Autogenous and efficient acceleration of energetic ions upstream of Earth's bow shock.

Earth and its magnetosphere are immersed in the supersonic flow of the solar-wind plasma that fills interplanetary space. As the solar wind slows and deflects to flow around Earth, or any other obstacle, a 'bow shock' forms within the flow. Under almost all solar-wind conditions, planetary bow shocks such as Earth's are collisionless, supercritical shocks, meaning that they reflect and accelerate a fraction of the incident solar-wind ions as an energy dissipation mechanism1,2, which results in the formation of a region called the ion foreshock3. In the foreshock, large-scale, transient phenomena can develop, such as 'hot flow anomalies'4-9, which are concentrations of shock-reflected, suprathermal ions that are channelled and accumulated along certain structures in the upstream magnetic field. Hot flow anomalies evolve explosively, often resulting in the formation of new shocks along their upstream edges5,10, and potentially contribute to particle acceleration11-13, but there have hitherto been no observations to constrain this acceleration or to confirm the underlying mechanism. Here we report observations of a hot flow anomaly accelerating solar-wind ions from roughly 1-10 kiloelectronvolts up to almost 1,000 kiloelectronvolts. The acceleration mechanism depends on the mass and charge state of the ions and is consistent with first-order Fermi acceleration14,15. The acceleration that we observe results from only the interaction of Earth's bow shock with the solar wind, but produces a much, much larger number of energetic particles compared to what would typically be produced in the foreshock from acceleration at the bow shock. Such autogenous and efficient acceleration at quasi-parallel bow shocks (the normal direction of which are within about 45 degrees of the interplanetary magnetic field direction) provides a potential solution to Fermi's 'injection problem', which requires an as-yet-unexplained seed population of energetic particles, and implies that foreshock transients may be important in the generation of cosmic rays at astrophysical shocks throughout the cosmos.

Transient, small-scale field-aligned currents in the plasma sheet boundary layer during storm time substorms.

We report on field-aligned current observations by the four Magnetospheric Multiscale (MMS) spacecraft near the plasma sheet boundary layer (PSBL) during two major substorms on 23 June 2015. Small-scale field-aligned currents were found embedded in fluctuating PSBL flux tubes near the separatrix region. We resolve, for the first time, short-lived earthward (downward) intense field-aligned current sheets with thicknesses of a few tens of kilometers, which are well below the ion scale, on flux tubes moving equatorward/earthward during outward plasma sheet expansion. They coincide with upward field-aligned electron beams with energies of a few hundred eV. These electrons are most likely due to acceleration associated with a reconnection jet or high-energy ion beam-produced disturbances. The observations highlight coupling of multiscale processes in PSBL as a consequence of magnetotail reconnection.

Charge-State-Dependent Energization of Suprathermal Ions During Substorm Injections Observed by MMS in the Magnetotail.

Understanding the energization processes and constituent composition of the plasma and energetic particles injected into the near-Earth region from the tail is an important component of understanding magnetospheric dynamics. In this study, we present multiple case studies of the high-energy (≳40 keV) suprathermal ion populations during energetic particle enhancement events observed by the Energetic Ion Spectrometer (EIS) on NASA's Magnetospheric Multiscale (MMS) mission in the magnetotail. We present results from correlation analysis of the flux response between different energy channels of different ion species (hydrogen, helium, and oxygen) for multiple cases. We demonstrate that this technique can be used to infer the dominant charge state of the heavy ions, despite the fact that charge is not directly measured by EIS. Using this technique, we find that the energization and dispersion of suprathermal ions during energetic particle enhancements concurrent with (or near) fast plasma flows are ordered by energy per charge state (E/q) throughout the magnetotail regions examined (~7 to 25 Earth radii). The ions with the highest energies (≳300 keV) are helium and oxygen of solar wind origin, which obtain their greater energization due to their higher charge states. Additionally, the case studies show that during these injections the flux ratio of enhancement is also well ordered by E/q. These results expand on previous results which showed that high-energy total ion measurements in the magnetosphere are dominated by high-charge-state heavy ions and that protons are often not the dominant species above ~300 keV.

