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Cryopyrin-associated periodic syndromes (CAPS) are characterized by apparently unprovoked attacks of fever, rashes, and musculoskeletal and sensorineural inflammation accompanied by high acute-phase reactants. Excessive interleukin-1 (IL-1) signaling appears to be a constant feature in the pathomechanism of the disease, driven by a gain-of-function mutation in the NLRP3 gene. Herein, we present the case of a 9-month-old boy with recurrent nonpruritic rashes and episodes of fever. The difficulties of early diagnosis due to initially mild clinical symptoms and the dramatic response to anti-IL-1 therapy after diagnosis emphasize the practical relevance of considering CAPS as a differential diagnosis in these patients., (© 2012 Wiley Periodicals, Inc.)

From 2000 to 2007, 19 Austrian children (aged 6-18 years) had serologically verified nephropathia epidemica. Common clinical features were abdominal/flank/back pain, fever, nausea, vomiting, headache, and transient visual disturbances. Acute renal failure was present in 18 (95%) patients. All patients recovered completely. Childhood nephropathia epidemica in Austria takes a similar course to those reported for Northern European Puumala virus strains.

Objective: The aim of the CWS 96 Study was to achieve an optimal treatment in children and adolescents with soft tissue sarcoma (STS) implementing a further refinement of risk-adapted allocation to chemotherapy, surgery and radiotherapy., Methods: Treatment stratification was based on tumour histology, TNM status, postsurgical stage, localisation and age. Local tumour control was ensured by surgery and risk-adapted radiotherapy., Results: From 1995 to 2002, 89 patients were registered in Austria. The 3-year event-free survival (EFS) and overall survival rates (OS) were 63% +/- 6% and 71% +/- 6%, respectively. 59/89 patients had localised RMS-like (rhabdomayosarcoma) STS (EFS 73% +/- 7%), 14 had localised NON-RMS STS (EFS 54% +/- 16%) and 15 patients had metastatic disease at diagnosis (EFS 33% +/- 12%), 1 patient had fibromatosis. The EFS rates at 3 years in patients with localised RMS-like tumours according to risk group were 92% +/- 8% for low and standard risk (12 patients) and 67% +/- 8% for high risk (47 patients). Favourable primary tumour sites of nonmetastatic RMS-like STS i.e. orbit, head/neck nonparameningeal or genitourinary non-bladder/prostate were diagnosed in 15 patients (1/15 patients died). In 44 patients with unfavourable localisation such as parameningeal, genitourinary bladder/prostate, extremity and others, 7 deceased. The 3 year EFS according to histology in patients with RMS-like STS was 61% +/- 11% for RME (embryonal RMS ) (28 patients) and 71% +/- 15% for RMA (alveolar RMS) (10 patients). The most common treatment failure was local relapse occurring in 21% of patients in the high-risk group., Conclusion: Risk-adapted individualisation of treatment led to a reduction of chemotherapy in the low and standard risk group without compromising survival. The outcome of RME and RMA was similar in this cohort of patients. These preliminary results after a median observation time of 2.5 years confirm the CWS 96 strategy.

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.

Objective: To examine the usefulness of determining extended serum cytokine profiles in patients with juvenile rheumatoid arthritis (JRA), for the purpose of improving differential diagnosis and monitoring disease activity., Methods: In a 2-year prospective study, serum levels of interleukin-1 beta (IL-1 beta), soluble IL-2 receptor (sIL-2R), IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), and the p55 soluble TNF receptor (sTNFR) were repeatedly determined by enzyme-linked immunosorbent assay in 40 patients with JRA, 13 patients with postinfectious arthropathies, and 30 healthy controls. The data were compared with conventional parameters of inflammation, such as C-reactive protein (CRP), iron and hemoglobin levels, erythrocyte sedimentation rate (ESR), white blood cell (WBC) counts, and platelet counts. WBC subsets were analyzed by flow cytofluorometry., Results: At the first visit and at the peak of inflammatory activity according to CRP levels and/or ESR, serum levels of sIL-2R, IL-6, and sTNFR in JRA patients correlated significantly with conventional inflammation indicators, whereas IL-1 beta, IL-8, and TNF alpha did not. No changes in leukocyte subset distribution were noted. Among the different clinical subtypes of JRA, sIL-2R, IL-6, and sTNFR values at the time of the initial visit showed a pattern similar to CRP, whereby patients with systemic disease exhibited by far the highest values. TNF alpha and IL-1 beta were variably elevated in certain JRA subtypes. Patients with postinfectious arthropathies showed elevated levels of CRP, sIL-2R, TNF alpha, and sTNFR, which did not differ significantly from levels in the various JRA subtypes with the exception of systemic disease. Detailed analysis of types I and II pauciarticular JRA revealed that levels of CRP, IL-1 beta, and TNF alpha were elevated in patients with type I disease. While these parameters were invariably normal in patients with type II disease, sTNFR and sIL-2R were still found to be significantly elevated. Followup studies suggested that persistently high sTNFR values are a better indicator of JRA activity than are measurements of other cytokines or CRP., Conclusion: JRA is associated with significant and consistent changes in serum levels of inflammatory cytokines and soluble receptors. For the clinical monitoring of JRA, determination of levels of sTNFR, and to some extent sIL-2R, may be particularly useful, since these determinations yield information about subtype and/or activity of disease that is not available from conventional parameters of inflammation.

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.

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.

