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.

Trisomy first, translocation second, uniparental disomy and partial trisomy third: a new mechanism for complex chromosomal aneuploidy.

A 2-year-old, short, microcephalic and developmentally retarded boy revealed a pattern of multiple minor anomalies, hypospadias and a dysplastic right kidney. Maternal age at delivery was 41 years. His karyotype showed two cell lines, one apparently normal, the other with a 1p+ chromosome. FISH examinations showed that the segment attached to 1p was from chromosome 16, and molecular investigations disclosed maternal heterodisomy 16, except for the segment (16)(pter-->p13.1) for which there was mosaicism between trisomy and uniparental disomy (UPD). Most likely, the zygote was trisomic for chromosome 16 due to a maternal meiosis I nondisjunction; a somatic rearrangement would have then occurred at an early postzygotic stage whereby a segment of the paternal chromosome 16 was translocated onto 1p. Subsequently, the paternal chromosomes 16 and 16p- had been lost in the normal and the translocation cell line, respectively. The chromosome aberration was detected secondary to the disclosure of maternal UPD 16 because of the demonstration of a paternal band at several loci on distal 16p. This case shows that chromosome aberrations may be formed in a more complicated manner than primarily assumed. Hence, the phenotype might also be due to underlying factors such as UPD or undetected mosaicism in addition to the more obvious implications of the chromosome rearrangement itself (e.g. partial trisomy).

Frame shift by insertion of 2 basepairs in codon 394 of CYP11B1 causes congenital adrenal hyperplasia due to steroid 11 beta-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder of corticosteroid biosynthesis primarily caused by a deficiency in either of two heme-containing cytochrome P450-enzymes: steroid 21- or 11 beta-hydroxylase (causing approximately 90% and 5-8% of classical CAH cases, respectively). Depending on the patient's gender, the affected enzyme, and the extent of enzymatic dysfunction, symptoms include adrenal hyperplasia, androgen excess, virilization, growth disturbance, and electrolyte imbalance. To define the molecular basis of steroid 11 beta-hydroxylase-deficient CAH, we cloned and sequenced the CYP11B1 gene (encoding 11 beta-hydroxylase) of a female patient afflicted with this disorder. Exon 7 contained a 2-basepair insertion in codon 394, leading to a reading frame shift, multiple incorrect codons, and a premature stop in codon 469, resulting in complete destruction of the enzyme's heme-binding domain. Due to parental consanguinity, this defect was homozygous and, therefore, provides a full molecular explanation for this disease.

Long term remission of intrinsic brainstem gliomas: the case reports of two children.

Intrinsic brainstem gliomas carry the worst prognosis of all pediatric CNS tumors; only 10-25% of patients are expected to survive for more than two years. Over a period of four years seven intrinsic brainstem gliomas were diagnosed in children in one institution. Four of them underwent a rapidly fatal course, whilst one was diagnosed only two years ago, which is too recent for long-term evaluation. We report the case histories of the remaining two boys, who showed a favorable course of their disease. Presenting symptoms were headaches and signs of brainstem dysfunction with multiple bilateral cranial nerve palsies, ataxia and pyramidal tract signs. Diagnosis rested on neuroimaging (CAT scans and/or MRI scans). Both tumors were intrinsic brainstem gliomas, one diffuse and the other focal. They responded to treatment (radiotherapy and chemotherapy in the former patient and radiotherapy alone in the latter patient). The two boys became long-term survivors and have remained well, without evidence of disease, for more than 71 and 61 months, respectively, after completion of treatment. They are probably cured. Prompt therapy with curative intention is recommended, with consistent adherence to the chosen antitumor regimen even in poor-risk brainstem gliomas.

[A rare case of venous drainage in intralobar pulmonary sequestration]. / Seltener venöser Abfluss bei einer intralobären Lungensequestration.

We report on a 6-year-old boy with an area of opacity in the right lung that persisted after a feverish respiratory tract infection. Aortography confirmed the suspected diagnosis of pulmonary sequestration. An intralobar sequestration supplied with blood from a supradiaphragmatic and an infradiaphragmatic artery arising from the descending aorta was seen. The venous drainage occurred via the right upper lobe vein, and, most unusually, also to the right pulmonary artery. The clinical findings, diagnostic possibilities and differential diagnostic considerations are discussed.

Purine metabolism of human glioblastoma in vivo.