Ewing Sarcoma tumor cells express CD34: implications for autologous stem cell transplantation.

The significance of tumor cell contamination in marrow and peripheral blood stem cell (PBSC) collections of patients with solid tumors remains controversial. Various methods have been developed to purge tumor cells from autologous stem cell products, including CD34+ selection. PBSC harvests from patients with Ewing family of tumors (EFT) were analyzed for contaminating tumor cells prior and after CD34+ selection using reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry (FC) analyzes. The expression of CD34 was studied by RT-PCR and FC in 14 primary tumors and 13 PBSC harvests, respectively. Tumor cells were identified in the harvests by both methods. In two patients, contaminating tumor cells were evident by RT-PCR only after positive selection. FC analysis confirmed a higher level of tumor cells in the CD34+ fraction. In an attempt to explore this finding, expression of CD34 was detected in 93% of primary tumors and 67% of contaminated harvests. As CD34 is expressed on EFT cells, these cells may be enriched following CD34+ selection of harvests, although the total number of tumor cells is reduced. Other methods of purging, rather than CD34+ selection, should be explored in patients with EFT undergoing autologous stem cell transplantation.

Electron-scale measurements of magnetic reconnection in space.

Magnetic reconnection is a fundamental physical process in plasmas whereby stored magnetic energy is converted into heat and kinetic energy of charged particles. Reconnection occurs in many astrophysical plasma environments and in laboratory plasmas. Using measurements with very high time resolution, NASA's Magnetospheric Multiscale (MMS) mission has found direct evidence for electron demagnetization and acceleration at sites along the sunward boundary of Earth's magnetosphere where the interplanetary magnetic field reconnects with the terrestrial magnetic field. We have (i) observed the conversion of magnetic energy to particle energy; (ii) measured the electric field and current, which together cause the dissipation of magnetic energy; and (iii) identified the electron population that carries the current as a result of demagnetization and acceleration within the reconnection diffusion/dissipation region.

A novel germ line p53 mutation in intron 6 in diverse childhood malignancies.

Screening for p53 mutations in exons 5 to 8 in 124 pediatric malignancies identified 18 abnormal shifts using single strand conformation polymorphism: 12 were missense mutations and in 6, no mutation was detected in the exon or in the splice donor acceptor sequences. Sequencing was then performed in the adjacent introns, revealing a G to A base substitution at 39 base pairs upstream to exon 7. This mutation was identified in the germ line of five of the patients, and also in the father of one, whose parents were available. For comparison, of the 184 normal controls similarly screened, only one had this mutation (P=0.036). Positive staining of p53 protein was observed in three of the paraffin embedded tissues that were available: brain tumor, rhabdomyosarcoma, and lymphocytes from a normal lymph node from the rhabdomyosarcoma patient. All tumors with the identified intron mutation were Li-Fraumeni syndrome tumors. Sequencing of all exons including splice sites was performed and revealed no mutation. We suggest that this mutation in intron 6 of the p53 gene stabilizes the wild type p53 protein, resulting in its abnormal accumulation. Mutations in the noncoding region of p53 should be further studied.

Association between telomerase activity and outcome in patients with nonmetastatic Ewing family of tumors.

PURPOSE: Telomerase is considered a molecular marker for malignancy. The aim of this study was to determine telomerase activity (TA) as a prognostic factor at diagnosis and as a marker for minimal residual disease during therapy and follow-up in nonmetastatic Ewing family of tumors (EFT). PATIENTS AND METHODS: Primary tumor specimens and 97 peripheral blood (PBL) samples from 31 EFT patients were analyzed for TA by the Telomeric Repeat Amplification Protocol (TRAP assay). The telomerase catalytic subunit (human telomerase reverse transcriptase [hTERT]) gene expression was evaluated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and telomere length was determined by Southern blotting. The presence of the EFT chimeric transcripts was analyzed by RT-PCR. Correlations with progression-free survival were evaluated. RESULTS: At diagnosis, TA in primary tumors did not correlate with outcome. During therapy and follow-up, highly significant correlation was observed between high TA in PBL samples and adverse prognosis (P <.0001). None of the patients harboring low TA progressed, with a long follow-up (median, 60 months) and a progression-free survival (PFS) of 100%. In nine patients, high TA actually could predict relapse, long before overt clinical relapse. The group of patients with high TA and positive RT-PCR had the most adverse outcome; PFS of 20% (P =.0025). TA was found to be a better prognostic factor than RT-PCR and histopathologic response at surgery. CONCLUSION: The results suggest that TA is a significant prognostic variable, superior to the established clinical prognostic parameters during therapy and tumor surveillance. It could be used in combination with RT-PCR for a new risk classification.

