bluuebunny/crossref_metadata_2025 huggingface dataset:
An explanation for the origin of hemihedrism in wulfenite: the single-crystal structures ofI41/a andItungstenian wulfenites
Authors: Hibbs D. E. , Jury C. M. , Leverett P. , Plimer I. R. , Williams P. A.
Published: July 2002

The single-crystal X-ray structure of tungstenian wulfenite-I41/acontaining 10 mol.% WO3from the San Francisco mine, Sonora, Mexico, space groupI41/a,a= 5.436(2),c= 12.068(8)Å andZ= 4, has been refined toR= 0.052. The Mo and W are disordered over special position 4a(0,0,0) in the lattice. Tungstenian wulfenite-I4̄ (‘chillagite’) from the Christmas Gift mine, Chillagoe, Queensland, Australia (Museum of Victoria specimen M16934), crystallizes in the closely related tetragonal space groupI4̄, witha= 5.441(1),c= 12.068(6) Å andZ= 4. The structure was refined toR= 0.038. Refined site occupancy factors show that Mo and W are not distributed equally over the two crystallographically independent Mo/W positions, being 0.136(2) for Mo and 0.114(2) for W in special position 2a(0,0,0) and 0.184(2) for Mo and 0.066(2) for W in special position 2c(0,Ý,Ü). These give a composition corresponding to wulfenite64stolzite36, in agreement with analytical data. The Mo/W distributions in the unit cell provide one explanation for the origin of hemihedrism in the wulfenite-stolzite series.
Al-free gyrolite from the Lizard, Cornwall, England
Authors: Elton N. J. , Hooper J. J. , Holyer V. A. D.
Published: July 2002

Gyrolite containing no detectable Al (<0.04 wt.%) has been found as aggregates of platey crystals to 6 mm at Dean Quarry, the Lizard, Cornwall. The gyrolite occurs embedded in calcite which fills a fracture vein in gabbro. Paragenetic evidence is inconclusive, but suggests that gyrolite formed relatively early, after prehnite, and possibly around the same time as analcime and natrolite.
Polymorphic transformations between olivine, wadsleyite and ringwoodite: mechanisms of intracrystalline nucleation and the role of elastic strain
Authors: Kerschhofer Ljuba , Dupas Catherine , Liu Ming , Sharp Thomas G. , Durham William B. , Rubie David C.
Published: July 2002

Kinetic models and rate equations for polymorphic reconstructive phase transformations in polycrystalline aggregates are usually based on the assumptions that (a) the product phase nucleates on grain boundaries in the reactant phase and (b) growth rates of the product phase remain constant with time at fixed P-T. Recent observations of experimentally-induced transformations between (Mg,Fe)2SiO4 olivine (α) and its high pressure polymorphs, wadsleyite (β) and ringwoodite (γ), demonstrate that both these assumptions can be invalid, thus complicating the extrapolation of experimental kinetic data. Incoherent grain boundary nucleation appears to have dominated in most previous experimental studies of the α–β–γ transformations because of the use of starting materials with small (<10–20 µm) grain sizes. In contrast, when large (0.6 mm) olivine single crystals are reacted, intracrystalline nucleation of both β and γ becomes the dominant mechanism, particularly when the P-T conditions significantly overstep the equilibrium boundary. At pressures of 18–20 GPa intracrystalline nucleation involves (i) the formation of stacking faults in the olivine, (ii) coherent nucleation of γ-lamellae on these faults and (iii) nucleation of β on γ. In other experiments, intracrystalline nucleation is also observed during the β-γ transformation. In this case coherent nucleation of γ appears to occur at the intersections of dislocations with (010) stacking faults in β, which suggests that the nucleation rate is stress dependent. Reaction rims of β/γ form at the margins of the olivine single crystals by grain boundary nucleation. Measurements of growth distance as a function of time indicate that the growth rate of these rims decreases towards zero as transformation progresses. The growth rate slows because of the decrease in the magnitude of the Gibbs free energy (stored elastic strain energy) that develops as a consequence of the large volume change of transformation. On a longer time scale, growth kinetics may be controlled by viscoelastic relaxation.
A multi-method analysis of Si-, S- and REE-rich apatite from a new find
of kalsilite-bearing leucitite (Abruzzi, Italy)
Authors: Comodi P. , Liu Y. , Stoppa F. , Woolley A.R.
Published: July 2002

The crystal chemistry characteristics of a hydroxyl-fluor apatite from a
recently discovered kalsilite-bearing leucitite from Abruzzi, Italy, were
investigated by electron microprobe, single crystal X-ray diffraction, IR, Raman
and micro-Raman spectroscopy. The apatite has exceptionally high S and relatively
high Si, Sr and LREE, whereas the
HREE content is negligible. The IR spectra confirm
the presence of OH calculated from formula difference. A high positive correlation
between Ca-site Substitution Index (CSI = 100(10-Ca)/Ca) and Tetrahedral
Substitution Index (TSI = 100 (Si+C+S)/P atom/a.p.f.u.) and a systematic parallel
increase in REE, S and Si indicate two substitution
mechanisms, i.e. REE3+ +
Si4+ = Ca2+ +
P5+ and Si4+ +
S6+ = 2 P5+. Site occupancy data and
bond lengths, determined from structural refinements on selected samples,
demonstrate that LREE and Sr show a marked preference
for the Ca2 site, even though in the LREE-rich samples
a partial substitution of LREE for Ca in the Cal site
was observed.

Tetrahedral distances (from 1.535 to 1.541 Å.) reflect the substitution of
Si4+ and S6+ for
P5+, which is also confirmed by vibrational spectra. As
(SiO4)4− and
(SO4)2− substitute for
(PO4)3−, the relative intensity of
v1 Raman bands of
(SO4)2− (at 1007
cm−1) and
(SiO4)4− (at 865
cm−1) increase systematically, while that of phosphate
decreases and the five components of phosphate v3 modes
disappear. Moreover, the (PO4)3− Raman
peak broadening is linearly correlated with the Si and S concentrations.

