Precision Measurement of the Lamb Shift in Muonium.

We report a new measurement of the n=2 Lamb shift in Muonium. Our result of 1047.2(2.3)_{stat}(1.1)_{syst} MHz comprises an order of magnitude improvement upon the previous best measurement. This value matches the theoretical calculation within 1 standard deviation allowing us to set limits on Lorentz and CPT violation in the muonic sector, as well as on new physics coupled to muons and electrons which could provide an explanation of the muon g-2 anomaly.

Familial and acquired hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome in which an uncontrolled and ineffective immune response, triggered in most cases by infectious agents, leads to severe hyperinflammation. Familial forms of HLH (FHL), which are increasingly found also in adolescents and adults, are due to genetic defects leading to impaired function of natural killer cells and cytotoxic T cells. These mutations occur either in the perforin gene or in genes important for the exocytosis of cytotoxic granules. Cytotoxic granules contain perforin and granzymes, which induce apoptosis upon entering (infected) target cells. Additionally, perforin is important for the downregulation of the immune response. Acquired forms of HLH are encountered in association with (usually) viral infections, autoinflammatory/autoimmune diseases, malignant diseases, and acquired immune deficiency states (e.g., after organ transplantation). Treatment of HLH includes immune-suppressive and immune-modulatory agents, cytostatic drugs, and biological response modifiers. For patients with FHL, stem cell transplantation is indicated and can be curative.

Significantly increased CD70 up regulation on TEL-AML positive B cell precursor acute lymphoblastic leukemia cells following CD40 stimulation.

BACKGROUND: TEL-AML the most common genetic alteration in childhood precursor B acute lymphoblastic leukemia (BCP-ALL) is associated with a favorable prognosis. PATIENTS AND METHOD: We studied the expression of nerve growth factor/tumor necrosis factor receptor (NGFR/TNFR)/ligand family members on 108 primary BCP-ALL samples by flow cytometry and compared both their baseline expression and CD40-induced modulation on TEL-AML positive and negative leukemia samples. RESULTS: Our findings demonstrate that TEL-AML positive patients exhibit a significantly higher percentage of CD40, CD27 and p75NTR positive blasts at diagnosis. This might well contribute to the improved relapse-free survival of these patients assessed in Kaplan Meier analysis as CD27 and p75NTR directly mediate apoptotic signals. Furthermore CD40 ligation enhances antigen presenting and T cell stimulatory capacity via significant up regulation of CD70 while adequate response to physiological maturation signals as indicated by concomitant down regulation of CD27 is retained in TEL-AML positive leukemia. CONCLUSION: These data provide novel insights in immunological control mechanisms preserved in this leukemia subtype and suggest that not only treatment with chemicals such as HDAC inhibitors but also retained in vivo response to CD40 ligation contributes to improved immune surveillance in these patients which may add to a superior relapse-free survival observed particularly in the presence of other risk factors.

Fatal EBV infection and variable clinical manifestations in an XLP-1 pedigree - rapid diagnosis of primary immunodeficiencies may save lives.

Two related boys who died from fulminant infectious mononucleosis were diagnosed with X-linked lymphoproliferative disease type 1 (XLP-1). Family screening (n=17) identified 6 female mutation carriers and 2 more XLP-1 patients in whom, despite recurrent infections, agammaglobulinemia, and Hodgkin's Disease, the genetic basis had been unknown; demonstrating that awareness and early genetic testing are crucial to reveal underlying primary immunodeficiencies and improve outcome. Furthermore, XLP should be included routinely in the differential diagnosis of severe hypogammaglobulinemia and/or lymphoma in males.

Intense beam of metastable Muonium.