HLA-A11 is associated with poor prognosis in childhood acute lymphoblastic leukemia (ALL).

A possible association between HLA antigens, susceptibility or resistance to leukemia, and responsiveness to treatment has been studied in 144 patients with childhood acute lymphoblastic leukemia (ALL) and compared to other prognostic factors, i.e. white blood cell (WBC) counts, age at onset, sex, ethnic origin, and cell surface markers. All sequentially newly diagnosed children (97) comprised the group for the prospective study (PSG) and were followed for 6 years. The group included 37 patients classified as T-ALL, 41 as CALLA+, 27 as NULL, 12 as B and pre-B, and 27 unclassified patients, who were diagnosed before 1980. During the follow-up period, 45 patients of the PSG died. Forty-seven patients designated long-term survivors (LTS) have been followed 6-20 years after diagnosis, having completed a 3-5 year course of anti-leukemia therapy, and having remained disease free thereafter. High WBC counts at diagnosis and T-cell-surface markers were associated with poor prognosis, as were enthnic origin and specific HLA antigens. Thus, there was one (1) a significant increase in HLA-A30 and a decrease in HLA B-14 in the PSG Jewish patients; and (2) a complete absence of HLA-ALL in LTS while, in the PSG, 8 of 9 HLA-All-positive patients died during the follow-up period. This suggests that HLA-All is associated with poor prognosis in childhood ALL.

Heterogeneity of childhood acute lymphoblastic leukemia (ALL): monoclonal antibodies phenotyping and induction of differentiation in vitro.

Fifty-eight pediatric patients with non-T acute lymphoblastic leukemia (ALL) were diagnosed and evaluated at the Sambur Center of Pediatric Hematology Oncology. At least six subtypes of non-T ALLs were identified, corresponding to the various stages of B-cell differentiation, by utilizing an extensive panel of monoclonal antibodies directed against T- B- and myeloid-cell differentiation antigens. Moreover, leukemic cells expressing the phenotype of early B cells could be driven to differentiate along the B- cell lineage to express CALLA and BL antigens and cytoplasmic and/or surface immunoglobulins (IgM). A unique phenotype of non-T ALL was also identified. These leukemic cells expressed B cell antigen exclusively, i.e., HLA/DR and B4 (CD19). Myeloid-cell antigens, however, were expressed on these cells spontaneously after a 24-hour incubation in culture medium in vitro. In addition, leukemic cells of four patients with a phenotype of HLA/DR, CD19, and CD10 expressed antigens of the T-cell lineage: CD7 (3AI) and CD2 (leu 5), and/or of the myeloid cell lineage (My7). These results provide confirming evidence for the wide scope of the heterogeneity of ALL. It stresses the validity of accurate classification of leukemia to identify biologically and clinically unique subtypes of ALL, which bears specific prognostic parameters; and designates therapeutic protocols.

Metastatic brain involvement in Ewing family of tumors in children.

OBJECTIVE: To evaluate the incidence and clinical characteristics of CNS involvement in Ewing family of tumors (EF) in children. METHODS: Chart reviews of children with EF treated in our center from 1972 to 1997. Clinical and imaging data regarding possible CNS involvement were collected. RESULTS: During this 25-year period, 80 children with EF were treated. Intracranial involvement was found in eight (10%) children: the brain was involved in seven children (8.8%) and a retro-orbital metastasis without parenchymal brain involvement was noted in one child. Metastases were localized intrahemispherically, or in the cerebellum or the basal ganglia. Intracranial spread was hematogenous in five children and by contiguous spread from the skull in three children. Intracranial involvement was diagnosed 1.3 to 11 years from initial presentation. Seizures and hemiparesis were the main neurologic complications. CONCLUSIONS: The rate of parenchymal brain involvement in our patients with EF was 8.8%. Spread was mainly hematogenous. Substantial morbidity was associated with CNS disease, which appeared in most patients late in the course of disease.