Apatite crystals are sometimes zoned with compositions varying from
SiO2 = 1.15–2.07 wt.%,
Σ(LREE2O3)
= 0.56–1.08 wt.% and SrO = 0.58–1.02 wt.% in the core to 3.98–5.03, 4.14–6.73 and
1.97–2.17, respectively, in the rim. A sharp, strong enrichment in Sr and
LREE in the rim indicate that the apatite suddenly
became an acceptor of these elements in the late stages of
crystallization.
Shwachman-Diamond syndrome marrow cells show abnormally increased apoptosis mediated through the Fas pathway
Authors: Dror Yigal , Freedman Melvin H.
Published: July 2002

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow disorder with varying cytopenias and a strong predilection to myelodysplastic syndrome (MDS) and acute myeloid leukemia. Previously, it was found that the percentage of CD34+ cells in bone marrow and the in vitro colony formation from CD34+ cells of patients with SDS were markedly reduced. For these reasons, and because apoptosis is central in the pathogenesis of bone marrow dysfunction in MDS, this study was initiated to delineate the role of apoptosis in the pathogenesis of the marrow failure. Eleven children with SDS were studied. Compared to normal controls, patients' marrow mononuclear cells plated in clonogenic cultures showed a significantly higher tendency to undergo apoptosis. The defect in SDS was found in patients with and without MDS. Patients showed a more prominent decrease in colony formation and increased apoptosis after preincubation with activating anti-Fas antibody. Fas expression on marrow cells from patients was significantly higher than from normal controls. The difference between patients and controls for Fas expression was also significant for the following cell fraction subpopulations: CD34−/CD38−, CD34−/CD38+, and CD34+. In conclusion, SDS hematopoietic progenitors are intrinsically flawed and have faulty proliferative properties and increased apoptosis. Bone marrow failure in SDS appears mediated by increased apoptosis as the central pathogenetic mechanism. This increased propensity for apoptosis is linked to increased expression of the Fas antigen and to hyperactivation of the Fas signaling pathway.
Defective octamer-dependent transcription is responsible for silenced immunoglobulin transcription in Reed-Sternberg cells
Authors: Theil Jan , Laumen Helmut , Marafioti Theresa , Hummel Michael , Lenz Georg , Wirth Thomas , Stein Harald
Published: July 2002

The absence of immunoglobulin (Ig) expression in B-cell–derived Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin disease (cHD) was initially suggested to be caused by crippling mutations in the Ig promoter or coding region. More recent investigations have, however, challenged this concept. This study addressed the role of mutations in the Ig promoter region in HRS cells. Nine cases of cHD and 3 B-cell–derived HD lines were analyzed for mutations in the TATA box and octamer motif of the Ig promoter. Mutations in the octamer motif were found in only 1 of the 9 cases and in 1 of the 3 HD cell lines (L1236). Furthermore, in all cases either a complete lack or strong reduction in the expression of the Oct2 transcription factor and the BOB.1/OBF.1 coactivator were found. The relevance of the rare promoter mutations was investigated by assaying the activity of Ig promoter reporter constructs transfected into the HD cell line L1236, which harbors a mutated octamer motif. These Ig reporter constructs were completely inactive in L1236 cells; however, their activity could be reconstituted by the cotransfection of a BOB.1/OBF.1 expression vector. The additional transfection with an Oct2 expression vector did not further enhance the Ig promoter activity. The conclusions drawn from these results are that crippling mutations in the Ig promoter and coding region are not the sole cause for the lack of Ig expression in HRS cells and that defects in the transcription machinery such as absence of BOB.1/OBF.1 are more important for this phenomenon.
Identification of a novel, human multilymphoid progenitor in cord blood
Authors: Hao Qian-Lin , Zhu Judy , Price Mary A. , Payne Kimberly J. , Barsky Lora W. , Crooks Gay M.
Published: July 2002

The earliest stages of lymphoid commitment from human pluripotent hematopoietic stem cells have not been defined. A clonogenic subpopulation of CD34+CD38− cord blood cells were identified that expressed high levels of the CD7 antigen and possessed only lymphoid potential. CD34+CD38−CD7+ (CD7+) cells uniformly coexpressed CD45RA and HLA-DR;c-kit and Thy-1 expression was absent to low. Clonal analysis demonstrated that single CD7+ cells could generate B cells, natural killer cells, and dendritic cells but were devoid of myeloid or erythroid potential. In contrast, control CD34+CD38−CD7−(CD7−) cells generated both lymphoid and myelo-erythroid cells. The lymphoid potential (generation of lymphoid progeny in bulk and single cell cultures) of CD7+ cells was equivalent to that of the pluripotent CD7− cells. RNA expression studies showed that CD7+ cells expressed PU.1 and GATA-3, but did not express Pax-5, terminal deoxynucleotide transferase, or CD3ε. In contrast to the previously described murine common lymphoid progenitor, the α chain of the receptor for interleukin-7 was not detected by fluorescence-activated cell sorting analysis or RNA polymerase chain reaction in CD7+cells. These studies identify a clonogenic lymphoid progenitor with both B-cell and natural killer cell lineage potential with a molecular profile that suggests a developmental stage more primitive than previously identified lymphoid progenitors. The CD7+phenotype distinguishes primitive human lymphoid progenitors from pluripotent stem cells, thus allowing the study of regulation of early human lymphopoiesis and providing an alternative to pluripotent stem cells for genetic manipulation and transplantation.
Autoantibody against prothrombin aberrantly alters the proenzyme to facilitate formation of a complex with its physiological inhibitor antithrombin III without thrombin conversion
Authors: Madoiwa Seiji , Nakamura Yuichi , Mimuro Jun , Furusawa Shinpei , Koyama Takatoshi , Sugo Teruko , Matsuda Michio , Sakata Yoichi
Published: July 2002