Precision spectroscopy of the Muonium Lamb shift and fine structure requires a robust source of 2S Muonium. To date, the beam-foil technique is the only demonstrated method for creating such a beam in vacuum. Previous experiments using this technique were statistics limited, and new measurements would benefit tremendously from the efficient 2S production at a low energy muon ( < 20  keV) facility. Such a source of abundant low energy µ + has only become available in recent years, e.g. at the Low-Energy Muon beamline at the Paul Scherrer Institute. Using this source, we report on the successful creation of an intense, directed beam of metastable Muonium. We find that even though the theoretical Muonium fraction is maximal in the low energy range of 2-5 keV, scattering by the foil and transport characteristics of the beamline favor slightly higher µ + energies of 7-10 keV. We estimate that an event detection rate of a few events per second for a future Lamb shift measurement is feasible, enabling an increase in precision by two orders of magnitude over previous determinations.

Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations.

BACKGROUND: PRF1 gene mutations are associated with familial haemophagocytic lymphohistiocytosis type 2 (FHL2). Genotype-phenotype analysis, previously hampered by limited numbers of patients, was for the first time performed by data pooling from five large centres worldwide. PATIENTS AND METHODS: Members of the Histiocyte Society were asked to report cases of FHL2 on specific forms. Data were pooled in a common database and analysed. RESULTS: The 124 patients had 63 different mutations (including 15 novel mutations): 11 nonsense, 10 frameshift, 38 missense and 4 in-frame deletions. Some mutations were found more commonly: 1122 G-->A (W374X), associated with Turkish origin, in 32 patients; 50delT (L17fsX22) associated with African/African American origin, in 21 patients; and 1090-91delCT (L364fsX), in 7 Japanese patients. Flow cytometry showed that perforin expression was absent in 40, reduced in 6 and normal in 4 patients. Patients presented at a median age of 3 months (quartiles: 2, 3 and 13 months), always with fever, splenomegaly and thrombocytopenia. NK activity was absent in 36 (51%), 5% in 4 (6%), "reduced" in 2 (3%) (not reported, n = 54). Nonsense mutations were significantly associated with younger age at onset (p<0.001) and absent natural killer activity (p = 0.008). CONCLUSION: PRF1 mutations are spread over the functional domains. Specific mutations are strongly associated with Turkish, African American and Japanese ethnic groups. Later onset and residual cytotoxic function are observed in patients with at least one missense mutation.

Hemophagocytic lymphohistiocytosis: when the immune system runs amok.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome in which an exaggerated but ineffective immune response leads to severe hyperinflammation. Key players in HLH are activated lymphocytes and histiocytes which infiltrate all organs and secrete large amounts of cytokines. Cardinal symptoms are prolonged fever, hepatosplenomegaly, cytopenias, and hemophagocytosis. Biochemical markers include elevated ferritin, triglycerides, and low fibrinogen. HLH occurs on the basis of various inherited and acquired immune defects. Impaired function of natural killer cells and cytotoxic T cells is shared by all forms of HLH. Nearly all genetic defects identified in inherited cases of HLH are either mutations in the perforin gene or in genes important for the exocytosis of cytotoxic granules. Cytotoxic granules contain perforin and granzymes which induce apoptosis upon entering the target cell. Additionally perforin is important for the down-regulation of the immune response. Acquired forms of HLH are found in association with infectious agents, in patients with autoimmune diseases, in malignant diseases, and in patients receiving immune suppression or after organ transplantation. - HLH is still difficult to diagnose and may be overlooked since initially it may masquerade as a normal infection. HLH should be considered when symptoms are more pronounced than usual and in case of progression. Suppression of the severe hyperinflammation can be achieved with immunosuppressive and immunomodulatory agents and cytostatic drugs. Patients with genetic HLH have to undergo stem cell transplantation for cure.

Double hit reconstruction in large area multiplexed detectors.