Mutations of the adenomatous polyposis coli and p53 genes in a child with Turcot's syndrome.

Turcot's syndrome is a rare heritable complex that is characterized by an association between a primary neuroepithelial tumor of the central nervous system and multiple colonic polyps. The aim of this study was to analyze genetic alterations in a case of Turcot's syndrome in a 10.5-year-old boy in whom a colorectal tumor developed 3.5 years following astrocytoma. An APC germline non-sense mutation at codon 1284 leading to a truncated protein was identified, as was a somatic p53 mutation in the colorectal carcinoma in exon 7, codon 244. The latter was not identified in the primary astrocytoma. However, immunohistochemistry revealed high p53 protein expression in both tumors, suggesting an additional p53 mutation in the primary astrocytic tumor. The diverse p53 mutations observed in this unique syndrome in two different sites and stages of the disease may shed light on the multistep progression of the malignant events.

Antibodies to HIV in Israeli hemophiliacs: relationship between serological profile and disease development.

We studied 66 Israeli hemophiliacs for antibodies to HIV in blood samples collected between 1978 and 1985. By May 1985, 2 had AIDS, 2 had ARC, 4 had lymphadenopathy with some immunologic dysfunction, and 58 were asymptomatic. Antibodies to HIV were detected in 40 (60.6%) patients, including all 8 with disease. Presence of HIV antibodies was significantly associated with receipt of non-heat-treated commercial factor VIII concentrates (NHT fac VIII) between 1980 and 1983. Thirty-eight of 45 (84.44%) patients treated with NHT fac VIII developed antibodies to HIV, compared to 1 of 16 (6.25%) treated with cryoprecipitates and fresh plasma only. Of 40 seropositive patients, 1 (2.5%) had antibodies by 1980, 4 (10%) by 1982, 14 (35%) by 1983, 10 (25.0%) by 1984, and 11 (27.5%) by May 1985. The decline in the rate of seroconversion can be attributed to the replacement of NHT fac VIII concentrate with heat-inactivated factor VIII (HT fac VIII) concentrate by November 1983. As of January 1984 only HT fac VIII was administered. Twenty-nine multitransfused thalassemia patients as well as 20 healthy Israeli blood donors were seronegative to HIV. All 40 (100%) seropositive hemophiliacs had antibodies to viral env gene encoded gp120/gp160 antigens. Twenty-four (60.05%) also had antibodies to viral gag gene encoded p24 and/or p55 antigens. While antibodies to gp120/160 persisted during the follow-up time, a loss of antibodies to p24/55 was observed in 5 of 16 (31.25%) seropositive patients from whom multiple samples were available. gp120/160 positive, p24/55 negative hemophiliacs had significantly lower absolute T-helper cell counts and reversed Th/Ts ratios when compared to gp120/160 p24/55 seropositive patients. Four of the 16 (25.0%) asymptomatic gp120/160 positive, p24/55 negative patients developed overt disease within 15 months of the last blood collection. The data suggest that exposure to HIV antigens is widespread among hemophiliacs in Israel, and can be attributed to receipt of NHT fac VIII concentrates prior to 1984. Antibodies to gp120/160 are of the most important diagnostic value while loss of antibodies to p24/p55 may be of prognostic value.

Exon 5 mutations in the p53 gene in relapsed childhood acute lymphoblastic leukemia.