Acquired coagulation factor inhibitors include pathologic immunoglobulins that specifically bind to coagulation factors and either neutralize their procoagulant activity, accelerate their clearance from the circulation, or have proteolytic activity to degrade them into inactive polypeptides. Here, an autoantibody against prothrombin is described in a patient with serious hemorrhagic diatheses. The autoantibody exerts its influence by a previously unknown mechanism in which it inhibits coagulation through aberrant activation of the proenzyme in a catalytic manner. The antibody-bound prothrombin formed a stable stoichiometric complex with antithrombin III, consisting of intact prothrombin and an antithrombin III molecule cleaved at the 393Arg-394Ser bond. The antibody dissociated from prothrombin after the complex formation with antithrombin III. Although the bound antibody elicited protease activity from prothrombin, the complex was not able to convert fibrinogen to fibrin or to activate protein C. Thus, this is the first description of an autoantibody that induces protease-like activity from a human proenzyme, permitting subsequent neutralization by its physiological inhibitor.
Role of Fc receptor γ-chain in platelet glycoprotein Ib–mediated signaling
Authors: Wu Yi , Suzuki-Inoue Katsue , Satoh Kaneo , Asazuma Naoki , Yatomi Yutaka , Berndt Michael C. , Ozaki Yukio
Published: July 2002

Interaction between von Willebrand factor (vWF) and glycoprotein Ib (GPIb) stimulates tyrosine kinases and subsequent tyrosine phosphorylation events in human platelets. This study found that the combination of vWF and botrocetin, by interacting with GPIb, induced tyrosine phosphorylation of Fc receptor γ-chain (FcR γ-chain), Syk, linker for activation of T cells (LAT), and phospholipase C γ2 (PLCγ2). Pretreatment of platelets with 10 μM PP1 completely inhibited these tyrosine phosphorylation events. On GPIb stimulation, Src and Lyn formed a complex with FcR γ-chain and Syk, suggesting that Src and Lyn are involved in FcR γ-chain tyrosine phosphorylation and downstream signals. In spite of the PLCγ2 tyrosine phosphorylation, however, there was no intracellular calcium release and inositol 1,4,5-trisphosphate production. In Brij 35 lysates, FcR γ-chain was found to constitutively associate with GPIb. The number of GPIb expressed on FcR γ-chain–deficient platelets was comparable to that of the wild-type, as assessed by flow cytometry. However, tyrosine phosphorylation of Syk, LAT, and PLCγ2 in response to vWF plus botrocetin was significantly suppressed, suggesting that FcR γ-chain mediates activation signals related to GPIb. Compared with the aggregation response of wild-type platelets, that of FcR γ-chain–deficient platelets in response to vWF plus botrocetin was impaired, implying that FcR γ-chain is required for the full activation of platelets mediated by GPIb.
Xenotransplantation of immunodeficient mice with mobilized human blood CD34+ cells provides an in vivo model for human megakaryocytopoiesis and platelet production
Authors: Perez Lia E. , Rinder Henry M. , Wang Chao , Tracey Jayne B. , Maun Noel , Krause Diane S.
Published: July 2002

The study of megakaryocytopoiesis has been based largely on in vitro assays. We characterize an in vivo model of megakaryocyte and platelet development in which human peripheral blood stem cells (PBSCs) differentiate along megakaryocytic as well as myeloid/lymphoid lineages in sublethally irradiated nonobese diabetic/severe combined immunodeficient (NOD-SCID) mice. Human hematopoiesis preferentially occurs in the bone marrow of the murine recipients, and engraftment is independent of exogenous cytokines. Human colony-forming units–megakaryocyte (CFU-MK) develop predominantly in the bone marrow, and their presence correlates with the overall degree of human cell engraftment. Using a sensitive and specific flow cytometric assay, human platelets are detected in the peripheral blood from weeks 1 to 8 after transplantation. The number of circulating human platelets peaks at week 3 with a mean of 20 × 109/L. These human platelets are functional as assessed by CD62P expression in response to thrombin stimulation in vitro. Exogenous cytokines have a detrimental effect on CFU-MK production after 2 weeks, and animals treated with these cytokines have no circulating platelets 8 weeks after transplantation. Although cytokine stimulation of human PBSCs ex vivo led to a significant increase in CFU-MK, CD34+/41+, and CD41+ cells, these ex vivo expanded cells provided only delayed and transient platelet production in vivo, and no CFU-MK developed in vivo after transplantation. In conclusion, xenogeneic transplantation of human PBSCs into NOD/SCID mice provides an excellent in vivo model to study human megakaryocytopoiesis and platelet production.
Development of thymic and splenic dendritic cell populations from different hemopoietic precursors
Authors: Wu Li , D'Amico Angela , Hochrein Hubertus , O'Keeffe Meredith , Shortman Ken , Lucas Karen
Published: July 2002

