlebach, H. Messner, R. A. Seger, S. H. Orkin, and J. T. Curnutte. 1991. Proc. Natl. Acad. Sci. 88:11231). In PMA-stimulated neutrophils and in a cell-free translocation assay with neutrophil membranes and cytosol, association of the cytosolic proteins p47-phox and p67-phox with the membrane fraction of the patient's neutrophils was virtually absent. In contrast, when solubilized membranes of the patient's neutrophils were activated with phospholipids in the absence of cytosol (Koshkin, V., and E. Pick. 1993. FEBS [Fed. Eur. Biochem. Soc.] Lett. 327:57), the rate of NADPH-dependent oxygen uptake was observed at a rate similar to that of control membranes. We suggest that the binding of an SH3 domain of p47-phox to p22-phox, and thus activation of the oxidase, does not occur in the neutrophils of this patient, although under artificial conditions, electron flow from NADPH to oxygen in cytochrome b558 is possible.

Immunoglobulin and T cell antigen receptor gene arrangements indicate that the immune response in autoimmune thyroid disease is polyclonal.

To further define the degree of heterogeneity of the antibody and cellular immune responses in autoimmune thyroid disease, we used Southern blot hybridization techniques to analyze the arrangements of immunoglobulin and T cell antigen receptor genes in circulating lymphocytes and in those infiltrating the thyroid gland in nine patients with thyrotoxicosis due to Graves' disease and five patients with Hashimoto's thyroiditis. The sensitivity of these techniques was sufficient to detect a monoclonal population when there was as little as 1% clonal involvement in a mixed cell population. In the patients studied, DNA from non-T peripheral blood cells and non-T intrathyroid lymphocytes had only a germline gene pattern and no clonal nongermline rearrangements of immunoglobulin genes, as assessed using an immunoglobulin joining heavy chain (IgJH) gene probe. An analysis of the DNA from peripheral blood T cells or intrathyroidal lymphocytes revealed polyclonal gene rearrangement patterns and no clonal nongermline rearrangements of the T cell antigen receptor-beta and -gamma genes, as assessed using T constant-beta and T joining -gamma gene probes. These results indicate that the lymphocytes in peripheral blood and those infiltrating the thyroid gland in patients with autoimmune thyroid disease are of polyclonal origin.

Reduction of the dose to the lens in prophylactic cranial irradiation: a comparison of three different treatment techniques and two different beam qualities.

Three treatment techniques using two beam qualities have been compared on the basis of dose to the lens in prophylactic cranial irradiation. The dose to the lens and the globe was measured with thermoluminescent crystals in an anthropomorphic phantom and calculated by a computer-assisted planning system. A comparison was made of large field and small field techniques using 60Co and 8 MV photons. Modifications to the basic techniques studied included angulation of the gantry, angulation of the couch, and placement of an additional eye block close to the surface. The dose to the lens could be reduced to four percent of the midplane dose by applying the small-field technique combined with the use of 8 MV energy photons, by placing an additional block close to the surface, and by five degree occipitally angling the gantry, as well as rotating the treatment couch to account for the divergence of the beam. The use of 60Co produced an underdosage of the posterior segment of the globe in angled treatment techniques.

Endocrine function after bone marrow transplantation without the use of preparative total body irradiation.

Ten children who underwent allogeneic (n = 5) or autologous (n = 5) bone marrow transplantation (BMT) for chronic myelogenous leukaemia (n = 2), acute lymphoblastic leukaemia (n = 1), acute myelogenous leukaemia (n = 2), severe aplastic anaemia (n = 2), malignant histiocytosis (n = 1), neuroblastoma (n = 1) and teratoma (n = 1) were assessed for endocrinological function. Transplant preparative regimens consisted of high-dose cyclophosphamide, high-dose cyclophosphamide in combination with high-dose busulphan, high-dose melphalan as well as BACT (BCNU, cytarabine, cyclophosphamide and 6-thioguanine) chemotherapy. None of the patients received total body irradiation (TBI). Median survival following BMT was 37 months (range 7-115). Growth hormone deficiency was present in only one patient; none of the patients had abnormal thyroid or adrenocortical function. This is in contrast to previous reports in which growth hormone deficiency and abnormal thyroid and adrenocortical function occurred in a much higher percentage of patients after BMT conditioned with TBI.

Successful treatment of CMV retinitis with ganciclovir after allogeneic marrow transplantation.