The aim of this study was to identify targets for rational chemotherapy of glioblastoma. In order to elucidate differences in the biochemistry of tumor and normal human brain, in vivo pool sizes of purine nucleotides, nucleosides, and nucleobases and of purine metabolizing enzymes in biopsy material from 14 grade IV astrocytomas and 4 normal temporal lobe samples were analyzed. Specimens were collected during surgery using the freeze-clamp sampling technique and analyzed by high pressure liquid chromatography. Total purine nucleotides, adenylates, and guanylates in the tumors were 2186, 1865, and 310 nmol/g (wet weight), respectively, which corresponds to 61, 60, and 71% of normal brain tissue concentrations. Relative to normal brain the tumors had significantly lower ATP and GTP levels, essentially normal pool sizes of purine nucleosides and bases, unchanged activities of the salvage enzymes hypoxanthine-guanine phosphoribosyltransferase, adenine phosphoribosyltransferase, and adenosine kinase (659, 456, and 98 nmol/h/mg protein, respectively) and 4-fold higher activities of IMP dehydrogenase (11.6 nmol/h/mg protein); the latter is the rate limiting enzyme for guanylate de novo synthesis. IMP pools in the tumors were 64% of values in normal brain. Modulation of the guanylate pathway in glioblastoma by inhibition of IMP dehydrogenase with tumor specific agents such as tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) appears to be a rational therapeutic approach. Preliminary in vitro experiments with normal and malignant tissue specimens from 2 additional patients revealed that significant amounts of the active metabolite thiazole-4-carboxamide adenine dinucleotide are formed from tiazofurin. At a concentration of 200 microM this drug was able to deplete guanylate pools in the tumors to a median of 54% of phosphate buffered saline treated controls. Flux studies with [14C]formate showed that tiazofurin strongly inhibited de novo synthesis of guanylates in glioblastoma to an average of 10% of controls. This effect was more pronounced in the tumors as compared to normal brain. No inhibition of salvage of [14C]guanine by tiazofurin could be observed in normal and malignant tissues. Supportive measures have to be considered to inhibit the highly active salvage enzyme hypoxanthine-guanine phosphoribosyltransferase that can partly antagonize a tiazofurin induced decrease in guanine nucleotides.

Childhood acute lymphoblastic leukemia: results of the Austrian Cooperative Study Group with the ALL A 84 protocol.

We prospectively treated 127 children with ALL with a risk-adapted regimen. All patients received the identical induction-consolidation therapy. The early maintenance included intermediate dose methotrexate in patients with standard risk (n = 79) and medium risk (n = 39). In addition patients with high risk (n = 6) received high dose ARA-C followed by L-asparaginase. Intensification treatment and prophylactic cranial irradiation was also tailored according to the risk group. Treatment duration was 2 years. Complete remission was achieved in 97.6% of all patients. Treatment-related toxicity accounted for one death in complete remission. The probability of event-free survival (pEFS) for the combined group was 72% at a median follow-up of 42 months. The pEFS was higher in patients with standard risk (SR) than in patients with medium risk (MR) (80% versus 65%; p less than 0.05) at 30 months, but attenuated in the follow-up evaluation at 42 months (76% versus 63%; p less than 0.1). The number of high-risk patients was too small for statistical evaluation. Relapse within the first 18 months after diagnosis indicated a poor prognosis and was more common in patients with MR than in patients with SR. The immunophenotype of the leukemic cells was not found to constitute an independent risk factor after treatment has been risk-adapted. Patients with an initial white blood cell count of more than 50 X 10(9)/l had a worse prognosis than patients with a lower white blood cell count (p less than 0.01).

[Invagination as a complication of malignant lymphoma]. / Invagination als Komplikation beim malignen Lymphom.

Benign or malignant neoplasms are usually the underlying pathological factor initiating intussusception in the older child. Two cases of non-Hodgkin lymphoma are reported. The surgical procedure and chemotherapy are discussed.

[Selection of physiologic bacterial flora by chemotherapeutic agents]. / Selektionierung der physiologischen Keimflora durch Chemotherapeutika.

A variety of antimicrobial agents has been shown to induce alterations in the bacterial homeostasis of the human microflora. Although the role of the normal flora is still poorly understood, there is evidence that alterations in the flora have a number of important clinical consequences. The normal flora acts as a natural defence against colonization or infection with pathogens. In addition, the altered flora may assume importance as a reservoir of potential pathogens. Thus, antibiotic-induced colonization predisposes patients to subsequent endogenous infections with these organisms which, in turn, have been rendered partially or totally resistant to formerly highly active agents. Broad spectrum antimicrobials with a high degree of biliary elimination show a marked impact on the faecal flora. Susceptible enteric bacteria are eliminated within 48 hours and are replaced by enterococci and Candida albicans. Recolonization occurs after discontinuation of therapy by multiresistant organisms like Klebsiella/Enterobacter and Pseudomonas. Oral antibiotics also lead to substantial alterations in the composition and resistance patterns of the faecal flora. In clinical medicine we should be aware of the substantial alterations of the human microflora which may accompany the use of antimicrobial agents.

[Empirical antimicrobial therapy of infection and fever episodes in children and adolescents with neutropenia caused by cytotoxic chemotherapy]. / Empirische antimikrobielle Therapie von Sepsis- und Fieberepisoden bei Kindern und Jugendlichen mit Neutropenie infolge zytotoxischer Chemotherapie.