The antigen-presenting dendritic cells (DCs) found in mouse lymphoid tissues are heterogeneous. Several types of DCs have been identified on the basis of the expression of different surface molecules, including CD4, CD8α, and DEC-205. Previous studies by the authors showed that the mouse intrathymic lymphoid-restricted precursors (lin−c-kit+Thy-1lowCD4low) can produce DCs in the thymus and spleen upon intravenous transfer, suggesting a lymphoid origin of these DCs. In the current study, the potential for DC production by the newly identified bone marrow (BM) common lymphoid precursors (CLPs), common myeloid precursors (CMPs), and committed granulocyte and macrophage precursors was examined. It was found that both the lymphoid and the myeloid precursors had the potential to produce DCs. All the different DC populations identified in mouse thymus and spleen could be produced by all these precursor populations. However, CLPs produced predominantly the CD4−CD8α+ DCs, whereas CMPs produced similar numbers of CD4−CD8α+ and CD4+CD8α− DCs, although at different peak times. On a per cell basis, the CLPs were more potent than the CMPs at DC production, but this may have been compensated for by an excess of CMPs over CLPs in BM. Overall, this study shows that the expression of CD8α does not delineate the hemopoietic precursor origin of DCs, and the nature of the early precursors may bias but does not dictate the phenotype of the DC product.
Platelets from patients with the Quebec platelet disorder contain and secrete abnormal amounts of urokinase-type plasminogen activator
Authors: Kahr Walter H. A. , Zheng Shilun , Sheth Prameet M. , Pai Menaka , Cowie Alison , Bouchard Madeleine , Podor Thomas J. , Rivard Georges E. , Hayward Catherine P. M.
Published: July 2002

The Quebec platelet disorder (QPD) is an autosomal dominant platelet disorder associated with delayed bleeding and α-granule protein degradation. The degradation of α-granule, but not plasma, fibrinogen in patients with the QPD led to the investigation of their platelets for a protease defect. Unlike normal platelets, QPD platelets contained large amounts of fibrinolytic serine proteases that had properties of plasminogen activators. Western blot analysis, zymography, and immunodepletion experiments indicated this was because QPD platelets contained large amounts of urokinase-type plasminogen activator (u-PA) within a secretory compartment. u-PA antigen was not increased in all QPD plasmas, whereas it was increased more than 100-fold in QPD platelets (P < .00009), which contained increased u-PA messenger RNA. Although QPD platelets contained 2-fold more plasminogen activator inhibitor 1 (PAI-1) (P < .0008) and 100-fold greater u-PA–PAI-1 complexes (P < .0002) than normal platelets, they contained excess u-PA activity, predominantly in the form of two chain (tcu-PA), which required additional PAI-1 for full inhibition. There was associated proteolysis of plasminogen in QPD platelets, to forms that comigrated with plasmin. When similar amounts of tcu-PA were incubated with normal platelet secretory proteins, many α-granule proteins were proteolyzed to forms that resembled degraded QPD platelet proteins. These data implicate u-PA in the pathogenesis of α-granule protein degradation in the QPD. Although patients with the QPD have normal to increased u-PA levels in their plasma, without evidence of systemic fibrinogenolysis, their increased platelet u-PA could contribute to bleeding by accelerating fibrinolysis within the hemostatic plug. QPD is the only inherited bleeding disorder in humans known to be associated with increased u-PA.
Factors influencing B lymphopoiesis after allogeneic hematopoietic cell transplantation
Authors: Storek Jan , Wells Denise , Dawson Monja A. , Storer Barry , Maloney David G.
Published: July 2002

In 93 allograft recipients, the numbers of marrow B-cell precursors on days 80 and 365 correlated with the counts of circulating B cells, suggesting that the posttransplantation B-cell deficiency is at least in part due to insufficient B lymphopoiesis. Factors that could affect B lymphopoiesis were evaluated. The number of marrow B-cell precursors on days 30 and 80 was at least 4-fold lower in patients with grade 2 to 4 acute graft-versus-host disease (GVHD) compared with patients with grade 0 to 1 acute GVHD. The number of B-cell precursors on day 365 was 18-fold lower in patients with extensive chronic GVHD compared with patients with no or limited chronic GVHD. The number of B-cell precursors was not related to CD34 cell dose, type of transplant (marrow versus blood stem cells), donor age, or patient age. It was concluded that posttransplantation B-cell deficiency results in part from inhibition of B lymphopoiesis by GVHD and/or its treatment.
SH2D1A mutations in Japanese males with severe Epstein-Barr virus–associated illnesses
Authors: Sumazaki Ryo , Kanegane Hirokazu , Osaki Maki , Fukushima Takashi , Tsuchida Masahiro , Matsukura Hiroyoshi , Shinozaki Kentaro , Kimura Hiroshi , Matsui Akira , Miyawaki Toshio
Published: July 2002

X-linked lymphoproliferative disease (XLP), a genetic disorder characterized by immunodeficiency to Epstein-Barr virus (EBV) infection, has been linked to mutations in the SH2D1A gene. To search for the occurrence of SH2D1A mutations in Japan, we performed genetic analysis of the SH2D1A gene in 40 males presenting with severe EBV-associated illnesses, including fulminant infectious mononucleosis, EBV-positive lymphoma, and severe chronic active EBV infection. SH2D1A mutations were detected in 10 of these 40 patients. Five of these 10 cases were sporadic. Patients with SH2D1A mutations displayed severe acute infectious mononucleosis with hyperimmunoglobulin M, hypogammaglobulinemia, and B-cell malignant lymphoma. By contrast, chronic active EBV infection was not associated with SH2D1Amutations. XLP survivors exhibited normal levels of circulating EBV-DNA during convalescence, suggesting that SH2D1A protein is not directly responsible for control of EBV replication. Thus, genetic analysis of the SH2D1A gene is particularly useful in the diagnosis of sporadic cases and carriers of XLP.
Identification of anti–herpes simplex virus antibody–producing B cells in a patient with an atypical RAG1 immunodeficiency
Authors: Kumaki Satoru , Villa Anna , Asada Hiroshi , Kawai Shin , Ohashi Yoshiyuki , Takahashi Miyoko , Hakozaki Ikuko , Nitanai Etsuko , Minegishi Masayoshi , Tsuchiya Shigeru
Published: July 2002