A novel approach is presented to unfold particle hit positions in tracking detectors with multiplexed readout representing an underdetermined system of linear equations. The method does not use any prior information about the hit positions, and the only assumption in the procedure is that single strip charge values on consecutive detector strips follow a smooth distribution. Ambiguities introduced by charge sharing from multiplexing are reduced by using a regularization technique. We have tested this method on a multiplexed 50 × 50 cm2 Micromegas detector with 1037 strips and only 61 readout channels, using cosmic rays, and we have found that single and double clusters of hits can be reconstructed with high efficiency. In addition, simulations show that the algorithm is capable of reconstructing isolated hits in events with larger multiplicity.

Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, often fatal, disease of early infancy. The diagnosis of HLH is frequently delayed or made at autopsy because no genetic or biologic marker has been identified. To improve the classification and treatment of HLH, the Histiocyte Society has established an 'International Registry for HLH'. Data collected included family history, clinical and laboratory features at the onset of illness, and treatment outcome. Stringent diagnostic criteria (ie fever, splenomegaly, cytopenia, hypertriglyceridemia, and/or hypofibrinogenemia, and hemophagocytosis without evidence of malignancy) were used for patient selection. One hundred and twenty-two patients (61 males, 61 females) were enrolled from 17 centers in 11 countries. The rate of parental consanguinity was 24%. A positive family history was reported in 49% of cases including two pairs of affected male twins. The median age at disease onset was 2.9 months, with no difference between familial and sporadic cases. Age at onset was similar in affected sibs from 10 of 14 families, but in four up to 3-year differences were observed. Hemophagocytosis was present at diagnosis in 75%. An associated infection (usually by common viral pathogens) was reported in 50 of the 122 (41%) cases, of which 25 had familial disease. Natural killer activity was impaired in 36 of 37 patients studied. Chromosome analysis was normal in all tested patients. A decreased frequency of HLA-B7 and B8 alleles and increased frequency of HLA-B21 and DQ3 were observed. The estimated 5-year survival (SE) was 21% (18.7) for all patients. It was 66% (37.8) for patients who received allogeneic bone marrow transplant and 10.1% (9.6) for patients treated with chemotherapy alone (P=0.0001). None of the previously proposed prognostic indicators (age, associated infection, cerebrospinal fluid pleocytosis, family history) correlated with treatment outcome.

Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia--implications for treatment of infants.

The prognosis of infant ALL, characterized by a high incidence of the immature CD10 negative B-lineage ALL (proB ALL) is poor. This study aimed to determine the resistance profile of infant ALL cells. In vitro drug resistance was determined by the MTT assay of 395 children with ALL at initial diagnosis: there were 21 infants <1.5 years of which nine <1 year, 284 children aged 1.5-10 years (intermediate age group) and 90 children >10 years. Immunophenotyping resulted in 310 cALL/preB ALL, 69 T-ALL, 15 proB ALL and one unknown cases. The following drugs were tested: daunorubicin, doxorubicin, mitoxantrone, idarubicin (Ida), prednisolone (Pred), dexamethasone (DXM), vincristine (VCR), Asparaginase (Asp), 6-MP, 6-TG, AraC, VM26 and 4-HOO-ifosfamide (Ifos). Infants <1.5 years were significantly more resistant to Pred (>500-fold), Asp (11-fold) and VM26 (2.7-fold) but significantly more sensitive to Ara-C (2.3-fold) compared to the intermediate age group. When analyzing infants <1 year of age similar results were found. ProB ALL cells (seven infants <1.5 years; eight children >1.5 years) were significantly more resistant to glucocorticoids, Asp, thiopurines, anthracyclines and Ifos compared to cALL/preB ALL but more sensitive to Ara-C. Cells from children >10 years were significantly more resistant to Pred, DXM, Asp, Ida and 6-MP. T-ALL cells showed a strong resistance to Pred, Asp and VCR and a mild but significant resistance to all other drugs except thiopurines and VM26. We conclude that the poor prognosis of infant ALL is associated with a resistance to glucocorticoids and Asp. However, ALL cells from infants show a relatively high sensitivity to Ara-C which suggests that infants with ALL might benefit from treatment schedules that incorporate more Ara-C than the current treatment protocols.