The experience with empirical antimicrobial therapy of septicemia and febrile episodes in pediatric neutropenic patients was analyzed retrospectively. Between January 1985 and March 1988 in 49 patients 77 episodes were observed. Bacteremia was found in 15 (20%), culture proven localized bacterial infection in 11 (14%) and clinically diagnosed bacterial infection was found in 7 (9%) of the febrile episodes. Thus, 33 (43%) documented bacterial infections were observed. For initial therapy a combination of aminoglycoside plus 2nd/3rd generation cephalosporin (60%) or aminoglycoside plus piperacillin (30%) was usually chosen. Both regimens were equally effective. 52% and 56%, respectively, were sufficiently treated with the initial regimen. 95% of all episodes resolved completely, the mortality rate was 5%. Central venous catheters remained in situ in 84% of the cases. The period of time necessary for recovery of granulopoiesis had an influence on the therapy success.

[Experiences with the Port-A-Cath system, a fully implantable central venous access system, in children]. / Erfahrungen mit dem Port-A-Cath-System, einem vollständig implantierbaren zentralvenösen Zugangssystem, bei Kindern.

The Port-A-Cath-system is a totally implantable catheter system for central venous access. It consists of a subcutaneous injection port, fixed on the pectoral fascia, and a silicone catheter, positioned via a jugular vein into the right atrium. This system was utilised in 14 children (between 10 weeks and 14 years of age) for administration of chemotherapy, total parenteral nutrition, delivery of drugs or blood products, and venous blood sampling over a 15 months period. The device presents only few problems in respect of biocompatibility. Three complications occurred: one case of sepsis, one of catheter dislocation and one of catheter occlusion. The advantage of the total implantability of the system and the low complication rate are attractive alternatives to other methods of prolonged central venous access.

Clivus chordoma in a 9-year-old child: case report and review of the literature.

Chordomas are bone tumors of the axial skeleton. They arise from notochordal remnants. In children these tumors are extremely rare and are predominantly located in the skull base. The authors report on a clivus chordoma in a 9 7/12-year-old girl. It presented as a nasopharyngeal mass with destruction of the clivus and paralyses of the ninth, tenth, and eleventh cranial nerves on the right side. After incomplete resection by a transoral transclival route, high-dose radiotherapy was added. This treatment was effective as demonstrated by follow-up CAT scans. A short review of the current literature is given. The local recurrence rate is extremely high, and distant metastases may occur. Complete resection is rarely possible, and combined management with postoperative radiotherapy is propagated. Permanent cure is rare, and at the present time, chemotherapy appears to be of no value in the primary treatment of chordomas.

[Effect of long-term preventive use of TMPS on the composition and resistance behavior of aerobic fecal flora]. / Einfluss von TMPS-Dauerprophylaxe auf die Zusammensetzung und das Resistenzverhalten der aeroben Stuhlflora.

Trimethoprim Sulfa is a valuable agent in the prophylaxis of Pneumocystis carinii pneumonia in immunocompromised children. Like several other antimicrobial substances also TMPS has an impact on the normal bacterial flora of children. TMPS sensitive enterobacteria are eliminated from the gut flora within 48 hours. The impact on the total number of aerobic organisms and the composition of the fecal flora however is just moderate. Major changes in gut flora result from previous administration of antibiotic and chemotherapeutic agents or from environmental changes (e. g. discharge into ambulatory care). The gut flora of patients under such chemoprophylaxis is a major source of TMPS resistant aerobic bacteria in the hospital and requires careful disposal of these wastes.

[Retinopathia centralis serosa--initial symptom of acute lymphoblastic leukemia]. / Retinopathia centralis serosa--Erstsymptom einer akuten lymphoblastischen Leukämie.

Central serous retinopathy caused a gradual decrease in visual acuity in the left eye of a 14-year-old boy. During a general medical examination systematic investigation revealed an acute lymphoblastic leukemia. As a result of adequate therapy visual acuity improved from 0.1 to 1.0.

[Cooperative studies in the treatment of acute lymphoblastic leukemia in children in Austria--report of 10 years' experience]. / Kooperative Therapiestudien der kindlichen akuten lymphoblastischen Leukämie (ALL) in Osterreich--Erfahrungsbericht nach 10 Jahren.

437 children with acute lymphoblastic leukaemia (ALL) have been treated at 9 different institutions in Austria utilizing common protocols and central registration between 1974 and 1984. 227 patients (132 boys and 95 girls, group I) were treated between 1974 and 1980 using 3 consecutive protocols (KMK, O 76, A 78), which were essentially derived from the Memphis studies VII and VIII. Patients with a high risk of relapse were treated according to the LSA 2-L2 protocol. 210 patients (112 boys and 98 girls, group II) were consecutively treated following the BFM protocols 76/79 and 81/83. In this group, treatment intensity was adjusted to the initially determined individual risk of relapse (BFM risk score or risk factor). To date, the life table analysis demonstrates that the probability of continuous complete remission for patients in group II is 60% after 5 and 3 years (BFM 76/79 and BFM 81/83, respectively), whereas group I reaches a level of 37.3%. The prognostic difference between risk and non-risk patients in both studies of group II was eliminated. Despite a higher morbidity and non-leukaemia-related mortality in group II, the therapeutic success can be attributed to the intensification of induction therapy.