Mutations of the RAG1 or RAG2 protein that eliminate their recombination activity result in T-B-severe combined immunodeficiency (SCID), whereas mutations retaining partial recombination activity lead to Omenn syndrome, a peculiar SCID characterized by increased host T cells and absence of circulating B cells. The prognosis of this disease is fatal, unless hematopoietic stem cell transplantation is performed. This study reports a case of atypical SCID, carrying RAG1 mutations. The patient survived for 6 years without hematopoietic stem cell transplantation. The missense mutation, tested by in vivo recombination assay, revealed residual recombination activity. By the age of 5 years, the patient developed host B cells, but not T cells, possibly due to engrafted maternal T cells. In addition, the host B cells were able to produce antibodies, including anti–herpes simplex virus–antibodies. The fact that host B cells could produce antibodies in this patient could explain not only the mild phenotype observed but also, at least in part, how patients with Omenn syndrome produce immunoglobulin E and sometimes immunoglobulin M, as the same missense mutation of RAG1 gene has been reported in a patient with Omenn syndrome.
Expression of scinderin in megakaryoblastic leukemia cells induces differentiation, maturation, and apoptosis with release of plateletlike particles and inhibits proliferation and tumorigenesis
Authors: Zunino Rodolfo , Li Qinggang , Rosé Sergio Daniel , Romero-Benı́tez Marı́a Margarita Itatı́ , Lejen Tatiana , Brandan Nora Cristina , Trifaró José-Marı́a
Published: July 2002

Rapid proliferation of atypical megakaryoblasts is a characteristic of megakaryoblastic leukemia. Cells from patients with this disorder and cell lines established from this type of leukemia showed the presence of gelsolin but the absence of scinderin expression, 2 filamentous actin-severing proteins present in normal megakaryocytes and platelets. Vector-mediated expression of scinderin in the megakaryoblastic cell line MEG-01 induced a decrease in both F-actin and gelsolin. This was accompanied by increased Rac2 expression and by activation of the PAK/MEKK.SEK/JNK/c-jun, c-fos transduction pathway. The Raf/MEK/ERK pathway was also activated in these cells. Transduction pathway activation was followed by cell differentiation, polyploidization, maturation, and apoptosis with release of platelet-like particles. Particles expressed surface CD41a antigen (glycoprotein IIb/IIIa or fibrinogen receptor), had dense bodies, high-affinity serotonin transport, and circular array of microtubules. Treatment of particles with thrombin induced serotonin release and aggregation that was blocked by CD41a antibodies. PAC-1 antibodies also blocked aggregation. Exposure of cells to PD98059, a blocker of MEK, inhibited antigen CD41a expression, increases in cell volume, and number of protoplasmic extensions. Cell proliferation and cell ability to form tumors in nude mice were also inhibited by the expression of scinderin. MEG-01 cells expressing scinderin had the same fate in vivo as in culture. Thus, when injected into nude mice, they entered apoptosis and released platelet-like particles. The lack of scinderin expression in megakaryoblastic leukemia cells seems to be responsible for their inability to enter into differentiation and maturation pathways characteristic of their normal counterparts.
Activation of the nitric oxide synthase pathway represents a key component of tumor necrosis factor–related apoptosis-inducing ligand–mediated cytotoxicity on hematologic malignancies
Authors: Secchiero Paola , Gonelli Arianna , Celeghini Claudio , Mirandola Prisco , Guidotti Lia , Visani Giuseppe , Capitani Silvano , Zauli Giorgio
Published: July 2002

Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) induced both cytotoxic (apoptosis) and cytostatic (cell cycle perturbation) effects on the human myeloid K562 cell line. TRAIL stimulated caspase 3 and nitric oxide synthase (NOS) activities, and both pathways cooperate in mediating inhibition of K562 survival/growth. This was demonstrated by the ability of z-VAD-fmk, a broad inhibitor of effector caspases, and N-nitro-l-arginine methyl ester (L-NAME), an NOS pharmacologic inhibitor, to completely (z-VAD-fmk) or partially (L-NAME) suppress the TRAIL-mediated inhibitory activity. Moreover, z-VAD-fmk was able to block TRAIL-mediated apoptosis and cell cycle abnormalities and increase of NOS activity. The addition of the NO donor sodium nitroprusside (SNP) to K562 cells reproduced the cytostatic effect of TRAIL without inducing apoptosis. When TRAIL was associated to SNP, a synergistic increase of apoptosis and inhibition of clonogenic activity was observed in K562 cells as well as in other myeloblastic (HEL, HL-60), lymphoblastic (Jurkat, SupT1), and multiple myeloma (RPMI 8226) cell lines. Although SNP greatly augmented TRAIL-mediated antileukemic activity also on primary leukemic blasts, normal erythroid and granulocytic cells were less sensitive to the cytotoxicity mediated by TRAIL with or without SNP. These data indicate that TRAIL promotes cytotoxicity in leukemic cells by activating effector caspases, which directly lead to apoptosis and stimulate NO production, which mediates cell cycle abnormalities. Both mechanisms seem to be essential for TRAIL-mediated cytotoxicity.
Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients
Authors: Timmerman John M. , Czerwinski Debra K. , Davis Thomas A. , Hsu Frank J. , Benike Claudia , Hao Zheng Mei , Taidi Behnaz , Rajapaksa Ranjani , Caspar Clemens B. , Okada Craig Y. , van Beckhoven Adrienne , Liles Tina Marie , Engleman Edgar G. , Levy Ronald
Published: July 2002