In vivo production of childhood acute lymphoblastic leukemia cells in relation to ploidy and immunological subtype.

Eighteen pretreatment cases of acute lymphoblastic leukemia (ALL) in children were investigated by quantitative autoradiography in order to determine the labeling index (LI) as well as the DNA synthesis time (ts). The ploidy of the leukemic blasts was evaluated by Feulgen-microphotometry. The group consisted of 12 cases expressing the common ALL (CALL) antigen only, while 6 showed varying degrees of development along the T-cell axis. The latter subgroup was taken together and termed T-ALL for the sake of simplicity. By dividing LI by ts the fractional birth rate (FBR) was derived representing the percentage of the total leukemic cell mass newly formed per unit of time. The present study confirms a previous investigation in which a higher LI was detected in association with hyperdiploidy. It shows that ts is simultaneously prolonged, while the DNA synthesis rate remains unchanged. This proves that in hyperdiploid cases the longer ts is caused by a larger amount of DNA to be synthesized. The FBR is the same for eu- and hyperdiploid, as well as for CALL and T-ALL cases, and there is no correlation between the FBR and the white blood cell count. So far, ALL is the only type of leukemia in which a prolongation of ts has been demonstrated in comparison to normal human lymphatic cells. This prolongation is not caused primarily by differences in ploidy. The type of growth is accumulative, since the relative rate of cell production is lower than normal. As a finding of practical importance, the labeling index is shown to correlate quite closely with the FBR. In this cell system the LI can thus be used as a parameter reflecting the rate of relative cell production.

Familial hemophagocytic lymphohistiocytosis. Primary hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis represents a spectrum of pathogenetically different diseases including the rapidly fatal autosomal recessive disease of familial hemophagocytic lymphohistiocytosis (FHL). The onset is usually during the first years of life with fever, cytopenia, and hepatosplenomegaly. Neurologic symptoms may supervene. Similar symptoms may occur in the infection-(virus-)associated or malignancy-associated hemophagocytic syndromes (IAHS/MAHS). Triggering infections can be found in all these diseases and do not allow for reliable differentiation. An international treatment protocol (HLH-94) has been developed for FHL, but immunomodulatory treatment may be justified in IAHS and MAHS as well, since they also have a high fatality rate.

Infection- and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis represents a spectrum of pathogenetically different diseases in which a T-cell induced, uncontrolled activation of phagocytosing macrophages may lead to fever, organomegaly, and pancytopenia. The underlying immunologic disturbance can either be genetically transmitted, like in FHL, or acquired, as in IAHS or MAHS. Triggering infections can be found in all these diseases and do not allow a reliable differentiation. An international treatment protocol has been developed for FHL. IAHS and MAHS also have a high fatality rate, justifying immunomodulatory treatment if the disease is progressive.

Bone marrow transplantation in hemophagocytic lymphohistiocytosis.

Two important syndromes of hemophagocytic lymphohistiocytosis (HLH) have to be considered in infants and young children with recurrent fever, organomegaly and cytopenias. Familial hemophagocytic lymphohistiocytosis (FHLH) is a genetically heterogeneous autosomal recessive disease with histiocytic and lymphocytic infiltrations in multiple organs and is currently curable only by bone marrow transplantation (BMT). Secondary HLH most commonly results from viral infections and some patients may be cured by treating the causative organism, others will need chemotherapy and immunosuppression. Since infections can also trigger disease episodes in FHLH, making the correct diagnosis can prove difficult. The published experience of BMT in HLH is reviewed. Taken together, cure of the majority of patients with HLH by matched related BMT, unrelated or haploidentical BMT is possible. Incomplete resolution of disease activity does not necessarily impede a successful outcome. Central nervous system involvement will eventually develop in many HLH patients and may cause considerable morbidity. Appropriate early treatment and a timely BMT will hopefully decrease mortality rates and improve neurodevelopmental outcome in this disease.