Cytomegalovirus (CMV) infection of the retina is a well recognized complication in patients with the acquired immune deficiency syndrome but is rarely seen after bone marrow transplantation (BMT). Among a variety of drugs ganciclovir so far appears to be the most effective therapy for CMV retinitis, but in previous studies relapses occurred in all patients in whom ganciclovir was interrupted. We report the clinical findings in a 22-year-old BMT recipient who developed bilateral exudative CMV retinitis 64 days after BMT despite prophylactic treatment with high-titer CMV-immunoglobulins and transfusions of CMV-negative blood products and donor bone marrow. During a 12 day course of treatment with 7.5 mg/kg/day of ganciclovir the CMV retinitis improved and viruria ceased on day 4 of therapy. In contrast to the previous reports, CMV retinitis in this patient continued to improve even after ganciclovir was stopped and eventually complete healing of all intraretinal lesions as well as total reconstitution of the visual acuity was achieved. He is now free of disease and without relapse of CMV retinitis more than 1 year after transplantation.

Cytofluorimetric analysis of mitogen-activated peripheral blood lymphocytes of non-leukemic lymphoma patients reveals an abnormal disease-related expression pattern of activation antigens.

The purpose of this study was to examine patterns of peripheral T-cell-activation antigen expression after polyclonal in vitro stimulation in early stages of lymphoproliferative diseases. With 18 patients afflicted with recently diagnosed, non-leukemic stages of B and T cell lymphoma cytofluorimetric analysis was performed with peripheral blood lymphocytes (PBL) after 72 h in culture with and without phytohemagglutinin, using antibodies against the differentiation antigens CD3, CD8, CD4, CD16, CD19, CDw14, and the activation antigens interleukin-2 receptor (IL-2R, CD25), HLA-DR (DR), CD56 and transferrin receptor (TR). Compared to healthy controls and patients with other diseases, a very significant reduction of large T cells bearing activation markers was found in all lymphoma cases. Furthermore, a pronounced inhibition in the expression of the activation markers IL-2R and TR, but not of DR, was detected on CD3+ cells in phytohemagglutinin-stimulated PBL of all lymphoma cells independently of DNA synthesis, as measured by [3H]thymidine uptake. Determination of the natural-killer-cell-(NK)-associated antigens CD16 and CD56, available for our studies in a CD16 + CD56 combination kit, revealed, after phytohemagglutinin stimulation, significantly increased expression values in 8 lymphoma patients so far investigated, as compared to 12 healthy controls. Thus, polyclonal activation combined with cytofluorimetric screening of activation antigens seems to give useful information on the functional defect(s) of PBL in an early state of lymphoma, and may therefore be of considerable diagnostic value. The observed pattern of T cell activation antigen expression after phytohemagglutinin stimulation may give further clues to the understanding of immune dysfunction(s) associated with lymphoma.

The Austrian version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ).

We report herein the results of the cross-cultural adaptation and validation into the Austrian language of the parentís version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. The Austrian CHAQ CHQ were adapted from the German version of the CHAQ-CHQ, and revalidated in this study. A total of 134 subjects were enrolled: 74 patients with JIA (9.5% systemic onset, 42% polyarticular onset, 9.5% extended oligoarticular subtype, and 39% persistent oligoarticular subtype) and 60 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Austrian version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

Migratory activity of blood polymorphonuclear leukocytes during juvenile rheumatoid arthritis, demonstrated with a new whole-blood membrane filter assay.

Polymorphonuclear leukocyte (PMN) migration is measured in whole blood in a migration chamber consisting of a membrane filter (3-microns pores, 140 microns thick) with an integrated chemoattractant depot (FMLP in solid form) attached to a plastic container. Control chambers lack FMLP (blanks). One test unit requires 300 microliters blood. Numbers and distribution of the PMN immigrants into the filters are determined microscopically. Altogether 26 measurements of PMN migration in five juvenile rheumatoid arthritis (JRA) patients with varying disease activity were compared with the reactions of a healthy control group (N = 32). Correlations were calculated with conventional laboratory parameters (WBC, PLT, BSR, CRP, Hgb, serum Fe) and disease activity. In comparison with healthy controls, PMNs of JRA patients generally show a markedly increased penetration depth into the filters irrespective the presence of the chemoattractant or the disease activity. Increased migratory reactions to FMLP in comparison to blanks were found during high disease activity only. The PMN penetration depth correlates positively with the CRP, and reciprocally with the Hgb blood levels. The migration assay combines fast and simple processing with good preservation of the genuine PMN activation state.