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.

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 most common hematologic and oncologic indications for splenectomy in childhood are hereditary spherocytosis, chronic idiopathic thrombocytopenic purpura, hypersplenism, and Hodgkin's disease. Because of the increased incidence of septic complications after splenectomy, benefits to be gained from the operation should be weighed against the risks. A retrospective study was done on the charts of 42 consecutive children with hematologic and oncologic disorders, who underwent splenectomy between 1967 and 1982. The incidence of septic complications after splenectomy was 12%; sepsis, however, only occurred in patients with severe underlying diseases (three patients with Hodgkin's disease, one patient with systemic lupus erythematosus, and one patient with chronic pseudo-malignant immunoproliferation). In contrast, none of the patients who were splenectomized for other reasons (mainly hereditary spherocytosis and chronic immune thrombocytopenic purpura) had a septic complication. Two patients with end-stage Hodgkin's disease (5%) experienced fatal septic complications. Although splenectomy is well established for diagnostic and therapeutic considerations in patients with Hodgkin's disease, not all of them might benefit from this operation, and studies with a more limited approach to splenectomy might prove to be of the same therapeutical value.

To define the clonality of the intestinal lymphocytes involved in the immune response of inflammatory bowel disease, we performed a molecular genetic analysis of the arrangement of the immunoglobulin and antigen-specific T-cell receptor genes of isolated lamina propria lymphocytes derived from resected intestinal specimens of 12 patients with Crohn's disease, 5 patients with chronic ulcerative colitis, and 7 patients with other gastrointestinal diseases. The sensitivity of this technique is sufficient to detect a monoclonal population when there is as little as 1% clonal expansion in a mixed cell population. In all these groups of patients, deoxyribonucleic acid from the non-T cells demonstrated only a germ-line gene pattern, and no non-germ-line rearrangements of immunoglobulin genes as assessed by an immunoglobulin-joining heavy-chain gene probe. Deoxyribonucleic acid from the lamina propria T cells showed a rearrangement pattern of the antigen-specific T-cell receptor beta- and gamma-chain genes that is characteristic of polyclonal T cells as assessed by T-constant beta- and T-joining gamma-gene probes. These results indicate that the lamina propria non-T and T-lymphocyte populations in inflammatory bowel disease and controls are polyclonal.

To investigate the interaction between antibodies and the thyroid gland in Graves' disease, PBL were harvested from seven Graves' disease patients and transformed into lymphoblasts by the addition of EBV in the presence of cyclosporine A. These lymphoblasts were cloned by limiting dilution and then assayed for binding activity to human thyroglobulin, thyroid-stimulating hormone, thyroid microsome, and thyroid as well as guinea pig fat cell membranes. Four patients' cells produced antibody that bound to at least one of the Ag; a single clone from one patient that bound equally well to both thyroid and guinea pig fat cell membranes (but not to other thyroid Ag) was selected for further evaluation. Fusion of these cells with SHM-D33 heteromyeloma cells yielded three cell lines that produced genetically identical mAb. Immunostaining of human thyrocytes with this mAb demonstrated an Ag present on both nuclear and cell membranes. This Ag was identified as an 18,000 m.w. protein band on Western blots of both human thyroid and guinea pig fat cell membranes. The mAb was also able to alter thyrocyte physiology as the short term incubation of this mAb with FRTL-5 cells in vitro inhibited thyroid-stimulating hormone-mediated production of cAMP. Thus, this mAb and the Ag it identifies may be relevant to Graves' disease.

The use of probes to genes (IG and TCRB) encoding immunoglobulins (IG) and the beta chain of the T-cell antigen receptor (TCRB), respectively, have become a sensitive means to assess clonality and lineage in lymphoid malignancies. It has become apparent that some individual cases show rearrangements of both IG and TCRB genes. In an attempt to more accurately define cell lineage we have analyzed cells from patients with B- or T-cell leukemia (n = 26) at various stages of maturation with probes to two additional TCR genes, TCRG and TCRA (encoding the TCR gamma and alpha chains, respectively), as well as the IG heavy chain joining region (IGHJ) and TCRB genes. On Southern blot analysis, the mature T-cell leukemia cells studied had rearranged TCRG and TCRB while IGHJ remained as in the germ line. The mature B-cell leukemia cells studied had rearranged IGHJ with germ-line TCRG and TCRB. These data suggest that, in the majority of more mature leukemias, cells have rearranged IG or TCR genes but not both. In contrast, cells from five of nine precursor B-cell leukemia patients and cell lines from one of four precursor T-cell leukemia patients had rearranged both IGHJ and TCR genes. TCRG and TCRB mRNAs were expressed in the cells of precursor T- but not B-cell leukemia patients studied. The spectrum of leukemia cells studied within the T-cell series permitted an assessment of the order of TCR gene rearrangements. Two of 13 patients had cells with germ-line TCRG and TCRB, 2 patients had cells with rearranged TCRG alone, and the remainder had cells with rearranged TCRG and TCRB. TCRG and TCRB mRNAs were expressed in precursor T-cell leukemia cells, whereas TCRB and TCRA were expressed in mature T-cell leukemia cells. These results parallel observations from mouse studies on gene expression and support the view of a hierarchy of TCR gene rearrangements in T-lymphocyte ontogeny. TCRG genes are rearranged first, subsequently TCRB genes are rearranged, followed by TCRA gene activation.

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.

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.

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.