Tumor-specific clonal immunoglobulin expressed by B-cell lymphomas (idiotype [Id]) can serve as a target for active immunotherapy. We have previously described the vaccination of 4 patients with follicular lymphoma using dendritic cells (DCs) pulsed with tumor-derived Id protein and now report on 35 patients treated using this approach. Among 10 initial patients with measurable lymphoma, 8 mounted T-cell proliferative anti-Id responses, and 4 had clinical responses—2 complete responses (CRs) (progression-free [PF] for 44 and 57 months after vaccination), 1 partial response (PR) (PF for 12 months), and 1 molecular response (PF for 75+ months). Subsequently, 25 additional patients were vaccinated after first chemotherapy, and 15 of 23 (65%) who completed the vaccination schedule mounted T-cell or humoral anti-Id responses. Induction of high-titer immunoglobulin G anti-Id antibodies required coupling of Id to the immunogenic carrier protein keyhole limpet hemocyanin (Id-KLH). These antibodies could bind to and induce tyrosine phosphorylation in autologous tumor cells. Among 18 patients with residual tumor at the time of vaccination, 4 (22%) had tumor regression, and 16 of 23 patients (70%) remain without tumor progression at a median of 43 months after chemotherapy. Six patients with disease progression after primary DC vaccination received booster injections of Id-KLH protein, and tumor regression was observed in 3 of them (2 CRs and 1 PR). We conclude that Id-pulsed DC vaccination can induce T-cell and humoral anti-Id immune responses and durable tumor regression. Subsequent boosting with Id-KLH can lead to tumor regression despite apparent resistance to the primary DC vaccine.
Soluble HLA class I molecules induce natural killer cell apoptosis through the engagement of CD8: evidence for a negative regulation exerted by members of the inhibitory receptor superfamily
Authors: Spaggiari Grazia Maria , Contini Paola , Carosio Roberta , Arvigo Marica , Ghio Massimo , Oddone Daniela , Dondero Alessandra , Zocchi Maria Raffaella , Puppo Francesco , Indiveri Francesco , Poggi Alessandro
Published: July 2002

Herein, we show that CD8dull, CD8intermediate, and CD8bright natural killer (NK) cell clones can be identified. Triggering of CD8 with its natural ligand(s), represented by soluble HLA class I (sHLA-I), isolated either from serum of healthy donors or from HLA-I− 721.221 lymphoblastoid cell line transfected with HLA-A2, -Cw4, and -Bw46 alleles, or HLA-G1 leads to NK cell apoptosis. The magnitude of this effect directly correlated with the level of CD8 expression. sHLA-I–induced apoptosis depends on the interaction with CD8, as it was inhibited by masking this molecule with specific monoclonal antibodies (mAbs). Moreover, sHLA-I or CD8 cross-linking with specific mAbs elicited intracellular calcium increases, Fas ligand (FasL) messenger RNA transcription, and FasL secretion, which were needed for delivering the death signal. Indeed, this apoptosis was inhibited by preincubation of NK cell clones with Fas or FasL antagonist mAbs, indicating that the Fas/FasL pathway is involved. Furthermore, members of the inhibitory receptor superfamily, such as CD94/NKG2 complex or killer inhibitory receptors, were shown to exert an inhibitory effect on sHLA-I–mediated apoptosis and secretion of FasL. These findings suggest that interaction between sHLA-I and CD8 evokes an apoptotic signal that is down-regulated by inhibitory receptor superfamily that function as survival receptors in NK cells.
Comparison of Cytogenetic and Molecular Cytogenetic Detection of Chromosome Abnormalities in 240 Consecutive Adult Patients With Acute Myeloid Leukemia
Authors: Fröhling Stefan , Skelin Silvia , Liebisch Claudia , Scholl Claudia , Schlenk Richard F. , Döhner Hartmut , Döhner Konstanze
Published: July 2002

PURPOSE: To prospectively compare cytogenetic and molecular cytogenetic analysis for the detection of the most relevant chromosome abnormalities in a large series of patients with acute myeloid leukemia (AML).

PATIENTS AND METHODS: Two hundred forty consecutive adult patients with AML entered onto the multicenter treatment trial AML HD93 were studied. Chromosome banding and fluorescence in situ hybridization (FISH) applying a comprehensive set of genomic DNA probes were performed in a single reference laboratory.

RESULTS: Two cases of inv(16), three cases of t(11q23), and three cases of t(8;21)var were only detected by molecular cytogenetics. By FISH, aberrations were identified in three cases with normal karyotypes: inv(16), −Y (in a patient with low metaphase yield on chromosome banding) and a 12p microdeletion. Additional aneuploidies, in particular +8q and +11q, were diagnosed by FISH; however, virtually all these aberrations occurred in patients with complex karyotypes or as an additional abnormality in leukemias with an AML-specific translocation. Finally, aberrations were detected by FISH in eight of 14 patients with no assessable metaphases.

CONCLUSION: In most cases of AML, conventional cytogenetic study reliably detects chromosomal abnormalities, and this method should not be replaced by FISH. FISH should be used as a complementary method for the detection of more subtle abnormalities, such as inv(16) and t(11q23), in all patients with newly diagnosed AML and for suspected t(8;21)var. Furthermore, molecular cytogenetics using this comprehensive set of DNA probes provides a valuable diagnostic tool for patients with poor chromosome morphology, low or no yields of metaphase cells, or both.
Medications for Obesity
Authors: Gudzune Kimberly A. , Kushner Robert F.
Published: July 2024

Importance

Obesity affects approximately 19% of women and 14% of men worldwide and is associated with increased morbidity. Antiobesity medications (AOMs) modify biological processes that affect appetite and significantly improve outcomes, such as type 2 diabetes, hypertension, and dyslipidemia.