[Computed tomographic and clinical follow-up studies in intraventricular hemorrhage]. / Computertomographische und klinische Verlaufsuntersuchungen bei intraventrikulärer Hämorrhagie.

The investigation comprises 41 children with intraventricular hemorrhage (IVH). The CT-findings were divided into 4 groups, according to Papile. A CT and clinical follow-up study was performed on the survivors. The grade of IVH correlated with the rate of mortality and with neurological deficits. It is demonstrated in 3 cases that the CT-scan is only part of a prognostic aspect which is remarkable influenced by clinical events.

[Use of autologous bone marrow transplantation in pediatric malignant diseases--results and conclusions]. / Die Anwendung der autologen Knochenmarkstransplantation (AKMT) bei pädiatrischen malignen Erkrankungen--Ergebnisse und Schlussfolgerungen.

Ultrahigh-dose myeloablative antineoplastic therapy followed by autologous bone marrow transplantation (ABMT) has become an attractive therapeutic option for patients without HLA compatible bone marrow donors. Autologous bone marrow was harvested in 9 patients. In four cases the bone marrow was also treated ex vivo with a stable derivative of 4-hydroperoxycyclophosphamide, ASTA-Z 7654, to eliminate residual tumour cells. Altogether 5 patients, namely a patient with metastatic neuroblastoma, a patient with malignant histiocytosis, a patient with recurrent sacrococcygeal malignant teratoma and two patients with acute myelogenous leukaemia in first remission are in continuous remission so far from 125 + to 821 + days (median 657 + days). These patients were transplanted at the time of minimal tumour load (first remission) and in good clinical condition 3-7 months after diagnosis, while 3 of the four patients who died were transplanted in first or repeated relapse after one to several years of chemotherapy. It is concluded that the earliest possible recognition of a refractory therapeutic situation is of utmost importance for successful ABMT. Patients with an unfavourably responding neoplasm should, therefore, be already primary candidates for ABMT.

[High-dose busulfan with subsequent bone marrow transplantation in poor-risk forms of leukemia]. / Hochdosiertes Busulfan mit anschliessender Knochenmarkstransplantation bei ungünstigen Leukämieformen.

The toxicity and potential late side effects of total body irradiation, especially in children, have caused the evaluation of alternative myeloablative agents. We report the results obtained in 4 patients with acute myelocytic leukaemia, 2 patients with acute lymphocytic leukaemia and 1 patient with chronic myelocytic leukaemia who received high-dose busulfan followed by bone marrow transplantation (4 times allogeneic, 3 times autologous), according to the protocol published by G. W. Santos. 4 patients have survived 708+, 413+, 313+ and 234+ days, respectively, to date, 3 patients died, two of whom had acute myelocytic leukaemia in relapse and died of cardiac and combined organ failure 9 and 10 days post transplantation, respectively, without evidence of leukaemic cells in the bone marrow. One patient with acute lymphocytic leukaemia (T-All) in second remission died of an extramedullary relapse 485 days after bone marrow transplantation. We report our experience in the use of busulfan before transplantation not only in patients with acute myelocytic leukaemia, but also in patients with acute lymphocytic leukaemia and chronic myelocytic leukaemia and discuss the effectiveness and toxicity of high-dose busulfan as alternative to total body irradiation.

[Ultrasound diagnosis of malignant diseases in pediatrics]. / Ultraschalldiagnostik maligner Erkrankungen in der Pädiatrie.

Grey scale abdominal ultrasound was used in a total of 146 children for primary diagnostic evaluation of abdominal masses and for follow-up of patients with malignant diseases. Of 93 patients examined for a suspected abdominal mass, 6 showed to have an intraabdominal tumour. In each case the site of tumour origin could be ascertained by ultrasound. The remaining 87 patients showed no pathological findings and have been tumour-free at routine follow-up studies. Sonography proved to be also useful in the follow-up of patients with malignant diseases. Local recurrence or metastases could be ruled out on the basis of sonographic findings alone in 32 out of 35 surgically treated patients, in 3 children with non-resectable tumours, changes in tumour size during radio- and chemotherapy could be studied. Diagnostic ultrasound was also of great importance in the assessment of complications after surgery, radio- and chemotherapy. So the early detection of hydronephrosis in 2 patients with treated nephroblastoma prevented a damage of the remaining kidney. Due to the high accuracy of sonography, invasive diagnostic methods could be restricted to a small number of patients in whom ultrasound failed to provide adequate information.

[Life-threatening hypernatremia caused by faulty preparation of fully adapted infant formula]. / Lebensbedrohliche Hypernatriämie durch fehlerhafte Zubereitung volladaptierter Säuglingsmilch.