Thirty seven children with relapsed acute lymphoblastic leukemia (ALL), 25 B-lineage and 12 T-lineage, were analyzed for p53 alterations at different stages of the disease. Loss of heterozygosity (LOH) was detected in the relapse phase in three patients. p53 mutations were identified by single strand conformation polymorphism (SSCP) and sequencing analyzes in seven of the 37 ALL patients (19%); three B-lineage (12%) and four T-lineage (33%). Most of the mutations were identified in the relapse phase. In two exceptional cases, one of the mutations was indicated as a germ line and the other was already present at diagnosis. No p53 mutation was identified in any of the other 20 available bone marrow samples obtained at diagnosis. No correlation between the p53 status and clinical outcome could be determined. The majority of the mutations (four out of seven, 57%) were clustered at exon 5. Our data implicate that p53 exon 5 is a frequent site of mutations in relapsed childhood ALL.

Long-term culture of infant leukemia cells: dependence upon stromal cells from the bone marrow and bilineage differentiation.

Infant leukemia cells with 46XY,t(11; 17)(q23; p13) karyotype and a hybrid pre B myeloid phenotype (HLA-DR, (Ia), B4 and My7-positive and CALLA and T11-negative) and immunoglobulin heavy chain gene rearrangement were maintained in long-term culture for over 10 months. The in-vitro survival and growth of the leukemia cells were strictly dependent upon the presence of their autologous marrow stromal cells. The latter could be replaced by the 14F1.1 clone of preadipocytes derived from mouse bone marrow. Neither heterologous human marrow or foreskin fibroblasts nor fibroblast or endothelial like cell lines from mouse stroma could mimic the effect of autologous stroma or 14F1.1 adipocytes. The leukemia cells maintained their original phenotype throughout the 10-month culture period with either their autologous stroma or the 14F1.1 adipocytes. They could be induced to differentiate in two distinct directions. Phorbol myristate acetate induced adherence of the leukemia cells and development of macrophage properties. In contrast, conditioned medium from a hybridoma producing B-cell growth factor caused aggregation of the leukemia cells and expression of CALLA antigen and surface IgM. This bipotency of the leukemia cells and their dependence upon marrow stroma are properties in common with stem cells.

Molecular analysis of childhood acute lymphoblastic leukemia in Israel.

Ninety-two Israeli children with acute lymphoblastic leukemia (ALL) (67 B-lineage and 25 T-lineage) were analyzed for the immunological antigen receptor gene configuration. Thirty-nine of the patients (27 B-lineage and 12 T-lineage) relapsed. The incidence of the identified rearrangements within the immunoglobulin heavy chain (IgH) and T-cell receptor (TCR)beta, gamma and delta genes, at diagnosis, was in accordance with previous studies from other countries. Furthermore, the clinical relevance of bi/oligoclonal status, at diagnosis, and clonal selection was determined in this long-term follow-up study (median 112 months). A similar relapse rate was observed among the B-lineage patients with bi/oligoclonal and monoclonal patterns indicated by IgH gene rearrangement. Based on our results, we suggest that bi/oligoclonality has no prognostic significance (P=0.8533). Clonal variations between diagnosis and subsequent relapses were detected in 60% (12/20) of the patients; 64% (7/11) B-lineage and 55% (5/9) T-lineage. Clonal selection significantly correlated with shorter duration of remission and earlier recurrence (P=0.0025).

Linkage disequilibrium of common Gaucher disease mutations with a polymorphic site in the pyruvate kinase (PKLR) gene.

Gaucher disease (GD), caused by a deficiency of the lysosomal enzyme glucocerebrosidase (GBA), is the most common human glycolipid storage disease. The incidence of the disease is particularly high in the Ashkenazi Jewish population, with a carrier frequency of 0.068. The 1226A-->G and 84GG mutations are the two predominant disease-causing alleles. We investigated the association of various mutations in the GBA gene with different alleles of a highly polymorphic site in the adjacent pyruvate kinase (PKLR) gene. Ninety-seven unrelated type I GD patients of various genotypes were studied to determine their genotype for the PKLR gene trinucleotide repeat polymorphism. One hundred out of 104 (96%) alleles carrying the 1226G mutation also carried the A1 allele of the PKLR gene, which is present in only 6.7% of the control population. The calculated linkage disequilibrium between 1226G and the A1 allele of the PKLR gene is 0.957. Mutation 84GG was found to be uniquely associated with the PKLR A6 allele, with a linkage disequilibrium of 1.00. The association of several less frequent GD mutations with PKLR alleles was also studied. These results support the hypothesis that the 1226G and 84GG mutations in the Ashkenazi Jewish population each originated in a single founder. Further studies of the association of the 1226G and 84GG mutations with PKLR alleles in European non-Jewish GD patients could help in the study of the chronological order of these mutations and may shed light on the history of the Ashkenazi Jews in the past two millennia.