Observations

AOMs should be administered in combination with lifestyle interventions and can be classified according to their mechanisms of action. Orlistat modifies digestive tract absorption and causes gastrointestinal adverse effects, such as oily fecal spotting and urgency, in more than 25% of patients. Centrally acting drugs, such as phentermine-topiramate and naltrexone-bupropion, regulate appetite in the brain and are associated with constipation in approximately 20% of patients, although the incidence of other adverse effects (eg, paresthesia, nausea) varies by medication. Nutrient-stimulated hormone-based medications, such as liraglutide, semaglutide, and tirzepatide, mimic the actions of enteropancreatic hormones that modify central appetite regulation and provide multiple cardiometabolic weight-loss benefits. Adverse effects of these drugs include nausea (28%-44%), diarrhea (21%-30%), and constipation (11%-24%). The relative potency of adult obesity medications has been studied in meta-analyses. Compared with placebo, orlistat was associated with 3.1% greater weight loss (52 randomized clinical trials [RCTs]; 16 964 participants), phentermine-topiramate was associated with 8.0% greater weight loss (5 RCTs; 3407 participants), naltrexone-bupropion was associated with 4.1% greater weight loss (6 RCTs; 9949 participants), liraglutide was associated with 4.7% greater weight loss (18 RCTs; 6321 participants), semaglutide was associated with 11.4% greater weight loss (5 RCTs; 4421 participants), and tirzepatide 15 mg was associated with 12.4% greater weight loss (6 RCTs; 1972 participants).

Conclusion and Relevance

Obesity is associated with increased morbidity. Antiobesity medications are effective adjunctive therapy to lifestyle changes for improved weight loss and health outcomes.
The Origins of “Confidential Commercial Information” at the FDA
Authors: Daval C. Joseph Ross , Kesselheim Aaron S.
Published: July 2024

This Viewpoint reviews regulations regarding FDA’s handing of confidential commercial information, explains how these regulations serve as a barrier to disclosure of information in the interest of public health, and suggests how information could be carefully shared to improve health outcomes and advance research.
Overground Gait Training With a Wearable Robot in Children With Cerebral Palsy
Authors: Choi Ja Young , Kim Seung Ki , Hong Juntaek , Park Hankyul , Yang Shin-seung , Park Dongho , Song Min-Keun
Published: July 2024

Importance

Cerebral palsy (CP) is the most common developmental motor disorder in children. Robot-assisted gait training (RAGT) using a wearable robot can provide intensive overground walking experience.

Objective

To investigate the effectiveness of overground RAGT in children with CP using an untethered, torque-assisted, wearable exoskeletal robot.

Design, Setting, and Participants

This multicenter, single-blind randomized clinical trial was conducted from September 1, 2021, to March 31, 2023, at 5 rehabilitation institutions in Korea. Ninety children with CP in Gross Motor Function Classification System levels II to IV were randomized.

Intervention

The RAGT group underwent 18 sessions of RAGT during 6 weeks, whereas the control group received standard physical therapy for the same number of sessions during the same period.

Main Outcome and Measures

The primary outcome measure was the Gross Motor Function Measure 88 (GMFM-88) score. Secondary outcome measures were the GMFM-66, Pediatric Balance Scale, selective control assessment of the lower extremity, Pediatric Evaluation of Disability Inventory–Computer Adaptive Test (PEDI-CAT), 6-minute walking test scores (distance and oxygen consumption), muscle and fat mass via bioelectrical impedance analysis, and gait parameters measured via 3-dimensional analysis. All assessments were performed for all patients at baseline, at the end of the 6-week intervention, and after the 4-week follow-up.

Results

Of the 90 children (mean [SD] age, 9.51 [2.48] years; 49 [54.4%] male and 41 [45.6%] female) in the study, 78 (86.7%) completed the intervention, with 37 participants (mean [SD] age, 9.57 [2.38] years; 19 [51.4%] male) and 41 participants (mean [SD] age, 9.32 [2.37] years; 26 [63.4%] male) randomly assigned to the RAGT and control groups, respectively. Changes in the RAGT group significantly exceeded changes in the control group in GMFM-88 total (mean difference, 2.64; 95% CI, 0.50-4.78), GMFM-E (mean difference, 2.70; 95% CI, 0.08-5.33), GMFM-66 (mean difference, 1.31; 95% CI, 0.01-2.60), and PEDI-CAT responsibility domain scores (mean difference, 2.52; 95% CI, 0.42-4.63), indicating independence in daily living at postintervention assessment. At the 4-week follow-up, the RAGT group showed significantly greater improvements in balance control (mean difference, 1.48; 95% CI, 0.03-2.94) and Gait Deviation Index (mean difference, 6.48; 95% CI, 2.77-10.19) compared with the control group.

Conclusions and Relevance

In this randomized clinical trial, overground RAGT using a wearable robot significantly improved gross motor function and gait pattern. This new torque-assisted wearable exoskeletal robot, based on assist-as-needed control, may complement standard rehabilitation by providing adequate assistance and therapeutic support to children with CP.

Trial Registration

CRIS Identifier: KCT0006273
Stroke After Influenza Vaccines in Older Adults in the US, 2016 to 2019
Authors: Lu Yun , Matuska Kathryn , Ma Yuxin , Laniyan Layo , Chillarige Yoganand , Anderson Steven A. , Forshee Richard A.
Published: July 2024

This case series investigates whether an increase in stroke risk occurred after influenza vaccination among fee-for-service Medicare beneficiaries during the influenza seasons from 2016 to 2019.
Prevalence of Epilepsy in People of Sexual and Gender Minoritized Groups
Authors: Johnson Emily L. , Bui Esther , Tassiopoulos Karina , Koretzky Maya Overby , Zepeda Rodrigo , Gonzalez-Giraldo Ernesto , Gottesman Rebecca F.
Published: July 2024

Importance

Epilepsy is a highly treatable condition for many people, but there are large treatment gaps with suboptimal seizure control in minoritized groups. The sexual and gender minority (SGM) community is at risk for health disparities, yet the burden of epilepsy in this community is not known.