Two male newborns developed severe life threatening hypernatremia with serum sodium levels of 181 and 196 meq/l respectively. Both children were fed a two-to fivefold concentrated powdered infant formula since birth. Shortly before admission diarrhea developed in both patients. The children were admitted during the third week and fourth week respectively, of their lifes with clinical signs of severe hyperosmolar dehydration. In both, treatment of shock was instituted and was followed by rehydration therapy. Great care was taken to lower serum sodium by not more than 15 meq/l/day in order to prevent cerebral edema. Inspite of these measures, the first patient developed cerebral seizures 5 hours after initiation of fluid replacement. The patient was intubated, and measures aimed at prevention of cerebral edema were started (hyperventilation). The eventual outcome was satisfactory, on follow up the patient showed no signs of persistent cerebral damage. In the second patient the same management was started from the beginning and no cerebral problems occurred. Restoration of stable body functions with a normal electrolyte status was achieved within five days.

[Immunosuppressive treatment of severe aplastic anemia with high-dose methylprednisolone and antithymocyte globulin in 2 patients]. / Immunosuppressive Behandlung der schweren aplastischen Anämie mit hochdosiertem Methylprednisolon und Antithymozytenglobulin bei 2 Patienten.

This article describes the treatment of two patients with severe aplastic anaemia (SAA) by means of high-dose methylprednisolone ( HDMP ) and antithymocyte globulin (ATG). A complete normalization of the haematological data was obtained in one patient, which has persisted now for 10 months. ATG and HDMP seem to provide an alternative mode of treatment of SAA to bone marrow transplantation if there is no histocompatible bone marrow donor available.

[Molecular immunology in pediatrics]. / Molekularimmunologie in der Pädiatrie.

Immunoglobulin and T-cell antigen receptor genes in their germline form are organized as discontinuous DNA elements that are joined by recombinations during lymphocyte development. The analysis of immunoglobulin and T-cell receptor gene structure as well as the analysis of chromosomal translocations has been of great value in defining the lineage of neoplasms, determining the clonality of abnormal lymphocyte proliferations, diagnosis and monitoring of lymphoid malignancies and determining the state of maturation of B- and T-cells. The basic principles of molecular genetics have established some common basis for understanding immune activation and regulation, and thereby have opened new possibilities in studying immunodeficiency and autoimmune diseases. Thus, the application of this molecular genetic approach has great potential for complementing conventional marker analysis, cytogenetics and histopathology in the evaluation of these diseases.

[Biphasic splenic rupture in a hemophilic child (author's transl)]. / Zweizeitige Milzruptur bei einem hämophilen Kind.

This report describes a biphasic splenic rupture following trauma in a 12 1/2 years old boy with the severe form of hemophilia B. Immediately after the trauma the boy was treated with only one single dose of factor IX concentrate. He stayed free of symptoms for 9 days until finally severe abdominal bleeding occurred.

[Stress and susceptibility to infection]. / Stress und Infektionsbereitschaft.

The influence of various stressors upon the human immune system, was and presently is the subject of many clinically oriented as well as experimental studies. Even though it is not always clear how relevant the reported observations are in behalf to the beginning, the course and the outcome of infectious, neoplastic and autoimmune diseases, there is hardly any doubt, that stress may influence multiple aspects of the immune answer. The sensitivity of the immune system to stress factors is not merely fortuitous, but is an indirect consequence of the regulatory reciprocal influences between the immune system and the central nervous system. These interconnections seem to represent building blocks of a long-loop regulatory feedback-system, which plays an important role in the coordination of stressors and psychological influences upon the course of infections and inflammatory diseases.

[Changes in the vertebrae as an initial symptom of leukemia]. / Wirbelkörperveränderungen als Initialsymptom einer Leukämie.

Back pain due to vertebral changes as early feature of acute lymphocytic leukemia (ALL) in childhood has been infrequently reported. There are 8 previously described patients with similar clinical and laboratory data, suggesting a biologically unique subset of ALL. Characteristic findings of this rare primary manifestation of leukemia are lack of significant organomegaly or lymphadenopathy, normal or low white blood cell count with predominance of lymphocytes and rarely circulating lymphoblasts, normal platelet count, uric acid and lactate dehydrogenase values. In the following report we make a further attempt to confirm the hypothesis of a subset of ALL, demonstrating two additional patients with characteristic features of ALL presenting with vertebral changes and low leukemic burden.