Prognostic factors in non-metastatic limb osteosarcoma: A 20-year experience of one center.

The purpose of this study was to evaluate the prognostic significance of variables in osteosarcoma. We performed a retrospective analysis of 35 patients with non-metastatic limb osteosarcoma that were treated between 1973 and 1994. The following variables were evaluated: age, sex, ethnic group, tumor histology and primary site, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels at diagnosis, treatment regimen, and the histologic response to treatment. Three variables showed significant correlation with prognosis: i) histologic response to preoperative treatment. Disease-free survival (DFS) was 89% in patients with grade III-IV histologic response after a median follow-up (MFU) of 64 months, 67% in patients with grade II after an MFU of 64 months, the patients with grade I response died within 15 months (p<0.0001); ii) treatment regimen. DFS was 83% after an MFU of 42 months, 62% after an MFU of 82 months, and 30% after an MFU of 177 months in patients treated by the 90's, 80's, and 70's protocols, respectively (p<0.05); iii) corrected ALP (cALP) levels at diagnosis. DFS was 78% after an MFU of 88 months in patients with cALP levels <200, and 32% after an MFU of 56 months in patients with cALP levels >200 (p=0.01). Low ALP levels, good histologic response to preoperative chemotherapy, and the new therapeutic regimen correlated with good prognosis in patients with osteosarcoma.

Transient swelling of the costochondral and sternal region in infants.

Four children aged 9 months, 11 months, 1 year, and 1 year 4 months, respectively, presented to the emergency room with an acute tender swelling of the sternum or sternocostal cartilage. Three of these resolved spontaneously within a few weeks of presentation, and in one curettage was carried out. We were unable to find any other references in the literature of this condition occurring in infants. Acute swelling of the chest wall frequently is due to neoplastic or infectious disease, and culture of aspirated material and possibly biopsy has been recommended in all cases. Our experience suggests that this may not always be necessary.

Retrolental Fibroplasia. II. Pathologic correlation.

Retinas of 142 eyes from 71 premature infants on whom autopsies had been done were studied by gross observation and by using PAS-stained whole mount, trypsin-digest, and conventional histological techniques. With these techniques, vascular pathologic condition was correlated with fluorescein angiograms in living infants with acute retrolental fibroplasia. The specific lesions seen in acute phase were a major arteriovenous shunt in the eye, microvascular changes including tufting, and obliteration of capillaries around arteries and veins. Regression occurred by vascular budding from the anterior edge of the shunt. Observations on vascularization in the normal indicated a variability of the level of maturation of the retinal vasculature, only roughly correlated with gestational age.

Outcome of oncology patients in the pediatric intensive care unit.

We evaluated the outcome of oncology patients in the Pediatric Intensive Care Unit (PICU) from a total of 72 consecutive admissions. Severity of illness and quantity of care were measured by the Physiologic Stability Index (PSI) and the Therapeutic Intervention Scoring System (TISS), respectively. The overall mortality was 51% and was especially high in patients admitted for acute organ system failure (OSF)-66%. Acute respiratory failure was the most frequent OSF (73%) and the most common cause for PICU admission. A poor outcome was associated with severe leucopenia (less than 1000 WBC/mm3, 91% mortality), acute renal failure (94% mortality) and central nervous system deterioration (83% mortality). When the outcome was predicted using a quantitative algorithm the observed mortality was significantly higher than the predicted for all admissions with a PSI higher than 5. Improved scoring systems are required to enable characterization of pediatric cancer patients admitted to the PICU.