Objective

To estimate the prevalence of active epilepsy among SGM people in the United States.

Design, Setting, and Participants

This was a cross-sectional, nationally representative survey study of community-dwelling US adults who answered questions about epilepsy, sexual orientation, and gender identity in the 2022 National Health Interview Survey (NHIS).

Exposure

Self-identification of transgender or gender-diverse identity, or sexual orientation including gay, lesbian, bisexual, or other orientation, excluding straight (ie, heterosexual).

Main Outcomes and Measures

Participants self-reported epilepsy status, medical treatment, seizure frequency, demographic characteristics, sexual orientation, and gender identity. Logistic regression was used to estimate the association of epilepsy with SGM identification.

Results

A total of 27 624 participants (15 050 [54%] women; 3231 [12%] Black; mean [SD] age, 48.2 [18.5] years) completed the NHIS and were included. Active epilepsy was present in 1.2% (95% CI, 1.0%-1.3%) of the population. A higher proportion of SGM adults than non-SGM adults reported active epilepsy (2.4% [95% CI, 1.4%-3.3%] vs 1.1% [95% CI, 1.0%-1.3%], respectively). After adjusting for age, race, ethnicity, income, and education, SGM people were more than twice as likely to report active epilepsy than were non-SGM adults (adjusted odds ratio, 2.14; 95% CI, 1.35-3.37).

Conclusions and Relevance

The findings suggest that SGM adults in the United States have a disproportionate prevalence of epilepsy. The reasons for this disparity are likely complex and may be associated with biological and psychosocial determinants of health unique to this population; as such, these individuals are in need of protected access to medical care.
Optic Nerve Sheath Measurement on Ultrasound: A Novel Diagnostic Test for Giant Cell Arteritis
Authors: Baalbaki Hussein , Dubé David , Ross Carolyn , Ducharme‐Bénard Stéphanie , Hussein Samer , Meunier Rosalie‐Sélène , Pagnoux Christian , Makhzoum Jean‐Paul
Published: July 2024

Objective

Optic nerve sheath enhancement on magnetic resonance imaging has been reported in patients with giant cell arteritis (GCA), with or without visual manifestations. Whether similar findings can be documented on ultrasound is unknown. Optic nerve ultrasound is a point‐of‐care, easy to learn, rapid, and noninvasive technique. This study aims to investigate whether optic nerve sheath diameter (ONSD) measured on ultrasound is useful in the diagnosis of active, new‐onset GCA.

Methods

A single‐center, diagnostic accuracy study was performed from June to November 2022 on consecutive eligible patients referred for suspected GCA. Optic nerve ultrasound was performed on both eyes. The ONSD (includes the optic nerve and its sheath) and optic nerve diameter (OND) were measured 3 mm behind the ocular globe. The presence or absence of GCA was confirmed clinically 6 months later. Multivariable linear regression, adjusting for age and sex, was used to determine the association between optic nerve ultrasound measures and final GCA diagnosis.

Results

Thirty participants were enrolled, including nine participants with a final diagnosis of GCA. Mean ± SD ONSD was 5.98 ± 1.17 mm in patients with GCA and 4.02 ± 0.99 mm in patients without GCA. Mean ONSD was greater by 1.26 mm in patients with GCA (95% confidence interval 0.30–2.21 mm, P = 0.01) compared with those without GCA, adjusting for age and sex. Mean ± SD OND was 2.97 ± 0.46 mm in patients with GCA and 2.47 ± 0.58 mm in patients without GCA. There was no evidence of an association between GCA diagnosis and OND.

Conclusion

Patients with GCA had a significantly greater ONSD on ultrasound than patients without GCA. Optic nerve ultrasound may represent a novel, rapid, bedside diagnostic test for GCA. A large prospective study is required to confirm these findings and evaluate whether ONSD can be used as a disease activity biomarker in GCA.
From Reactive to Proactive – The Future Life Design to Promote Health and Extend the Human Lifespan
Authors: Yao Lan , Yang Chengyuan , Graff J. Carolyn , Wang Guiying , Wang Gang , Gu Weikuan
Published: July 2024

Disease treatment and prevention have improved the human lifespan. Current studies on aging, such as the biological clock and senolytic drugs have focused on the medical treatments of various disorders and health maintenance. However, to efficiently extend the human lifespan to its theoretical maximum, medicine can take a further proactive approach and identify the inapparent disorders that affect the gestation, body growth, and reproductive stages of the so‐called “healthy” population. The goal is to upgrade the standard health status to a new level by targeting the inapparent disorders. Thus, future research can shift from reaction, response, and prevention to proactive, quality promotion and vigor prolonging; from single disease‐oriented to multiple dimension protocol for a healthy body; from treatment of symptom onset to keep away from disorders; and from the healthy aging management to a healthy promotion design beginning at the birth.
Enhancing Microstructural, Thermal, Mechanical, and Corrosion Response of a Bio/Eco‐Compatible Mg–2Zn–1Ca–0.3Mn Alloy Using Two Types of Cryogenic Treatments
Authors: Sole Keyur , Johanes Michael , Gupta Manoj
Published: July 2024

Biocompatible Mg–2Zn–1Ca–0.3Mn is synthesized using the disintegrated metal deposition process and subjected to two types of cryogenic treatments (refrigeration [RF] at −20 and −196 °C using liquid nitrogen) with a target to improve microstructural, thermal, mechanical, and electrochemical responses. The material exhibits densification and grain refinement after these treatments, which improves the physical, thermal, compressive, and corrosion responses. While both RF and liquid nitrogen exposures improve the overall combination of properties, overall improvement in properties is best met with RF treatment at −20 °C. In the results of this work, the efficacy of low energy option (RF) is convincingly established rather than liquid nitrogen exposure (as conventionally practiced) to enhance microstructure and properties.